Goldfrank's Toxicologic Emergencies, 8 e 2006

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Front of Book > Editors

Editors Neal E. Flomenbaum MD, FACP, FACEP Emergency Physician-in-Chief New York-Presbyterian Hospital, Weill Cornell Medical Center; Professor of Clinical Medicine, Weill Medical College, Cornell University; Consultant, New York City Poison Center, New York, New York Lewis R. Goldfrank MD, FACEP, FAAEM, FAACT, FACMT, FACP Professor and Chair Department of Emergency Medicine, New Medicine; Director, Emergency Medicine, and New York University Medical Center; York City Poison Center, New York, New

York University School of Bellevue Hospital Center Medical Director, New York

Robert S. Hoffman MD, FAACT, FACMT Director New York City Poison Center; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center and New York University Medical Center; Associate Professor, Emergency Medicine and Medicine (Clinical Pharmacology), New York University School of Medicine, New York, New York Mary Ann Howland PHARMD, DABAT, FAACT

Clinical Professor of Pharmacy St. John's University, College of Pharmacy Consultant, Department of Emergency Medicine, Bellevue Hospital Center and New York University Medical Center; Senior Consultant in Residence, New York City Poison Center, New York, New York Neal A. Lewin MD, FACP, FACEP, FACMT Director Didactic Education; Attending Physician, Department of Emergency Medicine; Clinical Associate Professor of Emergency Medicine and Medicine (Clinical Pharmacology), New York University School of Medicine; Consultant, New York City Poison Center, New York, New York Lewis S. Nelson MD, FACEP, FACMT Director Medical Toxicology Fellowship Program; Associate Director, New York City Poison Center; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center and New York University Medical Center; Assistant Professor of Emergency Medicine, New York University School of Medicine, New York, New York

Secondary

Editors

This book was set in Times Roman by TechBooks, Inc. Martin J. Wonsiewicz Editor Karen G. Edmonson Editor Peter J. Boyle Editor Catherine H. Saggese

Production

Supervisor

Janice Bielawa Cover Designer The index was prepared by Kathrin Unger. Courier Kendallville was printer and binder.

Contributors Judith C. Ahronheim MD Chief Division of Geriatrics; Visiting Professor of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York Chapter

32,

“Geriatric

Principles―

Michael H. Allen MD Associate Professor of Psychiatry; Director of Emergency Psychiatry University of Colorado Health Sciences Center, Denver, Colorado Chapter

18,

“Psychiatric

Principles―

Vincent L. Anthony MD Fellow in Nephrology, Nassau University Medical Center, East Meadow, New York Chapter

27,

“Renal

Principles―

Kavita Babu MD Fellow in Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts Chapter

80,

“Hallucinogens―

Fermin Barrueto MD Assistant Professor of Surgery Division of Emergency Medicine, University of Maryland, Baltimore, Maryland Chapter 106, “Sodium Fluoroacetamide―

Monofluoroacetate

and

Dina Began MD Clinical Assistant Professor of Dermatology Weill Medical College, Cornell University, New York, New York Chapter

29,

“Dermatologic

Principles―

Martin G. Belson MD Medical Toxicologist National Center for Environmental Health, Centers for Disease Control and Prevention, Georgia Poison Control Center, Department of Pediatric Emergency Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia Chapter

36,

“Nonsteroidal

Antiinflammatory

Drugs―

Jeffrey N. Bernstein MD Medical Director Florida Poison Information Center/Miami; Voluntary Associate Professor of Pediatrics, University of Miami, Miller Medical School; Attending Physician, Emergency Care Center, Jackson Memorial Hospital, Miami, Florida Antidotes in Depth A32, “Antivenom (Scorpion and Spider)― Joseph M. Betz PhD Director

Dietary Supplement Methods and Reference Materials Program, Office of Dietary Supplements, National Institutes of Health, Bethesda, Maryland Chapter

114,

“Plants―

Steven B. Bird MD Assistant Professor of Emergency Medicine Department of Emergency Medicine, Division of Medical Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts Chapter

88,

“Chromium―

Kenneth E. Bizovi MD Assistant Professor of Emergency Medicine Department of Emergency Medicine, Oregon Health and Science University; Consultant, Oregon Poison Center, Portland, Oregon Chapter

34,

“Acetaminophen―

G. Randall Bond MD, FACMT Medical Director Cincinnati Drug and Poison Information Center; Attending Physician, Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center; Professor of Clinical Pediatrics and Clinical Emergency Medicine, University of Cincinnati, Cincinnati, Ohio Chapter

56,

“Antimalarials―

George M. Bosse MD Associate Professor of Emergency Medicine University of Louisville; Medical Director, Kentucky Regional Poison Center, Louisville, Kentucky

Chapter

48,

“Antidiabetics

and

Hypoglycemics―

Nicole C. Bouchard MD Fellow in Medical Toxicology Department of Emergency Medicine, New York University School of Medicine, New York City Poison Center, New York, New York Chapter

49,

“Thyroid

and

Antithyroid

Medications―

Edward W. Boyer MD, PhD Associate Professor of Emergency Medicine; Chief Division of Medical Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts; Instructor in Harvard Medical School, Boston, Massachusetts Chapter

55,

“Antituberculous

Pediatrics,

Medications―

Jeffrey R. Brubacher MD Clinical Associate Professor University of British Columbia; Emergency Physician, Department of Emergency Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada Chapter

59,

“β-Adrenergic

Antagonists―

D. Eric Brush MD Assistant Professor of Emergency Medicine Department of Emergency Medicine, Division of Medical Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts Chapter

116,

“Marine

Envenomations―

Keith K. Burkhart MD Professor of Clinical Emergency Medicine

Pennsylvania State University College of Medicine; Regional Medical Toxicologist, Division of Regional Operations, Agency for Toxic Substances and Disease Registry, Hershey, Pennsylvania Chapter 112, “Methyl Bromide and Other Fumigants― Michele Burns Ewald MD Medical Director Regional Center for Poison Control and Prevention serving Massachusetts and Rhode Island; Fellowship Director, Medical Toxicology, Children's Hospital Boston; Instructor in Pediatrics, Harvard Medical School; Attending Physician, Division of Emergency Medicine, Children's Hospital, Boston, Massachusetts Chapter

95,

“Silver―

Chapter

97,

“Zinc―

Chapter

107,

“Phosphorus―

Diane P. Calello MD Fellow in Medical Toxicology The Poison Control Center of Philadelphia, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Chapter

94,

“Selenium―

Louis R. Cantilena Jr. MD, PhD Professor of Medicine and Pharmacology; Director Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Services, Bethesda, Maryland Chapter 133, “Adverse Drug Events and Postmarketing Surveillance―

Gar Ming Chan MD Fellow in Medical Toxicology Department of Emergency Medicine, New York University School of Medicine, New York City Poison Center, New York, New York Chapter

89,

“Cobalt―

Yiu-Cheung Chan MD Medical Officer Accident and Emergency Department, United Christian Hospital, Hong Kong SAR, China Chapter

108,

“Strychnine―

Alan N. Charney MD Adjunct Professor of Medicine New York University School of Medicine, New York, New York Chapter 17, “Fluid, Electrolyte, and Acid-Base Principles― William K. Chiang MD Associate Director Department of Emergency Medicine, Bellevue Hospital Center; Associate Professor of Emergency Medicine, New York University School of Medicine, New York, New York Chapter

21,

“Otolaryngologic

Principles―

Chapter

73,

“Amphetamines―

Anne-Bolette J. Christophersen MD Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark Chapter 8, “Techniques Used to Prevent Gastrointestinal Absorption―

Jason Chu MD Assistant Professor of Clinical Medicine Columbia University College of Physicians and Surgeons; Associate Attending Emergency Physician, St. Luke's–Roosevelt Hospital Center, New York, New York Chapter

28,

“Genitourinary

Principles―

Chapter

51,

“Antimigraine

Medications―

Cathleen Clancy MD Associate Medical Director National Capital Poison Center; Assistant Professor of Emergency Medicine, Department of Emergency Medicine, George Washington University Medical Center; Attending Physician, Department of Emergency Medicine, National Naval Medical Center, Bethesda, Maryland; Attending Physician, Sibley Memorial Hospital, Washington, District of Columbia Chapter

5,

“Electrocardiographic

Principles―

Richard F. Clark MD Medical Director San Diego Division, California Poison Control System; Director, UCSD Division of Medical Toxicology; Professor of Medicine, University of California, San Diego, San Diego, California Chapter 109, “Insecticides: Organic Compounds and Carbamates―

Phosphorus

Pat Croskerry MD, PhD Associate Professor Department of Emergency Medicine and Faculty of Medical Education, Dalhousie University, Halifax, Nova Scotia, Canada Chapter 134, “Medications, Errors, and Patient Safety―

Steven C. Curry MD Director Department of Medical Toxicology, Banner Good Samaritan Medical Center; Associate Professor of Clinical Medicine, University of Arizona College of Medicine, Phoenix, Arizona Chapter 14, “Neurotransmitters Neuromodulators―

and

John Curtis MD Fellow in Medical Toxicology, Division of Medical Toxicology, Drexel University College of Medicine, Philadelphia, Pennsylvania Chapter

93,

“Nickel―

Andrew Dawson MD Visiting Professor of Medicine South Asian Clinical Toxicology of Peradeniya, Sri Lanka Chapter

105,

Research

Collaboration,

University

“Barium―

Kathleen A. Delaney MD Professor and Vice Chair Division of Emergency Medicine, University of Texas Southwestern Medical School; Medical Director, Emergency Department, Parkland Memorial Hospital, Dallas, Texas Chapter

13,

Chapter

16,

Chapter

26,

“Biochemical

and

“Thermoregulatory “Hepatic

Metabolic

Principles―

Principles―

Principles―

Antidotes in Depth A11, “Dextrose―

Francis DeRoos MD Residency Director Department of Emergency Medicine, Hospital of the University of Pennsylvania; Associate Professor of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Chapter 58, “Calcium Channel Blockers― Chapter

60,

“Other

Antihypertensives―

Suzanne Doyon MD Medical Director Maryland Poison Center, University of Maryland School of Pharmacy, Baltimore, Maryland Chapter

47,

“Anticonvulsants―

Dainius A. Drukteinis MD, JD Resident Department of Emergency Medicine, New York University School of Medicine, New York, New York Chapter 135, “Risk Management and Legal Principles― Michael Eddleston PhD, MRCP Wellcome Trust Career Development Fellow, Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Chapter 131, “International Perspectives in Medical Toxicology― Donald A. Feinfeld MD Nephrology Fellowship Director Beth Israel Medical Center; Professor of Medicine, Albert Einstein

College of Medicine; Consultant in Nephrology, New York City Poison Center, New York, New York Chapter

27,

“Renal

Principles―

Robert P. Ferm MD Associate Professor of Emergency Medicine Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School; Attending Physician, Department of Emergency Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts Chapter

80,

“Hallucinogens―

Jeffrey S. Fine MD Assistant Professor Pediatrics and Emergency Medicine, New York University School of Medicine; Assistant Director, Pediatric Emergency Medicine, Bellevue Hospital Center; Consultant, New York City Poison Center, New York, New York Chapter

30,

“Reproductive

Chapter

31,

“Pediatric

and

Perinatal

Principles―

Principles―

Mark Flomenbaum MD, PhD Chief Medical Examiner; Office of the Chief Medical Examiner State of Massachusetts, Boston, Massachusetts Chapter

33,

“Postmortem

Toxicology―

Marsha D. Ford MD Director Carolinas Poison Center; Director, Division of Medical Toxicology, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina; Clinical Professor of Emergency

Medicine, School of Medicine, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina Chapter

85,

“Arsenic―

Frederick W. Fraunfelder MD Cornea/Refractive Surgery, Casey Chapter

20,

“Ophthalmic

Eye

Institute,

Portland,

Oregon

Principles―

Jessica A. Fulton DO Fellow in Medical Toxicology Department of Emergency Medicine, New York University School of Medicine, New York City Poison Center, New York, New York Chapter

100,

“Caustics―

Beth Y. Ginsburg MD Fellow in Medical Toxicology Department of Emergency Medicine, New York University School of Medicine, New York City Poison Center, New York, New York Chapter

41,

“Vitamins―

Jeffrey A. Gold MD Assistant Professor of Medicine Department of Medicine; Medical Director of Critical Care, New York University School of Medicine, New York, New York Chapter

76,

“Ethanol

Withdrawal―

David S. Goldfarb MD Chief Nephrology Section, New York Harbor Veterans Affairs Medical Center; Professor of Medicine, Physiology and Neuroscience, New York University School of Medicine; Consultant, New York City

Poison Center, New York, New York Chapter 10, “Principles and Techniques Applied to Enhance Elimination― Michael I. Greenberg MD, MPH, FAAEM, FACPM, FACOEM, FACMT Professor of Emergency Medicine and Public Health Drexel University College of Medicine, Philadelphia, Pennsylvania Chapter

93,

“Nickel―

Howard A. Greller MD Assistant Professor of Emergency Medicine Department of Emergency Medicine, New York University School of Medicine; Consultant, New York City Poison Center, New York, New York Chapter

68,

“Lithium―

Martin Griffel MD Director Cardiovascular ICU, Department of Anesthesiology, New York University Medical Center; Associate Professor of Anesthesiology, New York University School of Medicine, New York, New York Chapter

65,

“Inhalational

Anesthetics―

David D. Gummin MD Medical Director Wisconsin Poison Center, Children's Hospital of Wisconsin; Assistant Clinical Professor, Medical College of Wisconsin; Attending Emergency Physician, Infinity HealthCare Incorporated, Milwaukee, Wisconsin Chapter

102,

“Hydrocarbons―

Jason B. Hack MD Associate Chair Division of Medical Toxicology; Assistant Professor, Department of Emergency Medicine, Brody Medical School at East Carolina University, Greenville, North Carolina Chapter

62,

“Cardioactive

Steroids―

In-Hei Hahn MD Assistant Professor of Clinical Medicine Columbia University College of Physicians and Surgeons; Associate Attending Emergency Physician; Assistant Director of Research, St. Luke's–Roosevelt Hospital Center, New York, New York Chapter

115,

“Arthropods―

S. Eliza Halcomb MD Fellow in Medical Toxicology Department of Emergency Medicine, New York University School of Medicine, New York City Poison Center, New York, New York Chapter 42, “Essential Oils― Christine A. Haller MD Assistant Adjunct Professor of Medicine and Laboratory Medicine; Assistant Medical Director San Francisco Division, California Poison Control System, San Francisco General Hospital, San Francisco, California Chapter 39, “Dieting Agents and Regimens― Richard J. Hamilton MD Associate Professor of Emergency Medicine; Program Director of Emergency Medicine Drexel University College of Medicine, Philadelphia, Pennsylvania

Chapter

15,

“Withdrawal

Principles―

Robert G. Hendrickson MD Assistant Professor of Emergency Medicine Department of Emergency Medicine, Oregon Health and Science University; Associate Medical Director, Oregon Poison Center, Portland, Oregon Chapter

34,

“Acetaminophen―

Fred M. Henretig MD Professor of Pediatrics and Emergency Medicine University of Pennsylvania School of Medicine; Director, Section of Clinical Toxicology, Division of Emergency Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Chapter

91,

“Lead―

Robert A. Hessler MD Associate Professor of Emergency Medicine New York University School of Medicine; Assistant Director, Department of Emergency Medicine, Bellevue Hospital Center, New York, New York Chapter

23,

“Cardiovascular

Principles―

Aaron Hexdall MD Assistant Professor of Emergency Medicine; Co-Director International Emergency Medicine, Bellevue Hospital Center, Department of Emergency Medicine, New York University School of Medicine, New York, New York Chapter 131, “International Perspectives in Medical Toxicology―

Lotte C. G. Hoegberg MS(Pharm), PhD Department of International Health, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark Chapter 8, “Techniques Used to Prevent Gastrointestinal Absorption― Robert J. Hoffman MD Research Director Beth Israel Medical Center; Assistant Clinical Professor, Department of Emergency Medicine, Albert Einstein College of Medicine; Consultant, New York City Poison Center, New York, New York Chapter 63, “Methylxanthines and Selective β2 Adrenergic

Agonists―

Michael G. Holland MD Clinical Assistant Professor of Emergency Medicine State University of New York, Upstate Medical University; Consultant Medical Toxicologist, Central New York Poison Center, Syracuse, New York; Occupational Medical Director, Glens Falls Hospital, Glens Falls, New York Chapter 110, “Insecticides: Organic Pyrethrins/Pyrethroids and DEET―

Chlorines,

Christopher P. Holstege MD Director Division of Medical Toxicology; Medical Director, Blue Ridge Poison Center; Associate Professor, Departments of Emergency Medicine and Pediatrics, University of Virginia, Charlottesville, Virginia Chapter 121, “Cyanide and Hydrogen Sulfide― Chapter

123,

“Smoke

Inhalation―

Daniel O. Hryhorczuk MD Professor and Director Great Lakes Centers for Occupational and Environmental Safety and Health, University of Illinois at Chicago School of Public Health; Director, Toxikon Consortium; Chief of Clinical Toxicology, Cook County Hospital, Chicago, Illinois Chapter

102,

“Hydrocarbons―

Oliver L. Hung MD Attending Physician Department of Emergency Medicine, Morristown Memorial Hospital, Morristown, New Jersey Chapter

43,

“Herbal

Preparations―

Gary E. Isom PhD Professor of Toxicology Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana Chapter 121, “Cyanide and Hydrogen Sulfide― David N. Juurlink MD, PhD Assistant Professor of Medicine Pediatrics and Clinical Epidemiology, University of Toronto; Attending Physician, Divisions of General Internal Medicine, Clinical Pharmacology, and Toxicology, Sunnybrook and Women's College Health Sciences Centre; Clinical Toxicologist, Ontario Regional Poison Information Centre, Toronto, Ontario Chapter

67,

“Antipsychotics―

Brian Kaufman MD Associate Professor of

Anesthesiology

Medicine, and Neurosurgery, New York University School of Medicine; Director, Critical Care Section, Department of Anesthesiology, New York University Medical Center, New York, New York Chapter

64,

“Local

Anesthetics―

Chapter

65,

“Inhalational

Chapter

66,

“Neuromuscular

Anesthetics― Blockers―

Antidote in Depth A20, “Dantrolene Sodium― Mark A. Kirk MD Director Medical Toxicology Fellowship, Division of Medical Toxicology; Associate Medical Director, Blue Ridge Poison Center; Assistant Professor, Departments of Emergency Medicine and Pediatrics, University Chapter

of 11,

Virginia,

Charlottesville,

“Intensive

Virginia

Care―

Chapter 121, “Cyanide and Hydrogen Sulfide― Chapter

123,

“Smoke

Inhalation―

Barbara M. Kirrane MD Fellow in Medical Toxicology Department of Emergency Medicine, New York University School of Medicine, New York City Poison Center, New York, New York Chapter 135, “Risk Management and Legal Principles― Kurt C. Kleinschmidt MD Associate Professor of Surgery Division of Emergency Medicine; Director, Toxicology Fellowship Program, University of Texas Southwestern Medical Center, Emergency Department; Associate Medical Director, Parkland

Memorial

Hospital,

Chapter

13,

Dallas,

Texas

“Biochemical

and

Metabolic

Principles―

Lada Kokan MD Kaiser Permanente, San Francisco, San Francisco, California Chapter

69,

“Monoamine

Donald P. Kotler MD Chief Gastrointestinal Division,

St.

Oxidase

Inhibitors―

Luke's–Roosevelt

Hospital

Center;

Professor of Medicine, Columbia University College of Physicians and Surgeons, New York, New York Chapter

25,

“Gastrointestinal

Principles―

Edwin K. Kuffner MD Assistant Clinical Professor University of Colorado; Attending Toxicologist, Rocky Mountain Poison and Drug Center, Denver, Colorado Chapter

77,

“Disulfiram

and

Disulfiramlike

Reactions―

Chapter 99, “Camphor and Moth Repellents― Melisa W. Lai MD Fellow in Medical Toxicology Regional Center for Poison Control and Prevention serving Massachusetts and Rhode Island, Harvard Medical School, Boston, Massachusetts Chapter

95,

“Silver―

David C. Lee MD Director of Research Department of Emergency Medicine, North Shore University

Hospital, Manhasset, New York; Assistant Professor of Emergency Medicine, New York University School of Medicine, New York, New York Chapter

72,

“Sedative-Hypnotics―

Erica L. Liebelt MD Associate Professor of Pediatrics and Emergency Medicine University of Alabama School of Medicine at Birmingham; Director, Medical Toxicology Services, Children's Hospital and University of Alabama Hospital, Birmingham, Alabama Chapter

71,

“Cyclic

Antidepressants―

Heather Long MD Attending Physician Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; Consultant, New York City Poison Center Chapter

79,

“Inhalants―

Daniel Matalon MD Fellow in Nephrology Department of Medicine, New York University School of Medicine, New York, New York Chapter 10, “Principles and Techniques Applied to Enhance Elimination― Michael McGuigan MD, CM, MBA Professor of Clinical Emergency Medicine State University of New York, Stony Brook, New York; Medical Director, Long Island Regional Poison and Drug Information Center, Winthrop University Hospital, Mineola, New York

Chapter

81,

“Cannabinoids―

Charles McKay MD Associate Medical Director Connecticut Poison Control Center; Associate Professor of Emergency Medicine, University of Connecticut School of Medicine; Chief, Division of Medical Toxicology, Department of Traumatology and Emergency Medicine, Hartford, Connecticut Chapter 124, “Risk Assessment and Risk Communication― Maria Mercurio-Zappala RPh, MS Managing Director New York City Poison Center, New York, New York Chapter

96,

“Thallium―

Sanford M. Miller MD Clinical Associate Professor

of

Anesthesiology

Department of Anesthesiology, New York University School of Medicine; Assistant Director of Anesthesiology, Bellevue Hospital Center, New York, New York Chapter

66,

“Neuromuscular

Blockers―

Antidotes in Depth A20, “Dantrolene Sodium― Kirk C. Mills MD Associate Residency Director Emergency Medicine, Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, Michigan Chapter 14, “Neurotransmitters Neuromodulators―

and

Heikki E. Nikkanen MD Attending Physician Medical Toxicology, Children's Hospital Boston; Attending Physician, Department of Emergency Medicine, Brigham and Women's Hospital; Instructor in Medicine, Harvard Medical School, Boston, Massachusetts Chapter

107,

“Phosphorus―

Sean Patrick Nordt MD, PharmD Resident Division of Emergency Medicine, Departments of Surgery and Pediatrics, University of Maryland, Baltimore, Maryland Chapter

53,

“Pharmaceutical

Additives―

Ruben Olmedo MD Assistant Professor of Emergency Medicine Mount Sinai School of Medicine; Chief, Division of Toxicology, Department of Emergency Medicine, Mount Sinai School of Medicine, New York, New York Chapter

83,

“Phencyclidine

and

Ketamine―

Kevin C. Osterhoudt MD, MSCE Associate Professor of Pediatrics; Associate Scholar Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine; Medical Director, Poison Control Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Chapter 132, “Principles of Epidemiology and Research Design― Edward J. Otten MD Professor of Emergency Medicine and Pediatrics; Director

Division of Toxicology, University of Cincinnati College of Medicine, Cincinnati, Ohio Chapter 117, “Snakes and Other Reptiles― Antidotes in Depth A33, “Antivenom (Crotaline and Elapid)― Mary E. Palmer MD Assistant Professor of Emergency Medicine George Washington University School of Medicine, Washington, District of Columbia Chapter

114,

“Plants―

Jeanmarie Perrone MD Director Division of Toxicology, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Associate Professor of Emergency Medicine, Pediatrics, and Laboratory Medicine, University of Pennsylvania School of Medicine; Attending Physician, Emergency Department, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Chapter

40,

“Iron―

Anthony F. Pizon MD Fellow in Medical Toxicology Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, Arizona Chapter 117, “Snakes and Other Reptiles― Antidotes in Depth A33, “Antivenom (Crotaline and Elapid)― J. Samuel Pope MD

Fellow in Pulmonary and Critical Care Medicine Department of Internal Medicine, University of Virginia, Charlottesville, Virginia Chapter

11,

“Intensive

Care―

Dennis Price MD Assistant Professor of Emergency Medicine New York University School of Medicine; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center, New York, New York Chapter

122,

“Methemoglobin

Inducers―

Lawrence S. Quang MD Assistant Professor of Pediatrics Case Western Reserve University, School of Medicine; Medical Director, Greater Cleveland Poison Control Center, Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children's Hospital, University Hospitals of Cleveland, Cleveland, Ohio Chapter 78, “γ Hydroxybutyric Acid― Petrie M. Rainey MD, PhD Professor of Laboratory Medicine; Head Division of Clinical Chemistry; Director, Clinical Chemistry Laboratory; Director, Toxicology Laboratory, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington Chapter

7,

“Laboratory

Principles―

Rama B. Rao MD Assistant Professor of Emergency Medicine and Forensic Pathology Department of Emergency Medicine, New York University School of

Medicine; Consultant, New York City Poision Center, New York, New York Chapter

19,

“Neurologic

Chapter

33,

“Postmortem

Chapter

86,

“Bismuth―

Chapter

100,

Principles― Toxicology―

“Caustics―

Chapter SC-1, “Special Considerations: Procurement from Poisoned Patients―

Organ

Joseph Rella MD Assistant Professor of Emergency Medicine University of Medicine and Dentistry of New Jersey, New Jersey Medical School; Attending Physician, Department of Emergency Medicine, The University Hospital, Newark, New Jersey Chapter

128,

“Radiation―

Bradley D. Riley MD Fellow in Medical Toxicology Department of Medical Toxicology, Banner Good Samaritan Medical Center, University of Arizona College of Medicine, Phoenix, Arizona Chapter 117, “Snakes and Other Reptiles― Antidotes in Depth A33, “Antivenom (Crotaline and Elapid)― James R. Roberts MD Chair Emergency Medicine, Mercy Catholic Medical Center; Professor and Vice Chair, Emergency Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania Chapter 117, “Snakes and Other Reptiles―

Antidotes in Depth A33, “Antivenom (Crotaline and Elapid)― Anne-Michelle Ruha MD Associate Fellowship Director Department of Medical Toxicology, Banner Good Samaritan Medical Center; Clinical Assistant Professor, Department of Emergency Medicine, University of Arizona College of Medicine, Phoenix, Arizona Chapter 14, “Neurotransmitters Neuromodulators―

and

Chapter 117, “Snakes and Other Reptiles― Antidotes in Depth A33, “Antivenom (Crotaline and Elapid)― Morton E. Salomon MD Chairman Department of Emergency Medicine, St. Vincent's Medical Center, Bridgeport, Connecticut; Professor of Clinical Emergency Medicine; Associate Professor of Pediatrics, Albert Einstein College of Medicine, Bronx, New York Chapter 82, “Nicotine and Tobacco Preparations― Joshua G. Schier MD Medical Toxicologist Centers for Disease Control and Prevention, Medical Toxicology Attending, Medical Toxicology Fellowship; Assistant Professor of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia Chapter

37,

“Colchicine

and

Podophyllin―

David R. Schwartz MD Section Chief Critical Care Medicine; Assistant Professor of Medicine, New York University School of Medicine, New York, New York Chapter

64,

“Local

Anesthetics―

David T. Schwartz MD Associate Professor of Emergency Medicine New York University School of Medicine; Attending Physician, Department of Emergency Medicine, New York University Medical Center/Bellevue HospitalCenter, New York, New York Chapter

6,

“Diagnostic

Imaging―

Lauren Schwartz MPH Public Education Coordinator New York City Poison Center, New York, New York Chapter 129, “Poison Prevention and Education― Mark R. Serper PhD Associate Professor of Psychology Hofstra University; Research Associate Professor of Psychiatry, New York University School of Medicine, New York, New York Chapter

18,

“Psychiatric

Principles―

Adhi Sharma MD Assistant Professor of Emergency Medicine Department of Emergency Medicine, Mount Sinai School of Medicine, Elmhurst Hospital Center, Elmhurst, New York; Consultant, New York City Poison Center, New York, New York Chapter

20,

“Ophthalmic

Principles―

Marco L. A. Sivilotti MD, MSc Consultant Ontario Regional Poison Information Center, Hospital for Sick Children, Toronto; Assistant Professor, Departments of Emergency Medicine, Pharmacology, and Toxicology, Queen's University, Kingston, Ontario, Canada Chapter

24,

“Hematologic

Principles―

Martin J. Smilkstein MD Adjunct Associate Professor Department of Emergency Medicine, Oregon Health and Science University; Research Associate, Portland VA Medical Center; Research Professor, Department of Chemistry, Portland State University, Portland, Oregon Chapter

20,

“Ophthalmic

Principles―

Christine M. Stork PharmD Clinical Associate Professor; Director Central New York Poison Control Center, Department of Emergency Medicine, University Hospital, State University of New York Health Science Center, Syracuse, New York Chapter

54,

“Antibiotics,

Antifungals,

and

Antivirals―

Chapter 70, “Serotonin Reuptake Inhibitors and Atypical Antidepressants― Mark Su MD Assistant Professor of Emergency Medicine; Assistant Residency Director; Director of Medical Toxicology State University of New York, Downstate Medical Center, Kings County Hospital Center, Brooklyn, New York; Consultant, New York City Poison Center Chapter

57,

“Anticoagulants―

Chapter 101, “Hydrofluoric Acid and Fluorides― Jeffrey R. Suchard MD Associate Professor of Clinical Emergency Medicine Department of Emergency Medicine, University of California Irvine Medical Center, Orange, California Chapter

126,

“Chemical

Chapter

127,

“Biological

Weapons― Weapons―

Young-Jin Sue MD Clinical Associate Professor Division of Pediatric Emergency Medicine, Department of Pediatrics, Albert Einstein College of Medicine; Attending Physician, Pediatric Emergency Services, Children's Hospital at Montefiore, Bronx, New York Chapter

92,

“Mercury―

Kenneth M. Sutin MD Associate Professor of Anesthesiology and Surgery Department of Anesthesiology, New York University School of Medicine; Director of Critical Care, Department of Anesthesiology, Bellevue Hospital Center, New York, New York Chapter

66,

“Neuromuscular

Blockers―

Antidotes in Depth A20, “Dantrolene Sodium― Asim F. Tarabar MD, MS Assistant Professor of Surgery Section of Emergency Medicine, Department of Surgery, Yale University School of Medicine, Yale New Haven Hospital, New Haven, Connecticut Chapter

84,

“Antimony―

Stephen R. Thom MD, PhD Professor of Emergency Medicine Department of Emergency Medicine; Chief of Hyperbaric Medicine, Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Antidotes in Depth A34, “Hyperbaric Oxygen― Anthony J. Tomassoni MD Medical Director Northern New England Poison Center, Department of Emergency Medicine, Maine Medical Center; Associate Professor, University of Vermont College of Medicine, Portland, Maine Chapter

50,

“Antihistamines

and

Decongestants―

Christian Tomaszewski MD Clinical Associate Professor of Emergency Medicine University of North Carolina–Chapel Hill; Medical Director, Hyperbaric Medicine, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina Chapter

120,

“Carbon

Monoxide―

Rebecca L. Tominack MD Assistant Medical Director Missouri Regional Poison Center; Clinical Associate Professor of Pediatrics, Division of Toxicology; Adjunct Associate Professor of Community Health, School of Public Health, Saint Louis University School of Medicine, Saint Louis, Missouri Chapter

111,

“Herbicides―

Stephen J. Traub MD

Instructor in Medicine Harvard Medical School; Co-Director, Division of Toxicology, Beth Israel Deaconess Medical Center, Boston, Massachusetts Chapter

12,

“Chemical

Principles―

Chapter

87,

“Cadmium―

Michael G. Tunik MD Associate Professor of Pediatrics and Emergency Medicine New York University School of Medicine; Director of Research, Pediatric Emergency Medicine; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center, New York, New York Chapter 45, “Food Poisoning― Susi U. Vassallo MD Assistant Professor of Emergency Medicine New York University School of Medicine; Consultant, New York City Poison Center, New York, New York Chapter

16,

Chapter

44,

“Thermoregulatory “Athletic

Principles―

Performance

Enhancers―

Larissa I. Velez MD Assistant Professor of Surgery Division of Emergency Medicine; Associate Residency Director, Emergency Medicine, University of Texas Southwestern Medical School, Dallas, Texas Antidotes in Depth A11, “Dextrose― Lisa E. Vivero PharmD Teaching Fellow Trinity College, School of Pharmacy (Pharmacology), Dublin,

Ireland Chapter

53,

“Pharmaceutical

Additives―

Peter H. Wald MD, MPH Assistant Vice-President Wellness, USAA, San Antonio, Texas Chapter 118, Control―

“Industrial

Poisoning:

Information

and

Frank G. Walter MD Associate Professor Division of Medical Medicine, University Clinical Toxicology, Chapter

125,

of Emergency Medicine; Chief Toxicology, Department of Emergency of Arizona College of Medicine; Director of University Medical Center, Tucson, Arizona

“Hazmat

Incident

Response―

Richard Y. Wang DO Senior Medical Officer Organic Analytical Toxicology Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia Chapter

52,

“Antineoplastics―

William A. Watson PharmD Associate Director Toxicosurveillance, American Association of Centers, Washington, District of Columbia Chapter

36,

“Nonsteroidal

Paul M. Wax MD Medical Toxicology

Fellowship

Poison

Antiinflammatory

Director

Control

Drugs―

Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, Arizona Chapter

1,

“Historical

Principles

and

Perspectives―

Chapter 2, “Toxicologic Plagues and Disasters in History― Chapter

98,

“Antiseptics,

Disinfectants

and

Sterilants―

Antidotes in Depth A1, “Antiquated Antidotes― Antidotes in Depth A6, “Sodium Bicarbonate― Richard S. Weisman PharmD Director Florida Poison Information Center, Miami; Research Associate Professor of Pediatrics, University of Miami School of Medicine, Miami, Chapter

Florida 50,

“Antihistamines

and

Decongestants―

Sage W. Wiener MD Assistant Director of Medical Toxicology; Assistant Professor of Emergency Medicine Department of Emergency Medicine, State University of New York, Downstate Medical Center, Kings County Hospital Center, Brooklyn, New York; Consultant, New York City Poison Center Chapter

103,

“Toxic

Alcohols―

Luke Yip MD Attending Physician Rocky Mountain Poison and Drug Center, Denver Medical Center, Department of Medicine, Section of Clinical Toxicology; Clinical Assistant Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado

Chapter

75,

“Ethanol―

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Front of Book > Notice

Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The editors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the editors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Front of Book > Dedicated to …

Dedicated to … The staffs of our hospital emergency departments who have worked with remarkable courage, concern, compassion, and understanding in treating the patients discussed in this text and many thousands more like them The staff of the New York City Poison Control Center who have quietly and conscientiously integrated their skills with ours to serve these patients; and to the many others who never needed a hospital visit because of their efforts To the memories of my parents Mollie and Lieutenant H. Stanley Flomenbaum whose constant encouragement to help others nonjudgmentally led me to consider toxicologic emergencies many years ago. To my wife Meredith Altman Flomenbaum, RNP, and to my children Adam, David, and Sari who have competed with this text for my attention but who have underscored the importance of these efforts N. F.

To my children Rebecca, Jennifer, Andrew and Joan, Michelle and James; to my grandchildren Benjamin, Adam, Sarah, Kay, and Samantha who have kept me acutely aware of the ready availability of possible poisons; and to my wife, partner, and best friend Susan whose support was and is essential and whose

contributions will be found throughout the text L. G.

To my wife Ali, my children Casey Jesse, my parents, my friends, family, and colleagues for their never-ending patience and forgiveness for the time spent away from them R. H.

To my husband Bob; to my children Robert and Marcy; to my mother and to the loving memory of my father; and to family, friends, colleagues, and students for all their help and continuing inspiration M. A. H.

To my wife Gail; to my children Justin and Jesse; for their support and patience; and to my parents, who made it possible N. L.

To my wife Laura for her unwavering support; to my children Daniel, Adina, and Benjamin for their boundless enthusiasm and infinite wisdom; to my parents Dr. Irwin and Myrna Nelson for the foundation which they provided; and to my family and friends who keep me focused on that which is important L. N.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Front of Book > Acknowledgments

Acknowledgments We are grateful to Joan Demas, who not only helped manage the growth of this eighth edition and development but also transformed scrawl into manuscript with precision and dedication. The many letters and verbal communications we have received with the reviews of the previous editions of this book continue to improve our efforts. We are deeply indebted to our friends, associates, and students, who stimulated us to begin this book with their questions and then faithfully criticized our answers. We appreciate the compulsive and critical review of the entire seventh edition by Dr. Steven C. Curry, which has improved this edition. We appreciate the detailed and thoughtful analysis of the acetaminophen chapter by Barry H. Rumack. We appreciate the careful and thoughtful review of the pralidoxime antidote in depth by Professor Dr. Peter Eyer of the Walter-Straub-Institute of Pharmacology and Toxicology at the Ludwig-MaximiliansUniversity, Munich, Germany. We are indebted to Michael Eddleston for his thoughtful editing with regard to the management of organic phosphorus pesticides. We thank the many volunteers, students, librarians, and particularly the St. John's University College of Pharmacy students and drug information staff who provide us with vital technical assistance in our daily attempts to deal with toxicologic

emergencies. No words can adequately express our indebtedness to the many authors who worked on earlier editions of many of the chapters in this book. As different authors write and rewrite topics with each new edition, we recognize that without the foundation work of their predecessors this book would not be what it is today. We appreciate the conscientious and tireless work of James Semidey, who has found so many essential articles and prepared so many copies for editorial review. We thank Doson Chua, BSc(Pharm), and Dr. Heather D'Oyley for assistance with Lada Kokan's research; we thank Eric Schweiger for his assistance with Dina Began's research. We gratefully acknowledge the contributions of Oliver Hung, MD, to the alkaline diuresis section and Donald Feinfeld, MD, to the renal pathophysiology and extracorporeal management sections of the chapter on salicylates. We appreciate the contribution of Dawn Hui and Nadine Levick to the analysis of the Web-based Injury Statistics Query and Reporting System (WIQARS) database. We appreciate David T. Schwartz's analytic discussion of diagnostic imaging in the chapter on caustics. Dr. Patrick Croskerry is indebted to his pharmacist colleagues Drs. David U, Neil MacKinnon, and David Rosenbloom for helpful comments and suggestions in the preparation of his chapter; he gratefully acknowledges the assistance of Sherri Lamont at Dartmouth General Hospital and Pamela Gray at the Department of Emergency Medicine at Dalhousie University and the support provided to him by a Senior Clinical Research Fellowship from Dalhousie University. The authors of the chapter on neuromuscular blockers appreciate the thoughtful comments of Dr. Aaron F. Kopman, Department of Anesthesiology, St. Vincent's Hospital, New York. We greatly appreciate the artistic efforts of Joseph Lewy, graphic

designer who created several of our new graphics. We appreciate the calm, thoughtful, and cooperative spirit of Karen Edmonson at McGraw-Hill. Her intelligence and commitment to our efforts has been wonderful. We are pleased with the creative copy editing efforts of Freelance Editorial Services. We greatly appreciate the compulsion and rigor that Kathi Unger has applied to make this edition's index one of unique value. We appreciate the editorial leadership and assistance offered by Peter Boyle.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Front of Book > Preface

Preface In this eighth edition of Goldfrank's Toxicologic Emergencies, we continue to proudly offer readers an approach to medical toxicology based on case studies. The addition of almost 30 new chapters and five Antidotes in other chapters are a reflection understanding new intellectual expanding role of toxicologists century.

Depth and the elimination of seven of major advances, changes in approaches, and of the ever at the beginning of the twenty-first

We have expanded the number of authors in this edition and have reassigned more than 15 percent of the chapters in an attempt to capture new and unique perspectives on toxicology. Critical events and concerns at the turn of the new century led us to add a chapter on chemical and biological weapons to the seventh edition, which we now have expanded into two independent chapters. We have also tried to prepare an appropriate context for discussing these issues more effectively by adding a chapter on risk assessment and risk communication. The increasing emphasis on improving our use of medications is reflected by new chapters on patient safety and poison prevention that focus on public health, the potential of medical informatics, and the critical roles that providers play in improving clinical care. We have added a new chapter on international toxicology that

describes the worldwide epidemiology of toxicology and further added to our international focus by enlisting international authors to broaden the scope of many chapters. Goldfrank's Toxicologic Emergencies, originally a collection of medical toxicology case discussions by two authors, is now a multi-authored text of more than 2000 pages prepared by utilizing the principles we apply at the New York City Poison Center. As the text has expanded in size and scope over the past two decades, we have sought to address issues in medical toxicology in unique and creative ways that would continue to make the book a valuable resource to the growing number of clinicians and researchers working in the field. In the second edition of our text (1982), we expanded the case study material to make the work a more comprehensive clinical resource. In the third edition (1986), we added an organ-system approach to medical toxicology and also began a series of Antidotes in Depth to provide specific detailed information about newer and, in some cases, experimental antidotes. In the fourth edition (1990), we expanded both of these newer sections and began to address such subjects as nursing care, medical-legal issues, and the toxicology of AIDS treatments. For the fifth edition (1994), we added a section addressing the needs of special populations, including reproductive, perinatal, pediatric and geriatric principles, and intensive care unit patients; we also began to extensively expand basic science issues such as neurotransmitters and biochemical and metabolic pathways. In the last two editions we have continued our analytic approach to medical toxicology by adding, fusing, and splitting chapters based on the evolving educational principles and in response to reviews by and suggestions of our many readers and colleagues. For example, a single chapter on metals in prior editions has been divided into separate chapters on antimony, bismuth, cadmium, chromium, cobalt, copper, selenium, silver, and zinc in order to describe these important elements and other related xenobiotics in greater detail. Similarly, the single chapter on rodenticides has

been divided into an introductory discussion of rodenticides among other pesticides followed by detailed discussions of barium, monofluoroacetate and fluoroacetamide, phosphorus, and strychnine. The appearance of the eighth edition marks our first extensive use of the “electronic delivery― of the text. The complete “text― now consists of a hard copy component that faithful readers can read and consult as they have previously and also an electronic component available by pass code and user registration to Goldfrank's Toxicologic Emergencies Web site (http://www.goldfrankstoxicology.com). The electronic version includes six core chapters with a large number of faithfully reproduced visual images that are critical to the understanding of these chapters. The six chapters are Dermatology, Plants, Mushrooms, Marine Envenomations, Snakes, and Arthropods. Electronic delivery allows us to offer you a large selection of pertinent images for these highly visual chapters as well as several other valuable images. Similarly, the workbook including case studies and annotated multiple choice questions will now be available on this Web site. Some of the cases are still relevant classic examples of toxicologic emergencies from previous editions, and the remainder are new, extensively discussed cases from our regional monthly meetings at the New York City Poison Center. The collective wisdom of many of the current and former text authors continues to guide these sessions as it has for more than 20 years. Lewis Nelson and Robert Hoffman have analyzed these problems, distilled the discussions, and recreated the spirit of these meetings in the printed versions of the cases. As previously, 10 annotated multiple choice questions based on each chapter were developed by the respective chapter authors in an attempt to enhance self-learning and meet the intellectual needs of our readers. All our principles developed in detail in the textbook and workbook

will be adapted into a concise handbook of medical toxicology. We expect this lighter and less expensive version of our text to be more portable and affordable yet equally rigorous. We hope this new approach to the description of medical toxicology will be useful for students and many others who may not as yet be fully committed to an in-depth study of our field. After long and serious discussions in preparation of the seventh edition we came to the conclusion that the format of utilizing cases to begin each chapter in: Part C. The Clinical Basis of Medical Toxicology is an important and useful feature that distinguishes our text from others and therefore should be retained. At the same time, we decided that the ease with which readers can find needed information in a traditionally organized comprehensive medical textbook is also valuable. We have therefore formatted each chapter into standard sections to allow readers to find essential information easily when reviewing a topic or preparing for and treating a toxicologic emergency. Most chapters in this section now begin with a case followed by a brief Introduction, the History and Epidemiology, Pharmacology, Pharmacokinetics and Toxicokinetics, Pathophysiology, Clinical Manifestations, Diagnostic Testing, and Management, concluding with a brief summary. The usefulness of this chapter organization is improved by our further development of the indexing features of the text. The index has now been restructured in such a way that each chapter component is listed under the aforementioned subheads and includes almost all cross-references from other chapters within their subheads. Additional alphabetical listings of unique and important terms are also retained. Even more than previously, the rewriting and reorganization of this edition of the text has required an enormous personal effort by each author which we hope will facilitate your learning, reading and patient care. Work on the next edition of this text literally begins the day that the current edition is published. Although

many of the chapters in this eighth edition may appear familiar to readers of previous editions, every chapter has been discussed, analyzed, criticized, dissected, updated, and rewritten accordingly by its old or new authors. Although “tearing down― and reconstructing the text between each edition may seem like an extreme exercise to some, only in this manner can we hope to prevent ourselves from accepting and promulgating unfounded treatments and outdated concepts. We hope that you agree that this exercise is worthwhile and that each “new text― continues to serve you well. As always, we encourage your comments and thoughtful criticism, and we will do our best once again to incorporate your suggestions into future editions. If this text helps to provide better patient care and stimulates interest in medical toxicology by students of medicine, nursing, and pharmacy; by residents in emergency medicine, internal medicine, pediatrics, preventive health, critical care, family practice, and others; by fellows in medical and clinical toxicology; and by attending physicians and faculty, as well as diverse toxicologists, then our efforts; will have indeed been worthwhile. Neal E. Flomenbaum Lewis R. Goldfrank Robert S. Hoffman Mary Ann Howland Neal A. Lewin Lewis S. Nelson

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Front of Book > Table of Antidotes in Depth

Table of Antidotes in Depth Readers of previous editions of Goldfrank's Toxicologic Emergencies are undoubtedly aware that the editors have always felt that an emphasis on general management of poisoning or overdoses coupled with sound medical management is more important or as important as the selection and use of a specific antidote in the vast majority of cases. Nevertheless, there are some instances where nothing other than the timely use of a specific antidote or antagonist will save a patient. For this reason, and also because the use of such antidotes may be problematic, controversial, or unfamiliar to the practitioner (as new antidotes continue to emerge), we have included a section (or sections) at the end of each chapter where an in-depth discussion of such antidotes is relevant. The following Antidotes in Depth are included in this edition. N-Acetylcysteine Mary Ann Howland Activated Charcoal Mary Ann Howland Antiquated Antidotes Paul M. Wax Antivenom

(Crotaline

and

Elapid)

Anthony F. Pizon, Bradley D. Riley, Anne-Michelle Ruha, James R. Roberts, Edward J. Otten Antivenom (Scorpion and Spider) Jeffrey N. Bernstein Atropine Mary Ann Howland Botulinum Antitoxin Lewis R. Goldfrank Calcium Mary Ann Howland L-Carnitine Mary Ann Howland Dantrolene Sodium Kenneth M. Sutin, Brian Kaufman, and Sanford M. Miller Deferoxamine Mary Ann Howland Dextrose Larissa I. Velez and Kathleen A. Delaney Digoxin-Specific Antibody Mary Ann Howland

Fragments

(Fab)

Dimercaprol (British Anti-Lewisite or BAL) Mary Ann Howland Edetate Calcium Disodium (CaNa2 EDTA) Mary Ann Howland Ethanol Mary Ann Howland Flumazenil Mary Ann Howland Fomepizole

Mary Ann Howland Glucagon Mary Ann Howland Hydroxocobalamin Mary Ann Howland Hyperbaric Oxygen Stephen R. Thom Leucovorin (Folinic Acid) and Folic Acid Mary Ann Howland Methylene Blue Mary Ann Howland Octreotide Mary Ann Howland Opioid Antagonists Mary Ann Howland Physostigmine

Salicylate

Mary Ann Howland Pralidoxime Mary Ann Howland Protamine Mary Ann Howland Prussian Blue Robert S. Hoffman Pyridoxine Mary Ann Howland Sodium and Amyl Nitrites Mary Ann Howland Sodium Bicarbonate Paul M. Wax

Sodium Thiosulfate Mary Ann Howland Succimer (2,3-Dimercaptosuccinic Mary Ann Howland

Acid)

Syrup of Ipecac Mary Ann Howland Thiamine Hydrochloride Robert S. Hoffman Vitamin K1 Mary Ann Howland Whole-Bowel Irrigation Mary Ann Howland

and

Other

Intestinal

Evacuants

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Chapter 1 - Historical Principles and Perspectives

Chapter 1 Historical Principles Perspectives

and

Paul M. Wax The term poison first appeared in the English literature around the year 1230 A.D. to describe a potion or draught that was prepared with deadly ingredients.42 , 141 The history of poisons and poisoning, however, dates back thousands of years. Throughout the millennia, poisons have played an important role in human history—from political assassination in Roman times, to weapons of war, to contemporary environmental concerns, and to weapons of terrorism. This chapter offers a perspective on the impact of poisons and poisoning on history. It also provides a historic overview of human understanding of poisons and the development of toxicology from antiquity to the present. The development of the modern poison control center, the genesis of the field of medical toxicology, and the recent increasing focus on medication errors and biologic and chemical weapons are examined. An Antidote in Depth at the end of the chapter scrutinizes changes in poison management over the years, analyzing obsolete antidotes and other discarded

therapeutic modalities. Chapter 2 describes poison plagues and unintentional disasters throughout history and examines the societal consequences of these unfortunate events. An appreciation of past failures and mistakes in dealing with poisons and poisoning promotes a keener insight and a more critical evaluation of present-day toxicologic issues, and helps in the assessment and management of future toxicologic problems.

Poisons, Poisoners, Antiquity

and

Antidotes

of

The earliest poisons consisted of plant extracts, animal venoms, and minerals. They were used for hunting, waging war, and sanctioned and unsanctioned executions. The Ebers Papyrus , an ancient Egyptian text written about 1500 B.C. that is considered to be among the earliest medical texts, describes many ancient poisons, including aconite, antimony, arsenic, cyanogenic glycosides, hemlock, lead, mandrake, opium, and wormwood.94 , 141 These poisons were thought to have mystical properties, and their use was surrounded by superstition and intrigue. Some agents, such as the Calabar bean (Physostigma venenosum ) containing physostigmine, were referred to as “ordeal poisons.― Ingestion of these substances was believed to be lethal to the guilty and harmless to the innocent.94 The “penalty of the peach― involved the administration of peach pits, which we now know contain the cyanide precursor amygdalin, as an ordeal poison. Magicians, sorcerers, and religious figures were the toxicologists of antiquity. The Sumerians, in about 4500 B.C., were said to worship the deity Gula, who was known as the “mistress of charms and spells― and the “controller of noxious poisons― (Table 1-1 ). 141

Arrow and Dart Poisons

The prehistoric Masai hunters of Kenya, who lived 18,000 years ago, used arrow and dart poisons to increase the lethality of their weapons.20 One of these poisons appears to have consisted of extracts of Strophanthus species, an indigenous plant that contains strophanthin, a digitalis-like substance.94 Cave paintings of arrowheads and spearheads reveal that these weapons were crafted with small depressions at the end to hold the poison.142 I n fact, the term toxicology is derived from the Greek terms toxikos (“bow―) and toxikon (“poison into which arrowheads are dipped―).8 , 142 References to arrow poisons are cited in a number of other important literary works. The ancient Indian text Rig Veda , written in the 12th century B.C., refers to the use of Aconitum species for arrow poisons.20 In the Odyssey , Homer (ca. 850 B.C.) wrote that Ulysses anointed his arrows with a variety of poisons, including extracts of Helleborus orientalis (thought to act 109 as a heart poison) and snake venoms. Aristotle (384–322 B.C.) described how the Scythians prepared and used arrow poisons.143 Finally, reference to weapons poisoned with the blood of serpents can be found in the writings of Ovid (43 B.C.– 18 A.D.).148

Classification

of

Poisons

The first attempts at poison identification and classification, and the introduction of the first antidotes, took place during Greek and Roman times. An early categorization of poisons divided them into fast poisons, such as strychnine, and slow poisons, such as arsenic. In his treatise, Materia Medica , the Greek physician Dioscorides (40–80 A.D.), categorized poisons by their origin: animal, vegetable, or mineral.142 This categorization remained the standard classification for the next 1500 years.142

Animal

Poisons

Animal poisons usually referred to the venom from poisonous animals. Although the venom from poisonous snakes has always been among the most commonly feared poisons, poisons from toads, salamanders, jellyfish, stingrays, and sea hares are also of concern. Nicander of Colophon (204–135 B.C.), a Greek poet and physician who is considered to be one of the earliest toxicologists, experimented with animal poisons on condemned criminals.128 Nicander's poems Theriaca and Alexipharmaca are considered to be the earliest extant Greek toxicologic texts, describing the presentations and treatment of poisonings from animal P.2 toxins.141

A notable fatality from the effects of an animal toxin

was Cleopatra (69–30 B.C.), who reportedly committed suicide by deliberately falling on an asp.72 Gula ca. 4500 B.C. First deity associated with poisons Shen Nung ca. 2000 B.C. Chinese emperor who experimented with poisons and antidotes and wrote treatise on herbal medicine Homer ca. 850 B.C. Wrote how Ulysses anointed arrows with the venom of serpents Aristotle 384–322 B.C. Described the preparation and use of arrow poisons Theophrastus ca. 370–286 B.C. Referred to poisonous plants in De Historia Plantarum Socrates ca. 470–399 B.C. Executed by poison hemlock

Nicander 204–135 B.C. Wrote two poems that are among the earliest works on poisons: Theriaca and Alexipharmaca King Mithridates VI ca. 132–63 B.C. Fanatical fear of poisons; developed mithradatum, one of first universal antidotes Sulla 81 B.C. Issued Lex Cornelia , the first antipoisoning law Cleopatra 69–30 B.C. Committed suicide from deliberate cobra envenomation Andromachus 37–68 A.D. Refined mithradatum; known as the Theriac of Andromachus Dioscorides 40–80 A.D. Wrote Materia Medica , which classified poison by animal, vegetable, and mineral Galen ca. 129–200 A.D. Prepared “Nut Theriac― for Roman emperors, a remedy against bites, stings, and poisons; wrote De Antidotis I and I I , which provided recipes for different antidotes, including mithradatum and panacea Ibn Wahshiya 9th Century Famed Arab toxicologist; wrote toxicology treatise Book on Poisons , combining contemporary science, magic, and astrology Moses Maimonides 1135–1204 Wrote Treatise on Poisons and Their Antidotes

Petrus Abbonus 1250–1315 Wrote De Venenis , major work on poisoning Person

Date

Importance

TABLE 1-1. Important Early Figures in the History of Toxicology

Vegetable

Poisons

Theophrastus (ca. 370–286 B.C.) described vegetable poisons in his treatise De Historia Plantarum . 74 Notorious poisonous plants included Aconitum species (aconite, monkshood), Conium maculatum (poison hemlock), Hyoscyamus niger (henbane), Mandragora officinarum (mandrake), Papaver somniferum (opium poppy), and Veratrum album (hellebore). Aconite was among the most frequently encountered poisonous plants and was described as the “queen mother of poisons.―141 Hemlock was the official poison used by the Greeks and was employed in the execution of Socrates (ca. 470–399 B.C.) and many others. 130 Poisonous plants used in India at this time included Cannabis indica (marijuana), Croton tiglium (croton oil), and Strychnos nux vomica (poison nut, strychnine).74

Mineral

Poisons

The mineral poisons of antiquity consisted of the metals antimony, arsenic, lead, and mercury. Undoubtedly the most famous of these was lead. Lead was discovered as early as 3500 B.C. Although controversy continues about whether an epidemic of lead poisoning among the Roman aristocracy contributed to the fall of the Roman Empire, lead was certainly used extensively during this period.54 , 108 In addition to its considerable use in plumbing, lead was also used in the production of food and drink containers.61 I t

was common practice to add lead directly to wine, or to intentionally prepare the wine in a lead kettle to improve its taste. Not surprisingly, chronic lead poisoning became widespread. Nicander described the first case of lead poisoning in the 2nd century B.C.145 Dioscorides, writing in the 1st century A.D., noted that fortified wine was “most hurtful to the nerves.―145 Lead-induced gout (“saturnine gout―) may have also been widespread among the Roman elite.108

Gases Although not animal, vegetable, or mineral in origin, the toxic effects of gases were also appreciated during antiquity. In the 3rd century B.C., Aristotle commented that “coal fumes (carbon monoxide) lead to a heavy head and death―71 and Cicero (106–43 B.C.) referred to the use of coal fumes in suicide and execution.

Poisoners

of

Antiquity

Given the increasing awareness of the toxic properties of some naturally occurring substances and the lack of analytical detection techniques, homicidal poisoning was common during Roman times. In an attempt to curtail this practice, in 81 B.C. the Roman dictator Sulla issued the first law against poisoning, the Lex Cornelia . According to its provisions, if convicted of poisoning, the perpetrator was sentenced to either loss of property and exile (if the perpetrator was of high social rank) or exposure to wild beasts (if the perpetrator was of low social rank). During this period, members of the aristocracy commonly employed “tasters― to shield themselves from potential poisoners, a practice that was also in vogue during the reign of Louis XIV in 16th century France.148 One of the most infamous poisoners of Ancient Rome was Locusta, who was known to experiment on slaves with poisons, including

aconite, arsenic, belladonna, henbane, and poisonous fungi. In 54 A.D., Nero's mother, Agrippina, hired Locusta to poison Emperor Claudius (Agrippina's husband and Nero's stepfather) as part of a scheme to make Nero emperor. As a result of these activities, Claudius, who was a great lover of mushrooms, died from Amanita phalloides poisoning,18 and in the next year, Britannicus (Nero's stepbrother) also became one of Locusta's victims. In this case, Locusta managed to fool the taster by preparing unusually hot soup that required additional cooling after the soup had been officially tasted. At the time of cooling, the poison was surreptitiously slipped into the soup. Almost immediately after drinking the soup Britannicus collapsed and died. The exact poison remains debatable, but some authorities suggest that it was a cyanogenic glycoside.134

Early Quests for the Universal Antidote The recognition, classification, and use of poisons in Ancient Greece and Rome were accompanied by an intensive search for a universal antidote. In fact, many of the physicians of this period P.3 devoted significant parts of their careers to this endeavor.141 Mystery and superstition surrounded the origin and source of these proposed antidotes. One of the earliest specific references to a protective agent can be found in Homer's Odyssey , when Ulysses is advised to protect himself by taking the antidote “moli.― Recent speculation suggests that moli referred to Galanthus nivalis , which contains a cholinesterase inhibitor. This agent could have been used as an antidote against poisonous plants such as Datura stramonium (jimsonweed) that contain the anticholinergic alkaloids scopolamine, atropine, and hyoscyamine.115

Theriacs

and

the

Mithradatum

The Greeks referred to the universal antidote as the alexipharmaca

or theriac . 141 The term alexipharmaca was derived from the words alexipharmakos (“which keeps off poison―) and antipharmakon (“antidote―). Over the years, alexipharmaca increasingly was used to refer to a method of treatment, such as the induction of emesis by using a feather. Theriac , which originally had referred to poisonous reptiles or wild beasts, was later used to refer to the antidotes. Consumption of the early theriacs (ca. 200 B.C.) was reputed to make people “poisonproof― against bites of all venomous animals except the asp. Their ingredients included aniseed, anmi, apoponax, fennel, meru, parsley, and wild thyme.141 The quest for the universal antidote was epitomized by the work of King Mithradates VI of Pontus (132–63 B.C.).73 After repeatedly being subjected to poisoning attempts by his enemies during his youth, Mithradates sought protection by the development of universal antidotes. To find the best antidote, he performed acute toxicity experiments on criminals and slaves. The theriac he concocted, known as the “mithradatum,― contained a minimum of 36 ingredients and was thought to be protective against aconite, scorpions, sea slugs, spiders, vipers, and all other poisonous substances.71 Mithradates took his concoction every day. Ironically, when an old man, Mithradates attempted suicide by poison but supposedly was unsuccessful because he had become poison-proof. Having failed at self-poisoning, Mithradates was compelled to have a soldier kill him with a sword. Galen described Mithradates' experiences in a series of three books: D e Antidotis I, De Antidotis II , and De Theriaca ad Pisonem . 73 , 146 The Theriac of Andromachus, also known as the “Venice treacle― or “galene,― is probably the most famous theriac. According to Galen, this preparation, formulated during the 1st century A.D., was considered an improvement over the mithradatum.146 It was prepared by Andromachus (37–68 A.D.), physician to Emperor Nero. Andromachus added to the mithradatum ingredients such as the flesh of vipers, squills, and

generous amounts of opium.151 Other ingredients were removed. Altogether, 73 ingredients were required. It was advocated to “counteract all poisons and bites of venomous animals,― as well as a host of other medical problems, such as colic, dropsy, and jaundice, and it was used both therapeutically and prophylactically.141 , 146 As evidence of its efficacy, Galen demonstrated that fowl receiving poison followed by theriac had a higher survival rate than fowl receiving poison alone.141 It is likely, however, that the scientific rigor and methodology employed differed from current scientific practice. By the Middle Ages, the Theriac of Andromachus contained more than 100 ingredients. Its synthesis was quite elaborate; the initial phase of production lasted months, followed by an aging process that lasted years, somewhat like vintage wine.90 The final product was often more solid than liquid in consistency. Other theriac preparations were named after famous physicians (Damocrates, Nicolaus, Amando, Arnauld, and Abano) who contributed additional ingredients to the original formulation. Over the centuries certain localities were celebrated for their own peculiar brand of theriac. Notable centers of theriac production included Bologna, Cairo, Florence, Genoa, Istanbul, and Venice. At times, theriac production was accompanied by great fanfare. For example, in Bologna, the mixing of the theriac could take place only under the direction of the medical professors at the university.141 Whether these preparations were of actual benefit is uncertain. Some suggest that the theriac may have had an antiseptic effect on the gastrointestinal tract, whereas others state that theriac's sole benefit derived from its formulation with opium.90 Theriacs remained in vogue throughout the Middle Ages and Renaissance, and it was not until 1745 that their efficacy was finally questioned by William Heberden in Antitheriaka: An Essay on Mithradatum and Theriaca . 73 Nonetheless, pharmacopeias in France, Spain, and

Germany continued to list these agents until the last quarter of the 19th century and theriac was still available in Italy and Turkey in the early 20th century.19 , 90

Sacred

Earth

Beginning in the 5th century B.C., an adsorbent agent called terra sigillata was promoted as a universal antidote. This agent, also known as the “sacred sealed earth,― consisted of red clay that could be found on only one particular hill on the Greek island of Lemnos. Perhaps somewhat akin to the 20th-century “universal antidote,― it was advocated as effective in counteracting all poisons.141 With great ceremony, once per year, the terra sigillata was retrieved from this hill and prepared for subsequent use. According to Dioscorides, this clay was formulated with goat's blood to make it into a paste. At one time, it was included as part of the Theriac of Andromachus. Demand for terra sigillata continued into the 15th century. Similar antidotal clays were found in Italy, Malta, Silesia, and England.141

Charms Charms, such as toadstones, snakestones, unicorn horns, and bezoar stones, were also promoted as universal antidotes. Toadstones, found in the heads of old toads, were reputed to have the capability to extract poison from the site of a venomous bite or sting. In addition, the toadstone was supposedly able to detect the mere presence of poison by producing a sensation of heat upon contact with a poisonous substance.141 Similarly, snakestones extracted from the heads of cobras (known as piedras della cobra de Capelos ) were also reported to have similar magical qualities. 15 The 17th-century Italian philosopher Athanasius Kircher (1602–1680) became an enthusiastic supporter of snakestone therapy for the treatment of snakebite after conducting experiments, demonstrating the antidotal

attributes of these charms “in front of amazed spectators.― Kircher attributed the snakestone's efficacy to the theory of “attraction of like substances.― Francesco Redi (1626–1698), a court physician and contemporary of Kircher, debunked this quixotic approach. A harbinger of future experimental toxicologists, Redi was unwilling to accept isolated case reports and field demonstrations as proof of the snakestone's utility. Using a considerably more rigorous approach, provando et riprovando (by testing and retesting), Redi assessed the antidotal efficacy of snakestone on different animal species and different toxins and failed to confirm any benefit.15 Much lore has surrounded the antidotal effects of the mythical unicorn horn. Ctesias, writing in 390 B.C., was the first to chronicle the wonders of the unicorn horn, claiming that drinking water or P.4 wine from the “horn of the unicorn― would protect against poison.141 The horns were usually narwhal tusks or rhinoceros horns and during the Middle Ages, the unicorn horn may have been worth as much as 10 times the price of gold. Similar to the toadstone, the unicorn horn was used both to detect poisons and to neutralize them. Supposedly a cup made of unicorn horn would sweat if a poisonous substance was placed in it.88 To give further credence to its use, a 1593 study on arsenic-poisoned dogs reportedly showed that the horn was protective.88 Bezoar stones, also touted as universal antidotes, consisted of stomach or intestinal calculi formed by the deposition of calcium phosphate around a hair, fruit pit, or gallstone. They were removed from wild goats, cows, and apes and administered orally to humans. The Persian name for the bezoar stone was pad zahr (“expeller of poisons―); the ancient Hebrews referred to the bezoar stone as bel Zaard (“every cure for poisons―). Over the years, regional variations of bezoar stones were popularized, including an Asian variety from wild goat of Persia, an Occidental

variety from llamas of Peru, and a European variety from chamois of the Swiss mountains.49 , 141

Opium,

Coca,

and

Hallucinogens

in

Antiquity Although it was not until the mid-19th century that the peril of opiate addiction was first recognized, juice from the Papaver somniferum was known for its medicinal value in Egypt at least as early as the writing of the Ebers Papyrus in 1500 B.C. Egyptian pharmacologists of that time reportedly recommended opium poppy extract as a pacifier for children who exhibited incessant crying.127 In Ancient Greece, Dioscorides and Galen were early advocates of opium as a therapeutic agent. During this time, it was also used as a means of suicide. Mithradates' lack of success in his own attempted suicide by poisoning may have been the result of an opium tolerance that had developed from previous repetitive use. 127 One of the earliest descriptions of the abuse potential of opium is attributed to Epistratos (304–257 B.C.), who criticized the use of opium for earache because it “dulled the sight and is a narcotic.―127 Cocaine use dates back to at least 300 B.C., when South American Indians reportedly chewed coca leaves during religious ceremonies.102 Chewing coca to increase work efficacy and to elevate mood has remained commonplace in some South American societies for thousands of years. An Egyptian mummy from about 950 B.C. revealed significant amounts of cocaine in the stomach and liver, suggesting oral use of cocaine during this time period.106 Large amounts of tetrahydrocannabinol (THC) were found in the lung and muscle of the same mummy. Another investigation of 11 Egyptian (1079 B.C.– 395 A.D.) and 72 Peruvian (200–1500 A.D.) mummies, found cocaine, thought to be indigenous only to South America, and hashish, thought to be indigenous only to Asia, in both groups.114

Other currently abused agents that were known to the ancients include cannabis, hallucinogenic mushrooms, nutmeg, and peyote. As early as 1300 B.C., Peruvian indian tribal ceremonies included the use of mescaline-containing San Pedro cacti.102 The hallucinogenic mushroom, Amanita muscaria , known as “fly agaric,― was used as a ritual drug and may have been known in India as “soma― around 2000 B.C. Cannabis use in China dates back even further, to around 2700 B.C., when it was known as the “liberator of sin.―102 In India and Iran, cannabis was used as early as 1000 B.C. as an intoxicant known as bhang .105

Early Attempts at Decontamination

Gastrointestinal

Nicander's Alexipharmaca (“Antidotes for Poisons―) recommended induction of emesis by one of several methods: (a) ingesting warm linseed oil; (b) tickling the hypopharynx with a feather; or (c) “emptying the gullet with a small twisted and curved paper.―90 Nicander also advocated the use of suction to limit envenomation.142 The Romans referred to the feather as the “vomiting feather― or “pinna.― Most commonly, the feather was used after a hearty feast to avoid the gastrointestinal discomfort associated with overeating. At times, the pinna was dipped into a nauseating mixture to increase its efficacy.93

Toxicology Renaissance

During

the

Medieval

and

Periods

After Galen (ca. A.D. 129–200), there is relatively little documented attention to the subject of poisons until the works of Ibn Wahshiya in the 9th century. Citing Greek, Persian, and Indian texts, Wahshiya's work, entitled Book of Poisons , combines contemporary science, magic, and astrology during his discussion of poison mechanisms (as they were understood at that time),

symptomatology, antidotes, including his own recommendation for a universal antidote, and prophylaxis. He categorized poisons as lethal by sight, smell, touch, and sound, as well as by drinking and eating. For victims of an aconite-containing dart arrow, Ibn Wahshiya recommended excision, followed by cauterization and topical treatment with onion and salt.85 Another significant medieval contribution to toxicology can be found in Moses Maimonides' (1135–1204) Treatise on Poisons and Their Antidotes (1198). In part one of this treatise, Maimonides discussed the bites of snakes and mad dogs, and the stings of bees, wasps, spiders, and scorpions.125 He also discussed the use of cupping glasses for bites (a progenitor of the modern suctioning device), and was one of the first to differentiate the hematotoxic (hot) from the neurotoxic (cold) effects of poison. In part two, he discussed mineral and vegetable poisons and their antidotes. He described belladonna poisoning as causing a “redness and a sort of excitation.― 125 He suggested that emesis should be induced by hot water, Anethum graveolens (dill), and oil, followed by fresh milk, butter, and honey. Although he rejected some of the popular treatments of the day, he advocated the use of the great theriac and the mithradatum as first- and second-line agents in the management of snakebite.125 On the subject of oleander poisoning, Petrus Abbonus (1250–1315) wrote that those who drink the juice, spines, or bark of oleander will develop anxiety, palpitations, and syncope. 22 He described the clinical presentation of opium overdose as someone who “will be dull, lazy, and sleepy, without feeling, and he will neither understand nor feel anything, and if he does not receive succor, he will die.― Although this “succor― is not defined, he recommended that treatment of opium intoxication include drinking the strongest wine, rubbing the extremities with alkali and soap, and olfactory stimulation with pepper. To treat snakebite, Abbonus suggested the immediate application of a tourniquet, as well as oral suctioning of the bite

wound—preferably performed by a servant. Interestingly, from a 21st-century perspective, Abbonus also suggested that St. John's wort had the magical power to free anything from poisons and attributed this virtue to the influence of the stars.22 Paracelsus 1493–1541 Introduced dose-response concept to toxicology Ambroise Pare 1510–1590 Spoke out against unicorn horns and bezoars as antidotes William Piso 1611–1678 First to study emetic qualities of ipecacuanha Bernardino Ramazzini 1633–1714 Father of occupational medicine; wrote De Morbis Artificum Diatriba Richard Mead 1673–1754 Wrote English-language book dedicated to poisoning Percivall Pott 1714–1788 First description of occupational cancer, relating the chimney sweep occupation to scrotal cancer Felice Fontana 1730–1805 First scientific study of venomous snakes Philip Physick 1767–1837 Early advocate of orogastric lavage to remove poisons Baron Guillaume Dupuytren 1777–1835 Early advocate of orogastric lavage to remove poisons Edward Jukes

1820 Self-experimented with orogastric lavage apparatus known as Jukes' syringe Grand Marshall Bertrand 1813 Demonstrated the efficacy of charcoal in arsenic ingestion Pierre Touery 1831 Demonstrated the efficacy of charcoal in strychnine ingestion Alfred Garrod 1846 First systematic study of charcoal in an animal model Benjamin Howard Rand 1848 First study of the efficacy of charcoal in humans Bonaventure Orfila 1787–1853 Father of modern toxicology; wrote Traite des Poisons ; first to isolate arsenic from humans organs Robert Christison 1797–1882 Wrote Treatise on Poisons , one of the most influential texts in early 19th century Francois Magendie 1783–1855 Discovered emetine and studied mechanism of cyanide and strychnine Claude Bernard 1813–1878 Studied mechanism of toxicity of carbon monoxide and curare O.H. Costill 1848 Wrote first book on symptoms and treatment of poisoning Theodore Wormley

1826–1897 Wrote Micro-Chemistry of Poisons , the first American book devoted exclusively to toxicology James Marsh 1794–1846 Developed reduction test for arsenic Hugo Reinsch 1842–1884 Developed qualitative tests for arsenic and mercury Max Gutzeit 1847–1915 Developed method to quantitate small amounts of arsenic Albert Niemann 1860 Isolated cocaine alkaloid Rudolf Kobert 1854–1918 Studied digitalis and ergot alkaloids Louis Lewin 1850–1929 Studied many toxins, including methanol, chloroform, snake venom, carbon monoxide, lead, opiates, and hallucinogenic plants Alice Hamilton 1869–1970 Conducted landmark investigations associating worksite chemical hazards with disease; led reform movement to improve worker safety Person

Date

Importance

TABLE 1-2. Important Figures in the Field of Toxicology from Paracelsus to the 1900s P.5

The

Scientists

Paracelsus' (1493–1541) study on the dose–response relationship is usually considered the beginning of the scientific approach to toxicology (Table 1-2 ). He was the first to emphasize the chemical nature of toxic agents.112 Paracelsus stressed the need for proper observation and experimentation regarding the true response to chemicals. He underscored the need to differentiate between the therapeutic and toxic properties of chemicals when he stated in his Third Defense , “What is there that is not poison? All things are poison and nothing [is] without poison. Solely, the dose determines that a thing is not a poison.―41 Although Paracelsus is the best known Renaissance toxicologist, Ambroise Pare (1510–1590) and William Piso (1611–1678) also contributed to the field. Pare argued against the use of the unicorn horn and bezoar stone.92 He also wrote an early treatise on carbon monoxide poisoning. Piso is credited as one of the first to recognize the emetic properties of ipecacuanha.122

Medieval

and

Renaissance

Poisoners

Along with these advances in toxicologic knowledge, the Renaissance is mainly remembered as the age of the poisoner, a time when the art of poisoning reached new heights (Table 1-3 ). In fact, poisoning was so rampant during this time that in 1531 King Henry VIII decreed that convicted poisoners should be boiled alive.51 From the 15th to 17th centuries, schools of poisoning existed in Venice and Rome. In Venice, poisoning services were provided by a group called the Council of Ten, whose members were hired to perform murder by poison.148 Members of the infamous Borgia family were credited with many poisonings during this period. They preferred to use a poison called “La Cantarella,― a mixture of arsenic and

phosphorus.143 Rodrigo Borgia (1431–1503), who became Pope Alexander VI, and his son, Cesare Borgia, were reportedly responsible for the poisoning of cardinals and kings. In the late 16th century, Catherine de Medici, wife of Henry II of France, introduced Italian poisoning techniques to France. She experimented on the poor, the sick, and the criminal. By analyzing the subsequent complaints of her victims, she is said to have learned the site of action and time of onset, the clinical signs and symptoms, and the efficacy of poisons.55 Murder by poison remained quite popular during the latter half of the 17th and the early part of the 18th centuries in Italy and France. The Marchioness de Brinvilliers (1630–1676) tested her poison concoctions on hospitalized patients and on her servants, and allegedly murdered her husband, father, and two siblings.53 , 134 Among the favorite poisons of the Marchioness were arsenic, copper sulfate, corrosive sublimate (mercury bichloride), lead, and tartar emetic (antimony potassium tartrate).143 Catherine Deshayes (1640–1680), a fortuneteller and sorcerer, was one of the last “poisoners for hire,― and was implicated in countless poisonings, including the killing of more than 2000 infants.55 Better known as “La Voisine,― she reportedly sold poisons to women wishing to rid themselves of their husbands. Her particular brand of poison was a P.6 concoction of aconite, arsenic, belladonna, and opium known as “la poudre de succession.―143 Ultimately, de Brinvilliers was beheaded and Deshayes was burned alive for their crimes. In an attempt to curtail these rampant poisonings, Louis XIV issued a decree in 1662 banning the sale of arsenic, mercury, and other poisons to customers not known to the apothecaries and requiring poison buyers to sign a register declaring the purpose for their purchase.134

Locusta 54–55 Claudius

A.D. and Britannicus

Amanita phalloides , cyanide Cesare Borgia 1400s Cardinals and kings La Cantarella (arsenic and phosphorus) Catherine de Medici 1519–1589 Poor, sick, criminals Unknown agents Hieronyma Spara Died 1659 Taught women how to poison their husbands Mana of St. Nicholas of Bari (arsenic trioxide) Marchioness de Brinvilliers Died 1676 Hospitalized patients, husband, father Antimony, arsenic, copper, lead, mercury Catherine Deshayes Died 1680 >2000 infants, many husbands La poudre de succession (arsenic mixed with aconite, belladonna, and opium) Madame Giulia Toffana Died 1719 >600 people Aqua toffana (arsenic trioxide) Mary Blandy 1752 Father Arsenic Anna Maria Zwanizer

1807 Random people Antimony, arsenic Marie Lefarge 1839 Husband Arsenic (first use of Marsh test) John Tawell 1845 Mistress Cyanide William Palmer, MD 1855 Fellow gambler Strychnine Madeline 1857 Lover Arsenic

Smith

(acquitted)

Edmond de la Pommerais, MD 1863 Patient and mistress Digitalis Edward William Pritchard, MD 1865 Wife and mother-in-law Antimony George Henry Lamson, MD 1881 Brother-in-law Aconite Adelaide Bartlett (acquitted) 1886 Husband

Chloroform Florence Maybrick 1889 Husband Arsenic Thomas Neville Cream, MD 1891 Prostitutes Strychnine Johann Hoch 1892–1905 Serial wives Arsenic Cordelia Botkin 1898 Feminine rival Arsenic (in chocolate candy) Roland Molineux 1898 Acquaintance Cyanide of mercury Hawley Harvey Crippen, MD 1910 Wife Hyoscine Frederick Henry Seddon 1911 Boarder Arsenic (fly paper) Henri Girard Landru 1912 Acquaintances Amanita phalloides Robert Armstrong

1921 Wife Arsenic (weed killer) Landru 1922 Many women Cyanide Suzanne Fazekas 1929 Supplied poison to 100 wives to kill husbands Arsenic Sadamichi Hirasawa 1948 Bank employees Potassium cyanide Christa Ambros Lehmann 1954 Friend, husband, father-in-law E-605 (parathion) Nannie Doss 1954 11 relatives, including 5 husbands Arsenic Carl Coppolino, MD 1965 Wife Succinylcholine Graham Frederick Young 1971 Stepmother, coworkers Antimony, thallium Judias V. Buenoano 1971 Husband, son

Arsenic Ronald Clark O'Bryan 1974 Son and neighborhood children Cyanide (in Halloween candy) ??? 1978 Georgi Markov, Bulgarian diplomat Ricin Jim Jones 1978 911 people in mass suicide Cyanide Harold Shipman, MD 1974–1998 Patients (up to 297) Heroin “Tylenol― tamperer 1982 7 people Extra Strength Tylenol mixed with cyanide Donald Harvey 1983–1987 Patients Arsenic George Trepal 1988 Neighbors Thallium Michael Swango, MD 1980s–1990s Hospitalized patients Arsenic, potassium chloride, Charles Cullen, RN

succinylcholine

1990s–2003 Hospitalized patients Digoxin ??? 2004 Viktor Yushchenko, Ukrainian Dioxin Poisoner

Date

Victim(s)

presidential

candidate

Poison(s)

TABLE 1-3. Notable Poisoners from Antiquity to the Present1 3 4 , 1 4 1 , 1 4 3 A major center for poison practitioners was Naples, the home of the notorious Madame Giulia Toffana. She reportedly poisoned more than 600 people, preferring a particular solution of white arsenic (arsenic trioxide), better known as “aqua toffana,― and dispensed under the guise of a cosmetic. Eventually convicted of poisoning, Madame Toffana was executed in 1719.21

Eighteenthand Developments in

Nineteenth-Century Toxicology

The development of toxicology as a distinct specialty began during the 18th and 19th centuries (see Table 1-2 ).113 The poison mystique—mythologic and magical—was gradually replaced by an increasingly rational, scientific, and experimental approach to the study of these agents. Much of the poison lore that had survived for almost 2000 years was finally debunked and discarded. The 18th-century Italian Felice Fontana was one of the first to usher in the modern age. He was an early experimental toxicologist who studied the venom of the P.7 European viper and wrote the classic text Traite sur le Venin de la

Vipere in 1781. 77 Through his exacting experimental study on the effects of venom, Fontana brought a scientific insight to toxicology that had previously been lacking, demonstrating that clinical symptoms are a result of the poison (venom) acting on specific target organs. During the 18th and 19th centuries, attention focused on the detection of poisons and the study of toxic effects of drugs and chemicals in animals.107 Issues relating to adverse effects of industrialization and unintentional poisoning in the workplace and home environment were raised. Also during this time, early experience and experimentation with methods of gastrointestinal decontamination took place.

Development of Analytical and the Study of Poisons

Toxicology

The French physician Bonaventure Orfila (1787–1853) is often called the father of modern toxicology.107 He emphasized toxicology as a distinct, scientific discipline, separate from clinical medicine and pharmacology.12 He also was an early medical-legal expert who championed the use of chemical analysis and autopsy material as evidence to prove that a poisoning had occurred. His treatise Traite des Poisons (1814)111 had five editions and was regarded as the foundation of experimental and forensic toxicology.149 This text classified poisons into six groups: acrids, astringents, corrosives, narcoticoacrids, septics or putrefiants, and stupefacients and narcotics. A number of other landmark works on poisoning also first appeared during this period. In 1829, Robert Christison (1797–1882), a professor of medical jurisprudence and Orfila's student, wrote A Treatise on Poisons .31 This work simplified Orfila's poison classification schema by categorizing poisons into three groups: irritants, narcotics, and narcoticoacrids. Less concerned with jurisprudence than with clinical toxicology, O.H. Costill's A Practical Treatise on Poisons , published in 1848, was

the first modern clinically oriented text to emphasize the symptoms and treatment of poisoning. 35 In 1867, Theodore Wormley (1826–1897) published the first American book written exclusively on poisons entitled the Micro-Chemistry of Poisons .47 , 150

During this time, important breakthroughs in the chemical analysis of poisons resulted from the search for a more reliable assay for arsenic. Arsenic was widely available and was the suspected etiology of a large number of deaths. In one study, arsenic was employed in 31% of 679 homicidal poisonings.143 A reliable means of detecting arsenic was much needed by the courts. Until the 19th century, poisoning was mainly diagnosed by symptoms rather than by analytic tests. The first use of a chemical test as evidence in a poisoning trial occurred in the 1752 trial of Mary Blandy, who was accused of poisoning her father with arsenic.96 Although Blandy was convicted and hanged publicly, the test employed in this case was not very sensitive and depended in part on eliciting a garlic odor upon heating the gruel that the accused had fed to her father. During the 19th century, James Marsh (1794–1846), Hugo Reinsch, and Max Gutzeit (1847–1915) each worked on this problem. Assays bearing their names are important contributions to the early history of analytic toxicology.97 , 107 The “Marsh test― to detect arsenic was first used in a criminal case in 1839 during the trial of Marie Lefarge, who was accused of using arsenic to murder her husband.134 Orfila's trial testimony that the victim's viscera contained minute amounts of arsenic helped to convict the defendant although subsequent debate suggested that contamination of the forensic specimen may have also played a role. In a further attempt to curtail criminal poisoning by arsenic, the British Parliament passed the Arsenic Act in 1851. This bill, which was one of the first modern laws to regulate the sale of poisons,

required that the retail sale of arsenic be restricted to chemists, druggists, and apothecaries, and that a poison book be maintained to record all arsenic sales.16 Homicidal poisonings remained common during the 19th and early 20th century. Infamous poisoners of the late 19th century and early 20th century included William Palmer, Edward Pritchard, Harvey Crippen, and Frederick Seddon.143 Many of these poisoners were physicians who used their knowledge of medicine and toxicology in an attempt to solve their domestic and financial difficulties by committing the “perfect― murder. Some of the poisons employed were aconitine (Lamson, who was a classmate of Christison), Amanita phalloides (Girard), arsenic (Maybrick, Seddon, others), antimony (Pritchard), cyanide (Molineux, Tawell), digitalis (Pommerais), hyoscine (Crippen), and strychnine (Palmer, Cream)

(see Table 1-3 ).24 , 141 , 143

In the early 20t h century, forensic investigation into suspicious deaths, including poisonings, was significantly advanced with the development of the medical examiner system that replaced the much-flawed coroner system that was subject to widespread corruption. In 1918, the first centrally controlled medical examiner system was established in New York City. Alexander Gettler, considered the father of forensic toxicology in the United States, established a toxicology laboratory within the newly created New York City Medical Examiner's Office. Gettler pioneered new techniques for the detection of a variety of substances in biologic fluids including carbon monoxide, chloroform, cyanide, and heavy metals.48 , 107 Systematic investigation into the underlying mechanisms of toxic substances also commenced during the 19th century. To cite just a few important accomplishments, Francois Magendie (1783–1855) studied the mechanisms of toxicity and sites of action of cyanide, emetine, and strychnine.46 Claude Bernard (1813–1878), the pioneering physiologist and a student of Magendie, made

important contributions to the understanding the toxicity of carbon monoxide and curare.84 Rudolf Kobert (1854–1918) studied digitalis and ergot alkaloids, and also authored a textbook on toxicology for physicians and students.79 , 109 Louis Lewin (1850–1929) was the first person to intensively study the differences between the pharmacologic and toxicologic actions of drugs. Lewin studied chronic opium intoxication, as well as the toxicity of carbon monoxide, chloroform, lead, methanol, and snake venom. He also developed a classification system for psychoactive drugs, dividing them into euphorics, phantastics, inebriants, hypnotics, and excitants.91

The

Origin

of

Occupational

Toxicology

The origins of occupational toxicology can be traced to the early 18th century and to the contributions of Bernardino Ramazzini (1633–1714). Considered the father of occupational medicine, Ramazzini wrote De Morbis Artificum Diatriba (Diseases of Workers ) in 1700, relationship Ramazzini's epitomized

which was the first comprehensive text discussing the between disease and workplace hazards.52 essential contribution to the care of the patient is by the addition of a question to the medical history,

“What occupation does the patient follow?―50 Altogether Ramazzini described diseases associated with 54 occupations, including hydrocarbon poisoning in painters, mercury poisoning in mirror makers, and pulmonary diseases in miners. P.8 In 1775, Sir Percivall Pott proposed the first association between workplace exposure and cancer when he noticed a high incidence of scrotal cancer in English chimney sweeps. Pott's belief that the scrotal cancer was caused by prolonged exposure to tar and soot was confirmed by other investigation in the 1920s, indicating that the polycyclic aromatic hydrocarbons contained in coal tar (including benzo[a ]pyrene) are carcinogenic.69

Dr. Alice Hamilton (1869–1970) was another pioneer in occupational toxicology, whose rigorous scientific inquiry had a profound impact on linking chemical toxins with human disease. A physician, scientist, humanitarian, and social reformer, Hamilton, who would become the first female professor at Harvard University, conducted groundbreaking studies of many different occupational exposures and problems, including carbon monoxide poisoning in steelworkers, mercury poisoning in hatters, and wrist drop in lead workers. Her overriding concerns about these “dangerous trades― and her commitment to improve the health of workers would lead to extensive voluntary and regulatory reforms in the workplace.59 , 63

Advances in Gastrointestinal Decontamination Using gastric lavage and charcoal to treat the poisoned patient was introduced in the late 18th and early 19th century. A stomach pump was first designed by Munro Secundus in 1769 to administer neutralizing substances to sheep and cattle for the treatment of bloat.25 The American surgeon Philip Physick (1768–1837) and the French surgeon Baron Guillaume Dupuytren (1777–1835) were two of the first physicians to advocate gastric lavage for the removal of poisons.25 As early as 1805, Physick demonstrated the use of a “stomach tube― for this purpose. Using brandy and water as the irrigation fluid, he performed stomach washings in twins to wash out excessive doses of tincture of opium.25 Dupuytren performed gastric emptying by first introducing warm water into the stomach via a large syringe attached to a long flexible sound and then withdrawing the “same water charged with poison.―25 Edward Jukes, a British surgeon, was another early advocate of poison removal by gastric lavage. Jukes first experimented on animals, performing gastric lavage after the oral administration of tincture of opium. Attempting to gain human

experience, he experimented on himself, by first ingesting 10 drams (600 g) of tincture of opium and then performing gastric lavage using a 25-inch-long, 0.5-inch-diameter tube, which became known as Jukes' syringe.101 Other than some nausea and a 3-hour sleep he suffered no ill effects, and the experiment was deemed a success. The principle of using charcoal to adsorb poisons was first described by Scheele (1773) and Lowitz (1785), but the medicinal use of charcoal dates to ancient times. 34 The earliest reference to the medicinal uses of charcoal is found in the Egyptian Papyrus of about 1500 B.C. 34 The charcoal employed during Greek and Roman times, referred to as wood charcoal, was used to treat anthrax, chlorosis, epilepsy, and vertigo. By the late 18th century, topical application of charcoal was recommended for gangrenous skin ulcers, and internal use of a charcoal-water suspension was recommended for use as a mouthwash and in the treatment of bilious conditions. 34 The first hint that charcoal might have a role in the treatment of poisoning came from a series of courageous self-experiments in France during the early 19th century. In 1813, the French chemist M. Bertrand publicly demonstrated the antidotal properties of charcoal by surviving a 5-g ingestion of arsenic trioxide that had been mixed with charcoal.66 Eighteen years later, before the French Academy of Medicine, the pharmacist P.F. Touery survived an ingestion consisting of 10 times the lethal dose of strychnine mixed with 15 g of charcoal.66 One of the first reports of charcoal used in a poisoned patient was in 1834 by the American Hort, who successfully treated a mercury bichloride-poisoned patient with large amounts of powdered charcoal.4 In the 1840s, A. Garrod performed the first controlled study of charcoal when he examined its utility on a variety of poisons in animal models.66 Garrod used dogs, cats, guinea pigs, and rabbits to demonstrate the potential benefits of charcoal in the

management of strychnine poisoning. He also emphasized the importance of early use of charcoal and the proper ratio of charcoal to poison. Other toxic substances, such as aconite, hemlock, mercury bichloride, and morphine were also studied during this period. The first charcoal efficacy studies in humans were performed by the American physician B. Rand in 1848.66 It was not until the early 20th century that an activation process was added to the manufacture of charcoal. In 1900, the Russian Ostrejko demonstrated that treating charcoal with superheated steam significantly enhanced its adsorbing power.34 Despite this improvement and the favorable reports mentioned, charcoal was only occasionally used in gastrointestinal decontamination until the early 1960s, when Holt and Holz repopularized its use.62

The Increasing Recognition Perils of Drug Abuse

of

the

Opioids Although the medical use of opium was promoted by Paracelsus in the 16th century, the popularity of this agent was given a significant boost when the distinguished British physician Thomas Sydenham (1624–1689) formulated laudanum, which was a tincture of opium containing cinnamon, cloves, saffron, and sherry. Sydenham also formulated a different opium concoction known as “syrup of poppies.―82 A third opium preparation called Dover's powder was designed by Sydenham's protégé, Thomas Dover; this preparation contained ipecac, licorice, opium, saltpeter, and tartaric acid. John Jones, the author of the 18th century text The Mysteries of Opium Reveal'd , was another enthusiastic advocate of the medicinal uses of opium.82 A well-known opium user himself, Jones provided one of the earliest descriptions of opiate addiction.

He insisted that opium offered many benefits if the dose was moderate, but that discontinuation or a decrease in dose, particularly after “leaving off after long and lavish use,― would result in such symptoms as sweating, itching, diarrhea, and melancholy. His recommendation for the treatment of these withdrawal symptoms included decreasing the dose of opium by 1% each day until the drug was totally withdrawn. During this period, a number of English writers became well-known opium addicts, including Elizabeth Barrett Browning, Samuel Taylor Coleridge, and Thomas De Quincey. De Quincey, author of Confessions of an English Opium Eater , was an early advocate of the recreational use of opiates. The famed Coleridge poem Kubla Khan referred to opium as the “milk of paradise,― and De Quincey's Confessions suggested that opium held the “key to paradise.― In many of these cases, the initiation of opium use for medical reasons led to recreational use, tolerance, and dependence.82 Although opium was first introduced to Asian societies by Arab physicians some time after the fall of the Roman Empire, the use of opium in Asian countries grew considerably during the 18th and P.9 19th centuries. In one of the more deplorable chapters in world history, China's growing dependence on opium was spurred on by the English desire to establish and profit from a flourishing drug trade.127 Opium was grown in India and exported east. Despite Chinese protests and edicts against this practice, the importation of opium persisted throughout the 19th century, with the British going to war twice in order to maintain their right to sell opium. Not surprisingly, by the beginning of the 20th century, opium abuse in China was endemic. In England, opium use continued to increase during the first half of the 19th century. During this period, opium was legal and freely available from the neighborhood grocer. To many, its use was considered no more problematic than alcohol.57 The Chinese

usually self-administered opium by smoking, a custom that was brought to the United States in the mid-19th century by Chinese immigrants, whereas the English use of opium was more often by ingestion, that is, “opium eating.― The liberal use of opiates as infant-soothing agents was one of the most unfortunate aspects of this period of unregulated opiate use.81 Godfrey's Cordial, Mother's Friend, Mrs. Winslow's Soothing Syrup, and Quietness were among the most popular of children's opiates.86 They were advertised as producing a natural sleep and recommended for teething and bowel regulation, as well as for crying. Because of the wide availability of opiates during this period, the number of acute opiate overdoses in children was consequential and would remain problematic until these unsavory remedies were condemned and removed from the market. With the discovery of morphine in 1805 and Alexander Wood's invention of the hypodermic syringe in 1853, parenteral administration of morphine became the preferred route of opiate administration for therapeutic use and abuse.68 A legacy of the generous use of opium and morphine during the United States Civil War was “soldiers' disease,― referring to a rather large veteran population that returned from the war with a lingering opiate habit.119 One hundred years later, opiate abuse and addiction would again become common among US military serving during the Vietnam War. Surveys indicated that as many as 20% of American soldiers in Vietnam were addicted to opiates during the war—in part because of its widespread availability and high purity in Vietnam.124 Growing concerns about opiate abuse in England led to the passing of the Pharmacy Act of 1868, which restricted the sale of opium to registered chemists. But in 1898, the Bayer Pharmaceutical Company of Germany synthesized heroin from opium (Bayer also introduced aspirin that same year).135 Although initially touted as a nonaddictive morphine substitute, problems with heroin use soon

became evident in the United States.

Cocaine Ironically, during the later part of the 19th century, Sigmund Freud and Robert Christison, among others, were enthusiastically recommending cocaine as a treatment for opiate addiction. After Albert Niemann's isolation of cocaine alkaloid from coca leaf in 1860, growing enthusiasm for cocaine as a panacea ensued.76 Some of the most important medical figures of the time, including William Halsted, the famed Johns Hopkins surgeon, enthusiastically promoted the use of cocaine. Halsted championed the anesthetic properties of this drug, although his own use of cocaine and subsequent morphine use in an attempt to overcome his cocaine dependency would later take a considerable toll.110 In 1884, Freud wrote Uber Cocaine ,27 advocating cocaine as a cure for opium and morphine addiction and as a treatment for fatigue and hysteria. During the last third of the 19th century, cocaine was added to many popular over-the-counter tonics of the day. In 1863, Angelo Mariani, a Frenchman, introduced a new wine, “Vin Mariani,― that consisted of a mixture of cocaine and wine (6 mg of cocaine alkaloid per ounce) and was sold as a digestive aid and restorative.102 In direct competition with the French tonic was the American-made Coca-Cola, developed by J.S. Pemberton. CocaCola was originally formulated with coca and caffeine and was marketed as a headache remedy and invigorator. With the public demand for cocaine increasing, patent medication manufacturers were adding cocaine to thousands of products. One such asthma remedy was “Dr. Tucker's Asthma Specific,― which contained 420 mg of cocaine per ounce and was applied directly to the nasal mucosa.76 By the end of the 19th century, the first American cocaine epidemic was underway.104 Similar to the medical and societal adversities associated with opiate use, the increasing use of cocaine led to a growing concern

about comparable adverse effects. In 1886, the first reports of cocaine-related cardiac arrest and stroke were published.120 Reports of cocaine habituation occurring in patients using cocaine to treat their underlying opiate addiction also began to appear. In 1902, a popular book, Eight Years in Cocaine Hell , described some of these problems. Century Magazine called cocaine “the most harmful of all habit-forming drugs,― and a report in the New York Times stated that cocaine was destroying “its victims more swiftly and surely than opium.―40 In 1910, President William Taft proclaimed cocaine to be Public Enemy Number 1. In an attempt to curb the increasing problems associated with drug abuse and addiction, the 1914 Harrison Narcotics Act mandated stringent control over the sale and distribution of narcotics (defined as opium, opium derivatives, and cocaine).40 I t was the first federal law in the United States to criminalize the nonmedical use of drugs. The bill required doctors, pharmacists, and others who prescribed narcotics to register and to pay a tax. A similar law, the Dangerous Drugs Act, was passed in the United Kingdom in 1920.57 To help enforce these drug laws in the United States, the Narcotics Division of the Prohibition Unit of the Internal Revenue Service (a progenitor of the Drug Enforcement Agency) was established in 1920. In 1924, the Harrison Act was further strengthened with the passage of new legislation that banned the importation of opium for the purpose of manufacturing heroin, essentially outlawing the medicinal uses of heroin. With the legal venues to purchase these drugs now eliminated, users were forced to buy from illegal street dealers, creating a burgeoning black market that still exists today.

Sedative-Hypnotics The introduction to medical practice of the anesthetic agents nitrous oxide, ether, and chloroform during the 19th century was accompanied by the recreational use of these agents and the first

reports of volatile substance abuse. Chloroform “jags,― ether “frolics,― and nitrous parties became a new type of entertainment. Humphrey Davies was an early self-experimenter with the exhilarating effects associated with nitrous oxide inhalation. In certain Irish towns, especially where the temperance movement was strong, ether drinking became quite popular.99 Horace Wells, the American dentist who introduced chloroform as an anesthetic, became dependent on this volatile solvent and later committed suicide. Until the last half of the 19th century aconite, alcohol, hemlock, opium, and prussic acid (cyanide) were the primary agents used for sedation.32 During the 1860s, new, more specific P.10 sedative-hypnotics, such as chloral hydrate and potassium bromide, were introduced into medical practice. In particular, chloral hydrate was hailed as a wonder drug that was relatively safe, as compared to opium, and recommended for insomnia, anxiety, and delirium tremens, as well as for scarlet fever, asthma, and cancer. But within a few years, problems with acute toxicity of chloral hydrate, as well as its potential to produce tolerance and physical dependence, became apparent.32 Mixing chloral hydrate with ethanol was noted to produce a rather powerful “knockout― combination that would become known as a “Mickey Finn.― Abuse of chloral hydrate, as well as other new sedatives such as potassium bromide, would prove to be a harbinger of 20th-century sedative-hypnotic abuse.

Hallucinogens American Indians used peyote in religious ceremonies since at least the 17th century. Hallucinogenic mushrooms, particularly Psilocybe mushrooms, were also used in the religious life of Native Americans. These were called “teonanacatl,― which means “God's sacred mushrooms― or “God's flesh.―116

Interest in the recreational use of cannabis also accelerated during the 19th century after Napoleon's troops brought the drug back from Egypt, where its use among the lower classes was widespread. In 1843, several French Romantics, including Balzac, Baudelaire, Gautier, and Hugo, formed a hashish club called “Le Club des Hachichins― in the Parisian apartment of a young French painter. Fitz Hugh Ludlow's The Hasheesh Eater , published in 1857, was an early American text espousing the virtues of marijuana.89 Absinthe, an ethanol-containing beverage that was manufactured with an extract from wormwood (Artemisia absinthium ), was very popular during the last half of the 19th century.83 This emeraldcolored, very bitter drink was memorialized in the paintings of Degas, Toulouse-Lautrec, and Van Gogh and was a staple of French society during this period.13 α-Thujone, a psychoactive component of wormwood, and a noncompetitive γ-aminobutyric acid type A (GABAA ) blocker is thought to be responsible for the pleasant feelings, as well as for the hallucinogenic effects, hyperexcitability, and significant neurotoxicity associated with this drink.65 Van Gogh's debilitating episodes of psychosis were likely exacerbated by absinthe drinking.138 Given the medical problems associated with its use, absinthe was banned throughout most of Europe by the early 20th century. A more recent event that would have significant impact on modern-day hallucinogen use was the synthesis of lysergic acid diethylamide (LSD) by Albert Hofmann in 1938.64 Working for Sandoz Pharmaceutical Company, Hofmann synthesized LSD while investigating the pharmacologic properties of ergot alkaloids. Subsequent self-experimentation by Hofmann led to the first description of its hallucinogenic effects and stimulated research into the use of LSD as a therapeutic agent. Hofmann is also credited with isolating psilocybin as the active ingredient in Psilocybe mexicana mushrooms in 1958.102

Twentieth-Century Early

Regulatory

Events Initiatives

The development of the specialty of medical toxicology and the role of poison control centers began shortly after World War II. Prior to this time, serious attention to the problem of household poisonings in the United States had been limited to a few federal legislative antipoisoning initiatives (Table 1-4 ). The 1906 Pure Food and Drug Act was the first federal legislation that sought to protect the public from problematic and potentially unsafe drugs and food. The driving force behind this reform was Dr. Harvey W. Wiley, the chief chemist at the Department of Agriculture. Beginning in the 1880s, Wiley investigated the problems of contaminated food. In 1902, he organized the “poison squad,― which consisted of a group of volunteers who did selfexperiments with food preservatives.5 Revelations from the “poison squad,― as well as the publication of Upton Sinclair's muckraking novel The Jungle 133 in 1906, exposing unhygienic practices of the meatpacking industry, led to growing support for legislative intervention. Samuel Hopkins Adams' reports about the patent medicine industry revealed that some drug manufacturers added opiates to soothing syrups for infants, and added to the call for reform.121 Although the 1906 regulations were mostly concerned with protecting the public from adulterated food, regulations protecting against misbranded patent medications also included.

were

The Federal Caustic Poison Act of 1927 was the first federal legislation to specifically address household poisoning. As early as 1859, bottles clearly demarcated “poison― were manufactured in response to a rash of unfortunate dispensing errors that occurred when oxalic acid was unintentionally substituted for a similarly appearing Epsom salts solution.28 Prior to 1927, however, “poison― warning labels were not

required on chemical containers, regardless of toxicity or availability. The 1927 Caustic Act was spearheaded by the efforts of Dr. Chevalier Jackson, an otolaryngologist, who showed that unintentional exposures to household caustic agents were an increasingly frequent cause of severe oropharyngeal and gastrointestinal burns. Under this statute, for the first time, alkali and acid-containing products had to clearly display a “poison― warning label.140 The most pivotal regulatory initiative in the United States prior to World War II, and perhaps the most significant American toxicologic regulation of the 20th century, was the Federal Food, Drug, and Cosmetic Act of 1938. Although the Food and Drug Administration (FDA) had been established in 1930, and legislation to strengthen the 1906 Pure Food and Drug Act was considered by Congress beginning with President Franklin Roosevelt's first inauguration in 1933, by 1938 proposed revisions still had not been passed. The Elixir of Sulfanilamide tragedy in 1938 (Chap. 2 ) claimed the lives of 105 people who ingested a prescribed liquid preparation of the antibiotic sulfanilamide inappropriately dissolved in diethylene glycol. This event finally provided the catalyst for legislative intervention.100 , 147 Prior to the elixir disaster, proposed legislation called only for the banning of false and misleading drug labeling and for the outlawing of dangerous drugs without mandatory drug safety testing. After the tragedy, the 1938 proposal was strengthened, requiring assessment of drug safety prior to marketing, and ultimately passed.

The Development Centers

of

Poison

Control

World War II led to the rapid proliferation of new drugs and chemicals in the marketplace and in the household.38 At the same time, suicide as a leading cause of death from these agents was recognized.10 Both of these factors led the medical community to

develop a response to the serious problems of both unintentional and intentional poisonings. In Europe during the late 1940s, special toxicology wards were organized in Copenhagen and Budapest,58 and a poison information service was begun in the Netherlands P.11 ).144

(Table 1-5 A 1952 American Academy of Pediatrics study revealed that more than 50% of childhood “accidents― in the United States were the result of unintentional poisonings.60 This study led to the opening of the first US poison control center in Chicago in 1953, under the leadership of Dr. Edward Press.117 Press believed that it had become extremely difficult for the individual physician to keep abreast of product information, toxicity, and treatment for the rapidly increasing number of potentially poisonous household products. This initial center was organized as a cooperative effort among the departments of pediatrics at several Chicago medical schools, with the goal of collecting and disseminating product information to inquiring physicians, mainly pediatricians.117 1906 Pure Food and Drug Act Early regulatory initiative. Prohibits interstate commerce of misbranded and adulterated foods and drugs. 1914 Harrison Narcotics Act First federal law to criminalize the nonmedical use of drugs. Taxed and regulated distribution and sale of narcotics (opium, opium derivatives, and cocaine). It required doctors, pharmacists, and others who prescribed narcotics to register and pay a tax. 1927 Federal Caustic Poison Act Mandated labeling of concentrated caustics. 1930 Food and Drug Administration (FDA) established

Successor to the Bureau of Chemistry; promulgation of food and drug regulations. 1937 Marijuana Tax Act Applied controls to marijuana similar to those applied to narcotics. 1938 Federal Food, Drug, and Cosmetic Act Required toxicity testing of pharmaceuticals prior to marketing. 1948 Federal Insecticide, Fungicide, and Rodenticide Act Provided federal control for pesticide sale, distribution, and use. 1951 Durham-Humphrey Amendment Restricted many therapeutic drugs to sale by prescription only 1960 Federal Hazardous Substances Labeling Act Mandated prominent labeling warnings on hazardous household chemical products. 1962 Kefauver-Harris Drug Amendments Required drug manufacturer to demonstrate efficacy before marketing 1963 Clean Air Act Regulated air emissions by setting maximum pollutant standards. 1966 Child Protection Act Banned hazardous toys when adequate label warnings could not be written. 1970 Comprehensive Drug Abuse and Control Act Replaced and updated all previous laws concerning narcotics and other dangerous drugs. 1970

Environmental Protection Agency (EPA) established Established and enforced environmental protection standards. 1970 Occupational Safety and Health Act (OSHA) Enacted to improve worker and workplace safety. Created National Institute for Occupational Safety and Health (NIOSH) as research institution for OSHA. 1970 Poison Prevention Packaging Act Mandated child-resistant safety caps on certain pharmaceutical preparations to decrease unintentional childhood poisoning. 1972 Clean Water Act Regulated discharge of pollutants into US waters. 1972 Consumer Product Safety Act Established Consumer Product Safety Commission to reduce injuries and deaths from consumer products. 1972 Hazardous Material Transportation Act Authorized the Department of Transportation to develop, promulgate, and enforce regulations for the safe transportation of hazardous materials. 1973 Drug Enforcement Administration (DEA) created Successor to the Bureau of Narcotics and Dangerous Drugs; charged with enforcing federal drug laws. 1973 Lead-based Paint Poison Prevention Act Regulated the use of lead in residential paint. Lead in some paints later banned by Congress in 1978. 1974 Safe Drinking Water Act Set safe standards for water purity.

1976 Resource Conservation and Recovery Act (RCRA) Authorized EPA to control hazardous waste from the “cradle-tograve,― including the generation, transportation, treatment, storage, and disposal of hazardous waste. 1976 Toxic Substance Control Act Emphasis on law enforcement. Authorized EPA to track 75,000 industrial chemicals produced or imported into the United States. Required testing of chemicals that pose environmental or human health risk. 1980 Comprehensive Environmental Response Compensation and Liability act (CERCLA) Set controls for hazardous waste sites. Established trust fund (Superfund) to provide cleanup for these sites. Agency for Toxic Substances and Disease Registry (ATSDR) created. 1983 Federal Anti-Tampering Act Response to cyanide-Tylenol deaths. Outlawed tampering with packaged consumer products. 1986 Controlled Substance Analogue Enforcement Act Instituted legal controls on analog (designer) drugs with chemical structures similar to controlled substances. 1986 Drug-Free Federal Workplace Program Executive order mandating drug testing of federal employees in sensitive positions. 1986 Superfund Amendments and Reauthorization Act (SARA) Amendment to CERCLA. Increased funding for the research and cleanup of hazardous waste (SARA) sites. 1988

Labeling of Hazardous Art Materials Act Required review of all art materials to determine hazard potential and mandated warning labels for hazardous materials. 1994 Dietary Supplement Health and Education Act Permitted dietary supplements including many herbal preparations to bypass FDA scrutiny. 1997 FDA Modernization Act Accelerated FDA reviews, regulated advertising of unapproved uses of approved drugs 2002 The Public Health Security and Bioterrorism Preparedness and Response Act Tightened control on biologic agents and toxins; increased safety of the US food and drug supply, and drinking water; and strengthened the Strategic National Stockpile. Date

Federal

Legislation

Intent

TABLE 1-4. Protecting Our Health: Important US Regulatory Initiatives Pertaining to Xenobiotics Since 1900 By 1957, 17 poison control centers were operating in the United States.38 With the Chicago center serving as a model, P.12 these early centers responded to physician callers by providing ingredient and toxicity information about drug and household products, and making treatment recommendations. Records were kept of the calls, and preventive strategies were introduced into the community. As more poison control centers opened, a second important function, providing information to callers from the general public, became increasingly commonplace. The physician

pioneers in poison prevention and poison treatment were predominantly pediatricians who focused on unintentional childhood ingestions.123 1949 First toxicology wards open in 1949 First poison information service 1952 American Academy of Pediatrics children's “accidents― are potential poisons 1953

Budapest and Copenhagen begins in the Netherlands study shows that 51% of the result of the ingestion of

First US poison control center opens in Chicago 1957 National Clearinghouse for Poison Control Centers established 1958 American Association of Poison Control Centers (AAPCC) founded 1961 First Poison Prevention Week 1963 Initial call for development of regional Poison Control Centers (PCCs) 1964 Creation of European Association for PCCs 1968 American Academy of Clinical Toxicology (AACT) established 1972 Introduction of microfiche technology to poison information 1974 American Board of Medical Toxicology (ABMT) established 1978 AAPCC introduces standards of regional designation 1983 First examination given for Specialist in Poison Information (SPI)

1985 American Board of Applied Toxicology (ABAT) established 1992 Medical Toxicology recognized by American Board of Medical Specialties (ABMS) 1994 First ABMS examination in Medical Toxicology 2000 Accreditation Council for Graduate Medical Education (ACGME) approval of residency training programs in Medical Toxicology 2000 Poison Control Center Enhancement and Awareness Act 2004 Institute of Medicine (IOM) Report on the future of poison centers is released calling on a greater integration between public health sector and poison control services Year

Milestone

TABLE 1-5. Milestones in the Development of Medical Toxicology During these early years in the development of poison control centers, each center had to collect its own product information, which was a laborious, and often redundant, task.37 In an effort to coordinate poison control center operations and to avoid unnecessary duplication, Surgeon General Dr. James Goddard responded to the recommendation of the American Public Health Service and established the National Clearinghouse for Poison Control Centers in 1957.98 This organization, placed under the Bureau of Product Safety of the Food and Drug Administration, disseminated 5-inch by 8-inch index cards containing poison information to each center to help standardize poison center information resources. The Clearinghouse also collected and

tabulated poison data from each of the centers. Between 1953 and 1972, a rapid, uncoordinated proliferation of poison control centers occurred in the United States.95 In 1962, there were 462 poison control centers.1 By 1970, this number had risen to 590,87 and by 1978, there were 661 poison control centers in the United States, including 100 centers in the state of Illinois.129 The nature of calls to centers changed as lay publicgenerated calls began to outnumber physician-generated calls. Recognizing the publicity value and strong popular support associated with poison centers, some hospitals started poison control centers for public relations reasons without adequately recognizing or providing for the associated responsibilities. Unfortunately, many of these centers offered no more than a parttime telephone service located in the back of the emergency department or pharmacy, staffed by poorly trained personnel.129 Despite the growing pains of the poison control services during this period, there were many significant achievements. A dedicated group of physicians and other healthcare professionals began devoting an increasing proportion of their time to matters pertaining to poisoning. In 1958, the American Association of Poison Control Centers (AAPCC) was founded to promote closer cooperation between poison centers, to establish uniform standards, and to develop educational programs for the general public and other healthcare professionals.60 Annual research meetings were held, and important legislative initiatives were stimulated by the organization's efforts.98 Examples of such legislation include the Federal Hazardous Substances Labeling Act of 1960, which improved product labeling; the Child Protection Act of 1966, which extended labeling statutes to pesticides and other hazardous substances; and the Poison Prevention Packaging Act of 1970, which mandated safety packaging. In 1961, in an attempt to heighten public awareness of the dangers of unintentional poisoning, the third week of March was designated as the Annual National Poison Prevention Week.

Another organization that would become important, the American Academy of Clinical Toxicology (AACT), was founded in 1968 by a diverse group of toxicologists. 33 This group was “interested in applying principles of rational toxicology to patient treatment― and in improving the standards of care on a national basis.126 The journal Clinical Toxicology , sponsored by AACT, also began publication in 1968. The first modern textbooks of clinical toxicology began to appear in the mid-1950s with the publication of Dreisbach's Handbook of Poisoning (1955),44 Gleason, Gosselin, and Hodge's Clinical Toxicology of Commercial Products (1957),56 and Arena's Poisoning (1963).11 Major advancements in the storage and retrieval of poison information were instituted during these years. Information regarding consumer products initially appeared on index cards distributed regularly to poison centers by the National Clearinghouse. By 1978, more than 16,000 individual product cards had been assembled.129 The introduction of microfiche technology in 1972 enabled the storage of much larger amounts of data in much smaller spaces at the individual poison centers. Toxifile and POISINDEX, two large drug and poison databases employing microfiche technology, were introduced and gradually replaced the much more limited index card system. 129 During the 1980s, POISINDEX, which had become the standard database, was made more accessible by using CD-ROM technology. Sophisticated information about the most obscure toxins was now instantaneously available by computer at every poison center. In 1978, the poison control center movement entered an important new stage in its development when the AAPCC introduced standards for regional poison center designation.95 By defining strict criteria, the AAPCC sought to upgrade poison center operations significantly and to offer a national standard of service. These criteria included employing poison specialists dedicated P.13 exclusively to operating the poison control center 24 hours per day and serving a catchment area of between 1 and 10 million people.

Not surprisingly, this professionalization of the poison center movement led to a rapid consolidation of services, and the number of centers decreased to 62 by 2005. Fifty-one of the 62 centers (82%) are regionally certified. An AAPCC credentialing examination for poison information specialists was inaugurated in 1983 to help ensure the quality and standards of poison center staff.9 In 2000, the Poison Control Center Enhancement and Awareness Act was passed by Congress and signed into law by President William Clinton. For the first time, federal funding became available to provide assistance for poison prevention and to stabilize the funding of regional poison control centers. This federal assistance has permitted the establishment of a single nationwide toll-free phone number (800-222-1222) to access poison

centers.

A poison control center movement has also evolved in Europe over the last 35 years, but unlike the movement in the United States, from the beginning its growth focused on the development of strong centralized toxicology treatment centers. In the late 1950s, Dr. M. Gaultier in Paris developed an inpatient unit that was dedicated to the care of poisoned patients.58 In Great Britain, the National Poison Information Service was developed at Guys Hospital in 1963 under Dr. Roy Goulding. 58 Dr. Henry Matthew initiated a regional poisoning treatment center in Edinburgh about the same time,118 and in 1964, the European Association for Poison Control Centers was formed at Tours, France.58

The Rise of Environmental Toxicology and Further Regulatory Protection from Toxic Substances The rise of the environmental movement during the 1960s can be traced, in part, to the publication of Rachel Carson's Silent Spring

in 1962, which revealed the perils of an increasingly toxic environment,29 and to the increasing awareness among those involved with the poison control movement of the growing menace of toxins in the home environment.26 Battery casing fume poisoning, which resulted from the burning of discarded lead battery cases, and acrodynia, which resulted from exposure to a variety of mercury-containing products, 39 demonstrated that young children seemed particularly vulnerable to low-dose exposures from certain toxins. Worries about the persistence of pesticides in the ecosystem and the increasing number of chemicals introduced into the environment added to the concern that the environment was a potential source of illness, heralding a drive for additional regulatory protection. Starting with the Clean Air Act in 1963, laws were passed to help reduce the toxic burden on our environment (see Table 1-4 ). The establishment of the Environmental Protection Agency in 1970 spearheaded this attempt at protecting our environment, and during the next 10 years, numerous protective regulations were introduced. Among the most important initiatives were the Occupational Safety and Health Act of 1970 that established the Occupational Safety and Health Administration (OSHA). This act mandated that employers provide safe work conditions for their employees. Specific exposure limits to toxic chemicals in the workplace were promulgated. The Consumer Product Safety Commission was created in 1972 to protect the public from consumer products that posed an unreasonable risk of illness or injury. Cancer-producing substances, such as asbestos, benzene, and vinyl chloride, were banned from consumer products as a result of these new regulations. Toxic waste disasters at Love Canal, New York, and Times Beach, Missouri, led to the passing of the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, also known as the Superfund) in 1980. This fund would help to pay for cleanup of hazardous substance releases that posed a potential threat to public health. The

Superfund legislation also led to the creation of the Agency for Toxic Substances and Disease Registry (ATSDR) a federal public health agency that is charged with determining the nature and extent of health problems at Superfund sites and advising the US Environmental Protection Agency and state health and environmental agencies on the need for clean-up and other actions to protect the public's health. In 2003, ATSDR became part of the National Center for Environmental Health of the Centers for Disease Control.

Medical Toxicology Comes of Age Over the last 25 years, the primary specialties of medical toxicologists have changed. The development of emergency medicine and preventive medicine as medical specialties led to the training of more physicians with a dedicated interest in toxicology. By the early 1990s, emergency physicians accounted for more than half the number of medical toxicologists.43 The increased diversity of medical toxicologists emergency medicine, pediatrics, medicine has helped to broaden and medical toxicologists beyond

with primary training in preventive medicine, or internal the goals of poison control centers the treatment of acute

unintentional childhood ingestions. The broad scope of medical toxicology now includes a much wider array of toxic exposures including acute and chronic, adult and pediatric, unintentional and intentional, occupational and environmental. The development of medical toxicology as a medical subspecialty began in 1974, when the AACT established the American Board of Medical Toxicology (ABMT) to recognize physician practitioners of medical toxicology.7 From 1974 to 1992, 209 physicians obtained board certification from the ABMT. Formal subspecialty recognition of medical toxicology by the American Board of Medical Specialties (ABMS) was granted in 1992, and a conjoint subboard with representatives from the American Board of Emergency Medicine,

American Board of Pediatrics, and American Board of Preventive Medicine was created. The first ABMS-sponsored examination in medical toxicology was offered in 1994. By 2004, more than 300 physicians were board-certified in medical toxicology by the ABMT and/or ABMS. The American College of Medical Toxicology was founded in 1994 as a physician-based organization designed to advance clinical, educational, and research goals in medical toxicology. In 1999, the Accreditation Council of Graduate Medical Education (ACGME) in the United States formally recognized postgraduate education in medical toxicology, and by 2004, 24 training programs had been approved. During the 1990s in the United States, some medical toxicologists began to work on establishing regional toxicology treatment centers. Adapting the European model, toxicology treatment centers would serve as referral centers for patients requiring advanced toxicologic evaluation and treatment. Goals of such inpatient regional centers included enhancing care of the poisoned patient, strengthening toxicology training, and facilitating research. The evaluation of the clinical efficacy and fiscal viability of such programs is ongoing. The professional maturation of advanced practice pharmacists and nurses with a primary interest in clinical toxicology has also P.14 taken place over the past two decades. In 1985, the AACT established the American Board of Applied Toxicology (ABAT), to administer a certifying examination for nonphysician practitioners of medical toxicology who meet their rigorous standards.6 B y 2004, more than 70 toxicologists were certified by this board, most of whom held either a PharmD or a PhD in pharmacology or toxicology.

Recent

Poisonings

and

Poisoners

Although accounting for just a tiny fraction of all homicidal deaths

(0.16% in the United States), notorious lethal poisonings continued throughout the 20th century (Table 1-3 ).2 In England, Graham Frederick Young developed a macabre fascination with poisons.75 In 1971, at age 14 he killed his stepmother and other family members with arsenic and antimony. Sent away to a psychiatric hospital, he was released at age 24 years, when he was no longer considered to be a threat to society. Within months of his release he again engaged in lethal poisonings, killing several of his coworkers with thallium. Ultimately, he died in prison in 1990. In 1978, Georgi Markov, a Bulgarian defector living in London, developed multisystem failure and died 4 days after having been stabbed by an umbrella carried by an unknown assailant. The postmortem examination revealed a pinhead-sized metal sphere embedded in his thigh where he had been stabbed. Investigators hypothesized that this sphere had most likely carried a lethal dose of ricin into the victim.36 This theory was greatly supported when ricin was isolated from the pellet of a second victim who was stabbed under similar circumstances. In 1982, deliberate tampering with nonprescription acetaminophen preparations with potassium cyanide caused 7 deaths in Chicago.45 Because of this tragedy, packaging of nonprescription medications was changed to decrease the possibility of future product tampering.103 The perpetrator(s) were never apprehended, and other deaths from nonprescription product tampering were reported in 1991.30 In 1998, Judias Buenoano, known as the “black widow,― was executed for murdering her husband with arsenic in 1971 in order to collect insurance money. She was the first female executed in Florida in 150 years. The fatal poisoning had remained undetected until 1983, when Buenoano was accused of trying to murder her fiancé with arsenic and by car bombing. Exhumation of the husband's body, 12 years after he died, revealed substantial

amounts of arsenic in the remains.3 Healthcare providers have been implicated in several poisoning homicides. An epidemic of mysterious cardiopulmonary arrests at the Ann Arbor Veterans Administration Hospital in Michigan, in July and August 1975, was attributed to the homicidal use of pancuronium by two nurses.139 Intentional digoxin poisoning by hospital personnel may have explained some of the increased number of deaths on a cardiology ward of a Toronto pediatric hospital in 1981, but the cause of the high mortality rate remained unclear.23 In 2000, an English general practitioner Harold Shipman was convicted of murdering 15 female patients with heroin and may have murdered as many as 297 patients during his 24-year career. These recent revelations prompted calls for strengthening the death certification process, for improving preservation of case records, and for better procedures for monitoring controlled drugs.67 Also in 2000, an American physician Michael Swango pleaded guilty to the charge of poisoning a number of patients under his care during his residency training. Succinylcholine, potassium chloride, and arsenic were some of the agents he used to kill his patients.137 Attention to more careful physician credentialing and to maintenance of a national physician database arose from this case because the poisonings occurred at several different hospitals across the country. Continuing concerns about health care providers acting as serial killers is highlighted by a recent case in New Jersey where a nurse Charles Cullen was found responsible for killing patients with digoxin.17 By the end of the 20th century, 24 centuries after Socrates was executed by poison hemlock, the means of implementing capital punishment had come full circle. Government-sanctioned execution in the United States again favored the use of a “state― poison: this time, the combination of sodium thiopental, pancuronium, and potassium chloride.

The use of a poison to achieve a political end resurfaced in December 2004 when it was announced that the Ukrainian presidential candidate Viktor Yushchenko was poisoned with the potent dioxin, 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD).131 The dramatic development of chloracne over the face of this public person during the previous several months suggested dioxin as a possibly culprit. Given the paucity of reports of acute dioxin poisoning, however, it wasn't until laboratory tests confirmed that Yushenko's dioxin levels were more than 6000 times normal that this diagnosis was confirmed.

Medical

Errors

In late 1999, the problem of medical errors became a highly visible issue in the United subsequent reaction to an suggesting that 44,000 to result of medical errors.80

States with the publication Institute of Medicine (IOM) 98,000 fatalities each year Many of these errors were

and report were the attributed to

preventable medication errors. The IOM report focused on the fact that errors usually resulted from system faults and not solely from the carelessness of individuals. Several recent, highly publicized, medication errors received considerable public attention and provided a stimulus for the initiation of change in policies and systems. Ironically, all of the cases occurred at nationally preeminent university teaching hospitals. In 1984, 18-year-old Libby Zion died from severe hyperthermia soon after hospital admission. Although the cause of her death was likely multifactorial, drug–drug interactions and the failure to recognize and appropriately treat her agitated delirium also contributed to her death.14 State and national guidelines for closer house staff supervision, improved working conditions, and a heightened awareness of consequential drug–drug interactions resulted from the medical, legislative, and legal issues of this case. In 1994, a prominent health

journalist for the Boston Globe , Betsy Lehman, was the unfortunate victim of another preventable dosing error when she inadvertently received four times the dose of the chemotherapeutic agent cyclophosphamide as part of an experimental protocol.78 Despite treatment at a world-renowned cancer center, multiple physicians, nurses, and pharmacists failed to notice this erroneous medication order. An overhaul of the medication-ordering system was implemented at that institution after this tragic event. Another highly publicized death occurred in 1999, when 18-yearold Jesse Gelsinger died after enrolling in an experimental genetherapy study. Mr. Gelsinger, who had ornithine transcarbamylase deficiency, died from multiorgan failure 4 days after receiving, by hepatic infusion, the first dose of an engineered P.15 adenovirus containing the normal death was not the direct result of interaction error, the FDA review violations had occurred, including

gene. While this unexpected a dosing or drug–drug concluded that major research failure to report adverse effects

with this therapy in animals and earlier clinical properly obtain informed consent.132 In 2001, year-old healthy volunteer in an asthma study University, developed a progressive pulmonary

trials and to Ellen Roche, a 24at John Hopkins illness and died 1

month after receiving 1 g of hexamethonium by inhalation as part of the study protocol.136 Hexamethonium, a ganglionic blocker, was once used to treat hypertension but was removed from the market in 1972. The investigators were cited for failing to indicate on the consent form that hexamethonium was experimental and not FDA approved. Calls for additional safeguards to protect patients in research studies resulted from these cases.

Chemical

Terrorism

and

Preparedness

The terrorist attacks on the World Trade Center and the Pentagon

on September 11, 2001, and the mailing of letters containing lethal amounts of anthrax in October 2001, resulted in profound changes in preparedness strategies against future terrorist strikes. Defending against biologic and chemical terrorism suddenly took on a much heightened sense of urgency. The asymmetric nature of the terrorism menace has led to increasing concerns that traditional industrial chemicals—so-called chemical agents of opportunity—may pose a more likely threat than a military chemical warfare agent attack. Responding to these events, medical toxicologists and poison control centers are playing an increasingly visible role in terrorism preparedness. Medical toxicologists from both emergency response and public health backgrounds provide leadership in preparedness planning and training. These events have led to a new realization that poison control centers serve an essential public health function that extends significantly beyond the traditional prevention of childhood poisonings. Responding to these new challenges an IOM report released in 2004 calls for a more formal integration of poison center services into local, state, and federal public health preparedness and response.70

Summary Since the dawn of recorded history, toxicology has had a great impact on human events. And although over the millennia the important poisons of the day have changed to some degree, toxic substances continue to challenge our safety. The era of poisoners for hire may have long ago reached its pinnacle, but problems with drug abuse, intentional self-poisoning, exposure to environmental chemicals, and the potential for biological and chemical terrorism continues to challenge us. Unfortunately, knowledge acquired by one generation is often forgotten or discarded inappropriately by the next generation, leading to a cyclical historic course. This

historic review is meant to describe the past and to better prepare toxicologists and society for the future.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Antidotes in Depth - Antiquated Antidotes

Antidotes in Depth Antiquated

Antidotes

Paul M. Wax While the judicious use of certain antidotes (eg, N -acetylcysteine, naloxone, pyridoxine) is critically important in the management of select poisoned patients, other antidotes do not necessarily offer a distinct clinical advantage and may create additional problems (eg, flumazenil, physostigmine). A perpetual search for better and improved antidotes features prominently in the history of toxicology. Unfortunately, many of the “antidotal breakthroughs― over the years have not lived up to their promise (Table A1-1 ). A number of these antidotes, such as caffeine, are ineffective. Others, such as propylene glycol, were insufficiently tested or were replaced by “safer,― more effective treatment such as paraldehyde.13 Most troubling, the use of some of these agents, such as analeptics and copper sulfate, actually worsened the clinical situation. Unfortunately, just as the various classic theriac preparations remained popular into the 20th century, the use of many of these “modern antidotes― had persisted long after scientific investigation demonstrated their ineffectiveness. An emphasis on physiologic antagonism with antidotes, such as analeptics, has often taken precedence over good supportive care. Not surprisingly, the use of modern-day

theriacs, such as the “universal antidote,― persisted until quite recently, despite a lack of serious scientific support. This section highlights some of the critical changes in poison management during the last century.

Analeptics One of the most interesting changes in poison management took place during the 1940s and 1950s with regard to the use of analeptics in the treatment of barbiturate overdose.58 Analeptics are nonspecific arousal agents and include such stimulants as strychnine, camphor, caffeine, picrotoxin, pentylenetetrazol, nikethamide, amphetamine, and methylphenidate. Barbiturates, the first widely available sedative-hypnotics, were introduced in the early 20th century. Within a few years they became the most common cause of serious overdose.6 In the 1920s, barbiturate overdose management recommendations still included bloodletting techniques.41 By the next decade, as interest in principles of antagonism between stimulants and depressants became widespread, much attention was focused on the use of analeptic agents to combat the sedative effects of barbiturates. Proponents of analeptics argued that because the effects of cocaine intoxication appeared to be neutralized by barbiturates, a reciprocal approach—treating depressant overdoses with stimulants—should also be effective.41 The principal goal of analeptic therapy was to awaken the patient as soon as possible. Numerous analeptic agents were recommended over the years. Prior to the development of the first synthetic analeptics in the late 1920s, naturally occurring stimulants, such as caffeine, lobeline, strychnine, cocaine, and camphor, were utilized for this purpose. According to Leschke's Clinical Toxicology , a standard textbook published in 1934, the most effective remedy for the treatment of a sedative-hypnotic overdose was the intrathecal injection of 10% camphorated oil.37

Picrotoxin, obtained from the berries of the Cocculus indicus plant, was first suggested as an antagonist to morphine in 1847.35 After a series of animal studies in the early 1930s, picrotoxin was enthusiastically endorsed as the analeptic of choice.40 Picrotoxin acts as a γ-aminobutyric acid type A (GABAA ) and type C (GABAC ) receptor antagonist and as a glycine-receptor antagonist facilitating excitatory neurotransmission.21 Although picrotoxin remains one of the most powerful CNS and respiratory stimulants in our pharmacopeia, it is a proconvulsant. The subsequent introduction of synthetic analeptics, such as pentylenetetrazol (Metrazol, Cardiazol) and nikethamide (Coramine), increased the growing dependence on analeptics as the major treatment modality for barbiturate overdose.31 , 34 , 42 During his search for an effective camphor substitute, Schmidt synthesized pentylenetetrazol, the first synthetic analeptic, in 1924, and it was initially introduced as a cardiac stimulant.57 Mechanistically, it reduces GABAergic inhibition and interacts with picrotoxin-binding sites. It may also work by changing extraneuronal potassium permeability, thereby partially depolarizing neuronal membranes and increasing excitability. Pentylenetetrazol was employed as a CNS stimulant in the treatment of depressant overdoses from the 1930s through the 1960s,19 , 31 but was considered less effective than picrotoxin or strychnine. Nikethamide was also used as a cardiac and respiratory stimulant and was reputed to be helpful in overcoming the respiratory depression of morphine, sedative-hypnotics, and volatile anesthetics.42 Further experience showed that it was a less efficacious analeptic than either picrotoxin or pentylenetetrazol.23 Its exact mechanisms of enhancing excitation are unknown. Analeptic treatment strategies were often referred to as “very energetic,― because large doses of multiple analeptics were frequently used.45 As recently as the 1950s, newer analeptics,

such as bemegride, were being introduced as the “real antidote― to barbiturate overdoses.53 During this time, methylphenidate was also used in the treatment of barbiturate overdoses. In 1967, one enthusiastic methylphenidate proponent emphasized, “Don't let comatose patients remain comatose after barbiturate overdose. Methylphenidate will waken them safely.―42 Toxicology textbooks published in the 1950s and 1960s continued to recommend caffeine, picrotoxin, and nikethamide as useful analeptic agents. 15 , 22 , 38 Subconvulsive electric shock therapy was also advocated as an alternative or adjunct to these chemical convulsants during this period.48 Unfortunately, many adverse effects occurred with the use of these analeptics, including hyperthermia, dysrhythmias, seizures, and psychoses.33 , 42 , 47 It gradually became evident that analeptic therapy, despite its theoretic benefits, offered no real advantage, did not reduce mortality, and, placed the patient at risk for significant iatrogenic complications. 9 A different strategy was required. Beginning in the mid-1940s, a distinctive approach to barbiturate overdose was pioneered by Eric Nilsson and Carl Clemmesen at the Bispebjerg Hospital in Copenhagen, Denmark.9 , 44 This treatment regimen, known as the Scandinavian method , abandoned the use of analeptics in the treatment of barbiturate overdoses. Instead P.19 of primarily emphasizing the termination of coma, attention was directed at intensive supportive therapy with respiratory ventilation, oxygenation, and cardiovascular support. This strategy was analogous to the postanesthetic recovery room care provided to surgical patients. Using this “revolutionary― approach, barbiturate overdose mortality significantly dropped from approximately 20% with stimulation therapy to 1–2% with the Scandinavian method.9 Analeptic

Amphetamine Sedative overdose Seizures, hyperthermia, Bemegride Sedative overdose Seizures, hyperthermia, Caffeine Sedative overdose Seizures, hyperthermia, Camphorated oil Sedative overdose Seizures, hyperthermia, Lobeline Sedative overdose Seizures, hyperthermia,

aspiration

aspiration

aspiration

aspiration

aspiration

Nikethamide (Coramine) Sedative overdose Seizures, hyperthermia, aspiration Pentylenetetrazol (Metrazol) Sedative overdose Seizures, hyperthermia, Picrotoxin Sedative overdose

aspiration

Seizures, hyperthermia, aspiration Strychnine Sedative overdose Seizures, hyperthermia, aspiration Adsorbent Universal antidote Gastrointestinal decontamination Ineffective; tannic acid hepatotoxicity Burnt toast Gastrointestinal decontamination Ineffective

Complexing agent Sodium phosphate (Phospho-Soda) Iron Hyperphosphatemia Emetic Apomorphine Gastric emptying CNS depression, aspiration Copper sulfate Gastric emptying Caustic; increased copper load Mechanical stimulation Gastric emptying Oropharyngeal trauma; ineffective Mustard powder Gastric emptying Ineffective Salt water Gastric emptying Hypernatremia Tartar emetic Gastric emptying GI toxicity Zinc sulfate Gastric emptying GI toxicity Metal antidote Ascorbic acid Lead, arsenic Ineffective Calcium bromide Lead Ineffective Ferric hydroxide/magnesium

hydroxide

Arsenic Ineffective Potassium ferrocyanide Copper Ineffective Potassium iodide Lead Ineffective Sodium formaldehyde sulfoxylate Mercury bichloride Ineffective Miscellaneous Acetazolamide Salicylate Acidemia; increased CNS salicylates Hypochlorites Snakebites Ineffective Potassium permanganate Alkaloids (morphine, Caustic Propylene glycol Phenolphthalein Raw rabbit brain Amanita phalloides Ineffective Neutralizing agent Calcium carbonate Acid Exothermic reaction; Hydrochloric acid Alkali Exothermic reaction;

strychnine,

aconite)

gas

formation;

ineffective

gas

formation;

ineffective

Lemon juice Alkali Exothermic reaction; gas Lime water Acid Exothermic reaction; gas Magnesium hydroxide Acid Exothermic reaction; gas Sodium bicarbonate Acid Exothermic reaction; gas Vinegar Alkali Exothermic reaction; gas

formation;

ineffective

formation;

ineffective

formation;

ineffective

formation;

ineffective

formation;

ineffective

Sedative Chloroform Delirium tremens, strychnine Hepatotoxin, dysrhythmias Digitalis Delirium tremens Ineffective Ethanol Delirium tremens Difficult to titrate; metabolic abnormalities Ether Delirium tremens; agitation/seizures Difficult to administer; irritating Paraldehyde Delirium tremens Acidosis; difficult to administer Sodium bromide Delirium tremens Difficult to use; bromism

Tribromoethanol (Avertin) Agitation/seizures Sedation Type of Antidote

TABLE

Early

A1-1.

Therapeutic Agent

Antiquated

Treatments

Uses

Adverse Effects

Antidotes

of

Opioid

Overdoses

Prior to the 1950s, opioid overdose was treated with many of the same analeptic agents. In the early 1950s, an important development in the history of poison management occurred when two P.20 specific opioid antidotes were introduced: nalorphine (Nalline) and levallorphan (Lorfan).16 These drugs were capable of reversing the respiratory effects of an opioid overdose by blocking opioid receptors. Nalorphine was also routinely administered to determine the presence or absence of opioids in suspected opioid abusers. This test, known as the Nalline test , was used as a monitoring tool in drug abuse programs.25 The test was considered positive if it precipitated signs of opioid withdrawal such as pupillary dilation. Unfortunately, neither nalorphine nor levallorphan was a pure opioid antagonist. Instead, the mixed agonist–antagonist properties of these drugs significantly limited their usefulness. Respiratory depression could be potentiated, especially in opioidfree patients. This was most likely to occur when these drugs were administered to comatose patients with mild hypoventilation who had overdosed on sedative-hypnotics or ethanol. Naloxone, which was introduced in the 1970s, is a much safer drug

because of its pure opioid antagonistic properties. It has completely replaced nalorphine and levallorphan in the treatment of opioid overdoses.18 Naloxone has no agonist properties, does not cause any additional respiratory depression, regardless of the ingestion, is short-acting and safe to use for patients with coma following an undefined overdose. In addition, it is useful in treating patients with an overdose of other mixed agonist–antagonist opioids, such as pentazocine, who do not typically respond to nalorphine.

Outmoded Treatments Withdrawal

for

Ethanol

The treatment modalities employed in the treatment of ethanol withdrawal have changed considerably over the last 200 years.17 Until the development of the first inhalational anesthetics in the mid 19th century, opium and, later, morphine were the primary pharmacologic treatments of severe ethanol withdrawal. Unfortunately, this approach was associated with problems related to opioid toxicity in these unmonitored patients. Adjuncts used with the opioids included digitalis that was thought to provide benefit to counteract the adverse cardiac effects associated with ethanol withdrawal. Once the first general anesthetics were introduced, a new treatment approach for delirium tremens was advocated in which ether or chloroform was inhalationally administered to induce sleep for up to 24 hours. Case reports from this time suggested that such an approach was effective and that patients would awaken without further signs of ethanol withdrawal.30 Other drugs that were employed included the bromide salts but they proved difficult to use and in some cases were associated with the development of bromism. By the early 20th century, chloral hydrate was routinely administered in the treatment of ethanol withdrawal and opioid use in this setting decreased.55 Soon thereafter, barbiturates and

paraldehyde also became a mainstay of ethanol withdrawal therapy. While some patients responded well to paraldehyde, it proved very difficult to administer at times and was also associated with the development of metabolic acidosis. It is considerably more toxic than benzodiazepines and is very difficult to titrate because of variable rates of absorption. Other disadvantages include hepatotoxicity, gastritis when given orally, sterile abscesses when given intramuscularly, and proctitis following rectal administration. It also has a notoriously unpleasant odor.28 Ethanol administered intravenously or orally also has been used to suppress withdrawal for many years. Recent advocacy for prophylactic use of ethanol in hospitalized patients can be found in the surgical literature.50 However, there are several problems with the use of ethanol in the treatment of ethanol withdrawal.27 It has a very short duration of action and is difficult to titrate, and its CNS and hepatotoxicity are well known. Continued intravenous use of ethanol intensifies the biochemical abnormalities associated with ethanol metabolism, shifting energy production toward lactate and ketogenesis. Finally, extravasation of ethanol may cause local tissue necrosis, which in a recent report required excision and grafting. Other discredited approaches popularized in the 1940s include insulin therapy49 as a means to replenish glycogen and improve hepatic function, and nonconvulsive electroshock therapy.7 Gradually, increased attention to adequate hydration, nutrition, vitamin replacement, and proper monitoring, as well as the need for appropriate sedation with cross-tolerant drugs such as the benzodiazepines, became the modern standard for the care of the ethanol-withdrawal patient.

Outdated

and

Dangerous

Emetics

The role of emetics in poison management, both in the home and

at the hospital, has undergone significant transformation over the years. The antimony salt commonly known as tartar emetic had a long history of use as an emetic, as well as a sedative, expectorant, cathartic, and diaphoretic. During the 19th century, tartar emetic was one of the three most widely prescribed drugs, the other drugs being opium and calomel (mercurous chloride).26 Tartar emetic is no longer recommended for any purpose because of its inherent toxicity.8 Standard gastrointestinal decontamination recommendations during the 1960s included mechanical stimulation of the throat and the ingestion of saltwater emetics, or mustard water in the home, and copper sulfate, zinc sulfate, or apomorphine in the hospital.1 , 32 Many authorities recommended mechanical stimulation of the pharynx (finger-down-the-throat technique) as a quick-and-easy home remedy when induction of emesis was desirable.1 , 11 This method, however, is both ineffective and potentially traumatic, and is no longer encouraged.11 Similarly, the use of saltwater emetics was abandoned after numerous cases of severe salt poisoning resulted from their administration.4 , 14 Mustard powder has never been proven effective.8 The use of copper sulfate as an emetic32 also fell out of favor because of its caustic properties, its potential to cause acute copper poisoning, and its unreliability.29 , 54 Zinc sulfate also is no longer used as an emetic.8 Until the 1980s, apomorphine was advocated as an emetic.10 , 43 One reason for its use was the thought that it was safer and more effective than copper sulfate.29 It was supposed to be particularly useful for the combative or uncooperative patient because it could be administered parenterally, it had a rapid onset of action, and in this setting, was frequently used instead of syrup of ipecac.44 Apomorphine's propensity to cause CNS depression, however, increased the risk of subsequent aspiration and made its use potentially very dangerous. Moreover, a sterile injectable form of apomorphine has not been available in the United States for many years. For all of these reasons, apomorphine is no longer used as

an emetic.39

The

Universal

Antidote

Two other “antidotes― that were once commonly used for decontamination but that have fallen into disfavor are the “universal antidote― and burnt toast. For many years the universal antidote, sold P.21 under the trade names Unidote and Res-Q, was a medical tradition46 and was advocated by many textbooks as part of the standard management of the poisoned patient.15 , 22 , 38 Commercial preparations consisted of one part magnesium oxide, one part tannic acid, and two parts activated charcoal. An alternative home recipe consisted of milk of magnesia, strong tea, and burnt toast. Combination therapy of this sort was thought to offer a broader spectrum of action than activated charcoal alone. It was theorized that the magnesium oxide would neutralize acids and the tannic acid would precipitate alkaloids and metals.38 The use of the universal antidote declined by the mid-1980s and is no longer available. Studies demonstrated that activated charcoal was superior to the universal antidote in decreasing absorption12 , 46 and that the decreased efficacy of the universal antidote was caused by tannic acid interfering with activated charcoal's adsorbence of other toxins.12 Furthermore, the potential hepatotoxicity of tannic acid was increasingly recognized.46 Although burnt toast had been advocated as an activated charcoal substitute in the home,3 its use was also abandoned because of its lack of significant adsorbent activity. 36

Other

Antiquated

Antidotes

The use of drugs for the chemical restraint of agitated individuals has also undergone significant evolution during the past decades. Depressant agents, such as tribromoethanol (Avertin) and ether,

are no longer used because of the availability of safer alternative agents. Likewise, paraldehyde and ethanol, which were commonly used for the treatment of alcohol withdrawal,24 have been replaced by the much safer and less toxic benzodiazepines. The use of analeptics to treat the depressive effects of ethanol is also obsolete.56 Another change in treatment involves the abandonment of neutralizing agents for caustic ingestions. Until the 1970s, typical recommendations for the treatment of alkali ingestions included the use of vinegar (acetic acid), lemon juice, or, in some cases, dilute hydrochloric acid.38 Suggestions for neutralizing acid ingestions included the use of magnesium hydroxide, lime water, or calcium carbonate.38 Because of the extremely rapid onset of action of caustic agents, concerns arose over whether it was already too late to reverse the caustic process. Furthermore, the addition of neutralizing agents could increase the potential for a consequential exothermic reaction and/or gas production.51 Such reactions in an already weakened hollow viscus may be poorly tolerated and lead to extension of the tissue injury or perforation. For all of these reasons, the use of neutralizing agents is no longer recommended. Other antiquated antidotes include ferric hydroxide (antidotum arsenici ), which was used in the treatment of arsenic poisoning. Acetazolamide, which was advocated for alkalinizing the urine in salicylate poisoning,52 causes a systemic acidemia that can worsen the salicylate toxicity, and is therefore no longer used. The use of sodium phosphate (Phospho-Soda) in the management of iron overdose in an attempt to create insoluble ferrous phosphate has also ceased because of problems with its marginal efficacy and resultant hyperphosphatemia.20 Some abandoned antidotes have found new uses. At one time potassium iodide was believed to be helpful as a means to enhance lead excretion, a practice that was later discarded. More recently,

potassium iodide has been touted as a specific blocker of thyroid radioiodine uptake which may reduce the risk of thyroid cancer after radiation exposure.2 Finally, enthusiasm has waned for raw rabbit brain, which was recommended as recently as the 1930s as a “chance of life― for patients with Amanita phalloides poisoning.37 The raw brain approach was pioneered in the early 1800s after it was observed that rabbits could eat poisonous mushrooms without ill effects.5 Postulating that rabbits had some sort of protective mechanism that neutralized the mushroom toxin, investigators formulated an antidotal concoction consisting of seven rabbit brains and three rabbit stomachs. The preparation was minced and ground into pellets and administered with a sweetener. When patients who received the rabbit brain antidote survived the mushroom poisoning, it was erroneously concluded that these uncontrolled observations provided proof of efficacy.5 Many of our current antidotes have not undergone rigorous scientific evaluation regarding efficacy and safety. In time, some of these antidotes will undoubtedly join this list of antiquated antidotes. Lessons learned from the past, such as the abandonment of analeptics, help to optimize present-day patient care and to better prepare us to investigate and evaluate the next generation of antidotes.

References 1. Adams W: Emetics in accidental poisoning. Pediatr Clin North Am 1961;8:351–352. 2. American Academy of Pediatrics Committee on Environmental Health: Radiation disasters and children. Pediatrics 2003;111: 1455–1466.

3. Arena J: Poisoning: Chemistry, Symptoms, Treatment. Springfield, IL, Charles C. Thomas, 1963. 4. Barer J, Hill LL, Hill RM, et al: Fatal poisoning from salt used as an emetic. Am J Dis Child 1973;125:889–890. 5. Benjamin D: Mushrooms: Poisons and Panaceas. New York, WH Freeman, 1995. 6. Berger FM: Drugs and suicide in the United States. Clin Pharmacol

Ther

1967;8:219–223.

7. Berkwitz N: The treatment of delirium tremens with faradic shock therapy: A new approach based upon the psychobiological concept. Ann Intern Med 1942;16:480–494. 8. Cashman TM, Shirkey HC: Emergency management of poisoning. Pediatr Clin North Am 1970;17:525–534. 9. Clemmesen C, Nilsson E: Therapeutic trends in the treatment of barbiturate poisoning: The Scandinavian method. Clin Pharmacol Ther 1961;2:220–229. 10. Corby DG, Decker WJ, Moran MJ, et al: Clinical comparison of pharmacologic emetics in children. Pediatrics 1968;42:361–364. 11. Dabbous I, Bergman A, Robertson W: The ineffectiveness of mechanically induced vomiting. J Pediatr 1965;66:952–954. 12. Daly JS, Cooney DO: Interference by tannic acid with the effectiveness of activated charcoal in “universal

antidote.―

Clin

Toxicol

1978;

12:515–522.

13. Decker W: Antidotes: Some ineffective, insufficiently tested, outmoded, and potentially dangerous therapeutic agents. Vet Hum Toxicol 1983;25:10–15. 14. DeGenaro F, Nyhan WL: Salt—A dangerous “antidote.― J Pediatr 1971;78:1048–1049. 15. Deichmann W, Gerarde H: Signs, Symptoms and Treatment of Certain Acute Intoxications. Springfield, IL, Charles C. Thomas, 1958. 16. Eckenhoff J, Funderburg L: Observations on the use of the opiate antagonists nalorphine and levallorphan. 1954;228:546–553. 17. Erwin WE, Williams DB, Speir WA: Delirium tremens. South Med

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1998;91:425–432.

18. Evans LE, Swainson CP, Roscoe P, et al: Treatment of drug overdosage with naloxone, a specific narcotic antagonist. Lancet 1973; 1:452–455. P.22 19. Freund JD: Metrazol treatment of barbiturate poisoning. Psychosomatics 1968;9:172–174. 20. Geffner ME, Opas LM: Phosphate poisoning complicating treatment for iron ingestion. Am J Dis Child 1980;134:509–510.

21. Gilman A, Goodman L, Gilman A: Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York, Macmillan, 1985. 22. Gleason M, Gosselin R, Hodge H: Clinical Toxicology of Commercial Products: Acute Poisoning (Home & Farm). Baltimore, Williams & Wilkins, 1963. 23. Goodman L: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1941. 24. Gower WE, Kersten H: Prevention of alcohol withdrawal symptoms in surgical patients. Surg Gynecol Obstet 1980;151:382–384. 25. Halbach H, Eddy N: Tests for addiction of morphine type. Bull

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Health

Organ

1963;28:139–173.

26. Haller JS Jr: The use and abuse of tartar emetic in the 19th-century materia medica. Bull Hist Med 1975;49:235–257. 27. Hodges B, Mazur JE: Intravenous ethanol for the treatment of alcohol withdrawal syndrome in critically ill patients. Pharmacotherapy 2004; 24:1578–1585. 28. Holloway HC, Hales RE, Watanabe HK: Recognition and treatment of acute alcohol withdrawal syndromes. Psychiatr Clin North Am 1984; 7:729–743. 29. Holtzmann NA, Haslam RH: Elevation of serum copper following copper sulfate as an emetic. Pediatrics

1968;42:189–193. 30. Hyde G: On a case of delirium tremens successfully treated by chloroform. Lancet 1849;10:132–133. 31. Jones A, Dooley J, Murphy J: Treatment of choice in barbiturate poisoning. JAMA 1950;143:884–888. 32. Karlsson B, Noren L: Ipecacuanha and copper sulfate as emetics in intoxications in children. Acta Pediatr Scand 1965;54:331–335. 33. Klaer-Larsen J: Delirious psychosis and convulsions due to Megimide. Lancet 1956;2:967–970. 34. Koppanyi T, Fazekas J: Acute barbiturate poisoning: Analysis and evaluation of current therapy. Am J Med Sci 1950;220:559–576. 35. Koppanyi T, Linegar C, Dille J: Analysis of the barbituratepicrotoxin antagonism. J Pharmacol Exper Ther 1936;58:199–228. 36. Lehman A: Substitution of burned toast for activated charcoal in the “universal antidote.― Assoc Food Drug Official US Q Bull 1957; 21:210–211. 37. Leschke E: Clinical Toxicology: Modern Methods in the Diagnosis and Treatment of Poisoning. Baltimore, William Wood, 1934. 38. Lucas G: The Symptoms and Treatment of Acute Poisoning.

Toronto, Canada, Clark Irwin, 1952. 39. MacLean WC Jr: A comparison of ipecac syrup and apomorphine in the immediate treatment of ingestion of poisons. J Pediatr 1973; 82: 121–124. 40. Maloney A: A comparative study of the antidotal action of picrotoxin, strychnine and cocaine in acute intoxication by the barbiturates. J Pharmacol Exp Ther 1933;49:133–140. 41. Maloney A, Fitch R, Tatum A: Picrotoxin as an antidote in acute poisoning by shorter-acting barbiturates. J Pharmacol Exp Ther 1931; 41:465–482. 42. Mark LC: Analeptics: Changing concepts, declining status. Am J Med Sci 1967;254:296–302. 43. Meester WD: Emesis and lavage. Vet Hum Toxicol 1980;22: 225–234. 44. Nilsson E: On treatment of barbiturate poisoning: Modified clinical aspects. Acta Med Scand 1951;139(Suppl 253):1–127. 45. Nilsson E, Eyrich B: On treatment of barbiturate poisoning. Acta Med Scand 1950;137:381–389. 46. Picchioni AL, Chin L, Verhulst HL, et al: Activated charcoal vs. “universal antidote― as an antidote for poisons. Toxicol Appl Pharmacol 1966;8:447–454. 47. Reed C, Driggs M, Foote C: Acute barbiturate intoxication:

Study of 300 cases based on physiologic system of classification of severity of intoxication. Ann Intern Med 1952;37:290–303. 48. Robie T: Treatment of acute barbiturate poisoning by nonconvulsive electrostimulation. Postgrad Med J 1951;253–256. 49. Robinson G: The treatment of delirium tremens with insulin in subshock doses. Am J Psychol 1940;97:136–151. 50. Rosenbaum M, McCarty T: Alcohol prescription by surgeons in the prevention and treatment of delirium tremens: Historic and current practice. Gen Hosp Psychiatry 2002;24:257–259. 51. Rumack BH, Burrington JD: Caustic ingestions: A rational look at diluents. Clin Toxicol 1977;11:27–34. 52. Schwartz R, Fellers F, Knapp J, et al: The renal response to administration of acetazolamide (Diamox) during salicylate intoxication. 1959;23:1103–1114. 53. Shulman A, Shaw F, Cass N, et al: A new treatment of barbiturate intoxication. Br Med J 1955;1:1238–1244. 54. Stein RS, Jenkins D, Korns ME: Letter: Death after use of cupric sulfate as emetic. JAMA 1976;235:801. 55. Steward

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56. Taberner PV: Pharmacological treatments for alcohol dependence and withdrawal—An historical perspective.

Alcohol Alcohol Suppl 1993; 2:259–262. 57. Wang SC, Ward JW: Analeptics. Pharmacol Ther [B] 1977;3: 123–165. 58. Wax PM: Analeptic use in clinical toxicology: A historical appraisal. J Toxicol Clin Toxicol 1997;35:203–209.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Chapter 2 - Toxicologic Plagues and Disasters in History

Chapter 2 Toxicologic Plagues and Disasters in History Paul M. Wax Throughout history, mass poisonings have caused suffering and misfortune. From the ergot epidemics of the Middle Ages to contemporary industrial disasters, these plagues have had great political, economic, social, and environmental ramifications. Particularly within the last 100 years, as the number of toxins and potential toxins has risen dramatically, toxic disasters have become an increasingly common event. The sites of some of these events—Bhopal (India), Chernobyl (Ukraine), Jonestown (Guyana), Love Canal (New York), Minamata Bay (Japan), Seveso (Italy), West Bengal (India)—have come to symbolize our increasingly toxic habitat. This chapter provides an overview of some of the most consequential and historically important toxinassociated disasters. Globalization has led to the proliferation of toxic chemicals throughout the world. Many chemical factories are not secure despite their storage of large amounts of potentially lethal chemicals. Given the increasing attention to terrorism preparedness, an appreciation of chemicals as agents of

opportunity for terrorists to employ as weapons has suddenly assumed much greater importance.

Gas

Disasters

Inhalation of toxic gases and oral ingestions resulting in food poisoning tend to subject the greatest number of people to adverse consequences of a toxic exposure. Toxic gas exposures may be the result of a natural disaster (volcanic eruption), industrial mishap (fire, chemical release), chemical warfare, or an intentional homicidal or genocidal endeavor (concentration camp gas chamber). Depending on the toxin, the clinical presentation may be acute, with a rapid onset of toxicity (cyanide), or subacute/chronic, with a gradual onset of toxicity (air pollution). One of the earliest recorded toxic gas disasters resulted from the eruption of Mount Vesuvius near Pompeii, Italy, in 79 A.D. (Table 2-1 ). Poisonous gases generated from the volcanic activity reportedly killed thousands.24 A much more recent natural disaster occurred in 1986 in Cameroon, when excessive amounts of carbon dioxide spontaneously erupted from Lake Nyos, a volcanic crater lake.8 Seventeen hundred human and countless animal fatalities resulted from exposure to this asphyxiant. A toxic gas leak at the Union Carbide pesticide plant in Bhopal, India, in 1984, resulted in one of the greatest civilian toxic disasters in modern history.126 An unintended exothermic reaction at this carbaryl-producing plant caused the release of over 24,000 kg of methyl isocyanate. This gas was quickly dispersed through the air over the densely populated area surrounding the factory where many of the workers lived, resulting in at least 2500 deaths and 200,000 injuries.74 The initial response to this disaster was greatly limited by a lack of pertinent information about the toxicity of this agent as well as the poverty of the residents. A followup study 10 years later showed persistence of small-airway obstruction among survivors.20 Chronic eye problems also were

reported.3 Calls for improvement in disaster preparedness and strengthened right-to-know laws regarding potential toxic exposures resulted from this tragedy.43 , 126 The release into the atmosphere of 26 tons of hydrofluoric acid at a petrochemical plant in Texas, in October 1987, resulted in 939 people seeking medical attention at nearby hospitals. Ninety-four people were hospitalized, but there were no deaths.133 More than any other single toxin, carbon monoxide has been involved with the largest number of toxic disasters. Catastrophic fires, such as the Cocoanut Grove Nightclub fire in 1943, have caused hundreds of deaths at a time, many of them from carbon monoxide poisoning.27 The 1990 fire at the Happy Land Social Club in the Bronx, New York, claimed 87 victims, including a large number of nonburn deaths,67 and the 2003 fire at The Station nightclub in West Warwick, Rhode Island, killed 98 people.109 Carbon monoxide poisoning was a major toxin in many of these deaths, although hydrogen cyanide gas and simple asphyxiation may also have contributed to the overall mortality. Another notable toxic gas disaster involving a fire occurred at the Cleveland Clinic, Cleveland, Ohio, in 1929, where a fire in the radiology department resulted in 125 deaths.23 The burning of nitrocellulose radiographs produced nitrogen dioxide, cyanide, and carbon monoxide gases that were thought to be responsible for many of the fatalities. In 2003, at least 243 people died and 10,000 people became ill after a drilling well exploded in Gaogiao, China, releasing hydrogen sulfide and natural gas into the air.136 A toxic gas cloud covered 25 square kilometers. Ninety percent of the villagers who lived in the village adjoining the gas well died. The release of a dioxin-containing chemical cloud into the atmosphere from an explosion at a hexachlorophene production factory in Seveso, Italy, in 1976, resulted in one of the most serious exposures to dioxin (2,3,7,8-tetrachlorodibenzo-p dioxin).42 The

P.24 lethality of this agent in animals has caused considerable concern for acute and latent injury from human exposure. Despite this apprehension, chloracne was the only significant clinical finding related to the dioxin exposure at 5-year followup.107 Poisonous gas Pompeii, Italy 79 A.D. >2000 died from eruption of Mt. Vesuvius Smog (SO2 ) London 1873 268 deaths from bronchitis N O2 , CO, CN Cleveland Clinic, Cleveland, OH 1929 Fire in radiology department, 125 deaths Smog (SO2 ) Meuse Valley, Belgium 1930 64 deaths CO, CN Cocoanut Grove Night Club, Boston 1942 498 deaths from fire CO Salerno, Italy 1944 >500 deaths on train stalled in tunnel Smog (SO2 ) Donora, PA 1948 20 deaths, thousands ill Smog (SO2 )

London 1952 4000 deaths attributed to the fog/smog Dioxin Seveso, Italy 1976 Unintentional industrial release of dioxin into environment; chloracne Methyl isocyanate Bhopal, India 1984 >2000 deaths; 200,000 injuries Carbon dioxide Cameroon 1986 >1700 deaths from release of gas from Lake Nyos Hydrofluoric acid Texas City, TX 1987 Atmospheric release, 94 hospitalized CO, ?CN Happy Land Social Club, Bronx, NY 1990 87 died in fire from toxic smoke Hydrogen sulfide Xiaoying, China 2003 243 died and 10,000 became ill from gas poisoning after a gas well exploded CO, ?CN West Warwick, RI 2003 98 died in fire Xenobiotic

Location

Date

Significance

TABLE 2-1. Gas Disasters Air pollution is another source of toxic gases causing significant disease and death. Complaints about smoky air date back to at least 1272, when King Edward I banned the burning of sea-coal.124 By the 19th century—the era of rapid industrialization in England—winter “fogs― became increasingly problematic. An 1873 London fog was responsible for 268 deaths from bronchitis. Excessive smog in the Meuse Valley of Belgium in 1930, and in Donora, Pennsylvania, in 1948, was also blamed for excess morbidity and mortality. In 1952, another dense sulfur dioxideladen smog in London was responsible for 4000 deaths.65 Both the initiation of long-overdue air-pollution reform in England and Parliament's passing of the 1956 Clean Air Act resulted from this latter “fog.―

Warfare

and

Terrorism

Exposure to xenobiotics with the deliberate intent to inflict harm claimed an extraordinary number of victims during the 20th century (Table 2-2 ). During World War I, chlorine and phosgene gases and the liquid vesicant mustard were used as battlefield weapons, with mustard causing approximately 80% of the chemical casualties.112 Reportedly, 100,000 deaths and 1.2 million casualties were attributable to these chemical attacks.24 These toxic exposures resulted in severe airway irritation, acute lung injury, hemorrhagic pneumonitis, skin blistering, and ocular damage. Chemical weapons were used again in the 1980s during the Iran-Iraq war. Chlorine, mustard gas, phosgene Ypres, Belgium 1915–1918 100,000 dead and 1.2 million casualties from chemicals during

World War I CN, CO Europe 1939–1945 Millions murdered by Zyklon-B (HCN) gas Agent Orange Vietnam 1960s Contains dioxin; excess skin cancer Mustard gas Iraq-Iran 1982 New cycle of war gas casualties Possible toxin Persian Gulf 1991 Gulf War syndrome Sarin Matsumoto, Japan 1994 First terrorist attack in Japan using sarin Sarin Tokyo 1995 Subway exposure; 5510 people seek medical attention Dust and other particulates New York City 2001 World Trade Center collapse from terrorist air strike resulted in persistent cough among some rescuers Toxin

Location

Date

Significance

TABLE 2-2. Warfare and Terrorism Disasters

The Nazis used poisonous gases during World War II to commit mass murder and genocide. Initially, the Nazis employed carbon monoxide to kill. To expedite the killing process, Nazi scientists developed Zyklon-B gas (hydrogen cyanide gas). As many as 10,000 people per day were killed by the rapidly acting cyanide, and millions of deaths were attributable to the use of these gases. Agent Orange was widely used as a defoliant during the Vietnam War. This herbicide consisted of a mixture of 2,4,5trichlorophenoxyacetic acid (2,4,5-T) and 2,4dichlorophenoxyacetic acid (2,4-D), as well as small amounts of a contaminant, 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD), better known as dioxin. Over the effects had been attributed Institute of Medicine study veterans there is sufficient

years a large number of adverse health to Agent Orange exposure. A 2002 concluded that among Vietnam evidence to demonstrate an association

between this herbicide exposure and chronic lymphocytic leukemia, soft-tissue sarcomas, non-Hodgkin lymphomas, disease, and chloracne.48

Hodgkin

Mass exposure to the very potent organic phosphorus compound sarin occurred in March 1995, when terrorists released this chemical warfare agent in three separate Tokyo subway lines.91 Eleven people were killed, and 5510 people sought emergency medical evaluation at more than 200 hospitals and clinics in the area.111 This mass disaster introduced the spectra of terrorism to the modern emergency medical services system, resulting in a P.25 greater emphasis on hospital preparedness, including planning for the psychological consequences of such events. Sarin exposure also resulted in several deaths and hundreds of casualties in Matsumoto, Japan, in June 1994.79 , 87 During recent wars and terrorism events, a variety of physical and neuropsychologic ailments have been attributed to possible exposure to toxic agents.16 , 47 Gulf War syndrome is a

constellation of chronic symptoms, including fatigue, headache, muscle and joint pains, ataxia, paresthesias, diarrhea, skin rashes, sleep disturbances, impaired concentration, memory loss, and irritability, noted in thousands of Persian Gulf War veterans without a clearly identifiable cause. A number of etiologies have been advanced to explain these varied symptoms, including exposure to the smoke from burning oil wells; chemical and biologic warfare agents, including nerve agents; and medical prophylaxis, such as the use of pyridostigmine bromide or anthrax and botulinum toxin vaccines, although the actual etiology remains unclear.29 , 38 , 47 , 49 , 58 , 123 Most recently, persistent cough and increased bronchial responsiveness was noted among 8% of New York City Fire Department workers who were exposed to large amounts of dust and other particulates following the collapse of World Trade Center in September 2001.97 The risk of development of hyperreactivity and reactive airways dysfunction was clearly associated with the intensity of exposure.6

Food

Disasters

Unintentional contamination of food and drink has led to numerous toxic disasters (Table 2-3 ). Ergot, produced by the fungus Claviceps purpurea , caused epidemic ergotism as the result of eating breads and cereals made from rye that was contaminated by C. purpurea . In some epidemics, convulsive manifestations predominated, and in others, gangrenous manifestations predominated.76 Ergot-induced severe vasospasm was thought responsible for both types of presentations.75 In 994 A.D., 40,000 people died in Aquitania, France, in one such epidemic.63 Convulsive ergotism was initially described as a “fire which twisted the people,― and the term “St. Anthony's fire― (ignis sacer ) was used to refer to the excruciating burning pain experienced in the extremities that is an early manifestation of

gangrenous ergotism. The events surrounding the Salem, Massachusetts witchcraft trials have also been attributed to the ingestion of contaminated rye. The bizarre neuropsychiatric manifestations exhibited by some of the individuals associated with this event may have been caused by the hallucinogenic properties of ergotamine, a lysergic acid diethylamide (LSD) precursor.12 , 72 Ergot Aquitania, France 994 A.D. 40,000 died in the epidemic Ergot Salem, Massachusetts 1692 Neuropsychiatric symptoms may be attributable to ergot Lead Devonshire, England 1700s Colic from cider contaminated during production Arsenious acid France 1828 40,000 cases of polyneuropathy from contaminated wine & bread Lead Canada 1846 134 men died during the Franklin expedition, possibly because of contamination of food stored in lead cans Arsenic Staffordshire, England 1900 Arsenic-contaminated sugar used in beer production Cadmium Japan

1939–1954 Itai-Itai (“ouch-ouch―) disease Hexachlorobenzene Turkey 1956 4000 cases of porphyria cutanea tarda Methyl mercury Minamata Bay, Japan 1950s Consumption of organic mercury poisoned fish Triorthocresyl phosphate Meknes, Morocco 1959 Cooking oil adulterated with turbojet lubricant Cobalt Quebec City, Canada and others 1960s Cobalt beer cardiomyopathy Methylenedianiline Epping, England 1965 Jaundice Polychlorinated biphenyls Japan 1968 Yusho (“rice oil disease―) Methyl mercury Iraq 1971 >400 deaths from contaminated grain Polybrominated biphenyls Michigan 1973 97% of state contaminated through food chain

Polychlorinated biphenyls Taiwan 1979 Yu-Cheng (“oil disease―) Rapeseed oil (denatured) Spain 1981 Toxic oil syndrome affected 19,000 people Arsenic Buenos Aires 1987 Malicious contamination of meat; 61 people underwent chelation Arsenic Bangladesh and West Bengal, India 1990s–present Ground water contaminated with arsenic; millions exposed; 100,000s with symptoms; greatest mass poisoning in history Nicotine Michigan 2003 Deliberate contamination of ground beef; 92 people became ill Xenobiotic

Location

Date

Significance

TABLE 2-3. Food Disasters During the last half of 20th century, unintentional mass poisoning from food and drink contaminated with toxic chemicals became all too common. One of the more unusual poisonings occurred in Turkey, in 1956, when wheat seed treated with the fungicide hexachlorobenzene and intended for planting was inadvertently used for human consumption. Approximately, 4000 cases of porphyria cutanea tarda were attributed to the ingestion of this wheat seed. 104

Another example of chemical food poisoning took place in Epping, England, in 1965. In this incident, a sack of flour became contaminated with methylenedianiline when the chemical unintentionally spilled onto the flour during transport to a bakery. Subsequent ingestion of bread baked with the contaminated flour produced hepatitis in 84 people. This outbreak of toxic hepatitis became known as Epping jaundice.55 The manufacture of polybromated biphenyls (PBBs) in a factory that also produced food supplements for livestock resulted in the unintentional contamination of a large amount of livestock feed in Michigan in 1973.13 Significant morbidity and mortality among the livestock population resulted. Increased human tissue levels of PBBs were reported,134 although human toxicity seemed limited to vague constitutional symptoms and abnormal liver function tests.2 P.26 The chemical contamination of rice oil in Japan in 1968 caused a syndrome called Yusho (“rice oil disease―). This occurred when heat-exchange fluid containing polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) leaked from a heating pipe into the rice oil. More than 1600 people developed chloracne, hyperpigmentation, an increased incidence of liver cancer, and/or adverse reproductive effects. In 1979, 2000 people in Taiwan developed similar clinical manifestations after ingesting another batch of PCB-contaminated rice oil. This latter epidemic was referred to as Yu-Cheng (“oil disease―).50 In another oil contamination epidemic, consumption of illegally marketed cooking oil in Spain, in 1981, was responsible for a mysterious poisoning epidemic that affected more than 19,000 people and resulted in at least 340 deaths. Exposed patients developed a multisystem disorder referred to as toxic oil syndrome (or toxic epidemic syndrome), which was characterized by pneumonitis, eosinophilia, pulmonary hypertension, sclerodermalike features, and neuromuscular changes. Although this syndrome

was associated with the consumption of rapeseed oil denatured with 2% aniline, the exact etiologic agent was never definitively identified.53 , 121 In 1999, an outbreak of Coca-Cola–related health complaints occurred in Belgium, when 943 people, mostly children, complained of gastrointestinal symptoms, malaise, headaches, and palpitations, after consuming Coca-Cola.88 Many of those affected complained of an off-taste or bad odor to the soft drink. Millions of cans and bottles were removed from the market at a cost of $103 million.88 In some of the bottles the carbon dioxide was contaminated with small amounts of carbonyl sulfide, which hydrolyzes to hydrogen sulfide, and may have been responsible for odor-triggered reactions. Mass psychogenic illness may have contributed to the large number of medical complaints as the concentrations of the carbonyl sulfide (5–14 µg/L) and hydrogen sulfide (8–17 µg/L) were very low and unlikely to cause systemic toxicity.31 Epidemics of heavy metal poisoning from contaminated food and drink have also occurred throughout history. Epidemic lead poisoning is associated with many different vehicles of transmission, including leaden bowls, kettles, and pipes. A famous 18th-century epidemic was known as the Devonshire colic. Although the exact etiology of this disorder was unknown for many years, later evidence suggested that the ingestion of leadcontaminated cider was responsible.127 Intentional chemical contamination of food may also occur. Multiple cases of metal poisoning occurred in Buenos Aires, in 1987, when vandals broke into a butcher's shop and poured an unknown amount of acaricide (45% sodium arsenite solution) over 200 kg of partly minced meat.101 The contaminated meat was purchased by 718 people. Of 307 meat purchasers who submitted to urine sampling, 49 had urine arsenic levels of 76–500 µg/dL, and 12 had urine arsenic levels above 500 µg/dL (normal urine

arsenic is 88 pediatric deaths

Xenobiotic

Location

Date

Significance

TABLE 2-4. Medicinal Disasters A lesser-known drug manufacturing event, also involving an early sulfa antimicrobial, occurred in 1940–1941, when at least 82 people died from the therapeutic use of sulfathiazole that was contaminated with phenobarbital (Luminal).117 The responsible pharmaceutical company, Winthrop Chemical, produced both sulfathiazole and phenobarbital, and the contamination likely occurred during the tableting process, because the tableting machines for the two medications were adjacent to each other and were used interchangeably. Each contaminated sulfathiazole tablet contained about 350 mg of phenobarbital (and no sulfathiazole), and the typical sulfathiazole dosing regimen was several tablets within the first few hours of therapy. Twenty-nine percent of the production lot was contaminated. Food and Drug Administration (FDA) intervention was required to assist with the recovery of the suspect sulfathiazole, although 22,000 contaminated tablets were never

found.117

In the early 1960s, one of the greatest modern-day events occurred with the release of thalidomide as an antiemetic and sedative-hypnotic.21 Its use as a sedative-hypnotic by pregnant women resulted in about 5000 babies born with severe congenital anomalies.76 This tragedy was largely confined to Europe, Australia, and Canada, where the drug was initially marketed. Only the length of time required for review and the rigorous scrutiny of new drug applications by the FDA prevented a concurrent disaster in the United States.73 A major therapeutic drug event that did occur in the United States involved the widespread use of diethylstilbestrol (DES) for the treatment of threatened and habitual abortions. Despite the lack of convincing efficacy data, as many as 10 million Americans received

DES during pregnancy, or in utero, during a 30-year period, until the drug was prohibited in pregnancy in 1971. Adverse health effects associated with DES use include increased risk for breast cancer in “DES mothers― and increased risk of a rare form of vaginal cancer, reproductive tract anomalies, and premature births in “DES daughters.―35 , 41 Thorotrast (thorium dioxide 25%) is an intravenous radiologic contrast medium that was widely used between 1928 and 1955. Its use was associated with the delayed development of hepatic angiosarcomas, as well as skeletal sarcomas, leukemia, and “thorotrastomas―—malignancies thorotrast.115 , 130

at

the

site

of

extravasated

The use of thallium to treat ringworm infections in the 1920s and 1930s also led to needless morbidity and mortality.36 Understanding that thallium caused alopecia, dermatologists and other physicians prescribed thallium acetate, both as pills and as a topical ointment (Koremlu), to remove the infected hair. A 1934 study found 692 cases of thallium toxicity after oral and topical application and 31 deaths after oral use.83 Medicinal thallium was subsequently taken off the market. The “Stalinon affair― in France, in 1954 involved the unintentional contamination of a proprietary oral medication that was marketed for the treatment of staphylococcal skin infections, osteomyelitis, and anthrax. Although it was supposed to contain diethyltin diiodide and linoleic acid, triethyltin, a potent neurotoxin and the most toxic of organotin compounds, and trimethyltin were present as impurities. Of the approximately 1000 people who received this medication, 217 patients developed symptoms, and 102 patients died.7 , 114 An unusual syndrome, featuring a constellation of abdominal symptoms (pain and diarrhea), followed by neurologic symptoms (peripheral neuropathy and visual disturbances including blindness), was experienced by approximately 10,000 Japanese

between 1955 and 1970, resulting in several hundred deaths.57 This presentation, subsequently labeled subacute myelooptic neuropathy (SMON), was associated with the use of the gastrointestinal disinfectant clioquinol, known in the West as Entero-Vioform and most often used for the prevention of travelers' diarrhea.86 In Japan, this drug was referred to as “sei-cho-zai― (“active in normalizing intestinal function―). It was incorporated into more than 100 nonprescription proprietary medications and was used by millions of people, often for weeks or months. The exact mechanism of toxicity has not been determined, but recent investigators theorize that clioquinol may enhance the cellular uptake of certain metals, particularly zinc, and that the clioquinol-zinc chelate may act as a mitochondrial toxin causing this syndrome.4 New cases declined rapidly when clioquinol was banned in Japan. In 1981, a number of premature neonates died with a “gasping syndrome,― manifested by severe metabolic acidosis, respiratory depression with gasping, and encephalopathy.34 Prior to the development of these findings, the infants had all received multiple injections of heparinized bacteriostatic sodium chloride solution (to flush their indwelling catheters) and bacteriostatic water (to mix medications), both of which contained 0.9% benzyl alcohol. P.28 Accumulation of large amounts of benzyl alcohol and its metabolite benzoic acid in the blood was thought responsible for this syndrome.34 A nursery mass poisoning occurred in 1967, when 9 neonates developed extreme diaphoresis, fever, and tachypnea, without rash or cyanosis. Two fatalities resulted, although the others responded dramatically to exchange transfusion. The illness was traced to sodium pentachlorophenate that had been used as an antimildew agent in the hospital laundry.93

In 1989 and 1990, eosinophilia-myalgia syndrome, a debilitating syndrome somewhat similar to toxic oil syndrome, developed in more than 1500 people who had taken the dietary supplement Ltryptophan.52 , 125 These patients presented with disabling myalgias and eosinophilia, often accompanied by extremity edema, dyspnea, and arthralgias. Skin changes, neuropathy, and weight loss sometimes developed. Intensive investigation revealed that all affected patients had ingested L-tryptophan produced by a single manufacturer that had recently introduced a new process involving genetically altered bacteria to improve L-tryptophan production. A contaminant produced by this process probably is responsible for this syndrome.9 The banning of L-tryptophan by the FDA set in motion the passage of the Dietary Supplement Health and Education Act of 1994. This legislation, which attempted to regulate an uncontrolled industry, inadvertently facilitated industry marketing of dietary supplements bypassing FDA scrutiny. In recent years, a number of therapeutic drugs, previously approved by the FDA, were withdrawn from the market because of concern about health risks. In a number of cases, the drugs that were withdrawn had been responsible for causing serious drug–drug interactions (astemizole, cisapride, mibefradil, terfenadine).82 Other drugs were withdrawn because of a propensity to cause hepatotoxicity (troglitazone), anaphylaxis (bromfenac sodium), valvular heart disease (fenfluramine, dexfenfluramine), rhabdomyolysis (cerivastatin), hemorrhagic stroke (phenylpropanolamine), and other adverse cardiac and neurologic effects (ephedra, rofecoxib). One of the most disconcerting drug problems to arise was the development of cardiac valvulopathy and pulmonary hypertension in patients taking the weight-loss drug-combination fenfluramine and phentermine (fen-phen) or dexfenfluramine.18 , 110 The histopathologic features observed with this condition were similar to the valvular lesions associated with ergotamine and carcinoid. Interestingly, appetite suppressant medications, as well as

ergotamine and carcinoid all increase available serotonin. Triorthocresyl phosphate US 1930–1931 Ginger Jake paralysis Methanol Atlanta, GA 1951 Epidemic from ingesting bootleg whiskey Methanol Jackson, MI 1979 Occurred in a prison MPTP San Jose, CA 1982 Illicit meperidine manufacturing parkinsonism 3-Methyl fentanyl Pittsburgh, PA

resulting

in

1988 “China-white― epidemic Methanol Baroda, India 1989 Moonshine contamination; 100 deaths Fentanyl New York City 1990 “Tango and Cash― epidemic Methanol New Delhi, India 1991 Antidiarrheal medication contaminated with

drug-induced

methanol;

>200

deaths Methanol Cuttack, India 1992 Methanol-tainted liquor; 162 deaths Scopolamine US East Coast 1995–1996 325 cases of anticholinergic poisoning in heroin users Methanol Cambodia 1998 >60 deaths Xenobiotic

Location

Date

Significance

TABLE 2-5. Alcohol and Illicit Drug Disasters While many of these withdrawals involved drugs were only recently approved, the withdrawal of phenylpropanolamine in 2000 removed an over-the-counter agent that was consumed as a component of many cough and cold remedies for several decades. Despite the accumulation of increasing numbers of case reports and case series of medical problems associated with phenylpropanolamine use, drug production was only halted after a well-designed case-control study demonstrated that phenylpropanolamine use was an independent risk factor for hemorrhagic stroke. 51

Alcohol

and

Illicit

Drug

Disasters

Unintended toxic disasters have also resulted from the use of alcohol and other drugs of abuse (Table 2-5 ). Arsenical neuropathy developed in an estimated 40,000 people in France in 1828, when wine and bread were unintentionally contaminated by

arsenious acid.71 The use of arsenic-contaminated sugar in the production of beer in England in 1900 resulted in at least 6000 cases of peripheral neuropathy and 70 deaths (Staffordshire beer epidemic).30 During the early 20th century, and particularly during prohibition, the ethanolic extract of Jamaican ginger (sold as “the Jake―) was a popular ethanol substitute in the southern and midwestern United States.77 It was sold legally because it was considered a medical supplement to treat headaches and aid digestion and was not subject to prohibition. For years, the Jake was sold adulterated with castor oil, but in 1930, as the price of castor oil rose, the Jake was reformulated with an alternative adulterant, triorthocresyl phosphate (TOCP). Little was previously known about the toxicity of this compound, but TOCP proved to be a potent neurotoxin. From 1930 to 1931 at least 50,000 people who drank the Jake developed TOCP poisoning, which was manifested by upper and lower extremity weakness (“ginger Jake paralysis―) and gait impairment (“Jake walk― or “Jake leg―).77 A quarter century later, in Morocco, the dilution of cooking oil with a turbojet lubricant containing TOCP caused an additional 10,000 cases of TOCP-induced paralysis.113 In the 1960s, cobalt was added to several brands of beer as a foam stabilizer. Certain local breweries in Quebec City, Canada, Minneapolis, Minnesota, Omaha, Nebraska, and Louvain, Belgium, added 0.5–5.5 ppm cobalt to their beer. This resulted in epidemics of fulminant heart failure among heavy beer drinkers (cobalt-beer cardiomyopathy).1 , 78 P.29 Epidemic methanol poisoning among those seeking ethanol other inebriants is well described. In one such incident in Georgia, in 1951, the ingestion of methanol-contaminated whiskey caused 323 cases of methanol poisoning, resulting deaths. In another epidemic in 1979, 46 prisoners became

and Atlanta, bootleg in 41 ill after

ingesting a methanol-containing diluent used in copy machines.118 In recent years, major mass methanol poisonings have continued to occur in developing countries where store-bought alcohol is often prohibitively expensive. In Baroda, India, in 1989, at least 100 people died and another 200 became ill after drinking a homemade liquor that was contaminated with methanol.26 In New Delhi, India, in 1991, an inexpensive antidiarrheal medicine, advertised as containing large amounts of ethanol, was contaminated with methanol, and caused more than 200 deaths.17 The following year, in Cuttack, India, 162 people died and an additional 448 were hospitalized after drinking methanol-tainted liquor.119 A major epidemic of methanol poisoning occurred in 1998 in Cambodia, when rice wine was contaminated with methanol.11 At least 60 deaths and 400 cases of illness were attributed to the methanol. So-called designer drugs are responsible for several toxicologic disasters. In 1982, several injection drug users living in San Jose, California, who were attempting to use a meperidine analog MPPP (1-methyl-4-phenyl-4-propionoxy-piperidine), developed a peculiar, irreversible neurologic disease closely resembling parkinsonism.60 Investigation revealed that these patients had unknowingly injected trace amounts of MPTP (1-methyl-4-phenyl1,2,3,6-tetrahydropyridine), present as an inadvertent product of the clandestine MPPP synthesis. The subsequent metabolism of MPTP to MPP+ resulted in a toxic compound that selectively destroyed cells in the substantia nigra, causing severe irreversible parkinsonism. The vigorous pursuit of the cause of this disaster led to a better understanding of the pathophysiology of parkinsonism and the development of possible future treatments. Another example of a “designer-drug― mass poisoning occurred in the New York City metropolitan area in 1991, when a sudden epidemic of opioid overdoses occurred among heroin users who bought envelopes labeled “Tango and Cash.―28

Expecting to receive a new brand of heroin, the drug users instead purchased the much more potent fentanyl. Increased and unpredictable toxicity resulted from the inability of the dealer to adjust (“cut―) the fentanyl dose properly. Some purchasers presumably received little or no fentanyl, while others received potentially lethal doses. A similar epidemic involving 3methylfentanyl occurred in 1988 in Pittsburgh, Pennsylvania.69 Polycyclic aromatic hydrocarbons England 1700s Scrotal cancer among chimney sweeps; first description of occupational cancer Mercury New Jersey Mid to late 1800s Outbreak of mercurialism in hatters White phosphorus Europe Mid to late 1800s Phossy-jaw in matchmakers β-Naphthylamine Worldwide Early 1900s Bladder cancer in dye makers Benzene Newark, NJ 1916–1928 Aplastic anemia among artificial leather manufacturers Asbestos Worldwide 20th century Millions at risk for asbestos-related disease Vinyl chloride Louisville, KY

1960s–1970s Hepatic angiosarcoma among polyvinyl chloride polymerization workers Chlordecone James River, VA 1973–1975 Neurologic abnormalities among insecticide workers 1, 2-Dibromochloropropane California 1974 Infertility among pesticide makers Xenobiotic

Location

TABLE

Occupational

2-6.

Date

Significance

Disasters

At least 325 cases of anticholinergic poisoning occurred among heroin users in New York City, Newark, New Jersey, Philadelphia, Pennsylvania, and Baltimore, Maryland, from 1995 to 1996.105 The “street drug― used in these cases was adulterated with scopolamine. Whereas naloxone treatment was associated with increased agitation and hallucinations, physostigmine administration resulted in resolution of symptoms. Why the heroin was adulterated was unknown, although the use of an opiatescopolamine mixture was reminiscent of the morphine-scopolamine combination therapy known as “twilight sleep― that was heavily used in obstetric anesthesia during the early 20th century.94 Another unexpected complication of heroin use was observed in the Netherlands in the 1980s, when 47 heroin users developed mutism and spastic quadriparesis that was pathologically documented to be spongiform leukoencephalopathy.135 In these cases, as well as in subsequent cases in Europe and the United States, the users inhaled heroin vapors after the heroin powder

had been heated on aluminum foil, a drug administration technique known as “chasing the dragon.―56 , 135 The exact toxic mechanism has not been elucidated.

Occupational-Related Disasters

Chemical

Unfortunately, occupation-related toxic epidemics have become increasingly common (Table 2-6 ). These poisoning syndromes tend to have an insidious onset and may not be recognized clinically until years after the exposure. A specific toxin may cause a myriad of problems; among the most worrisome being the carcinogenic

and

mutagenic

potentials.

Although the 18th-century observations of Ramazzini and Pott introduced the concept that certain diseases were a direct result of toxic exposures in the workplace, it was not until the height of the 19th-century industrial revolution that the problems associated with the increasingly hazardous workplace became apparent.46 During the 1860s, a peculiar disorder, attributed to the effects of inhaling mercury vapor, was described among manufacturers of felt hats in New Jersey.131 Mercury nitrate was used as an essential part of the felting process at the time. “Hatter's shakes― refers to the tremor that developed in an estimated 10–60% of hatters surveyed.131 Extreme shyness, another manifestation of P.30 mercurialism, also developed in many hatters in later studies. Five percent of hatters during this period died from renal failure. Radium Orange, NJ 1910s–1920s Increase in bone cancer in dial-painting workers Radium

US 1920s “Radithor― (radioactive water) sold as radium-containing patent medication Radiation Hiroshima and Nagasaki, Japan 1945 First atomic bombs dropped at end of World War II; clinical effects still evident today Radiation Chernobyl, Ukraine 1986 Unintentional radioactive release; acute radiation sickness Cesium Goiania, Brazil 1987 Acute radiation sickness and radiation burns Xenobiotic

Location

Date

Significance

TABLE 2-7. Radiation Disasters Other notable 19th-century and early 20th-century occupational tragedies included an increased incidence of mandibular necrosis (phossy jaw) among workers in the matchmaking industry who were exposed to white phosphorus,44 an increased incidence of bladder tumors among synthetic dye makers who used βnaphthylamine,37 and an increased incidence of aplastic anemia among artificial leather manufacturers who used benzene.108 The epidemic of phossy jaw among matchmakers had a latency period of 5 years and a mortality rate of 20% and has been called the “greatest tragedy in the whole story of occupational disease.―14 The problem continued in the United States until Congress passed the White Phosphorus Match Act in 1912, which

established a prohibitive tax on white phosphorus matches.85 Since antiquity, occupational lead poisoning has been a constant threat. Workplace exposure to lead was particularly problematic during the 19th century and early 20th century, because of the large number of industries that relied heavily on lead. One of the most notorious of the “lead trades― was the actual production of white lead and lead oxides. Palsies, encephalopathy, and death from severe poisoning were reported.40 Other occupations that entailed dangerous lead exposures included pottery glazing, rubber manufacturing, pigment manufacturing, painting, printing, and plumbing.68 Given the increasing awareness of harm suffered in the workplace, the British Factory and Workshop Act was enacted in 1895, which required governmental notification of occupational diseases caused by lead, mercury, and phosphorus poisoning, as well as of occupational diseases caused by anthrax.62 Exposure to asbestos during the 20th century has become one of the most consequential occupational and environmental disasters in recent memory.19 , 84 Despite the fact that the first case of asbestosis was reported in 1907, asbestos was heavily used in the shipbuilding industries in the 1940s as an insulating and fireproofing material. Since the early 1940s, 8–11 million individuals were occupationally exposed to asbestos,64 including 4.5 million individuals who worked in the shipyards. Asbestosrelated diseases include mesothelioma, lung cancer, and pulmonary fibrosis (asbestosis). A 3-fold excess of cancer deaths is observed in asbestos-exposed insulation workers, primarily as a consequence of excess lung cancer deaths.106 The manufacture and use of a variety of newly synthesized chemicals has also resulted in cases of mass occupational poisoning. In Louisville, Kentucky, in 1974, an increased incidence of angiosarcoma of the liver was first noticed among polyvinyl chloride polymerization workers who were exposed to vinyl

chloride monomer.25 In 1975, chemical factory workers exposed to the organochlorine insecticide chlordecone (Kepone) experienced a high incidence of neurologic abnormalities, including tremor and chaotic eye movements.120 An increased incidence of infertility among male Californian pesticide workers exposed to dibromochloropropane (DBCP) was noted in 1977.132

Radiation

Disasters

A discussion of mass poisonings is incomplete without mention of a growing number of radiation disasters that have occurred during the 20th century (Table 2-7 ). The first significant mass exposure to radiation occurred among several thousand teenage girls and young women employed in the dial-painting industry.15 These workers painted luminous numbers on watch and instrument dials with paint that contained radium. Exposure occurred by licking the paint brushes and inhaling radium-laden dust. Studies showed an increase in bone-related cancers, as well as aplastic anemia and leukemia, in exposed workers.70 , 95 At the time of the “watch― disaster, radium was also being sold as a nostrum touted to cure all sorts of ailments, including rheumatism, syphilis, multiple sclerosis, and sexual dysfunction. Referred to as “mild radium therapy,― in order to differentiate it from the higher-dose radium that was used in the treatment of cancer at that time, such α-particle-emitting isotopes were hailed as a powerful natural elixir that acted as a metabolic catalyst by delivering direct energy transfusions.66 During the 1920s, dozens of patent medications contained small doses of radium and were sold as radioactive tablets, liniments, or liquids. One of the most infamous preparations was Radithor. Each half-ounce bottle contained slightly more than 1 µCi of radium228 and radium-226. This radioactive water was sold all over the world “as harmless in every respect― and was heavily promoted as a sexual stimulant and aphrodisiac, taking on the

glamour of a recreational drug for the wealthy. 66 More than 400,000 bottles were sold. The 1932 death of a prominent socialite and Radithor connoisseur from chronic radiation poisoning drew increased public and governmental scrutiny to this unregulated radium industry and helped end the era of radioactive patent medications.66 Concerns about the health effects of radiation have continued to escalate since the dawn of the nuclear age in 1945. Long-term followup studies 50 years after the atomic bombings at Hiroshima and Nagasaki show an increased incidence of leukemia, other cancers, radiation cataracts, hyperparathyroidism, delayed and development, and chromosomal anomalies in exposed individuals.54

growth

The unintentional nuclear disaster at Chernobyl, Ukraine, in April 1986, again forced us to confront the medical consequences of 20th-century scientific advances that brought us the atomic age.32 The release of radioactive material resulted in the hospitalization of more than 200 people for acute radiation sickness P.31 and 31 deaths. By 2003, the predominant main long-term effects from the event appear to be childhood thyroid cancer and the psychological consequences.99 In some areas with heavy contamination, the increase in childhood thyroid cancer has increased 100-fold. 102 Another serious radiation event occurred in Goiania, Brazil, in 1987. When an abandoned radiotherapy unit was opened in a junkyard, 244 people were exposed to cesium-137. Of those people exposed to cesium-137, 104 showed evidence of internal contamination, 28 had local radiation injuries, and 8 developed acute radiation syndrome. There were at least 4 deaths. 92 , 100 In September 1999, a nuclear event at a uranium processing plant in Japan set off an uncontrolled chain reaction exposing 49 people to radiation.25 , 60 Radiation measured outside the facility reached

4000 times the normal ambient level. Two workers died from the effects of the radiation.

Mass Suicide by Poison Toxic disasters have also manifested themselves as events of mass suicide. In 1978, in Jonestown, Guyana, 911 members of the Peoples Temple died when they ingested a beverage to which cyanide had been added. 39 Although the majority of those deaths may have been by suicide, some appear to have been involuntary.61 In 1997, phenobarbital and ethanol (sometimes assisted by physical asphyxiation) was the suicidal method favored by 39 members of the Heavens Gate cult in Rancho Santa Fe, California. This means of suicide was recommended in the book Final Exit . 45 Apparently, the cult members committed suicide in order to shed their bodies in hopes of hopping aboard an alien spaceship they believed was in the wake of the Hale-Bopp comet.59

Summary Unfortunately, toxicologic plagues and disasters have had an all too prominent role in our history. An understanding of the pathogenesis of these toxic plagues that pertain to drug, food, and occupational safety is critically important if future disasters are to be prevented. These events teach us awareness that many of these toxic agents may have a potential role as agents of opportunity for terrorists and others who seek to harm. Given the practical and ethical limitations in studying the effects of many specific toxins in humans, lessons from these unfortunate tragedies must be fully mastered and retained for future generations.

References

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part A - The General Approach to Medical Toxicology > Chapter 3 - Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes

Chapter 3 Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Neal E. Flomenbaum Lewis R. Goldfrank Robert S. Hoffman Mary Ann Howland Neal A. Lewin Lewis S. Nelson For more than 200 years the American medical community has attempted to standardize its approach to the assessment of patients. At the New York Hospital in 1865, pulse rate, respiratory rate, and temperature were incorporated into the bedside chart and called “vital signs.―6 It was not until the early part of the 20th century, however, that blood pressure determination also become routine. Additional components of the standard emergency assessment, such as oxygen saturation by pulse oximetry and pain severity using standardized scales, are now also beginning to be considered vital signs. Although both oxygen saturation and pain severity are essential components of the clinical assessment and are important considerations

throughout this text, neither is considered a vital sign here. In the practice of medical toxicology, vital signs play an important role beyond assessing and monitoring the overall status of a patient, as they frequently provide valuable physiologic clues to the toxicologic etiology and severity of an illness. The vital signs also are a valuable parameter with which to assess and monitor a patient's response to supportive treatment and antidotal therapy.

Table 3-1 presents the normal vital signs for various age groups. However, this broad range of values considered normal should serve merely as a guide. Only a complete assessment of a patient can determine whether or not a particular vital sign is truly clinically normal. This table of normal vital signs is useful in assessing children, as normal values for children vary considerably with age, and knowing the range of variation is essential. The normal temperature is defined

as

95–100.4°F

(35–38°C).

The difficulty in defining the “normalcy― of vital signs in an emergency setting has been inadequately addressed and may prove to be an impossible

undertaking. Published normal values may have little relevance to an acutely ill or anxious patient in the emergency setting, yet that is precisely the environment in which we need to define abnormal vital signs and address them accordingly. For these reasons descriptions of vital signs as “normal― or

“stable― are too nonspecific to be meaningful, and therefore should never be accepted as defining normalcy in an individual patient. Conversely, no patient should be considered too agitated or too gravely ill to obtain a complete set of vital signs; indeed, these patients urgently need a thorough evaluation which includes all of the vital signs. Also the vital signs must be recorded as accurately as possible first in the prehospital setting, and again with precision and reliability as soon as a patient arrives in the emergency department, and serially thereafter.

Many xenobiotics affect the autonomic nervous system, which, in turn, affects the vital signs via the sympathetic and/or parasympathetic pathways. Meticulous attention to both initial and repeated determinations of vital signs is of extreme importance in identifying a pattern of changes suggesting a particular xenobiotic or group of xenobiotics. The value of serial monitoring of the vital signs is demonstrated by the patient who presents with an

anticholinergic overdose who is then given the antidote, physostigmine. In this situation it is important to recognize when tachycardia becomes bradycardia (ie, anticholinergic syndrome followed by physostigmine excess). Meticulous attention to these changes assures that the therapeutic interventions can be modified or adjusted accordingly. Another common situation, perhaps, is the course of a patient who has opioidinduced bradypnea (a decreased rate of breathing) who then develops tachypnea (an increased rate of breathing) following the administration of the opioid antagonist naloxone. However the analysis becomes exceedingly complicated when the patient may have been exposed to two or more substances, such as an opioid and cocaine. In this situation the effects of cocaine may be “unmasked― by the naloxone used to counteract the opioid, and the clinician must then be forced to differentiate naloxone-induced opioid withdrawal from cocaine toxicity. The assessment starts by analyzing a combination of information, including history, vital signs, and physical examination. Table 3-2 describes the most typical toxic syndromes. This table includes only those vital signs that are thought to be characteristically abnormal or pathognomonic and directly related to the toxicologic effect of the xenobiotic. The primary purpose of the table, however, is to include many findings, in addition to the vital signs, that together constitute a toxic syndrome. Mofenson and Greensher5 coined the term toxidromes from the words toxic syndromes to describe the groups of signs and symptoms that consistently result from particular toxins. These syndromes are usually best described by a combination of the vital signs and clinically obvious end-organ manifestations. The signs that prove most clinically useful are those involving the central nervous system (mental status); ophthalmic system (pupil size); gastrointestinal system (peristalsis); dermatologic system: skin (dryness vs. diaphoresis) and mucous membranes (moistness vs. incontinence). symptoms and manifestations.

P.38 dryness); and genitourinary system (urinary retention vs. Table 3-3 includes some of the most important signs and the xenobiotics most commonly responsible for these A detailed analysis of each sign, symptom, and toxic syndrome

can be found in the pertinent chapters throughout the text. In this chapter, the most typical toxic syndromes (Table 3-2 ) are considered to enable the appropriate assessment and differential diagnosis of a poisoned patient. Adult 120 80 60–100 16–24 16 years 120 80 80 16–30 12 years 119 76 85 16–30 10 years 115 74 90 16–30 6 years 107 69 100 20–30 4 years 104 65 110 20–30 2 years

102 58 120 25–30 1 year 100 55 120 25–30 6 months 90 55 120 30 4 months 90 50 145 30–35 2 months 85 50 145 30–35 Newborn 65 50 145 35–40 The normal rectal temperature is defined as 95–100.4°F (35–38°C) for all ages. For children ≤1 year of age these values are the mean values for the 50th percentile. For the older children these values represent the 90th percentile at a specific age for the 50th percentile of weight in that age group. *These values were determined in the emergency department and may be

environment Age

and

situation

Systolic BP (mm Hg)

dependent.

Diastolic BP (mm Hg)

Pulse (beats/min)

Respirations (breaths/min)*

TABLE 3-1. Normal Vital Signs by Age

In considering a toxic syndrome the reader should always remember that the actual clinical manifestations of an ingestion or exposure are far more variable than the syndromes described in Table 3-2 . The concept of the toxic syndrome is most useful when thinking about a clinical presentation and formulating a framework for assessment. Although some patients may present as “classic― cases, others will manifest partial toxic syndromes or formes frustes. Incomplete syndromes still may provide at least a clue to the correct diagnosis. It is important to understand that partial presentations (particularly in the presence of multiple toxins) do not necessarily imply less-severe disease and, therefore, are no less important to appreciate. In some instances, an unexpected combination of findings may be particularly helpful in identifying a toxin or a combination of toxins. For example, a dissociation between such typically paired changes as an increase in pulse with a decrease in blood pressure (cyclic antidepressants or phenothiazines), or the presentation of a decrease in pulse with an increase in blood pressure (ergot alkaloids) may be extremely helpful in diagnosing a toxic etiology. The use of these unexpected or atypical clinical findings is demonstrated in Chap. 23 . Anticholinergics –/↑ ↑ = ↑ Delirium ↑ ↓ ↓

Dry mucous membranes, flush, urinary retention Cholinergics = = –/↑ – Normal to depressed = ↑ ↑ Salivation, lacrimation, urination, diarrhea, bronchorrhea, paralysis Ethanol or sedative-hypnotics ↓ ↓ ↓ –/↓ Depressed = ↓ – Hyporeflexia, Opioids

ataxia

↓ ↓ ↓ ↓ Depressed ↓ ↓ – Hyporeflexia Sympathomimetics ↑

fasciculations,

↑ ↑ ↑ Agitated ↑ –/↑ ↑ Tremor, seizures Withdrawal from ethanol ↑ ↑ ↑ ↑ Agitated, disoriented ↑

or

sedative-hypnotics

↑ ↑ Tremor, seizures Withdrawal from opioids ↑ ↑ – – Normal, anxious ↑ ↑ ↑ Vomiting, rhinorrhea, piloerection, diarrhea, yawning ↑ = increases; ↓ = decreases; ± = variable; – = change unlikely Vital Signs

Group

BP

P

R

T

Mental Status

Puple Size

Peristaisis

Diaphoresls

Other

TABLE 3-2. Toxic Syndromes

Blood

Pressure

Xenobiotics cause hypotension by four major mechanisms: decreased peripheral resistance, decreased myocardial contractility, dysrhythmias, and intravascular volume depletion. Many xenobiotics can initially cause severe orthostatic hypotension, without marked supine hypotension, and any xenobiotic that affects autonomic control of the heart or peripheral capacitance vessels may lead to orthostatic hypotension (Table 3-4 ). Blood pressure and pulse rate may vary significantly as a result of change in receptor responsiveness, degree of physical fitness, and degree of atherosclerosis, or general cardiovascular function. Changing patterns of blood pressure often assist in the diagnostic evaluation: exposure to a monoamine oxidase inhibitor (MAOI) overdose characteristically causes an initial normal blood pressure, to be followed by severe hypertension which, in turn, may be followed abruptly by severe hypotension (Chap. 69 ). Agitation Anticholinergicsa , hypoglycemia, phencyclidine, withdrawal from ethanol and sedative-hypnotics

sympathomimeticsb ,

Alopecia Alkylating agents, radiation, selenium, thallium Ataxia Benzodiazepines, carbamazepine, carbon monoxide, ethanol, hypoglycemia, lithium, mercury, nitrous oxide, phenytoin Blindness or decreased visual acuity Caustics (direct), cocaine, cisplatin, mercury, methanol, quinine, thallium Blue skin Amiodarone, FD&C #1 dye, methemoglobin, silver Constipation Anticholinergicsa , botulism, lead, opioids, thallium (severe) Tinnitus, deafness

Aminoglycosides, cisplatin, metals, loop diuretics, quinine, salicylates Diaphoresis Amphetamines, cholinergicsc , hypoglycemia, opioid withdrawal, salicylates, serotonin syndrome, sympathomimeticsb , withdrawal from ethanol and sedative-hypnotics Diarrhea Arsenic and other metals, boric acid (blue-green), botanical irritants, cathartics, cholinergicsc , colchicine, iron, lithium, opioid withdrawal, radiation Dysesthesias, paresthesias Acrylamide, arsenic, ciguatera, cocaine, colchicine, thallium Gum discoloration Arsenic, bismuth, hypervitaminosis A, lead, mercury Hallucinations Anticholinergicsa , dopamine agonists, ergot alkaloids, ethanol, ethanol and sedative-hypnotic withdrawal, LSD, phencyclidine, sympathomimeticsb , tryptamines (eg, AMT) Headache Carbon monoxide, hypoglycemia, monoamine (hypertensive crisis), serotonin syndrome

oxidase

inhibitor/food

interaction

Metabolic acidosis (elevated anion, gap) [MUDPILES] Methanol, uremia, ketoacidosis (diabetic, starvation, alcoholic), paraldehyde, phenformin, metformin, iron, isoniazid lactic acidosis, cyanide, protease inhibitors, ethylene glycol, salicylates, toluene Miosis Cholinergicsc , clonidine, opioids, phencyclidine, phenothiazines Mydriasis Anticholinergicsa , botulism, opioid withdrawal, sympathomimeticsb Nystagmus Barbiturates, carbamazepine, carbon monoxide, ethanol, lithium, monoamine oxidase inhibitors, phencyclidine, phenytoin, quinine Purpura Anticoagulant rodenticides, clopidogrel, corticosteroids, heparin, pit viper venom, quinine, salicylates, warfarin Radiopaque ingestions

Arsenic, chloral hydrate, enteric coated tablets, halogenated hydrocarbons, metals (eg, iron, lead) Red skin Anticholinergicsa , boric acid, disulfiram, scombroid, vancomycin Rhabdomyolysis Carbon monoxide, doxylamine, HMG CoA reductase inhibitors, sympathomimetics b , Tricholoma equestre Salivation Arsenic, caustics, cholinergicsc , ketamine, mercury, phencyclidine, strychnine Seizures Bupropion, carbon monoxide, cyclic antidepressants, Gyromitra mushrooms, hypoglycemia, isoniazid, methylxanthines, withdrawal from ethanol and sedative-hypnotics Tremor Antipsychotics, arsenic, carbon monoxide, cholinergicsc , ethanol, lithium, mercury, methyl bromide, sympathomimeticsb , thyroid replacement Weakness Botulism, diuretics, magnesium, paralytic shellfish, steroids, toluene Yellow skin Acetaminophen (late), pyrrolizidine alkaloids, β carotene, amatoxin mushrooms, dinitrophenol a Anticholinergics: eg, antihistamines, atropine, cyclic antidepressants, scopolamine. b

Sympathomimetics: eg, amphetamines, β adrenergic agonists, cocaine, ephedrine. c Cholinergics: eg, muscarinic mushrooms, organic phosphorus compounds and carbamates including select Alzheimer drugs and physostigmine, pilocarpine and other direct acting drugs. TABLE 3-3. Clinical and/or Laboratory Findings in Poisoning

Î ±1 -Adrenergic antagonists Ergot alkaloids Î ±2 -Adrenergic agonists

Lead (chronic) β-Adrenergic antagonists Monoamine oxidase inhibitors (overdose early and drug–food interaction) Nicotine (early) Angiotensin converting enzyme inhibitors and angiotensin receptor blockers Antidysrhythmics Phencyclidine Calcium channel blockers Sympathomimetics Cyanide Yohimbine Cyclic antidepressants Ethanol and other alcohols Iron Methylxanthines Nitrates and nitrites Nitroprusside Opioids Phenothiazines Phosphodiesterase-5′ inhibitors Sedative-hypnotics Chap. 23 lists additional agents that affect hemodynamic function. Hypotension

Hypertension

TABLE 3-4. Common Xenobiotics That Affect Blood Pressure P.39

Pulse

Rate

Extremely useful clinical information can be obtained by evaluating the pulse rate (Table 3-5 and Chap. 23 ). Although the carotid artery is usually easily palpable, for reasons of both safety and reliability, the brachial artery is preferred in infants and adults greater than 60 years old. The normal heart

rate for adults was defined by consensus more than 50 years ago as a regular rate >60 beats/min and 106°F; >41.1°C) from any cause can lead to extensive rhabdomyolysis, myoglobinuric renal failure, and direct liver and brain injury, and must therefore be identified and corrected immediately. Hyperthermia can result either from a distinct neurologic response to a signal demanding thermal “upregulation― or from an externally imposed

physical or environmental factor, such as the environmental conditions causing heat stroke or the excessive swaddling in clothing causing hyperthermia in infants. Core temperatures higher than 106°F (41.1°C) are extremely rare unless normal feedback mechanisms are overwhelmed. Hyperthermia of this extreme nature is usually attributed to heat stroke, psychomotor agitation, or xenobiotic-related temperature disturbances such as malignant hyperthermia, and the neuroleptic malignant syndrome. P.41 Drug-induced fevers coincide with the administration of a drug and disappear within 48–96 hours of the discontinuation of the drug. A common xenobioticrelated hyperthermia pattern that frequently occurs in the emergency department is defervescence after an acute temperature elevation resulting from agitation or seizure activity. Table 3-7 is a representative list of xenobiotics that affect body temperature (Chap. 16 provides greater detail). Anticholinergics Î ±2 -Adrenergic agonists Chlorphenoxy herbicides Carbon monoxide Dinitrophenol and congeners Ethanol Malignant hyperthermia Hypoglycemic agents Monoamine oxidase inhibitors Opioids Neuroleptic malignant syndrome Sedative-hypnotics Phencyclidine Thiamine deficiency Salicylates Sedative-hypnotic or ethanol withdrawal Serotonin syndrome Sympathomimetics Thyroid replacement

Chap. 16 lists additional agents affecting temperature. Hyperthermia

Hypothermia

TABLE 3-7. Common Xenobiotics That Affect Temperature Hypothermia is probably less of an immediate threat to life than hyperthermia, but it requires rapid appreciation, accurate diagnosis, and skilled management. Hypothermia will impair the metabolism of many xenobiotics, leading to unpredictable delayed effects when the patient is warmed. Many xenobiotics impair judgment and CNS function, thereby placing patients at great risk for becoming hypothermic from exposure to cold climates. Most importantly, a hypothermic patient should never be declared dead without both an extensive assessment and a full resuscitative effort, particularly if the body temperature remains less than 95°F (35°C) (Chap. 16 ).

Summary Early, accurate determinations followed by serial monitoring of the vital signs

are as essential in medical toxicology as in any other type of emergency or critical care medicine. For this reason, the vital signs are an essential part of the initial evaluation of every case, and repeated vital signs are always necessary throughout the subsequent case management. Careful observation of the vital signs helps to determine appropriate therapeutic interventions and guide the clinician in making necessary adjustments to initial and subsequent therapeutic interventions. When pathognomonic clinical and laboratory findings are combined with accurate initial and sometimes changing vital signs, a toxic syndrome may become evident, which will aid in both general supportive and specific antidotal treatment. Toxic syndromes will also guide further diagnostic testing.

References 1. Gravelyn TR, Weg JG: Respiratory rate as an indicator of acute

respiratory

dysfunction.

JAMA

1980;244:1123–1125.

2. Hooker EA, O'Brien DJ, Danzl DF, et al: Respiratory rates in emergency department patients. J Emerg Med 1989;7:129–132. 3. Hooker EA, Danzl DF, Brueggmeyer M, Harper E: Respiratory rates in pediatric emergency patients. J Emerg Med 1992;10: 407–412. 4. Karajalainen J, Vitassalo M: Fever and cardiac rhythm. Arch Intern Med 1986;146:1169–1171. 5. Mofenson HC, Greensher J: The nontoxic ingestion. Pediatr Clin North Am 1970;17:583–590. 6. Musher DM, Dominguez EA, Bar-Sela A: Edouard Seguin and the social power of thermometry. N Engl J Med 1987;316:115–117. 7. Opthof T: The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 2000;45:177–184. 8. Spodick DH: Normal sinus heart rate: Appropriate rate thresholds for sinus tachycardia and bradycardia. South Med J 1996;89:666–667.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part A - The General Approach to Medical Toxicology > Chapter 4 - Principles of Managing the Poisoned or Overdosed Patient

Chapter 4 Principles of Managing the Poisoned or Overdosed Patient Neal E. Flomenbaum Lewis R. Goldfrank Robert S. Hoffman Mary Ann Howland Neal A. Lewin Lewis S. Nelson

Case 1 A 30-year-old woman was found unconscious in her apartment in the early afternoon. The paramedics found a suicide note alongside her, stating that the patient had ingested pills earlier in the morning. Reportedly, several empty bottles of pills were on the floor near her body, but unfortunately none were brought to the emergency department (ED). The woman's initial vital signs in the ED were blood pressure, 120/75 mm Hg; pulse, 90 beats/min; respirations, 18 breaths/min; and

temperature, 98.6°F (37.0°C). Pulse oximetry was 99% while the patient was breathing room air. A rapid reagent bedside glucose test done prior to the patient's arrival in the ED was 95 mg/dL; consequently, dextrose was not administered. Physical examination demonstrated no trauma. The patient localized noxious cutaneous stimulation but did not open her eyes or respond verbally. Pupils were 4 mm and normally reactive. The neck was supple and the cardiopulmonary and abdominal examinations were normal. There were no lesions on the patient's extremities and, specifically, no signs of injection drug use. Neither flumazenil nor naloxone was administered. An electrocardiogram revealed a sinus rhythm, normal electrical axis, and normal intervals without ectopy. A venous blood gas analysis was immediately available: pH, 7.35; PCO2 , 45 mm Hg; PO2 , 40 mm Hg. Serum acetaminophen and ethanol concentrations were zero. The patient was attached to a continuous cardiac monitor and pulse oximeter.

Case 2 A lethargic, 38-year-old woman presented to the ED at 6:45 A.M. According to her roommate, the patient had returned home from work at a nightclub at about 3 A.M. and “smelled like alcohol.― At 5:30 A.M., the roommate saw the patient crying and then witnessed the patient ingest about 40 pills, possibly from the patient's bottle of quetiapine, before going into the bathroom. When the roommate went to check on her a short time later, she found the patient lethargic. The patient had a past history of depression, and was currently being treated with quetiapine and paroxetine. The patient also had a history of cocaine use. In the ED, the patient was lethargic and had pinpoint pupils. Her vital signs were blood pressure, 90/60 mm Hg; pulse, 147 beats/min; respiratory rate, 20 breaths/min; and O2 saturation was

90% on a 100% non-rebreather mask; in addition, she was afebrile. The patient was given naloxone 0.8 mg IV with no response. A nasogastric tube was inserted, and the patient vomited. After the tube was removed and then replaced, the patient was given a dose of activated charcoal (AC) through the nasogastric tube. The patient vomited again. The patient was observed to have increased lethargy and “Kussmaul breathing.― Corresponding arterial blood gas (ABG) values at that time were: pH, 7.30; PCO2 , 57 mm Hg; PO2 , 105 mm Hg; and HCO3 , 30 mEq/L. Intubating the patient was an extremely difficult-to-perform procedure, lasting 45 minutes. The endotracheal tube initially was inserted into the esophagus. Postintubation ABG values were pH, 7.4; PCO2 , 36 mm Hg; PO2 , 317 mm Hg; and HCO3 , 23 mEq/L. Chemistry values were sodium, 137 mEq/L; potassium, 3.6 mEq/L; chloride, 104 mEq/L; bicarbonate 23 mEq, BUN 10 mg/dL; creatinine 0.6 mg/dL; and glucose 150 mg/dL. The complete blood count (CBC) showed a white blood cell count (WBC) of 5100/mm3 ; hemoglobin of 16 g/dL; hematocrit of 47%; and platelets of 192,000/mm3 . Ethanol was 79 mg/dL; acetaminophen and salicylates were negative. Urine toxicology studies were sent. ECG revealed normal ST segments and normal intervals. The patient's vital signs were: blood pressure, 139/86 mm Hg; pulse 132 beats/min, and O2 saturation 88% on 100% FiO2 . She was receiving IV fluids and lorazepam as needed for agitation. She also received clindamycin empirically for possible aspiration pneumonitis. The patient was then admitted to the ICU. At this point the poison center (PC) was consulted and recommended supportive care, continued IV fluids, and benzodiazepines for sedation. The patient remained intubated and sedated with a continuous propofol infusion until the next day, at which time her vital signs were blood pressure, 148/82 mm Hg; pulse, 126 beats/min; respiration, 32 breaths/min; and temperature, 102.3°F (39°C).

Chemistries were normal. CBC revealed a WBC of 14,000/mm3 . Chest radiography revealed an infiltrate and clindamycin was continued. The patient was extubated and continued to do well afterwards. Four days after the patient arrived, she was transferred out of the intensive care unit to a regular floor bed. P.43

Case 3 A 16-month-old girl was given a bottle of ferrous sulfate “as a toy.― The mother felt that the cap was firmly in place and was childproof. After an absence from the room for several minutes, the mother noted on returning that the child had opened the bottle and that several tablets were missing. The child was asymptomatic en route to the hospital and on arrival the child had a blood pressure of 80/40 mm Hg; a pulse of 100 beats/min; respirations of 28 breaths/min; and a temperature of 99.7°F (37.6°C). Examination of the head, eyes, ears, nose, and throat mouth was free of tablets or obvious red tablets. The heart and lungs were normal. nontender with no masses; bowel sounds neurovascular

examination

was

was unremarkable. The discoloration from the iron The abdomen was soft and were normal. The

normal.

Prior to the trip to the hospital, the child had been given 15 mL of syrup of ipecac and had vomited up several partially digested pills 30 minutes later. However, an abdominal radiograph revealed at least 4 tablets in the GI tract. At 3 hours following ingestion the serum iron concentration was 286 µg/dL. Although the child had already vomited several times, whole-bowel irrigation with polyethylene glycol electrolyte solution was administered via a nasogastric tube at 500 mL/h. Guaiac-negative, red-tinged stool and fluid with tablet fragments were passed via the rectum. Other than crying and persistent vomiting for an additional hour, the child remained asymptomatic and the clinical parameters remained

stable. A repeat abdominal radiograph taken 4 hours after the initial radiograph showed no remaining tablets. During the 24 hours that the child was hospitalized, she remained asymptomatic. The 3 cases above illustrate several principles in the modern management of poisonings and overdoses. In all confirmed or suspected cases, thorough but rapid evaluation and reevaluation are always required, even when no specific interventions are subsequently indicated (case 1). In other cases, although some interventions may be appropriate, others are either unnecessary, harmful, or counterproductive (case 2). The prehospital use of syrup of ipecac is no longer recommended in almost any instance, and its use may not obviate the need for a more effective and less dangerous procedure, such as whole-bowel irrigation, to achieve intestinal evacuation (the iron tablets in case 3) .

Overview For almost 4 decades, medical toxicologists and information specialists at poison centers have used a clinical approach to the poisoned or overdosed patient that emphasizes treating the patient rather than treating the poison. Too often in the past, patients were initially all but neglected while attention was focused on the ingredients listed on the containers of the product(s) to which they presumably were exposed. Although the astute clinician must always be prepared to administer a specific antidote immediately in those instances when nothing else will save a patient, all poisoned or overdosed patients will benefit from an organized, rapid, clinical management plan (Fig. 4-1) . In the past 15 years, some basic tenets and long-held beliefs regarding the initial therapeutic interventions in toxicologic management have been questioned and subjected to an “evidence-based― analysis. For example, in the mid-1970s most medical toxicologists began to advocate a standardized

approach to a comatose and possibly overdosed adult patient, typically calling for the intravenous administration of 50 mL of D50W , 100 mg of thiamine, and 2 mg of naloxone, as well as 100% oxygen at high flow rates. The rationale for this approach was to compensate for the previously idiosyncratic style of overdose management encountered in different healthcare settings and for the unfortunate likelihood that omitting any one of these measures at the time that care was initiated in the emergency department would result in omitting it altogether. It was not unusual then to discover from a laboratory chemistry report more than an hour after a supposedly overdosed comatose patient had arrived in the ED, that the initial blood glucose was 30 or 40 mg/dL—a critical delay in the management of unsuspected and consequently untreated hypoglycemic coma. Today, however, with the widespread availability of accurate rapid reagent bedside testing for blood glucose and pulse oximetry for oxygen saturation, coupled with a much greater appreciation by all physicians of what needs to be done for each suspected overdose patient, clinicians can safely provide a more rational, individualized approach to determine the need for and in some instances more precise amounts of dextrose, thiamine, naloxone, and oxygen. A second major approach to providing more rational individualized early treatment for toxicologic emergencies involves a closer examination of the actual benefits and risks of various gastrointestinal emptying interventions. Appreciation of the potential for significant adverse effects associated with all types of gastrointestinal emptying interventions and recognition of the absence of clear evidence-based support of efficacy, have led to a significant reduction in the routine use of syrup of ipecac-induced emesis or orogastric lavage as well as cathartic-induced intestinal evacuation. In 2004, the American Academy of Pediatricians (AAP) all but entirely abandoned its recommendations for the use of syrup of ipecac in the home. The efficacy of orogastric lavage, even when indicated by the nature or type of ingestion, is limited by the amount

of time elapsed since the ingestion. The value of whole-bowel irrigation (WBI) with polyethylene glycol electrolyte solution (PEGELS) appears to be much more specific and limited than originally thought. Some of the limitations and (uncommon) adverse effects of AC are now more widely recognized. Similarly, interventions to eliminate absorbed xenobiotics from the body are now much more narrowly defined or, in some cases, abandoned: Multiple-dose activated charcoal (MDAC) is useful for some but not all xenobiotics. Ion-trapping in the urine is only beneficial, achievable, and relatively safe when the urine can be maximally alkalinized after a significant salicylate, phenobarbital, or chlorpropamide poisoning. Finally, the roles of hemodialysis, hemoperfusion and other extracorporeal techniques are now much more specifically defined. With the foregoing in mind, this chapter represents our current efforts to formulate a logical and effective approach to managing a patient with probable or actual toxic exposure. Table 4-1 provides a recommended stock list of antidotes and therapeutics for the treatment of poisonings and overdoses.

Managing Patient

the

Poisoned

or

Overdosed

The 3 cases at the beginning of this chapter illustrate many of the problems clinicians face in managing ill patients with possible xenobiotic exposures. Rarely, if ever, are all of the circumstances known: the history may be incomplete, unreliable, or unobtainable; multiple drugs, xenobiotics may be involved; and even when a xenobiotic etiology is identified, it may not be easy to determine whether the P.44 problem is an overdose, an allergic or idiosyncratic reaction, or a drug–drug interaction. Similarly, it is sometimes difficult or

impossible to differentiate between adverse effects of a correct dose of medication or the consequences of a deliberate or unintentional overdose. The patient's presenting signs and symptoms may force an intervention at a time when there is almost no information available about the etiology of the patient's condition, and as a result therapeutics must be thoughtfully chosen empirically to treat or diagnose a condition without exacerbating the situation.

Figure 4-1. This algorithm is a basic guide to the management of poisoned patients. A more detailed description of the steps in management may be found in the accompanying text. This algorithm is only a guide to actual management, which must, of course, consider the patient's clinical status.

TABLE 4-1. Antidotes and Therapeutics for the Treatment of Poisonings and Overdosesa

Therapeuticsb Activated

charcoal

(p.

Uses Adsorbs xenobiotics in Gl tract

128)

Antivenom (Crotalinae) (p. 1657)

Crotaline

snake

Antivenom (Latrodectus mactans) (p. 1623)

Black widow spider envenomations

Antivenom (Elapidae) (p. 1657)

Coral

Atropine (p. 1519)

Bradydysrhythmias, cholinesterase inhibitors (organic phosphorus agents, physostigmine) muscarinic mushrooms (Clitocybe, Inocybe) ingestions

snake

envenomations

envenomations

Botulinum antitoxin (ABE-trivalent) (p. 728)

Botulism

Calcium chloride, calcium gluconate (p. 1424)

Fluoride, hydrofluoric acid, ethylene glycol, calcium channel blockers, hypomagnesemia, βadrenergic antagonists

L-Carnitine (p. 746)

Valproic

Cyanide kit (nitrites, p. 1725, sodium thiosulfate, p. 1728)

Cyanide

Dantrolene (p. 1037)

Malignant

Deferoxamine

Iron

mesylate

acid

hyperthermia

(Desferal) (p. 638)

Dextrose in water (50%

Hypoglycemia

adults; 20% pediatrics; 10% neonates) (p. 764)

Diazepam

or

lorazepam

Digoxin-specific antibody fragments (Digibind and Digifab) (p. 983)

Seizures, agitation, stimulants, ethanol and sedative-hypnotic withdrawal

Cardioactive

steroids

Dimercaprol (BAL, British anti-Lewisite) (p. 1265)

Arsenic, mercury, gold, and lead

Diphenhydramine

Dystonic reactions, reactions

Edetate calcium disodium (calcium disodium versenate,

Lead, and other selected metals

allergic

CaNa2 EDTA) (p. 1331) Ethanol (oral and parenteral dosage

Methanol and ethylene glycol

forms) (p. 1465)

Flumazenil

(Romazicon)

Benzodiazepine

(p. 1112)

Folinic acid (Leucovorin)

Fomepizole (p. 1460)

Methotrexate, (p.

826)

(Antizole)

Glucagon (p. 942)

Hydroxocobalamin 1731)

methanol

Ethylene

glycol,

methanol

β-Adrenergic antagonists calcium channel blockers

(p.

Cyanide

and

Ipecac, syrup of (p. 124)

Induces

emesis

Magnesium sulfate or magnesium citrate (p. 135)

Induces

catharsis

Magnesium injection

Cardioactive steroids, hydrofluoric acid, hypomagnesemia, ethanol withdrawal, torsades de pointes

sulfate

Methylene blue (1% solution) (p. 1746)

Methemoglobinemia

N-acetylcysteine (Mucomyst and Acetadote) (p. 544)

Acetaminophen and other causes of liver failure

Naloxone hydrochloride (Narcan) (p. 614)

Opioids,

Norepinephrine (Levarterenol)

Hypotension (preferred antidepressants)

Octreotide (Sandostatin)

Oral hypoglycemic hypoglycemia

(p.

770)

Oxygen (oxygen, hyperbaric) (p. 1705)

clonidine

Carbon monoxide, hydrogen sulfide

for

cyclic

agent-induced

cyanide,

D-Penicillamine (Cuprimine) (p. 1303)

Copper,

Phenobarbital

Seizures, agitation, stimulants, ethanol and sedative-hypnotic withdrawal

Phentolamine

(p.

1140)

lead

MAOI interactions, cocaine, epinephrine, and ergot alkaloids

Physostigmine salicylate (Antilirium) (p. 794)

Anticholinergics

Polyethylene glycol electrolyte solution (p. 135)

Decontaminates

Pralidoxime chloride (2PAM-chloride) (Protopam) (p. 1513)

Acetylcholinesterase inhibitors (organic phosphorus agents and carbamates)

Protamine sulfate (p. 907)

Heparin

Prussian blue (Radiogardase) 1373)

Thallium and radioactive cesium

Pyridoxine hydrochloride B 6 ) (p. 872)

GI

tract

anticoagulation

(p.

(Vitamin

Ethylene glycol, isoniazid, gyromitrin-containing mushrooms

Sodium 565)

bicarbonate

(p.

Ethylene glycol, methanol, salicylates, cyclic antidepressant, methotrexate, phenobarbital, quinidine, chlorpropamide, type 1 antidysrhythmics, chlorphenoxy herbicide

Sorbitol (p. 135)

Induces

SSKI (p. 1816)

Radioactive

Starch (p. 1388)

Iodine

Succimer 1325)

Thiamine

(Chemet)

(p.

hydrochloride

Lead,

catharsis

iodine

mercury,

Thiamine

arsenic

deficiency,

ethylene

(p. 1162)

glycol, chronic ethanol consumption (“alcoholism―)

Vitamin K1 (Aquamephyton) 903)

Warfarin or rodenticide anticoagulant

a Each

(p.

emergency department should have all the above agents readily available to its staff. Some of these antidotes may be stored in the pharmacy, and others may be available from the Centers for Disease Control and Prevention, but the precise mechanism for locating each one must be known by each staff member. b A detailed analysis of each of these agents is found in the

text, in the Antidotes in Depth section on the page cited to the right of each therapeutic agent listed.

P.45 P.46 Patients with a suspected overdose or poisoning and an altered mental status present some of the most serious initial challenges. Conscious patients, asymptomatic patients, and pregnant patients with possible xenobiotics exposures raise additional management issues, as do the victims of toxic cutaneous or ophthalmic exposures. One of the most frequent toxicologic emergencies that clinicians must deal with is a patient with a suspected toxic exposure to an unidentified xenobiotic (medication or substance), sometimes referred to as an unknown overdose. Considering not only those patients who have an altered mental status but those who are suicidal, those who use illicit drugs, or those who are exposed to xenobiotics that they are unaware of, many toxicologic emergencies at least partly involve an unknown component.

Initial Management of a Patient with a Suspected Exposure Similar to the management of any seriously compromised patient, the clinical approach to the patient potentially exposed to a xenobiotic begins with the recognition and treatment of lifethreatening conditions: airway compromise, breathing difficulties, and circulatory problems such as hemodynamic instability and serious dysrhythmias. Once the “ABCs― (airway, breathing, and circulation) are addressed, the patient's level of consciousness should be assessed, as this helps determine the techniques to be used for further management of the exposure.

The Patient with an Altered Mental

Statu s After airway patency is established or secured and, when indicated, cervical spine trauma either excluded or the cervical spine protected, an initial bedside assessment should be made regarding the adequacy of respiration. If it is not possible to assess the depth and rate of respiration, then at least the presence or absence of regular breathing should be determined. In this setting, any irregular breathing pattern should be considered a possible sign of the incipient cessation of breathing requiring ventilation with 100% oxygen by bag-valve-mask followed, as soon as possible, by endotracheal intubation and mechanical ventilation. Endotracheal intubation may be indicated for some cases of coma resulting from a toxic exposure in order to insure and maintain control of the airway and to enable safe performance of procedures to prevent gastrointestinal absorption or eliminate previously absorbed xenobiotics. Although the widespread availability of pulse oximetry to determine O 2 saturation has in many instances made an ABG analysis less of an immediate priority, pulse oximetry has not eliminated the importance of ABG analysis entirely: an ABG determination will more accurately define the adequacy not only of oxygenation (PO2 , O2 saturation) and ventilation (PCO2 ), but may also alert the physician to possible toxicmetabolic etiologies of coma characterized by acid base disturbances (pH, PCO2 ) (Chap. 17). In addition, when clinically indicated, a carboxyhemoglobin determination is necessary to diagnose or exclude carbon monoxide poisoning (Chap. 120). In all cases, a bedside rapid reagent blood glucose determination should be obtained as soon as possible. After the patient's respiratory status is assessed and managed appropriately, the strength, rate, and regularity of the pulse should be evaluated, the blood pressure determined, and a rectal temperature obtained. Both a 12-lead ECG and continuous ECG monitoring are essential. Monitoring will alert the clinician to

dysrhythmias that are related to toxic exposures either directly, or indirectly via hypoxemia or electrolyte imbalance. A 12-lead ECG demonstrating QRS widening and a right axis deviation might indicate a life-threatening exposure to a cyclic antidepressant, an IA or IC antidysrhythmics, or another xenobiotic with sodium-channelblocking properties. In these cases, the physician can anticipate such serious sequelae as ventricular tachydysrhythmias, seizures, and cardiac arrest, and consider both the early use of specific treatment (antidotes), such as intravenous sodium bicarbonate, and avoiding medications, such as procainamide and other IA and IC antidysrhythmics, that could exacerbate the situation. Other ECG changes such as PR and QTc interval lengthening or shortening, baseline changes, and T- and U-wave abnormalities may point to cardioactive drug toxicity or serious electrolyte abnormalities (Chap. 5) . Extremes of core body temperature must be addressed early in the evaluation and treatment of a comatose patient. Life-threatening hyperthermia (temperature >105°F; >40.5°C) is usually appreciated when the patient is touched (although the widespread use of gloves as part of standard precautions has made this less apparent than previously). Most of these individuals, regardless of the etiology, should have their temperatures immediately reduced to about 101.5°F (38.7°C) by ice water immersion to prevent catastrophic complications or death (Chap. 16). Hypothermia is probably easier to miss than hyperthermia, especially in northern regions during winter months, when most arriving patients feel cold to the touch. Early recognition of hypothermia, however, helps to avoid administering a variety of medications that may be ineffective until the patient becomes relatively euthermic when iatrogenic drug toxicity may result. For the hypotensive patient with clear lungs and an unknown overdose, a fluid challenge with intravenous 0.9% sodium chloride or lactated Ringer solution may be started. If the patient remains hypotensive or cannot tolerate fluids, a vasopressor or an inotropic

agent may be indicated, as well as more invasive monitoring. At the time that the IV catheter is inserted, blood samples for glucose, electrolytes, BUN, a CBC, and any indicated toxicologic analysis can be drawn. If the patient has an altered mental status, there may be a temptation to send blood and urine specimens to identify any CNS depressants and/or so-called drugs of abuse, along with other medications, but the indiscriminate ordering of these tests rarely provides clinically useful information. For the potentially suicidal patient, an acetaminophen concentration should be routinely requested, along with tests affecting the management of any specific xenobiotic such as carbon monoxide, lithium, theophylline, iron, salicylates, and digoxin (or other cardioactive steroids), as suggested by history, physical examination, or bedside diagnostic tests. In the vast majority of cases, the blood tests that are most useful in diagnosing toxicologic emergencies are not the toxicologic assays but the “nontoxicologic― routine metabolic profile tests such as BUN, glucose, electrolytes, and ABGs or venous blood gases (VBGs). P.47 Xenobiotic-related seizures may broadly be divided into three categories: (a) those that respond to standard anticonvulsant treatment (typically a benzodiazepine); (b) those that either require specific antidotes to control seizure activity or that do not respond consistently to standard anticonvulsant treatment, such as isoniazidinduced seizures requiring pyridoxine administration; and (c) those that may appear to respond to initial treatment with cessation of tonic–clonic activity, but which leave the patient exposed to the underlying, unidentified toxin or to continued electrical seizure activity in the brain, such as carbon monoxide or hypoglycemia. Within the first 5 minutes of managing a patient with an altered mental status, 4 therapeutic agents should be considered, and if indicated, administered: (a) hypertonic dextrose 0.5–1.0 g/kg of D 50W for an adult, or a more dilute dextrose solution (D10W or D25W )

for a child. The dextrose is administered to diagnose and treat or exclude hypoglycemia; (b) thiamine 100 mg IV for an adult (usually unnecessary for a child) to prevent or treat Wernicke encephalopathy; (c) naloxone 0.05 mg IV for an adult or child with opioid (or clonidine)-induced respiratory compromise; and (d) highflow oxygen (8–10 L/min) to treat a variety of xenobiotic-induced hypoxic conditions. The clinician must consider that hypoglycemia may be the sole or contributing cause of coma even when the patient manifests focal neurologic findings and therefore dextrose administration should only be omitted when hypoglycemia can be definitely excluded by accurate rapid reagent bedside testing. Also, while examining a patient with an altered mental status (AMS) for clues to the etiology of a presumably toxic-metabolic form of AMS, it is important to search for any indication that trauma may have caused, contributed to, or resulted from the patient's condition. Conversely, the possibility of a concomitant drug ingestion or toxic metabolic disorder in the patient with obvious head trauma should also be considered. The remainder of the physical examination should be performed rapidly, but thoroughly. In addition to evaluating the patient's level of consciousness, the physician should note abnormal posturing (decorticate or decerebrate), abnormal or unilateral withdrawal responses, and pupil size and reactivity. Pinpoint pupils suggest exposure to opioids or organic phosphorus insecticides, and widely dilated pupils suggest anticholinergic or sympathomimetic poisoning. The presence or absence of nystagmus, abnormal reflexes, and any other focal neurologic findings may provide important clues to a structural cause of AMS. For those clinicians accustomed to applying the Glasgow Coma Score (GCS) to all patients with altered mental status, assigning a score to the overdosed or poisoned patient may provide a useful measure for assessing changes in neurologic status, but in this situation, the GCS should never be used for prognostic purposes, because complete recovery from properly managed toxicmetabolic coma despite a low GCS is the rule rather than the

exception. Characteristic breath or skin odors may identify the etiology of coma. The fruity odor of ketones on the breath suggests diabetic or alcoholic ketoacidosis, but also the possible ingestion of acetone or isopropyl alcohol, which is metabolized to acetone. The pungent, minty odor of oil of wintergreen on the breath or skin suggests methyl salicylate poisoning. The odors of other substances such as cyanide (“bitter almonds―), hydrogen sulfide (“rotten eggs―), and organic phosphorus compounds (“garlic―) are described in detail in Chap. 21 and summarized in Table 21-1.

Further Evaluation of all Patients with Suspected

Xenobiotic

Exposures

Reauscultation of breath sounds, particularly after a fluid challenge, helps to diagnose pulmonary edema, acute lung injury, or aspiration pneumonia when present. Coupled with an abnormal breath odor of hydrocarbons or organic phosphorus compounds, for example, crackles and rhonchi may point to a pulmonary etiology instead of a cardiac etiology; this is important because the administration of cardiac medications may be inappropriate or dangerous in these circumstances. Heart murmurs in an injection drug user, especially when accompanied by fever, may indicate bacterial endocarditis. Dysrhythmias may suggest overdoses or inappropriate use of cardioactive medications (such as digoxin and other cardioactive steroids, β-adrenergic antagonists, calcium channel blockers, and cyclic antidepressants). The abdominal examination may reveal signs of trauma or alcoholrelated hepatic disease. The presence or absence of bowel sounds helps to exclude or to diagnose anticholinergic toxicity and is important in considering whether to manipulate the gastrointestinal tract in an attempt to remove toxin.

Examination of the extremities might reveal clues to current or former drug use (track marks, skin-popping scars), metal poisoning (Mees lines, arsenical dermatitis), and the presence of cyanosis or edema suggesting preexisting cardiac, pulmonary, or renal disease. Repeated evaluation of the patient suspected of an overdose is essential for identifying new or developing findings or toxic syndromes, and for early identification and treatment of a deteriorating condition. Until the patient is completely recovered or considered no longer at risk for the consequences of a xenobiotic exposure, frequent reassessment must be provided, even as the procedures described below are carried out. Toxicologic etiologies of abnormal vital signs and physical findings are summarized in Tables 3-1, 3-2, 3-3, 3-4, 3-5, 3-6 and 3-7. Toxic syndromes, sometimes called “toxidromes,― are summarized in Table 3-2. Typically in the management of patients with toxicologic emergencies, there is both a necessity and an opportunity to obtain various diagnostic studies and ancillary tests interspersed with stabilizing the patient's condition, obtaining the history, and performing the physical examination exist. Chaps. 5, 6, and 7 discuss the timing and indications for qualitative and quantitative diagnostic laboratory studies, the use and interpretation of the electrocardiogram, and diagnostic imaging procedures and managing the poisoned or overdosed patient.

The

Role

for

Gastrointestinal

in

evaluating

Evacuation

A series of highly individualized treatment decisions must now be made. As noted previously and as discussed in detail in Chap. 8, the decision to evacuate the GI tract and/or administer AC can no longer be considered standard or routine toxicologic care for all patients. Instead, the decision should be based on the type of ingestion; estimated quantity and size; time since ingestion; concurrent ingestions; ancillary medical conditions; and age and size of the patient. The indications, contraindications, and procedures for

performing orogastric lavage and for administering WBI, AC, P.48 MDAC, and cathartics are listed in Tables 8-1, 8-2, 8-3 and 8-4 and discussed both in Chap. 8 and in the specific Antidotes in Depth sections immediately following Chap. 8.

Eliminating the Body

Absorbed

Xenobiotics

from

After deciding whether or not an intervention to try to prevent absorption of a xenobiotic is indicated, the clinician must next consider the applicability of techniques available to eliminate xenobiotics already absorbed. Detailed discussions of the indications for and techniques of manipulating urinary pH (ion trapping), diuresis, hemodialysis, hemoperfusion, hemofiltration, and exchange transfusion are found in Chap. 10. Briefly, patients who may benefit from these procedures are those who have systemically absorbed xenobiotics amenable to one of these techniques and whose clinical condition is both serious (or potentially serious) and unresponsive to supportive care, or whose physiologic route of elimination (liver–stools, kidney–urine) is impaired. Alkalinization of the urinary pH for acidic xenobiotics has only limited applicability. Commonly, sodium bicarbonate can be used to alkalinize the urine (as well as the blood) and enhance salicylate, phenobarbital, and chlorpropamide elimination and prevent toxicity from methotrexate (see Antidotes in Depth: Sodium Bicarbonate) . Attempts to acidify the urine in order to hasten the elimination of alkaline substances is difficult to accomplish, probably useless, possibly dangerous, and therefore has no role in poison management. Forced diuresis has no indication and may endanger the patient by causing pulmonary or cerebral edema. If extracorporeal elimination is contemplated, consider hemodialysis (HD) for salicylates, methanol, ethylene glycol, lithium, and drugs

that are both dialyzable and cause fluid and electrolyte problems. If available, consider hemoperfusion (HP) for theophylline, phenobarbital, phenytoin, and carbamazepine (though rarely, if ever, for the last three). When HP is the method of choice (as for a theophylline overdose) but not available, HD is a logical, effective alternative and certainly preferable to delaying treatment until HP becomes available. Peritoneal dialysis (PD) is too ineffective to be of practical utility, and hemofiltration (HF) is not as efficacious as HD or HP, although it may play a role between multiple runs of dialysis. In theory, both HD and HP in series may be useful for certain lifethreatening overdoses such as salicylates.

Avoiding

Pitfalls

The history alone is not a reliable indication of which patients require naloxone, hypertonic dextrose, thiamine, and oxygen. Instead, these therapies should be considered for all patients with altered mental status, unless specifically contraindicated. The physical examination should be used to guide the use of naloxone. If dextrose or naloxone is indicated, sufficient amounts should be administered to exclude and/or treat hypoglycemia or opioid toxicity, respectively. In a patient with a suspected or unknown overdose, avoid the use of vasopressors in the initial management of hypotension prior to administering fluids or assessing filling pressures. Attributing an altered mental status to alcohol because of its odor on a patient's breath is potentially dangerous and misleading: Small amounts of alcohol and its congeners generally produce the same breath odor as do intoxicating amounts. Conversely, even when an extremely high blood-ethanol concentration is confirmed by the laboratory, it is dangerous to ignore other possible etiologies of an altered mental status; chronic alcoholics may be awake and seemingly alert with ethanol concentrations in excess of 500 mg/dL, a concentration that would result in coma and possibly apnea and death in a nonalcoholic patient.

The metabolism of ethanol is fairly constant at 15–30 mg/dL/h. Therefore, as a general rule, regardless of the initial blood alcohol concentration, a presumably “inebriated― comatose patient who is still unarousable 3–4 hours after arrival should be considered to have structural CNS damage (head trauma) and/or another toxic-metabolic etiology for the alteration in consciousness, until proven otherwise. Careful neurologic evaluation supplemented by a head CT scan is frequently indicated in such a case. This is especially important in dealing with a seemingly “intoxicated― patient who appears to have only a minor bruise, as the early treatment of a subdural or epidural hematoma or subarachnoid hemorrhage is critical to a successful outcome.

Additional Considerations in Managing Patient with a Normal Mental Status

a

As in the case of the patient with AMS, vital signs must be obtained and recorded. Initially, an assumption may have been made that the patient was breathing adequately, and if the patient is alert, talking and in no respiratory distress, all that remains to document is the respiratory rate and rhythm. Because the patient is alert, additional history should be obtained, keeping in mind that information regarding the number and types of xenobiotics ingested, time elapsed, prior vomiting and other critical information may be unreliable, depending in part on whether the ingestion was intentional or unintentional. When indicated for the potential benefit of the patient, another history should be privately and independently obtained from a friend or relative after the patient has been initially stabilized. Recent emphasis on compliance with the federal Health Insurance Portability and Accountability Act (HIPAA) may inappropriately discourage clinicians from attempting to obtain information necessary to evaluate and treat patients. Obtaining such information from a friend or relative without unnecessarily giving that person information

about the patient may be the key to successfully helping such a patient without violating confidentiality. Speaking to a friend or relative of the patient may provide an opportunity to learn useful and reliable information regarding the ingestion, the patient's frame of mind, a history of previous ingestions, and the type of support that is available should the patient be discharged from the ED. At times, it may be essential to initially separate the patient from any relatives or friends in order to obtain greater cooperation from the patient, avoid violating confidentiality and also because their anxiety may interfere with therapy. Even if the history obtained from a patient with an overdose proves to be unreliable, it may nevertheless provide clues to an overlooked possibility or a second ingestant or reveal the patient's mental and emotional condition. As is often true of the history, physical examination, or laboratory assessment in other clinical situations, the information obtained may confirm but never exclude possible etiologies. P.49 At this point in the management of a conscious patient, a focused physical examination should be performed, concentrating on the pulmonary, cardiac and abdominal examinations. A neurologic survey should emphasize reflexes and/or any focal findings.

Approaching the Patient with an Intentional Exposure Initial efforts at establishing rapport with the patient by indicating to the patient concern about the problems that led to the ingestion and the availability of help after the xenobiotic is removed (if such procedures are planned), may help make management easier. If gastrointestinal decontamination is deemed necessary, the reason for and nature of the procedure should be clearly explained to the patient together with reassurance that after the procedure is

completed, there will be ample time to discuss related problems and provide additional care. These considerations are especially important in managing the patient with an intentional overdose who may be seeking psychiatric help or emotional support. In deciding on the necessity of gastrointestinal decontamination, it is important to consider that a resistant patient may transform a procedure of only potential value into one with predictable adverse consequences.

Special Considerations Pregnant Patient

for

Managing

the

In general, a successful outcome for both mother and fetus is dependent on optimum management of the mother and proven effective treatment for a potentially serious toxic exposure to the mother should never be withheld based on theoretical concerns regarding the fetus.

Physiologic

Factors

A pregnant woman's total blood volume and cardiac output are elevated through the second trimester and into the later stages of the third trimester. This means that signs of hypoperfusion and hypotension will manifest later than they would in a woman who is not pregnant and when they do, uterine blood flow may already be compromised. For these reasons, the possibility of hypotension in the pregnant woman must be more aggressively sought and, if found, more rapidly treated. Maintaining the patient in the left-lateral decubitus position will help prevent supine hypotension resulting from impairment of systemic venous return by compression of the inferior vena cava. The left lateral decubitus position is also the preferred position for orogastric lavage, deemed necessary. Because the tidal volume is increased in pregnancy, the baseline PCO2 will normally be lower by approximately 10 mm Hg. Appropriate adjustment for this effect should be made when interpreting arterial

blood gas results.

Use

of

Antidotes

Few data are available on the use of antidotes in pregnancy. In general, antidotes should not be used if the indications for use are equivocal. On the other hand, antidotes should not be withheld if their use may reduce potential morbidity and mortality. Risks and benefits of either decision must be considered. For example, reversal of opioid-induced respiratory depression calls for the use of naloxone, but in an opioid-dependent woman, the naloxone can precipitate acute withdrawal, including uterine contractions and possible induction of labor. Very slow, careful, intravenous titration starting with 0.05 mg naloxone may be indicated, unless apnea is present, cessation of breathing appears imminent, or the PO2 or O2 saturation is already grossly inadequate. In these instances, naloxone may have to be administered in higher doses (ie, 0.4–2.0 mg) or assisted ventilation provided or a combination of assisted ventilation and small doses of naloxone used. An acetaminophen overdose is a serious maternal problem when it occurs throughout pregnancy, but the fetus is at greatest risk in the third trimester. Although acetaminophen crosses the placenta easily, N-acetylcysteine has somewhat diminished transplacental passage. During the third trimester, when both the mother and the fetus may be at substantial risk from a significant acetaminophen overdose, immediate delivery of a mature or viable fetus may need to be considered. In contrast to the situation with acetaminophen, the fetal risk from iron poisoning is less than the maternal risk. Because deferoxamine is a large charged molecule with little transplacental transport, deferoxamine should never be withheld out of unwarranted concern for fetal toxicity when indicated to treat the mother. Carbon monoxide (CO) poisoning is particularly threatening to fetal

survival. The normal PO2 of the fetal blood is approximately 15–20 mm Hg. Oxygen delivery to fetal tissues is impaired by the presence of carboxyhemoglobin, which shifts the oxyhemoglobin dissociation curve to the left, potentially compromising an already tenuous balance. For this reason, hyperbaric oxygen (HBO) is recommended for much lower carboxyhemoglobin concentrations in the pregnant compared to the nonpregnant woman (Chap. 120 and Antidotes in Depth: Hyperbaric Oxygen). Early notification of the obstetrician and close cooperation among involved physicians are essential for best results in all of these instances.

Management Exposure

of

Patients

with

Cutaneous

The xenobiotics that people are commonly exposed to externally include household cleaning materials; organic phosphorus or carbamate insecticides from crop dusting, gardening, or pest extermination; acids from leaking or exploding batteries; alkalis, such as lye; and lacrimating agents that are used in crowd control. In all cases, the principles of management are as follows: Avoid secondary exposures by wearing protective (rubber or plastic) gowns, gloves, and shoe covers. Cases of serious secondary poisoning have occurred in emergency personnel after contact with xenobiotics such as organic phosphorus compounds on the victim's skin or clothing. Remove the patient's clothing and place it in plastic bags, then seal it. Wash the patient with soap and copious amounts of water twice, regardless of how much time has elapsed since the exposure. Make no attempt to neutralize an acid with a base, or a base with an acid. Further tissue damage may result from the heat generated by this reaction.

Avoid using any greases or creams as they will only keep the xenobiotic in close contact with the skin and ultimately make removal more difficult. Chap. 29 discusses the principles of managing cutaneous exposures. P.50

Management Ophthalmic

of Patients Exposures

with

Although the vast majority of toxicologic emergencies result from ingestion, injection, or inhalation, the eyes are occasionally the routes of systemic absorption or are the organs at risk. The eyes should be irrigated with lids fully retracted for no less than 20 minutes. To facilitate irrigation, a drop of an anesthetic (eg, proparacaine) in each eye may be used and the eyelids should be kept open with a lid retractor. An adequate irrigation stream may be obtained by running 1 L of normal saline through regular IV tubing held a few inches from the eye or by using an irrigating lens. Checking the lid fornices with pH paper strips is important to ensure adequate irrigation; the pH should normally be 6.5–7.6 if accurately tested, although when using paper test strips, the measurement will often be near 8.0. Chap. 20 describes the management of toxic ophthalmic exposures in more detail.

Identifying the Patient with a Nontoxic Exposure There is ample opportunity to needlessly subject a patient to potential harm when the patient with a nontoxic exposure is treated aggressively with gastrointestinal evacuation techniques and other forms of management indicated for serious exposures. More than 40% of exposures reported to poison centers annually are judged to be nontoxic. The following general guidelines for considering an

exposure nontoxic or minimally toxic will assist clinical decision making: Identification of the product and its ingredients is possible. None of the US Consumer Product Safety Commission “signal words―—CAUTION, WARNING, or DANGER—appear on the product label. The history permits the route(s) of exposure to be determined. The history permits a reliable approximation of the maximum quantity involved with the exposure. Based on the available medical literature and clinical experience, the potential effects related to the exposure are expected to be at most benign and self-limited, and do not require referral to health

care.

The patient is asymptomatic, or has developed the expected benign self-limited toxicity. (Adapted from McGuigan MA, Guideline Consensus Panel: Guideline for the out-of-hospital management of human exposures to minimally toxic substances. J Toxicol Clin Toxicol 2003;41:907–917; and Mofenson HC, Greensher J: The nontoxic ingestion. Pediatr Clin North Am 1970;17:583–590.)

Assuring Patient

Optimal

outcome

for

the

The best way to assure an optimal outcome for the patient with a suspected toxic exposure is to apply the principles of basic and advanced life support in conjunction with a planned and staged approach, always bearing in mind that a toxicologic etiology or coetiology for any abnormal conditions necessitates modifying whatever standard approach is brought to the bedside of a severely

ill patient. For example, it is extremely important to recognize that xenobiotic-induced dysrhythmias and cardiac instability require alterations in standard protocols that assume a primary cardiac or nontoxicologic etiology (Chap. 23) . Typically, only some of the xenobiotics to which a patient is exposed will ever be confirmed by laboratory analysis. The thoughtful combination of stabilization, general management principles, and specific treatment when indicated, will result in successful outcomes in the vast majority of patients with actual or suspected exposures.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part A - The General Approach to Medical Toxicology > Chapter 5 - Electrocardiographic Principles

Chapter 5 Electrocardiographic Cathleen

Principles

Clancy

The electrocardiogram (ECG) is ubiquitous in emergency departments and intensive care units and its interpretation is widely understood by physicians of nearly all disciplines. It is an invaluable diagnostic tool for patients with acute cardiovascular complaints. However, it is also a valuable source of information in poisoned patients and has the potential to enhance and direct their care. Although it seems obvious that an ECG would be required following exposure to a drug used for cardiovascular indications, many drugs with no overt cardiovascular effects with therapeutic dosing become cardiotoxic in overdose. In patients with unknown exposures, the ECG can suggest specific xenobiotics or demonstrate electrolyte abnormalities, long before blood is even drawn. For example, oropharyngeal or dermal burns in a patient whose ECG has evidence of hyperkalemia or hypocalcemia suggests exposure to hydrofluoric acid.47 , 48 Alternatively, a patient manifesting signs of the opioid toxidrome with runs of ventricular tachycardia might have been exposed to propoxyphene.25 QTc prolongation may be a clue to the etiology of an overdose with an atypical antipsychotic agent such as

quetiapine. The ECG can also be used to predict complications of poisoning, such as seizures following a tricyclic antidepressant overdose. Therefore, an ECG should be examined critically early in the initial evaluation of most poisoned patients.

History The knowledge of a relationship between electricity and muscular movement can be traced back to 1790, when Luigi Galvani electrically stimulated an ex vivo preparation of the legs of a frog, and made them “dance.― In 1887, Waller developed a “capillary electrometer― that transmitted electrical impulses from a man's skin to a capillary tube. Pulsations similar to the patient's heartbeat were visible in the tube.43 In the 1900s, Willem Einthoven graphically displayed the electrical activity of the heart and named the different waves—P, QRS, and T. He called this tracing an “elektrokardiogramme.― In 1924, he was awarded a Nobel Prize for his efforts. The acronym EKG , still employed by some authors, was derived from Einthoven's spelling. The acronym ECG , which is consistent with our current spelling of electrocardiogram, is used throughout this text. Since this initial description, both the normal electrophysiology of the heart and the pharmacologic effects of various xenobiotics on the ECG have been described. Despite the large number, diversity, and complexity of the various cardiac toxins, there are only a limited number of electrocardiographic manifestations.

Basic Electrophysiology Myocardial Cell

of

the

The resting myocardial cell, or myocyte, is negatively charged, or polarized. When the myocytes in the sinus node depolarize, ion channels in the nearby myocardium open and allow a net influx of positively charged sodium and calcium ions. This influx raises the

electrical potential of the cell toward and then past neutral and initiates an impulse that propagates throughout the myocardium, producing electrical and mechanical systole. The membrane depolarization is maintained by an outward potassium current and an inward calcium current throughout systole. After a well-defined time period the myocardial membrane is repolarized by a growing outward current of potassium and a reduction in the inward calcium current. Final repolarization requires the repartitioning of sodium out of the cell and potassium into the cell by an adenosine triphosphate (ATP)-using pump [ATPase] (Table 5-1 ). Figure 5-1 shows schematically the relationship of the major ion flux across the myocardial cell membrane, the phases of the action potential, and the surface ECG recording. Chap. 23 provides a more detailed description of ion fluxes and channels.

Basic

Electrophysiology

of

an

Electrocardiogram Simplistically, a positive or upward deflection on the oscilloscope is generated when an electrical force moves toward an electrical sensor or electrode, and a downward deflection occurs if the force moves away. An ECG represents the sum of movement of all electrical forces in the heart in relation to the surface electrode, and the height above baseline represents the magnitude of the force P.52 (Fig. 5-2 ). Only during depolarization or repolarization does the ECG tracing leave the isoelectric baseline, because it is only during these periods that measurable currents are flowing in the heart. During the other periods, mechanical effects are occurring in the myocardium, but large amounts of current are not flowing. Calcium Positive

Inward Inward Depolarization Sodium Positive Inward Inward Depolarization Potassium Positive Outward Outward Repolarization Chloride Negative Inward Outward Repolarization Reproduced, with permission, from Katz AM: Cardiac ion channels. N Engl J Med

Ion

Charge

Direction of Passive Flux

Current Generated

Effect of Membrane Potential

TABLE 5-1. Ions as Charge Carriers Across Cell Membranes

Figure 5-1. Relationship of electrolyte movement across the cell membrane to the action potential and the surface ECG recording.

Leads Although the reading from a single electrocardiogram lead provides an immense amount of information, to visualize the heart in a nearly three-dimensional perspective, multiple leads must be assessed simultaneously. Given the cylindrical nature of both the heart and thorax, at any given moment some of these leads will

record positive voltage and others negative. The lead placement that was described and refined in the early 1900s by Einthoven forms the basis for the bipolar or limb leads, described as I, II, and III (Fig. 5-3 ). The Einthoven triangle is an equilateral triangle formed by the sum of these leads. Unipolar limb leads and precordial leads were subsequently added to the standard electrocardiogram. Wilson and colleagues connected limb leads, called VR , VL , and VF , to a common point where the sum of the potentials from P.53 measured.44

leads I, II, and III was zero. A unipolar potential was The currently used, augmented (a) leads (aVR , aVL , and aVF ) are based on these unipolar leads (Fig. 5-4 ). 16 The precordial leads, called V1 through V6 , are also unipolar measurements of the change in electric potential measured from a central point to the 6 anterior and left lateral chest positions (Fig. 5-5 ). If V2 is placed over the right ventricle, part of the initial positive ventricular deflection (QRS complex) reflects right ventricular activation, with electrical forces moving toward the electrode. The majority of the subsequent terminal negative deflection reflects activation of other muscle tissue (septum, left ventricular wall) when the electrical forces are moving away from the electrode. Recordings from each of these 12 leads (I, II, III, aV R , aVL , aVF , V1–6 ) evaluate the heart from two different planes in 12 different positions, yielding a three-dimensional electrical “picture― of the heart, with respect to time and voltage.

Figure 5-2. A simplistic correlation between cardiac anatomy and electrocardiographic

representation.

Figure 5-3. The relationships of the original three limb leads are illustrated. The equiangular (60°) Einthoven triangle formed by leads I, II, and III is shown (dotted lines) with positive and negative poles of each of the leads indicated. Leads I, II, and III are also presented as a triaxial reference system that intersects in the center of the ventricles.

Figure 5-4. The hexaxial reference system derived from the Einthoven equilateral triangle defining the electrical potential vectors of electrocardiography.

Figure 5-5. Visualized as a cross-section, each of the chest leads is oriented through the atrioventricular (AV) node and exits through the patient's back, which is negative.

A continuous cardiac monitor usually relies on recordings from one of two bipolar leads: a modified left chest lead (MCL1 ) or a lead II. The recording from an MCL1 , in which the positive electrode is in the V1 position, is similar in appearance to a V1 recording on a 12-lead ECG. This lead visualizes ventricular activity well; however, lead II shows atrial activity (ie, the P wave) much more clearly.

The Various Intervals and Waves The ECG tracing has specific nomenclature to define the

characteristic patterns. Waves refer to positive or negative deflections from baseline, such as the P, T, or U wave. A segment is defined as the distance between two waves, such as the ST segment, and an interval measures the duration of a wave plus a segment, such as QT or PR interval. Complexes are a group of waves without intervals or segments between them (QRS). Electrophysiologically, the P wave and PR interval on the ECG tracing represent the depolarization of the atria. The QRS complex represents the depolarization of the ventricles. The plateau is depicted by the ST segment and repolarization is visualized as the T wave and the QT interval (QTc). The U wave, when present, generally represents an afterdepolarization (Fig. 5-6 ).

Figure 5-6. The normal ECG: P wave, atrial depolarization; QRS, ventricular depolarization; ST segment, T wave, QT interval, and U wave, ventricular repolarization. The U wave is the small, positive deflection following the T wave.

The P Wave The P wave is the initial deflection on the ECG that occurs with the initiation of a new cardiac cycle.

Electrophysiology The early, middle, and late portions of the P wave are represented sequentially by the electrical potential initiated by the sinus node. The impulse is propagated directly through the right atrial muscle, producing contraction. The impulse is also propagated by specialized conduction tissue across the interatrial septum, to produce contraction of the left atrium. Additionally, internodal pathways rapidly conduct the impulse to the atrioventricular (AV) node. The electrical excitation of the sinus node differs from that of the ventricular myocardium in that current is mediated primarily by calcium ion influx via slow T-type calcium channels, not by sodium entering through fast sodium channels. Furthermore, the vagus nerve exerts a profound suppressive influence on the nodal tissues.

The Abnormal P Wave Clinically, abnormalities of the P wave occur with xenobiotics that depress automaticity of the sinus node, causing sinus arrest and nodal or ventricular escape rhythms (β-adrenergic antagonists, calcium channel blockers). The P wave is absent in rhythms with sinus arrest, such as occurs with xenobiotics that produce vagotonia such as cardioactive steroids and cholinergic agents. A notched P wave suggests delayed conduction across the atrial septum and is characteristic of quinidine poisoning. P waves decrease in amplitude as hyperkalemia becomes more severe until they become indistinguishable from the baseline (Chap. 17 ).

The PR Interval The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex (normal is 120–200 milliseconds).

Electrophysiology Despite rapid conduction by specialized conduction tissue from the sinoatrial (SA) to the AV node, the AV node delays transmission of the impulse into the ventricles, ostensibly to allow for complete atrial emptying. Thus, the PR interval represents the interval between the onset of atrial depolarization and the onset of ventricular depolarization. Children usually have more rapid conduction and a shorter PR interval, and older adults generally have a longer PR interval. The segment between the end P.54 of the P wave and the beginning of the QRS complex (the PQ segment) reflects atrial contraction and is usually isoelectric. Atrial repolarization coincides with the Q wave, but its ECG findings, or atrial T waves, are obscured by the QRS complex.

The

Abnormal

PR

Interval

Xenobiotics that decrease interatrial or AV nodal conduction cause marked lengthening of the PR segment until such conduction completely ceases. At this point, the P wave no longer relates to the QRS complex; this is AV dissociation, or complete heart block. Some xenobiotics suppress AV nodal conduction by blocking calcium channels in nodal cells, as does magnesium, antagonizing at the β-adrenergic receptors, or enhancing vagal tone. Although the therapeutic use of digoxin, as well as early cardioactive steroid poisoning, causes PR prolongation through vagotonic effects, direct electrophysiologic effects account for the bradycardia of poisoning (see “Bradydysrhythmias ― section later in this chapter, as well as Chap. 62 and Antidotes in Depth: DigoxinSpecific Antibody Fragments [Fab] ).

The QRS Complex The QRS complex is the second and typically larger deflection on

the ECG. The normal QRS duration in adults varies between 60 and 120 msec. The normal range for the QRS axis in the frontal plane is between -30° and 90°, although most people will have values between 30° and 75°. This axis will vary with the weight and age of the patient. Alterations in myocardial function may also alter the electrical axis of the heart.

Electrophysiology The QRS complex reflects the electrical forces generated by ventricular depolarization mediated primarily by sodium influx into the myocardial cells. Although under normal conditions both ventricles depolarize nearly simultaneously, the greater mass of the left ventricle causes it to contribute the majority of the electrical forces. The QRS complex is primarily positive in leads I and aVL on the surface ECG recording because under normal conditions the depolarization vector is directed at 60° and is thus moving toward the positive electrodes in these leads. The simultaneous and rapid depolarization of the ventricles results in a very short period of electrical activity recorded on the electrocardiogram. Of course, mechanical systole lasts well past the end of the QRS complex and is maintained by continued depolarization during the plateau phase of the action potential. The return and maintenance of the baseline, or isoelectric potential, is simply a result of the fact that the entire heart is depolarized and there is no significant flow of current during this period.

Figure 5-7. ECG showing leads I, II, aVR , and aVL of a patient with a tricyclic antidepressant overdose. The prominent S wave in leads I and aVL and R wave in aVR demonstrate the terminal 40msec rightward axis shift.

The axis of the terminal 40 msec (0.04 seconds) of the QRS complex represents the late stages of ventricular depolarization and generally follows the direction of the overall axis. This axis is determined by examining the last box (0.04 seconds or 40 msec) of the QRS complex on the electrocardiogram paper.

The

Abnormal

QRS

Complex

In the presence of a bundle-branch block, the two ventricles depolarize sequentially rather than concurrently. Although, conceptually, conduction through either the left or right bundle may be affected, many xenobiotics preferentially affect the right bundle. This effect typically results in the left ventricle depolarizing slightly more rapidly than the right. The consequence on the ECG is both a widening of the QRS complex and the

appearance of the right ventricular electrical forces that were previously obscured by those of the left ventricle. These changes are a result of the effects of a xenobiotic that blocks fast sodium channels. Implicated xenobiotics include cyclic antidepressants, quinidine and other type IA and IC antidysrhythmic agents, phenothiazines, 3 amantadine, diphenhydramine,11 carbamazepine, and cocaine. In the setting of tricyclic antidepressant poisoning, this finding has both prognostic and therapeutic value (Chap. 71 ) .1 , 14 , 18 , 19 , 34 Specifically, in a prospective analysis of ECGs the maximal limb lead QRS duration was prognostic of seizures (0% if 500 ng/mL with >200 ng/mL of metabolite, amphetamine. Barbiturates 200 ng/mL secobarbital 2–4 d Phenobarbital may be detected for up to 4 weeks. Benzodiazepines

100–300

ng/mL

1–30 d Benzodiazepines vary in reactivity and potency. Hydrolysis of glucuronides increases sensitivity. False positives with oxaprozin. Cannabinoids 50 ng/mL; 20 ng/mL; 25 ng/mL; 100 ng/mL THCA 15 ng/mL THCA 1–3 d (>1 mo) Screening assays detect inactive and active cannabinoids; confirmatory assay detects inactive metabolite tetrahydrocannabinoic acid (THCA). Duration of positivity highly dependent on screening assay detection limits. Cocaine 300 ng/mL BZE 150 ng/mL BZE 2 d (1 wk) Screening and confirmatory assays (BZE). False positives unlikely. Opiates 2000 ng/mL;

detect

inactive

metabolite

benzoylecgonine

300 ng/mL 2000 ng/mL; morphine or codeine 1–2 d; 2–4 d (10 ng/mL of heroin metabolite 6-monoacetyl morphine is also confirmatory. Semisynthetic opiates derived from morphine show variable cross-reactivity. Fully synthetic opioids (eg, fentanyl, meperidine, methadone, propoxyphene, tramadol) have minimal cross-reactivity. Methadone 300 ng/mL

1–4 d Doxylamine may cross-react. Phencyclidine 25 ng/mL 25 ng/mL 4–7 d (>1 mo) Dextromethorphan and ketamine Propoxyphene 300 ng/mL

diphenhydramine

may

cross-react.

3–10 d Duration of positivity depends on cross-reactivity of metabolite norpropoxyphene. a Performance characteristics vary with manufacturer and may change over time. For most accurate information, consult the package insert of the current lot or contact the manufacturer. b SAMHSA recommendations7 are shown as first value for amphetamines, cannabinoids, cocaine, opiates, and phencyclidine immunoassays, and as only

values for confirmatory assays. Other commercial immunoassay cutoffs are also listed. Other GC/MS cutoffs are set by the laboratory. c Values are after typical use; values in parentheses are after heavy or prolonged use. Drug/Class

Detection Limitsb

Confirmation Limitsb

Detection Intervalc

Comments

TABLE 7-10. Performance Characteristics of Common Drug-Abuse Screening Immunoassays a The stigma attached to a positive test for an abused drug requires that special care be exercised in performing and reporting the tests. To protect citizens' rights, many states have legislated specific requirements for workplace drug screening. In some states, the requirements apply only to screening in the

workplace, exempting testing for medical purposes. Laws in other states might apply to all drug screening. Although they are not always legally required, some workplace drug-screening practices have been widely applied to all drug screening. The use of specific cutoff concentrations is nearly universal. Test results are considered positive only when the concentration of drugs in the specimen exceeds a predetermined threshold. This threshold should be set sufficiently high that false-positive results as a consequence of analytic variability or because cross-reactivity are extremely infrequent. They should also be low enough to consistently give a positive result in persons who are using drugs.

Cutoff concentrations used vary with the drug or drug class under investigation. In some drug-screening immunoassays, the laboratory has the option of selecting from several cutoff values. The use of cutoff values sometimes creates confusion when a patient who is known to have recently used a drug has a negative result reported on a drug screen. In such instances, the drug is usually present, but at a concentration below the cutoff value. Another potential problem occurs screening test is positive after previously having become usually interpreted as indicating renewed drug use, but it Urine drug concentrations are directly proportional to the

when a patient's drugnegative. This is may be an artifact. serum drug

concentrations, but inversely proportional to the rate of urine production. The rate of the urine flow may vary up to 100-fold, with a resulting possible 100fold change in the urine drug concentration. This effect is often exploited by individuals who drink large quantities of water prior to taking a urine drug test in order to increase urine flow and decrease urine drug concentrations. In contrast, a decrease in the rate of urine production can result in a positive test following a negative one, despite no new drug exposure. A similar effect may be produced by changes in urine pH. Drugs containing a basic nitrogen may demonstrate ionic trapping, with increasing concentrations as urine pH decreases. Similarly, excretion of the phenobarbital anion may increase with increasing pH. (This phenomenon is medically exploited by alkalinizing the urine to increase phenobarbital excretion.) P.105

Another widely used practice is the confirmation of positive screening results using an analytical methodology different from that used in the screen, such as an immunoassay screen followed by chromatographic confirmation. The possibility of simultaneous false-positive results by two distinct methods is quite low. Clinical laboratories may differ in their policies with regard to confirmatory testing. Some may confirm all positive results from screening immunoassays, whereas others may not provide any confirmatory testing unless it is explicitly requested. The most common confirmatory method is GC/MS. The high specificity afforded by the combination of the retention time and the mass spectrum makes falsepositive results extremely unlikely. GC/MS also has greater sensitivity than the screening immunoassays, minimizing failed confirmations because of drug concentrations below the sensitivity of the confirmatory assay. Some states require GC/MS confirmation for workplace drug screening and it may be legally required for all drug screening. If confirmation by GC/MS is not required, a common practice is to confirm

screening immunoassays by TLC and vice versa. Positive findings by both methods provide a high degree of specificity. A disadvantage of the approach is the low sensitivity of TLC relative to immunoassays. True positive immunoassays may fail to be confirmed, leading to false-negative final results.

Some laboratories accept this, because false negatives are unlikely in the presence of serious overdoses. Other laboratories may retest TLC-negative specimens with a more sensitive method, such as GC/MS. Sometimes, confirmatory testing may be done on positive results for illicit drugs, but not for legal drugs such as barbiturates, benzodiazepines, and ethanol. Immunoassay results can generally be obtained within 1 hour. Confirmatory testing usually requires at least several hours. This can create a problem when confirmation of initial immunoassay results is considered mandatory. Most laboratories will provide a verbal report of a presumptive positive result to facilitate medical management, but may not enter the result into a permanent record, such as the laboratory computer, until after confirmation has been completed. The importance of confirmatory testing in workplace drug screening follows

from the relatively low prevalence of positive results. A screening test with both sensitivity and specificity of 98% will produce 2 false-positive results per 100 subjects tested. A workforce with a 2% prevalence of illicit drug use will yield 2 true-positive results per 100 subjects. The predictive value of a positive test will only be 50% (2 of 4). This is an unacceptable level of certainty for results that might be used to terminate employment. While the prevalence of recent drug use in the workforce is low, rates of positivity of 34–86% have been reported for selective drug screening of emergency department populations. Given a 50% prevalence of recent drug use, the positive predictive value of same screening test rises to 98% (see Table 7-6 ). A high results testing finding

prior probability of drug positivity for patients tested in medical settings in a very high posterior probability after a positive test. Confirmatory is much less critical in such a setting, particularly because a positive infrequently has consequences that extend beyond the medical

management of the patient. An exception may occur where results of testing performed on motor vehicle crash victims can be subsequently subpoenaed as evidence in legal proceedings. One workplace drug screening practice that is not widely followed in medical toxicology is maintenance of a chain of custody. Employers generally insist on chain of custody for workplace testing because actions taken in response to a positive result may be contested in court. A chain of custody provides results that are readily defended in court. Laboratories providing testing for medical purposes rarely keep a chain of custody because it is quite expensive and does not benefit the patient. Additionally, the medical personnel responsible for obtaining the specimens are rarely trained in collection requirements for a chain of custody.

The lack of chain of custody can create problems when persons with no medical complaints present at an emergency department or other medical facility requesting the performance of a drug-screening test. Unless the facility is prepared to initiate the chain of custody at the time of specimen collection and the laboratory is prepared to maintain it, such persons should be redirected to a site maintained by a commercial laboratory that routinely performs workplace drug testing and has appropriate procedures in place. Many laboratories have

had the experience of unwittingly performing drug-abuse testing for nonmedical purposes, because the reason for the testing is not always included on the test requisition. To avoid liability issues, the laboratory may choose to include a disclaimer with every drug-screening report indicating that the results are for purposes of medical management only. Another practice common in workplace testing but rare in medical laboratories is testing for specimen validity. It is common for individuals to try to “beat― a workplace drug test through a variety of means, including diluting the specimen (either physiologically by water ingestion or by direct addition of water to the specimen), substituting “clean― urine obtained from another individual, or adding various substances that will either destroy drugs in the specimen or will inactivate the enzymes and/or antibodies used in the screening immunoassays. Such substances include acids, bases, oxidizing agents (bleach, nitrite, peroxide, peroxidase, iodine, chromate),

glutaraldehyde, pyridine, detergents, and soap. SAMHSA requires validity testing for all specimens in federal workplace testing, including measurement of urinary pH, specific gravity, and creatinine concentration, as well as tests for the presence of adulterants.7 Dipsticks are available that detect the most common adulterants. However, manipulation or adulteration is rarely a problem in medical specimens, and clinical laboratories infrequently provide validity testing.

Performance Characteristics Screening Assays

of

Common

Drug-

Medical toxicologists, toxicology laboratory directors, and practicing physicians may frequently get questions about the significance of drug-screening assays, particularly about the causes of false-positive results. Often these questions come from an individual who recently had a positive test. Table 7-10 summarizes drug-screening test performance characteristics, which are discussed in more detail below. Immunoassays for opiates are directed toward morphine but have good crossreactivity with many (but not all) structurally similar natural and semisynthetic

opiates. The extent of cross-reactivity may vary between manufacturers. For example, oxycodone exhibits approximately 30% cross-reactivity relative to morphine in a fluorescence polarization immunoassay, but less than 5% crossreactivity in a number of other screening assays.19 A failure to appreciate the poor detection of oxycodone can create problems when opiate-screening immunoassays are used to confirm that patients receiving prescription oxycodone for chronic pain are indeed

P.106 taking it, rather than diverting it for illicit sale. If a low cross-reactivity assay is used, a patient taking oxycodone as prescribed might have a negative result, whereas another patient who was selling the oxycodone and using the proceeds to buy heroin would have a positive result. To address this problem, a new assay specific for oxycodone has been introduced. This assay is sensitive to therapeutic amounts of oxycodone, but relatively insensitive to other opiates. Synthetic

opioids

such

as

dextromethorphan,

fentanyl,

meperidine,

methadone,

propoxyphene, and tramadol show little or no cross-reactivity in opiate immunoassays. Urine immunoassays specific for methadone and propoxyphene are available. Given the increasing importance of buprenorphine in maintenance therapy for opiate dependency, it is worth noting that the combination of high

potency and low cross-reactivity means that buprenorphine will generally not be detected by opiate immunoassays. A positive immunoassay result may reflect multiple contributions from various opiates and opiate metabolites. Concentrations of morphine glucuronide in the urine may be up to 10-fold higher than the concentrations of unchanged morphine and can contribute substantially to positive results. A positive opiate result following use of heroin (diacetylmorphine) is primarily a result of the morphine and morphine glucuronide that result from heroin metabolism. Distinguishing heroin from other opiates requires detection of 6monoacetylmorphine, the heroin-specific metabolite. Small amounts of the metabolite may be detected by GC/MS for up to 24 hours after use. A half-life of 5 minutes means that unchanged heroin can only be found in the urine if sampling is done immediately after use. The duration of positivity of an opiate immunoassay after last use depends on

the identity and amount of the opiate used, the specific immunoassay, the cutoff value, and the pharmacokinetics of the individual. Currently, SAMHSA recommends a cutoff equivalent to 2000 ng/mL of morphine for workplace screening, because poppy seeds can rarely produce transient positive results with the previously recommended cutoff of 300 ng/mL. Most toxicology laboratories continue to use a 300 ng/mL cutoff. Drug-screening assays for “cocaine― are actually assays for the inactive cocaine metabolite benzoylecgonine, which is eliminated more slowly than cocaine. This extends the duration of positivity after last use from a few hours to 2 days, and sometimes to a week or longer after prolonged heavy use.

Because the assay is directed toward an inactive metabolite, positive results do not equate with intoxication but merely indicate recent exposure. The assay is highly specific for benzoylecgonine, and false-positive results are extremely uncommon. Immunoassays for cannabinoids are also directed toward an inactive metabolite, in this case tetrahydrocannabinoic acid. These immunoassays

exhibit cross-reactivity with other cannabinoids, but little else. Because cannabinoids are structurally unique and occur only in plants of the genus Cannabis , false positives are quite uncommon. It is unusual, although possible, to become exposed to sufficient “second-hand― or sidestream marijuana

smoke to develop a positive urine test.5 Legal hemp products include fiber, oil, and seedcake derived from Cannabis varieties with low levels of cannabinoids. Although hemp food products contain insufficient amounts of tetrahydrocannabinol to produce psychoactive effects, their ingestion may raise urinary cannabinoid concentrations above screening thresholds.6

Interpretation of a positive result for cannabinoids can be problematic. Urine may be positive for up to 3 days after occasional recreational use. However, with heavy or prolonged use, there may be significant accumulation of cannabinoids in adipose tissue. These stored cannabinoids are slowly released into the bloodstream and can produce positive findings for a month or more. Consequently, little can be concluded from a positive finding in terms of current intoxication. Because positive results in the absence of intoxication are very common, and because tetrahydrocannabinol rarely is responsible for serious

acute toxicity, NACB guidelines recommend against its routine inclusion in drug screening for patients with acute symptoms.35

Amphetamine-screening tests have the greatest problems with false-positive results. A number of structurally related compounds may have significant crossreactivity, including nonprescription decongestants such as pseudoephedrine, as well as L-ephedrine, which is found in a variety of herbal preparations. This cross-reactivity is beneficial from the point of view of the medical toxicologist, because all of these compounds may produce serious stimulant toxicity. But it is problematic in drug-abuse screening because of the widespread legitimate use of cold medications. Assays with greater selectivity for amphetamine and/o methamphetamine have been developed. Although these assays produce fewer false-positive results caused by decongestant cross-reactivity, they are also less sensitive for the detection of other abused amphetamine-like compounds, including methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA, Ecstasy), and phentermine. Crossreactivity patterns vary from assay to assay.19 Manufacturer's literature should be consulted for specific details.

Testing for benzodiazepines is complicated by the wide array of benzodiazepines that differ substantially in their potency, cross-reactivity, and half-lives. There are also substantial differences in the detection patterns of the various immunoassays.19 This heterogeneity complicates the interpretation of benzodiazepine-screening assays. Screening results may be positive in persons using low therapeutic doses of diazepam, but negative after an overdose of a highly potent benzodiazepine such as clonazepam. To improve breadth of detection, some assays employ antibodies to oxazepam, which is a metabolite of a number of different benzodiazepines. These assays may have poor sensitivity to benzodiazepines that are not metabolized to oxazepam. Falsenegative results may occur for benzodiazepines that are excreted in the urine almost entirely as glucuronides that have poor cross-reactivity with antibodies directed toward an unmodified benzodiazepine. This is one reason for the poor detectability of lorazepam in some screening assays. The latter situation has led to the recommendation that specimens be treated with β-glucuronidase prior to analysis.22 Some assays now include β-glucuronidase in the reagent mixture, or employ antibodies directed toward glucuronidated metabolites. The

frequency of false negative results, as well as the fact that benzodiazepines are relatively benign in overdose, have led the NACB guidelines to withhold recommendation for routine screening of urine for benzodiazepines until these problems with the immunoassays are addressed.35 Barbiturates are comparable to benzodiazepines in heterogeneity of potency, cross-reactivity, and half-lives, although the differences are less substantial. Specific assays for serum phenobarbital can often help to clarify the significance of a positive barbiturate screen. Some phencyclidine (PCP) screening assays may give positive results with dextromethorphan, ketamine or diphenhydramine, but only when these are used in amounts well above usual therapeutic quantities. A positive result may serve as a clue to a possible overdose with either of these substances. P.107

Measurement

of

Ethanol

Concentrations

Measuring ethanol may have ramifications beyond guiding medical management, particularly when performed on crash victims. Although testing for ethanol in urine is common in workplace drug screening, most testing in clinical laboratories is done using serum or plasma. Concentrations are most commonly measured enzymatically using alcohol dehydrogenase. In larger

toxicology laboratories, ethanol measurements are often done using a GC assay that can also distinguish and measure isopropanol and methanol, as well as the isopropanol metabolite acetone. Alcohols with lower volatility, including ethylene and propylene glycol, are usually not detected by this assay. Because both enzymatic and chromatographic assays have substantial specificity for ethanol, confirmatory testing with a second method is uncommon.

Breath alcohol analyzers may also be employed in assessing ethanol intoxication, as may point-of-care devices that measure salivary ethanol. These measurements are less precise than laboratory assays16 , 30 and more subject to interference by other alcohols and other organic solvents. Breath-alcohol analyzers require good cooperation from the patient to obtain an appropriate breath sample and are typically calibrated to give results approximating whole-

blood alcohol concentrations. For the above reasons, confirmation of positive findings with a laboratory measurement may sometimes be desirable.

Blood alcohol concentrations used legally to define driving under the influence have no particular clinical significance, but may have risk management implications for patient discharge. Legal standards are written in terms of whole-blood alcohol concentrations, whereas clinical laboratories usually measure alcohol in serum or plasma. Serum and plasma alcohol concentrations are essentially identical, but both will be higher than the alcohol concentration measured in a whole-blood specimen obtained at the same time. This is a result of the lower concentration of alcohol in the red blood cells. The ratio of serum alcohol to whole-blood alcohol varies from individual to individual, with a median value of 1.15.28 It is more likely than not that an individual with a serum alcohol concentration of less than 115 mg/dL will have a whole-blood alcohol concentration of less than 100 mg/dL (10 g of acetaminophen by history and had received activated charcoal were significantly less likely to have a concentration of acetaminophen requiring antidotal therapy when compared to patients who received no decontamination. However, orogastric lavage in addition to activated charcoal did not further decrease that risk.20 Thus, the combination of orogastric lavage followed by activated charcoal only seems appropriate in cases where orogastric lavage is indicated and the xenobiotic is adsorbed to activated charcoal. In cases where activated charcoal alone is usually beneficial, there is little rationale to expose the patient to the additional risks of orogastric lavage. Although acetaminophen is a reasonable drug to study, the universal availability of a benign and inexpensive antidote contraindicates aggressive gastric emptying in acetaminophen overdose even if some benefit could be demonstrated. The combination of activated charcoal and whole-bowel irrigation would seem to make sense in that it might speed up gastrointestinal passage and at the same time have the protective adsorptive effect of activated charcoal. However, based on the studies cited previously, it seems that if activated charcoal is administered with WBI, the adsorptive capacity of activated charcoal is reduced, and the recommendation is to administer the activated charcoal prior to the administration of PEG-ELS. There is concern about the practice of treating asymptomatic cocaine bodypackers with WBI combined with activated charcoal because severe peritonitis can result if activated charcoal spills into the peritoneum following surgical intervention. The administration of activated charcoal is not expected to prevent routine surgery and because the use of activated charcoal may increase the risk of

surgical complications, activated charcoal should not be used under these circumstances.

General

Aspects

Only a few gastrointestinal decontamination studies provide guidance based on meaningful clinical end points. One of the few studies addressing meaningful clinical parameters was a retrospective analysis reviewing the management of all patients presenting to an emergency department with a diagnosis of deliberate self-poisoning.52 The study evaluated 561 patients who were treated in 1999, comparing them with patients treated in 1989, 1992, and 1996.52 The authors found that despite dramatically changing trends of gastrointestinal decontamination, there were no significant admitted to the hospital, rate of admission to the change significantly over

changes in the proportion of patients although there was a reduction in the ICU. The patient populations did not the years with regard to the female-to-

male ratio, the age distribution, and the types of xenobiotics ingested. The authors mention that there might be unmeasured differences between the populations and unrecognized differences in practice that might have been influential. However, in 1989 most of the patients were treated with orogastric lavage, almost no patients received activated charcoal, and approximately 33% did not receive any gastric decontamination at all. In comparison, in 1996, more than 50% of patients received activated charcoal alone and less than 25% had no gastrointestinal decontamination at all. In 1999, only 13% of patients received activated charcoal, 0.7% a combination of orogastric lavage followed by activated charcoal, 0.5% were given WBI, and nearly 86% received no decontamination at all. There were no changes in overall mortality from poisonings over the years, although the mortality was generally very low. Thus, although the trends in gastrointestinal decontamination dramatically shifted toward less intervention over the years studied, there was no measurable worsening in outcome

when large groups of patients were studied. It must be emphasized that this was a retrospective analysis with fairly nonspecific outcome measures, and possible improvements in other aspects of clinical treatment of poisoned patients were not considered. The trends in practice noted in the study above are reflective of the overall combined philosophy of the position statements, which are applicable to the vast majority of poisoned patients. They highlight the benign nature of many exposures and the benefits of good supportive care. In contrast, the previously mentioned survey of recommendations for a theoretical patient with a serious enteric-coated aspirin overdose reveal less consensus in that 36 different courses of action were proposed for the same case. Most of the poison centers and toxicologists did, however, recommend at least one dose of activated charcoal.63 This distinction serves as a reminder that the existing studies and consensus statements cannot be applied to all cases, and that a lack of data produce significant uncertainty in choices for gastrointestinal decontamination in either atypical or severely poisoned patients.58 It is essential to note that only one study has ever demonstrated a survival advantage for any form of gastrointestinal decontamination of poisoned patients.37 Its unique design, involving a cohort of patients with life-threatening toxicity, forces a reassessment of all previous literature and confirms that the principles of decontamination are sound. It also suggests that the failure of most studies to demonstrate a benefit results not from a failure of the techniques employed, but from applying decontamination techniques to subsets of patients who were likely to have good outcomes regardless of intervention.

Summary The approach to gastrointestinal decontamination needs to be more individualized than previously thought. No decontamination

method is completely free of risks. The indications for when and when not to perform gastrointestinal decontamination must be well defined for each patient and the method of choice must depend P.120 largely on what was ingested, how much was ingested, and when it was ingested. The absolute time frame for when decontamination is indicated is dependent on many factors, such as rate of gastric emptying, rate of xenobiotic absorption, and the possibility of enterohepatic cycling. The commonly stated short time frame of up to 1 hour postingestion for intervention is most likely an underestimation of the time frame during which a benefit is likely to be realized, although this has not yet been adequately investigated. Judging from the evidence available today, activated charcoal must be the first choice, only accompanied by orogastric lavage when the desirable ratio of activated charcoal-to-xenobiotic cannot be achieved, and the xenobiotic is still thought to be accessible in the stomach. Orogastric lavage as a single intervention is reserved for those cases where the ingested xenobiotic is not adsorbed by activated charcoal and there is reason to believe that the ingested xenobiotic is both life-threatening and still in the stomach. Syrup of ipecac-induced emesis has a very small therapeutic role, but might be reserved for those situations where there is an absolute need for gastrointestinal decontamination, activated charcoal is not expected to be effective, and orogastric lavage and whole bowel irrigation are, for practical purposes, impossible. Multipledose activated charcoal and whole-bowel irrigation have defined indications, which may broaden in the future as more studies focus on subsets of significantly poisoned patients. The advancement of medical toxicology is dependent on welldesigned clinical studies that concentrate on measuring the effect of gastrointestinal decontamination using sound and relevant clinical end points. For each approach it must be determined if the benefits of decontamination outweigh the potential risks. If proven

beneficial, we need to set firm criteria for the future selection of patients for whom these treatments are beneficial and therefore indicated. One goal must be to reduce complications by identifying those patients who can be safely managed without decontamination. At the same time, we must be ever vigilant for patients with ingestions of unstudied highly lethal xenobiotics and massive amounts of studied xenobiotics, as well as those who present early in their clinical course with life-threatening signs and symptoms. This uncommon subset is most likely to benefit from more aggressive gastrointestinal decontamination. Thus it is recommended that some form of gastrointestinal decontamination be considered in every patient with potentially life-threatening toxicity regardless of the time since ingestion, as long as no absolute contraindications exist.

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105. Pond SM, Lewis-Driver DJ, Williams GM, et al: Gastric emptying in acute overdose: A prospective randomised controlled trial. Med J Aust 1995;163:345–349. 106. Position paper: Ipecac syrup. J Toxicol Clin Toxicol 2004;42: 133–143. 107. Position paper: Whole bowel irrigation. J Toxicol Clin Toxicol 2004; 42:843–854. 108. Rangan C, Nordt SP, Hamilton R, et al: Treatment of acetaminophen ingestion with a superactivated charcoal-cola mixture. Ann Emerg Med 2001;37:55–58. 109. Roivas L, Neuvonen PJ: Drug adsorption onto activated charcoal as a means of formulation. Methods Find Exp Clin Pharmacol

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during the first hour after drug ingestion in human volunteers. J Toxicol Clin Toxicol 1997;35:609–615. 114. Satar S, Toprak N, Gokel Y, Sebe A: Intoxication with 100 grams of mercury: A case report and importance of supportive therapy. Eur J Emerg Med 2001;8:245–248. 115. Sato RL, Wong JJ, Sumida SM, et al: Efficacy of superactivated charcoal administered late (3 hours) after acetaminophen overdose. Am J Emerg Med 2003;21:189–191. 116. Schaper A, Hofmann R, Ebbecke M, et al: Cocaine-bodypacking. infrequent indication for laparotomy. Chirurg 2003;74:626–631. 117. Sellers EM, Khouw V, Dolman L: Comparative drug adsorption by activated charcoal. J Pharm Sci 1977;66:1640–1641. 118. Sherman A, Zingler BM: Successful endoscopic retrieval of a cocaine packet from the stomach. Gastrointest Endosc 1990;36:

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136. Yamashita M, Yamashita M, Azuma J: Urinary excretion of ipecac alkaloids in human volunteers. Vet Hum Toxicol 2002;44:257–259. 137. Yancy RE, O'Barr TP, Corby DG: In vitro and in vivo evaluation of the effect of cherry flavoring on the adsorptive capacity of activated charcoal for salicylic acid. Vet Hum Toxicol 1977;19:163–165. 138. Yeates PJ, Thomas SH: Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose. Br J Clin Pharmacol 2000;49:11–14.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part A - The General Approach to Medical Toxicology > Antidotes in Depth - Syrup of Ipecac

Antidotes in Depth Syrup of Ipecac Mary Ann Howland

Emetine

The role of syrup of ipecac has changed dramatically in the last decade. Once the mainstay of poison management for children and adults, a critical evaluation of animal, volunteer, and a limited number of clinical studies suggests that ipecac administration

should be reserved for a few selected circumstances rather than administered on a routine basis.3 The rationale for this change is based on the facts that (a) most poisonings in children are benign; (b) many adults overdose with xenobiotics that rapidly cause an altered mental status which constitutes a contraindication to the administration of ipecac; (c) ipecac-induced vomiting may be delayed and/or persistent, thereby resulting in a delay in the administration of activated charcoal. Syrup of ipecac is an emetic that has been used for the management of poisonings since the 1950s and has been available without prescription since the late 1960s. Pediatricians were encouraged to advise parents to keep syrup of ipecac in their homes. Many pediatricians currently believe that there is no role for syrup of ipecac in the prehospital or hospital setting and that the abuse of syrup of ipecac by patients with bulimia outweighs any benefit originating from keeping syrup of ipecac as a nonprescription drug. The FDA is reviewing whether to make syrup of ipecac available only by prescription. Advocates for maintaining the nonprescription status of syrup of ipecac support home stocking of ipecac for use in remote areas and limiting use in healthcare facilities to those rare instances when activated charcoal, orogastric lavage, or whole-bowel irrigation with polyethylene glycol lavage solution may be inappropriate or inadequate. Changing the availability of syrup of ipecac to prescription status only, could result in the complete disappearance of syrup of ipecac from the pharmaceutical market if the FDA required a new drug application. Under these circumstances it might not be profitable for any drug company to invest in a new drug application.

Composition Ipecac is derived from the dried rhizome and roots of plants found in Brazil belonging to the family Rubiaceae, such as Cephaelis

acuminata or Cephaelis ipecacuanha. 51 Ipecacuanha originates from the plant's Portuguese name “ipecaaguen― which translates to “smaller roadside sick-making plant.―52 Cephaeline and emetine are the two alkaloids largely responsible for the production of nausea and vomiting, with cephaeline being the more potent.28 Each 15-mL dose of syrup of ipecac contains 16–21 mg of cephaeline and 6.4–21 mg of emetine, resulting in variable cephaeline-to-emetine ratios. Syrup of ipecac also contains a small amount of psychotrine, which does not contribute to emesis but is currently under investigation for its potential antiHIV effects.

Pharmacokinetics

of

Ipecac

Alkaloids

After human volunteers were administered 20 or 30 mL of syrup of ipecac, plasma, vomitus and urine concentrations of emetine and cephaeline were determined by the use of high-performance liquid chromatography (HPLC).56 Peak plasma levels of the alkaloids were reached by 1 hour and were undetectable at 6 hours. Only 2% of the total amount of alkaloids in the ipecac were excreted in the urine within 48 hours, and remained detectable in the urine for 2 weeks in all 12 volunteers and for 12 weeks in 1 of 2 subjects who were tested subsequently.

Mechanism

of

Action

Syrup of ipecac induces vomiting by local activation of peripheral emetic sensory receptors in the proximal small intestine, and by central stimulation of the chemoreceptor trigger zone that serves as a sensory area resulting in subsequent activation of the central vomiting center.47 5HT3 receptors mediate the nausea and vomiting produced by syrup of ipecac by both mechanisms. This was demonstrated in 40 volunteers by administering a specific 5HT3 antagonist 30 minutes prior to administration of the syrup of ipecac; the 5HT 3 antagonist prevented or attenuated the nausea

and vomiting in a dose-dependent fashion.18 In fact, syrup of ipecac is used to assess the efficacy of new 5HT3 antagonists and other antiemetics.13,45

Time to onset of Vomiting and Number of Vomiting Episodes In one of the earliest studies evaluating the delay in onset to vomiting after syrup of ipecac administration, 88% of 214 children who were given 20 mL of syrup of ipecac and copious amounts of water vomited within 30 minutes (mean of 18.7 minutes).40 Adverse events secondary to syrup of ipecac were not noted. Subsequent studies demonstrate findings.6,12,14,16,20,27,29,49,50

similar

The onset of emesis following syrup of ipecac administration does not appear to be affected by fluid administration before or after syrup of ipecac, by the temperature of the fluids, or by gentle patient motion or walking.16,17,20,46 Consequently, it is inadvisable to force fluids and safer to maintain the patient in an P.125 appropriate stationary setting (chair or stretcher). Milk should not be given with the syrup of ipecac, as the onset of emesis may be delayed, although the success of inducing vomiting does not appear to be affected.17 This delay is consistent with the ability of milk to delay gastric emptying and thereby retard ipecac's contact with the peripheral emetic sensory receptors.53 Because when followed by water, syrup of ipecac is absorbed so quickly, vomiting still occurred in the majority of overdose patients who were also given activated charcoal 10 minutes after the syrup of ipecac.19 The average number of episodes of vomiting following syrup of ipecac administration is 3, with a range of 1 to 8.27 The duration of syrup of ipecac-induced vomiting averaged 23–60 minutes.27,39 Although some investigators suggested durations

lasting up to 3–4 hours,35 it is probably reasonable to assume that vomiting that persists for more than 2 hours is unrelated to syrup of ipecac and another cause should be sought. This warning is of particular importance when syrup of ipecac is used in the home.

Volunteer

Studies

Many studies have assessed the effectiveness of syrup of ipecacinduced emesis in decreasing absorption of a xenobiotic, and then compared the results to other methods of gastric decontamination, such as gastric lavage or activated charcoal.35,37,43 These same studies support the concept that the sooner syrup of ipecac is administered after ingestion, the greater the amount of the ingested xenobiotic that will be recovered. The decrease in the amount of xenobiotic absorbed varies from study to study as a result of differences in study design, including time to initiation of the various techniques and the particular xenobiotic used to assess efficacy. Volunteer studies using small lavage tubes were further limited because of the quantity of xenobiotic that was administered and the limited potential of the tube to recover xenobiotic. In a small, well-quantified study, when 6 adult volunteers were given 20 mL of syrup of ipecac at 5 or after acetaminophen ingestion, absorption was inhibited and 0%, respectively.37 In this same volunteer model, was inhibited by 80% and 40% when 50 g of activated was given at 5 and 30 minutes postingestion.36

30 minutes by 65% absorption charcoal

A subsequent investigation demonstrated that the reduction in the area under the plasma drug concentration versus time curve was equivalent for patients treated with syrup of ipecac-induced emesis and patients treated with activated charcoal plus a cathartic. Comparison of orogastric lavage, syrup of ipecacinduced emesis, and activated charcoal, all given at 60 minutes after ingestion of ampicillin by adult volunteers, showed reductions

of 32%, 38%, and 57%, respectively.50 Adult volunteers given syrup of ipecac 5 minutes after 30 capsules containing a radionucleotide marker demonstrated a mean 54% removal (range, 21–89%) as compared to a mean removal of 35.5% (range, 1–71%) with orogastric lavage.57 Other researchers demonstrated recoveries from 0% to 85%.6,14,15,49 Children given a magnesium hydroxide marker before administration of syrup of ipecac demonstrated a mean recovery of 28%, although the range was 0–78%.14

Overdosed

Patients

In a study of self-poisoned adults randomized to receive either syrup of ipecac or orogastric lavage with a 33-French lavage tube, all patients had subsequent gastric endoscopy.42 Thirteen patients were given syrup of ipecac and vomited within 23 minutes (range, 11–25 minutes). Two of these patients had tablets in the vomitus. On endoscopy, only those 2 patients had residual tablets in the in the at the tablets

stomach. Ten of 17 patients who were lavaged had tablets lavage fluid. All of these patients had tablets in the stomach time of endoscopy. Two additional patients also had residual in the stomach. This study suggests that the presence of

tablets in the vomitus or lavage fluid supports the presence of additional tablets in the stomach.42 This same group of investigators subsequently used bariummarked 3 mm3 pellets to evaluate the effectiveness of gastric emptying.43 Forty self-poisoned patients were given 20 pellets on admission and randomized immediately to therapy with either orogastric lavage or syrup of ipecac-induced emesis. Approximately 45% of the pellets were removed in both the orogastric lavage and the syrup of ipecac groups. Two patients in the lavage group and 1 in the syrup of ipecac group had 100% removal of pellets, and 2 patients in the lavage group had no removal.43

Outcome

Studies

A large emergency department (ED) study addressed whether gastric emptying with either syrup of ipecac followed by activated charcoal or orogastric lavage followed by activated charcoal was more effective than activated charcoal alone in overdosed patients.25 Syrup of ipecac did not affect the outcome in treated patients. Three subsequent studies (2 adult and 1 pediatric) failed to show a benefit of gastric emptying before activated charcoal administration2,34 compared with the administration of activated charcoal alone. 23 Furthermore, aspiration was more common in patients who had the combined regimen.2,34 A study using the Toxic Exposure Surveillance System (TESS) database determined that home use of syrup of ipecac did not reduce the rate of ED referrals.11 That this study did not identify an improvement in patient outcome was not unexpected. Most children have no clinical sequelae from exposure and group statistics cannot identify a potentially beneficial effect that occurs rarely.

Contraindications Syrup of ipecac should not be administered to patients who have ingested acids or alkalis, are younger than 6 months of age, are expected to deteriorate rapidly, have a depressed mental status, have a compromised gag reflex, have ingested objects such as batteries or sharps, or have a need for rapid gastrointestinal evacuation to prevent absorption. Syrup of ipecac should not be administered to those for whom the hazards of vomiting and aspiration of the ingested substance outweigh the risks associated with systemic absorption (eg, hydrocarbons), those who have significant prior vomiting, or those for whom vomiting will delay administration of an oral antidote, or to those with a hemorrhagic

diathesis, or a nontoxic ingestion, or when toxin is no longer expected to be in the stomach.

Adverse

Effects

Considering the number of times it has been administered without incident in this country, syrup of ipecac should be considered a P.126 relatively safe drug when given in therapeutic doses to patients for whom there are no contraindications. Uncommon problems that have occurred after therapeutic doses of syrup of ipecac include a Mallory-Weiss esophageal tear in an adult given 30 mL of syrup of ipecac for a multidrug overdose;48 herniation of the stomach into the left chest in a child who had a previously unrecognized underlying congenital defect of the diaphragm; 41 intracerebral hemorrhage;22 and pneumomediastinum.54 Additional problems associated with syrup of ipecac administration include pulmonary aspiration of stomach contents, volatile hydrocarbons or foreign bodies, and the associated time delay before it is possible to perform a necessary therapeutic intervention such as administration of activated charcoal or an oral antidote. Another reported problem is the emesis-induced vagal response of bradycardia.33 The surreptitious self-administration of frequent doses of syrup of ipecac by patients with bulimia and other related eating disorders results in substantial morbidity such as extreme muscle weakness and congestive cardiomyopathy, and mortality.1,8,28,30,38,44,55 Myofibril analysis of ipecac abusing patients reveals degeneration, a “moth-eaten― appearance, and electron microscopy reveals Z-band streaming and disorganization.26 When emetine was routinely used for the treatment of amebiasis in the early 1900s, cardiovascular and neuromuscular toxicity occurred. Similarly, inadvertent administration of the fluid extract of ipecac, which is 14 times more potent than syrup of ipecac, produces

violent and protracted vomiting; diarrhea; seizures; cardiac toxicity including PR interval prolongation, T-wave abnormalities, QRS complex abnormalities, atrial dysrhythmias, premature ventricular beats, and ventricular fibrillation; neuromuscular toxicity, including weakness and neuropathy; shock; and death.28 Surreptitious chronic intentional ipecac poisoning of children, a form of Munchausen syndrome by proxy, is reported.9,31 The findings in these children included vomiting, diarrhea, lethargy, irritability, hypothermia, and hypotonia. The children described were brought to healthcare providers by their parents for atypical patterns of vomiting and had multiple unsuccessful clinical evaluations. When surreptitious use of syrup of ipecac is suspected as the cause of chronic vomiting, screening the urine, plasma, and vomitus for emetine (thin-layer chromatography screen—ToxiLab or HPLC) may be useful.5,31,56

Current Role of Syrup of Ipecac in Poison Management Most authorities agree with the American Academy of Pediatrics' statement that syrup of ipecac should no longer be used routinely.3,4 Instead of promoting the concept of the maintenance of syrup of ipecac in the home, the Academy of Pediatrics currently states that “the first action for a caregiver of a child who may have ingested a toxic substance is to consult with the local poison control center.―4 Logically, the sooner that syrup of ipecac is administered after ingestion, the more effective it may be in reducing absorption of the agent. For this reason, rather than completely abandoning syrup of ipecac, perhaps a targeted approach should be developed. This would mean continuing to promote the stocking of syrup of ipecac in the home setting in remote areas. Although the Academy of Pediatrics believes that it is premature to recommend the routine home stocking of activated charcoal, home stocking of activated charcoal in remote areas

seems

logical.

Only a few groups of patients are considered appropriate candidates for the use of syrup of ipecac. Patients who are candidates for syrup of ipecac are those who (a) overdose on xenobiotics that do not cause a rapid change in mental status, such as acetaminophen or salicylates; (b) consume massive amounts of a toxin that may exceed the binding capacity of activated charcoal, such as salicylates; or (c) ingest a toxin not bound to activated charcoal, such as lithium. Under these circumstances, if the presence of unabsorbed drug in the stomach remains a potential problem, then the be appropriate in rare instances when of activated charcoal or whole-bowel glycol electrolyte lavage solution. The

use of syrup of ipecac may weighed against the utility irrigation with polyethylene time frame for this decision

is usually within 1 to 2 hours following ingestion.

Administration The dose of syrup of ipecac is 15 mL in children 1–12 years old and 30 mL in older children and adults. If vomiting does not ensue after the first dose, the same dose may be repeated once 20–30 minutes after administration of the first dose. For children 6–12 months of age, ipecac use should be limited to a maximum single dose of 10 mL.10,24 Water can be offered, but is not essential for success. Vomiting will occur in most patients. Home users should be warned that persistent vomiting for more than 2 hours may indicate toxicity from the primary xenobiotics ingested and not the antidote, and necessitates medical evaluation.

Conclusion There are very few cases in which syrup of ipecac is indicated in the home setting because typically either most ingestions are nontoxic or, conversely, are of such consequence that an imminent

deterioration in mental status may occur that would make syrup of ipecac administration dangerous. Parents in areas with poor access to a healthcare facility should still be encouraged to keep syrup of ipecac and activated charcoal at home as potential first aid measures, but caregivers should be cautioned to use them only on the advice of a regional poison center or physician. In the ED, the role of syrup of ipecac the only possible candidates for syrup setting is a child or adult who arrives ingestion of a large number of poorly

is extremely limited. One of of ipecac in the overdose in the ED shortly after the soluble tablets of a size

unlikely to be removed by lavage and also unlikely to rapid change in mental status. One other candidate is adult who has taken such a large amount of a highly substance that a favorable activated charcoal-to-drug

cause a the child or toxic ratio cannot

be attained with certainty. Whole-bowel irrigation should be considered as a suitable alternative in either case.

References 1. Adler AG, Walinsky P, Krall RA, Cho SY: Death resulting from ipecac syrup poisoning. JAMA 1980;243:1927–1928. 2. Albertson TE, Derlet RW, Foulke GE, et al: Superiority of activated charcoal alone compared with ipecac and activated charcoal in the treatment of acute toxic ingestions. Ann Emerg Med 1989;18:56–59. 3. American Academy of Clinical Toxicology, European Association of Poison Center and Clinical Toxicologists: Position statement: Ipecac syrup. J Toxicol Clin Toxicol 1997;35:699–709. P.127

4. American Academy of Pediatrics Committee on Injury, Violence and Poison Prevention. Poison treatment in the home. Pediatrics 2003; 112:1182–1185. 5. Asano T, Sadakane C, Ishihara K et al: High performance liquid chromatographic assay with fluorescence detection for the determination of cephaeline and emetine in human plasma and urine. J Chromatogr B Biomed Sci Appl 2001;757:197–206. 6. Auerbach P, Osterloh J, Braun O, et al: Efficacy of gastric emptying: Gastric lavage versus emesis induced with ipecac. Ann Emerg Med 1986;15:692–698. 7. Banner W, Veltri J: The case of ipecac syrup [editorial]. Am J Dis Child 1988;142:596. 8. Bennett H, Spiro A, Pollack M, et al: Ipecac-induced myopathy simulating dermatomyositis. Neurology 1982;32:91–94. 9. Berkner P, Kaster T, Skolnick L: Chronic ipecac poisoning in infancy:

A

case

report.

Pediatrics

1988;82:384–386.

10. Boehnert M, Lewander W, Gaudreault P, et al: Advances in clinical toxicology. Pediatr Clin North Am 1985;32:193–211. 11. Bond GR: Home syrup of ipecac does not reduce emergency department use or improve outcome. Pediatrics 2003;112:1061–1064. 12. Boxer L, Anderson F, Rowe D: Comparison of ipecac-

induced emesis with gastric lavage in the treatment of acute salicylate ingestion. J Pediatr 1969;74:800–803. 13. Cooper M, Sologuren A, Valiente R, Smith J. Effects of lerisetron, a new 5-HT3 receptor antagonist, on ipecacuanhainduced emesis in healthy volunteers. Arzneimittelforschung. 2002;52:689–694. 14. Corby D, Decker W, Moran M, et al: Clinical comparison of pharmacologic emetics in children. Pediatrics 1968;42:361–364. 15. Curtis R, Barone J, Giacona N: Efficacy of ipecac and activated charcoal and cathartic: Prevention of salicylate absorption in a simulated overdose. Arch Intern Med 1984;144:48–52. 16. Dean B, Krenzelok E: Syrup of ipecac: 15 mL versus 30 mL in pediatric poisonings. J Toxicol Clin Toxicol 1985;23:165–170. 17. Eisenga B, Meester W: Evaluation of the effect of motility on syrup of ipecac-induced emesis [abstract]. Vet Hum Toxicol 1978;20:462. 18. Forster ER, Palmer JL, Bedding AW, Smith JTL: Syrup of ipecacuanha-induced nausea and emesis is medicated by 5HT3 receptors in man. J Physiol (London) 1994;477:72. 19. Freedman G, Pasternak S, Krenzelok E: A clinical trial using syrup of ipecac and activated charcoal concurrently. Ann Emerg Med 1987;16: 164–166.

20. Grande G, Ling L: The effect of fluid volume on syrup of ipecac emesis time. J Toxicol Clin Toxicol 1987;25:473–481. 21. Isner JM: Effects of ipecac on the heart. N Engl J Med 1986;314:1253. 22. Klein-Schwartz W, Gorman R, Oderda G, et al: Ipecac use in the elderly: The unanswered question. Ann Emerg Med 1984;13: 1152–1154. 23. Kornberg AE, Dolgen J: Pediatric ingestions: Charcoal alone versus ipecac and charcoal. Ann Emerg Med 1991;20:648–651. 24. Krenzelok K, Dean B: syrup of ipecac in children less than one year of age. J Toxicol Clin Toxicol 1985;23:171–176. 25. Kulig K, Bar-Or D, Cantrill SV, et al: Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 1985;14: 562–567. 26. Lancomis D: Case of the month. Anorexia nervosa. Brain Pathol 1996;6:535–536. 27. MacLean W: A comparison of ipecac syrup and apomorphine in the immediate treatment of ingestion of poisons. J Pediatr 1973;82:121–124. 28. Manno B, Manno J: Toxicology of ipecac. Clin Toxicol 1977;10: 221–242.

29. Manoguerra A, Krenzelok E: Rapid emesis from high dose ipecac syrup in adults and children intoxicated with antiemetics and other drugs. Am J Hosp Pharm 1978;35:1360–1362. 30. Mateer J, Farrell B, Chou SM, Gutman L: Reversible ipecac myopathy. Arch Neurol 1985;42:188–190. 31. McClung H, Murray R, Braden N, et al: Intentional ipecac poisoning in children. Am J Dis Child 1988;142:637–639. 32. McNamara R, Aaron C, Gemborys M, Davidheiser S: Efficacy of charcoal versus ipecac in reducing serum acetaminophen in a simulated overdose. Ann Emerg Med 1988;17:243–246. 33. Meester W: Emesis and lavage. Vet Hum Toxicol 1981;22:225–234. 34. Merigian KS, Woodard M, Hedges JR, et al: Prospective evaluation of gastric emptying in the self-poisoned patient. Am J Emerg Med 1990; 8:479–483. 35. Neuvonen P: Clinical pharmacokinetics of oral activated charcoal in acute intoxications. Clin Pharmacokinet 1982;7:465–489. 36. Neuvonen P, Vartiainen M, Tokola O: Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Eur J Clin Pharmacol 1983;24:557–562. 37. Neuvonen P, Olkkola K: Activated charcoal and syrup of ipecac in the prevention of cimetidine and pindolol absorption in man after administration of metoclopramide as an

antiemetic.

J

Toxicol

Clin

Toxicol

1984;22:103–114.

38. Palmer E, Guay A: Reversible myopathy secondary to abuse of ipecac in patients with major eating disorders. N Engl J Med 1985;313:1457–1459. 39. Rauber A, Maroncelli R: The duration of emetic effect of ipecac: Duration and frequency of vomiting [abstract]. Vet Hum Toxicol 1982;24:281. 40. Robertson WO: Syrup of ipecac: A slow or fast emetic? Am J Dis Child 1962;103:136–139. 41. Robertson WO: Syrup of ipecac associated fatality: A case report. Vet Hum Toxicol 1979;21:87–89. 42. Saetta JP, March S, Gaunt ME, Quinton DN: Gastric emptying procedures in the self-poisoned patient: Are we forcing gastric content beyond the pylorus? J R Soc Med 1991;84:274–277. 43. Saetta JP, Quinton DN: Residual gastric content after gastric lavage and ipecacuanha induced emesis in self-poisoned patients: An endoscopic study. J R Soc Med 1991;84:35–38. 44. Schiff R, Wurzel C, Brunson S, et al: Death due to chronic syrup of ipecac use in a patient with bulimia. Pediatrics 1986;78:412–416. 45. Soderpalm AH, Schuster A, de Wit H: Antiemetic efficacy of smoked marijuana. Subjective and behavioral effects on nausea induced by syrup of ipecac. Pharmacol Biochem Behav

2001;69:343–350. 46. Spiegel R, Addouch I, Munn D: The effect of temperature on concurrently administered fluid on the onset of ipecacinduced emesis. Clin Toxicol 1979;14:281–284. 47. Stewart J: Effects of emetic and cathartic agents on the gastrointestinal tract and the treatment of toxic ingestion. J Toxicol Clin Toxicol 1983;20:199–253. 48. Tandberg D, Liechty E, Fishbein D: Mallory-Weiss syndrome: An unusual complication of ipecac-induced emesis. Ann Emerg Med 1981;10:521–523. 49. Tandberg D, Diven B, McLeod J: Ipecac-induced emesis versus gastric lavage: A controlled study in normal adults. Am J Emerg

Med

1986;4:205–209.

50. Tenenbein M, Cohen, Sitar D: Efficacy of ipecac-induced emesis, orogastric lavage, and activated charcoal for acute drug overdose. Ann Emerg Med 1987;16:838–841. 51. United States Pharmacopeia 21 and National Formulary 16: Suppl 2. Rockville, MD, US Pharmacopeia Convention, 1985. 52. Vandaveer C: How ipecac was discovered. Available at http://www.killerplants.com/what's-in-a-name/20030110.asp. Accessed April 25, 2005. 53. Varipapa RJ, Oderda GM: Effect of milk on ipecac-induced emesis. J Am Pharm Assoc 1977;17:510.

54. Wolowodiuk O, McMicken D, O'Brien P: Pneumomediastinum and pneumoretroperitoneum: An unusual complication of syrup of ipecac induced emesis. Ann Emerg Med 1984;13:1148–1151. 55. Woolf AD, Grew JM: Acute poisonings among adolescents and young adults with anorexia nervosa. Am J Dis Child 1990;144:785–788. 56. Yamashita M, Yamashita M, Azuma J: Urinary excretion ipecac alkaloids in human volunteers. Vet Hum Toxicol 2002;44:257–259. 57. Young WF, Bruin SMG: Evaluation of gastric emptying using radionucleotides: Gastric lavage versus ipecac-induced Ann Emerg Med 1993;22:1423–1427.

emesis.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part A - The General Approach to Medical Toxicology > Antidotes in Depth - Activated Charcoal

Antidotes in Depth Activated

Charcoal

Mary Ann Howland

History Activated charcoal (AC), a fine, black, odorless powder, has been recognized for almost 2 centuries as an effective adsorbent of many substances. In 1930, the French pharmacist Touery dramatically demonstrated his belief in the powerful adsorbent qualities of AC by ingesting several times the lethal dose of strychnine mixed with 15 g of AC in front of colleagues; he suffered no ill effects.6 An American physician, Holt, first used AC to save a patient from mercury bichloride poisoning in 1934.6 However, it was not until the 1940s that Anderson began to systematically investigate the adsorbency of AC and unquestionably demonstrated that AC is an excellent broadspectrum gastrointestinal adsorbent.6,7 a n d 8 The current debate regarding the role of AC in poison management centers on reconciling evidence-based studies in volunteers and small numbers of heterogeneous overdosed patients with clinical experience.4 AC should be considered for administration to a poisoned or overdosed patient following a risk-to-benefit

assessment for the substance presumably ingested and ideally also for the circumstances of the exposure for a particular patient. The benefits include inactivating a potentially toxic xenobiotic, whereas the risks include vomiting and subsequent aspiration. The merits of AC as a decontamination strategy are discussed in detail in Chap. 8.

Adsorption:

Mechanisms

and

Considerations AC is produced in a two-step process, beginning with the pyrolysis of various carbonaceous materials such as wood, coconut, petroleum, or peat. This processing is followed by treatment at high temperatures with a variety of oxidizing (activating) agents such as steam or carbon dioxide to increase the adsorptive capacity of the agent through the formation of an internal maze of pores with a huge surface area.29,53,104,129 The rate of adsorption depends on external surface area, while the adsorptive capacity is dependent on the far larger internal surface area.29,97,103 The adsorptive capacity can be modified by altering the size of the pores. Current AC products have pore sizes that range from 10 to 1000 angstroms (Å) with most of the internal surface area created by the summation of 10–20-Å-sized pores.25,27,29 Most xenobiotics are of moderate molecular weight (100–800 daltons) and adsorb well to pores in the range of 10–20 Å. Mesoporous charcoals with a pore size of 20–200 Å have a greater capacity to adsorb larger xenobiotics as well as those in their larger hydrated forms.77 The relationship between AC surface area and adsorptive capacity was studied in vitro and in vivo in animals and in humans. When surface area is large, adsorptive capacity is increased, but affinity is decreased because van der Waals forces and hydrophobic forces are diminished.131 In 1996, a superactivated charcoal with a surface area approximately double the current AC formulations

was marketed. Both in vitro and in vivo studies of this preparation indicated a greater maximum adsorptive capacity.30,116 The actual adsorption of a xenobiotic by activated charcoal is believed to rely on hydrogen bonding, ion-ion, dipole, and van der Waals forces, suggesting that most xenobiotics are best adsorbed by activated charcoal in their dissolved, nonionized form.29 Thus, according to the Henderson-Hasselbalch equation, weak bases are best adsorbed at basic pHs and weak acids are best adsorbed at acid pHs. For example, cocaine, a weak base, binds to AC with a maximum adsorptive capacity of 273 mg of cocaine per gram of AC at pH 7.0; this capacity is reduced to 212 mg of cocaine per gram of AC at pH 1.2.76 Strongly ionized and dissociated salts like sodium chloride or potassium chloride are not adsorbed, whereas nonionized or weakly dissociated salts like iodine and mercuric chloride, respectively, are adsorbed. The adsorption to AC of a weakly dissociated metallic salt like mercuric chloride (HgCl2 ) decreases with decreasing pH because the number of complex ions of the type HgCl3 and HgCl 4 increases and the number of electroneutral molecules (HgCl2 ) is reduced.7 Nonpolar, poorly water soluble organic substances are more likely to be adsorbed from an aqueous solution than polar, water-soluble substances.29 Among the organic molecules, aromatics are better adsorbed than aliphatics, molecules with branched chains are better adsorbed than those with straight chains, and molecules containing nitro groups are better adsorbed than those containing hydroxyl, amino, or sulfonic groups.29 In vitro studies demonstrate that adsorption begins within about 1 minute of administration of AC, but may not reach equilibrium for 10–25 minutes.30,92 Accordingly, desorption (drug dissociation from activated charcoal) may occur, especially for weak acids, as the activated charcoaldrug complex passes from the stomach through the intestine and as the pH changes from acidic to basic.12,42,98,103,128 Desorption may lead to systemic absorption of larger total amounts of xenobiotic over several days; in this case, the elimination half-life

of the xenobiotic appears to increase, but peak levels remain unaffected.98 The clinical effects of desorption can be minimized by giving a sufficiently large dose of AC to overcome the decreased affinity of the xenobiotic secondary to pH change such as by using multiple-dose activated charcoal. Either whole-bowel irrigation or cathartic may reduce gastrointestinal transit time and possibly increase xenobiotic elimination. However, in spite of numerous human volunteer studies,62,85,96,107,121 increased xenobiotic elimination has been demonstrated for cathartics only in a single study.62 Although ethanol and other solvents such as polyethylene glycol are minimally adsorbed by AC, they nonetheless may decrease the adsorptive capacity of AC for a coingested xenobiotic by competing for AC binding with that xenobiotic.13,98,101 AC decreases the systemic absorption of most xenobiotics, including aspirin, acetaminophen, barbiturates, glutethimide, phenytoin, theophylline, cyclic antidepressants, and most inorganic and organic materials.41,92,106 Notable xenobiotics not amenable to AC are the alcohols, acids and alkalis, and iron,45 potassium, magnesium, sodium, and lithium salts. Although the binding of AC to P.129 cyanide is less than 4%, the toxic dose is small and 50 g of AC would theoretically be able to bind more than 10 lethal doses of potassium cyanide. Efficacy of AC is directly related to the amount of AC administered. The effect of the AC-to-drug ratio on adsorption was demonstrated both in vitro and in vivo with para-aminosalicylate (PAS): In vitro, the fraction of unadsorbed PAS decreased from 55% to 3% as the AC-to-PAS ratio increased from 1:1 to 10:1 at pH 1.2.102 This study most likely provides the best scientific basis for the 10:1 AC-to-drug ratio dose recommendation. In human volunteers, as the AC-to-PAS ratio increased from 2.5:1 to 50:1, the total 48-

hour urinary excretion decreased from 37% to 4%.103 Presumably this occurred because more of the PAS was adsorbed by AC in the lumen of the gastrointestinal tract rather than being absorbed systemically. These same studies demonstrate AC saturation at low ratios of AC to drug and argue for a 10:1 ratio of AC to xenobiotic. The clinical efficacy of administered AC is also inversely related to the time elapsed following ingestion of the substance to be adsorbed and depends largely on the rate of absorption of the drug. For example, early administration is much more important with rapidly absorbed drugs. In this situation, AC functions to prevent the absorption of drug into the body by achieving rapid adsorption in the GI tract. Once a drug is systemically absorbed or parenterally administered AC may still enhance elimination through a mechanism referred to as gastrointestinal dialysis. This is accomplished with multiple doses of AC.

Palatability The black and gritty nature of AC has led to many formulations to increase palatability and patient acceptance. Bentonite, carboxymethyl cellulose, and starch 49,91,119 are used as thickening agents; cherry syrup, chocolate syrup, sorbitol, sucrose, saccharin, ice cream, and sherbet 30,71,78,135 are used as flavoring agents. Most of these additives do not decrease adsorptive capacity; however, improvement in palatability and acceptance is minimal or nonexistent with all of these formulations.28 Although a milk chocolate formulation of AC evaluated by a group of children was rated superior in palatability to standard AC preparations,38 it was never marketed. A marketed AC product with cherry flavoring was rated by adult human volunteers as preferable over plain AC and a statistically significant larger quantity of the flavored AC was ingested.24 However, in adult overdosed patients, this was not the case, as

most patients consumed the entire bottle of AC with or without cherry flavoring. Many of the subjects did not like the taste and surprisingly preferred the plain AC.58 Two studies in adult overdosed patients compared different brands of AC without additives or flavoring to determine the quantity of activated charcoal typically ingested.17,43 In one study, approximately half of the 50 g of activated charcoal offered was ingested and 7% of the patients vomited.17 In the other study, 60 g of AC as LiquiChar or CharcoAid G was offered and approximately 95% of each formulation was consumed in 20 minutes. There was no difference in the amount consumed even though the palatability of the granular form of AC (CharcoAid G) was rated higher.43 Recently cold cola was used to enhance palatability in volunteer children and adults. Children preferred regular cola as compared to diet cola. The adults rated the cola charcoal combination preferable to the plain charcoal.113,118

Adverse

Effects

The use of AC is relatively safe, although vomiting (which especially occurs after rapid administration), constipation, and diarrhea frequently occur following AC administration.97 Constipation and diarrhea are more likely to result from the ingestion itself than from the AC. However, black (heme-negative) stools, tongues, and mucous membranes are frequently observed. Serious adverse effects of AC include the complications that may result from the pulmonary aspiration of AC with or without gastric contents,9,39,47,50,51,59,86,92,108,120 peritonitis from spillage of AC into the peritoneum from gastrointestinal perforation caused by orogastric lavage,79 and intestinal obstruction and pseudoobstruction, especially following repeated doses of AC in the presence of either dehydration18,73,88,114,132 or prior bowel adhesions.48 Although a significant number of patients aspirate gastric contents

prior to endotracheal intubation and administration of AC,90,117 the incidence of AC aspiration following endotracheal intubation varies from 4% to 25%, depending on the nature of the study. A more recent retrospective investigation demonstrated a 1.6% incidence of aspiration pneumonitis in unselected overdosed patients. Altered mental status, spontaneous emesis, and tricyclic antidepressant overdose were associated risk factors, whereas AC was not.57

Home

and

Prehospital

Administration

Prehospital administration of AC by emergency medical technicians and paramedics may offer a significant advantage in facilitating the administration of AC more rapidly following the time of overdose.2,133 However, the cost of implementation of such a program would have to be weighed against the small number of patients who would actually benefit.56 In a study intended to simulate home administration of AC the acceptance of a dose of AC given as a water slurry in a paper cup was studied in 50 young children.20 The children were told to drink the contents, that the substance did not taste bad, and that it would make them feel better and not feel ill. Eighty-six percent of the children readily drank the AC slurry, and 76% of them consumed 95–100% of the total dose. Of 7 children in a simulated home environment administered AC in regular cola, 3 drank 1 g/kg, 2 drank very little, and the other 2 drank about half a therapeutic dose.118 A prospective poison center case series demonstrated successful administration of AC in the home. In this series the median age of the patients was 3 years and the median dose ingested was 12 g.124 However, other attempts at getting children to ingest AC were not as successful; in one study difficulty was noted in 70% of attempts to administer a standard dose of AC to children in the home setting.35

Administration

and

Dosing

AC should not be administered routinely to all overdosed patients. Single-dose AC should be administered when xenobiotic is still expected to be available for adsorption in the GI tract benefit outweighs the risk. The optimal dose of AC is However, most authorities recommend a dose of AC of body weight when the amount of xenobiotic exposure or when

and the unknown.4 1 g/kg of is unknown P.130

known in a 10:1 ratio of AC to xenobiotic, up to an amount that is tolerated by the patient and safely administered. AC that is not premixed is best administered as a slurry in a 1:8 ratio of AC to suitable liquid, such as water or cola. Using cold cola may offer improved palatability.113,118 Administering the mixture to children from an opaque, covered cup decorated with stickers and through a straw may be helpful.134 Contraindications to AC include presumed GI perforation and the need for endoscopic visualization, as may be the case with caustic ingestion. To prevent aspiration pneumonitis from oral AC administration it is imperative that the patient's airway be assessed. When the potential for airway compromise is substantial, oral AC should be withheld until a decision about airway protection is made. A risk-to-benefit assessment with regard to the need for airway protection and the need for AC should be made. Other considerations that must be made prior to the administration of AC are the determination of normal gastrointestinal motility, normal bowel sounds, and a normal abdominal examination without distension or signs of an acute abdomen. If bowel function is compromised, the stomach should be decompressed to decrease the risk of subsequent vomiting and aspiration prior to administration of AC.

The use of Activated Charcoal, Cathartics,

and

Whole-Bowel

Irrigation

with Polyethylene Lavage Solution

Glycol

Electrolyte

Cathartics are often used with AC, however the evidence suggests that AC alone is comparably effective to AC plus a single dose of cathartic (sorbitol or magnesium citrate).3,62,80,81,85,91,97,105 If a cathartic is used, it should be used only once as repeated doses of magnesium-containing cathartics are associated with hypermagnesemia89,123 and repeated doses of any cathartic can be associated with severe fluid and electrolyte problems. A child died following repeated doses of AC-sorbitol mixtures.40 Whole-bowel irrigation with polyethylene glycol electrolyte lavage solution may significantly decrease the in vitro and in vivo adsorptive capacity of AC 52 depending on the individual xenobiotic and the drug's formulation.10,68 The most likely explanation is competition with the activated charcoal's surface for solute adsorption.

Multiple-Dose

Activated

Charcoal

Multiple-dose activated charcoal (MDAC) functions in two ways: (a) to prevent the absorption of xenobiotics that are slowly absorbed from the GI tract, and (b) to enhance the elimination of suitable xenobiotics that have already been absorbed. MDAC decreases xenobiotic absorption when large amounts of xenobiotics are ingested and dissolution is delayed (eg, masses, bezoars), when xenobiotic formulations exhibit a delayed or prolonged release phase (eg, enteric coated, sustained release), or when reabsorption can be prevented (eg, enterohepatic circulation of either active drug, active metabolites, or conjugated xenobiotic hydrolyzed by gut bacteria to active xenobiotic). The ability of MDAC to enhance elimination once absorption had already occurred was first reported in 1982.14 This report

concluded that orally administered MDAC enhanced the total body clearance (nonrenal clearance) of 6 healthy volunteers given 2.85 mg/kg of body weight of intravenous (IV) phenobarbital.14 The serum half-life of phenobarbital decreased from 110 ± 8 to 45 ± 6 hours. An accompanying editorial suggested that MDAC enhanced the diffusion of phenobarbital from the blood into the gastrointestinal tract and trapped it there, to be excreted later in the stool. In this manner, AC was said to perform as an “infinite sink― allowing for “gastrointestinal dialysis― to take place.70 These findings were subsequently confirmed by studies in dogs and rats using intravenous aminophylline.34,83 Using an isolated perfused rat small intestine the concept of gastrointestinal dialysis83 was elegantly demonstrated, as AC dramatically affected the pharmacokinetics of theophylline and produced a constant intestinal clearance that was approximately equivalent to intestinal blood flow.83 Although MDAC increases the elimination of digitoxin;109 phenobarbital;111 carbamazepine;16 phenylbutazone;93 dapsone;94 nadolol;37 theophylline;15,75,127 salicylate;112 quinine;5 cyclosporine;54 propoxyphene;60 nortriptyline; and amitriptyline, its clinical utility remains to be defined.5,61,125 The adsorptive capacities for these and other agents are well documented.5,21,22,29,84

Volunteer

and

Experimental

Studies

An analysis of 28 volunteer studies involving 17 xenobiotics was unable to correlate the physiochemical properties of a particular xenobiotic with the ability of MDAC to decrease the plasma half-life of that xenobiotic.21 Although the half-life was not thought to be the best marker of enhanced elimination, it was the only parameter consistently mentioned in all of the studies that otherwise substantially differed from one another with regard to study design. The xenobiotics with the longest intrinsic plasma half-lives seemed to demonstrate the largest percent reduction in plasma half-life when MDAC was used. A subsequent animal model

with therapeutic doses of four simultaneously administered intravenous xenobiotics (acetaminophen, digoxin, theophylline, and valproic acid) clarified the role of pharmacokinetics on the effectiveness of AC.23 Theophylline, acetaminophen, and valproic acid all have small volumes of distribution. However, of the three, only valproic acid is highly protein-bound at the doses employed, which probably accounted for the inability of AC to increase its clearance. An increased clearance was demonstrated for the three other xenobiotics with MDAC. The most rapid and dramatic effect of MDAC was demonstrated on the clearance of theophylline. Large volumes of distribution alone may not exclude benefit from MDAC. Although digoxin has a large volume of distribution, it requires several hours to distribute from the blood to the tissues. MDAC is beneficial before distribution is complete, and the digoxin still remains accessible in the blood compartment. The benefits of MDAC undoubtedly depend on a number of patient variables and xenobiotic exposure characteristics. Most important to remember, however, is that volunteer studies do not accurately reflect the overdose situation84 in which saturation of plasma protein binding, saturation of first-pass metabolism, and acid–base disturbances may make more free xenobiotics available for an enteroenteric effect and therefore more amenable to MDAC use.

Overdose

Studies

As noted, MDAC appears to enhance many xenobiotics by interfering with interrupting enterohepatic circulation, desorption. Shortening the half-life of would

gastrointestinal elimination of enteroenteric circulation, and/or minimizing a xenobiotic in overdose P.131

logically benefit the patient clinically by limiting the time of associated central nervous system depression, risk of aspiration,

intensive care, nursing hours, and hospitalization, although the actual clinical evidence for these benefits is limited. In a randomized clinical study designed to determine whether these potential benefits could be achieved, some patients who overdosed with phenobarbital were given a single dose of AC, while others were given multiple doses.111 Although the half-life of phenobarbital was significantly decreased in the MDAC group (36 vs. 93 hours), the length of intubation time required by each group did not differ from one another. This study has been criticized as being too small, having unevenly matched groups, and focusing on a single end point (extubation) that may be dependent on factors other than patient condition (such as the time of day) to determine potential clinical benefit. The most compelling demonstration of the benefits of MDAC in the overdose setting to date comes from a study done in Sri Lanka of patients with severe cardiac toxicity caused by intentional overdose with yellow oleander seeds.33 An initial dose of 50 g of AC was administered to all patients who were then randomized to 50 g of AC every 6 hours for 3 days or placebo. There were statistically fewer deaths and fewer life-threatening cardiac dysrhythmias in the MDAC group.

Administration

of

MDAC

An initial loading dose of AC should be administered to adults and children in an AC-to-xenobiotic ratio of 10:1 or 1 g/kg of body weight (if drug exposure amount is unknown). The correct dose and interval of AC for multiple dosing, when it is indicated, is best tailored to the amount and dosage form of the xenobiotic ingested, the severity of the overdose, the potential lethality of the xenobiotic, and the patient's ability to tolerate AC. Benefit should always be weighed against risk. Doses of AC for multiple dosing have varied considerably in the past, ranging from 0.25 to 0.5 g/kg of body weight every 1–6 hours, to 20–60 g for adults every 1, 2, 4, or 6 hours. There is some evidence that the total dose administered may be more important than the frequency of

administration.55,130 In some cases, continuous nasogastric administration of AC can be employed, especially when vomiting is a problem.42,100,130 The editors of this text consider a dose of 0.5 g/kg of body weight every 2 to 4 hours for up to 12 hours to be an appropriate regimen in most circumstances.

Adverse

Effects

The adverse effects of MDAC include diarrhea (only when sorbitolcontaining charcoal preparations are used), constipation, vomiting with a subsequent risk of aspiration, intestinal obstruction, and reduction of serum concentrations of therapeutically employed xenobiotics.36,88,92,108 Obviously any complication observed with single-dose AC is a possibility with MDAC.

Summary When administration is timely, AC is a very effective nonspecific adsorbent. AC should be of benefit to a patient with a potentially life-threatening ingestion involving a xenobiotic still expected to be accessible in the GI tract, adsorbable by AC, and for whom there are no contraindications. MDAC is useful to prevent systemic absorption of a xenobiotic with a prolonged absorptive phase such as a sustained-release formulation. In the postabsorptive phase of managing an exposure, MDAC can decrease the elimination halflives of a variety of xenobiotics through diverse mechanisms, including gastrointestinal dialysis, thereby providing treatment even to some nonoral xenobiotic overdoses and exposures. For this postabsorptive effect to be of clinical importance the xenobiotic or active metabolite must first be characterized by a lengthy elimination phase, as MDAC is given every 2–6 hours. In addition, those xenobiotics with a small volume of distribution or that fit a two-compartment model with a prolonged initial distribution phase, and low or saturable plasma protein binding are theoretically most accessible to MDAC. In both the use of AC and

MDAC care must be taken to avoid pulmonary aspiration and intestinal obstruction. With respect to the use of AC prior to the patient's arrival at the hospital, home availability of AC should be encouraged especially in remote locations where organized healthcare is not immediately available. As more palatable forms of AC are developed, children may accept this agent more readily, but even without such forms, the problems may not be as significant as some believe them to be.67,69

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P,

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A:

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pseudo-obstruction

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part A - The General Approach to Medical Toxicology > Antidotes in Depth - Whole-Bowel Irrigation and Other Intestinal Evacuants

Antidotes in Depth Whole-Bowel Irrigation and Other Intestinal Evacuants Mary Ann Howland Drugs that promote intestinal evacuation are referred to as laxatives, cathartics, purgatives, promotility agents, and evacuants. Using different doses, the same drug may often accomplish any or all of these tasks, but with different side-effect profiles. Laxatives promote a soft-formed or semifluid stool within 6 hours to 3 days, depending on the agent and the dose employed. Cathartics promote a rapid watery evacuation within 1–3 hours.30 Purgatives relate to the force associated with bowel evacuation. Promotility agents stimulate gastrointestinal motor function via the enteric nervous system by affecting acetylcholine, serotonin, or motilin. Evacuants are commonly used to cleanse the bowel prior to a procedure, with an onset of action of as little as 30 to 60 minutes, but typically requiring 4 hours for a more complete effect. The most effective process of evacuating the intestinal tract in poisoned patients is referred to as whole-bowel irrigation (WBI). WBI is typically accomplished using polyethylene

glycol 3350 (PEG) and an added electrolyte lavage solution (PEGELS). The traditional classification of laxatives into the categories of bulk-forming, softener or emollient, lubricant, stimulant or irritant, saline, hyperosmotic, and evacuant is largely empirical. Bulkforming agents include high-fiber products like methylcellulose, polycarbophil, and psyllium; softeners or emollients include docusate calcium. Mineral oil is the sole lubricant. None of these three classes of agents is employed therapeutically in medical toxicology because their onsets of action are often delayed several days. In addition, softeners cause an increase in intestinal permeability for a few hours and may therefore increase the absorption of some xenobiotics.69 Mineral oil may enhance the absorption of lipid soluble drugs and aspiration could result in a lipoid

pneumonia.92

Stimulant

or

irritant

laxatives

include

anthraquinones

(sennosides,

aloe, and casanthranol), diphenylmethane (bisacodyl), and castor oil. Abdominal discomfort, cramping, and tenesmus often occur acutely. Long-term use produces bowel habituation and damage to intestinal tissue. Thus, stimulant and irritant laxatives are rarely used today in medical toxicology because of their significant gastrointestinal side effects. Saline cathartics, which include magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium phosphate, and sodium sulfate, are used cautiously in medical toxicology. Hyperosmotic agents, including sorbitol and lactulose, are also considered in poisoned patients. When different cathartics were compared with respect to time to first stool and number of stools,31,38,59,60,80 sorbitol produced 10–15 watery stools and the most abdominal cramping before catharsis. Additionally, its taste was rated second to that of magnesium citrate because of its nauseating sweetness. Sorbitol produced stools in the shortest amount of time but with the

highest incidence of nausea and vomiting. In comparison, the first bowel movement should occur about 1 hour after the start of WBI with PEG-ELS. In other studies, sorbitol resulted in nausea, vomiting, generated gas, abdominal cramping, and increased flatus.34,35,62 Potential adverse effects associated with cathartics and promotility agents include dehydration, absorption of magnesium or other absorbable electrolytes, hypokalemia and metabolic alkalosis from dehydration, activation of the renin–angiotensin–aldosterone system, and colonic fermentation of digestible sugars. Catharticinduced rectal prolapse occurred in 2 geriatric patients.37 The use of repetitive doses of cathartics, either by design or unintentionally, has led to further exaggeration of the serious sequelae such as hypermagnesemia and death. 33,61,76 Following the use of hypertonic phosphate enemas and oral sodium phosphate, hypocalcemia, hyperphosphatemia, and hypokalemia were reported.19,25,27,44,49,70,78 In many of these cases, the recommended dose of the therapeutic agent was used.19 Frail elderly patients, children, and those with decreased renal function may be most susceptible to adverse effects.9,11 Multiple-dose activated charcoal regimens containing 70% sorbitol used to enhance elimination resulted in severe cathartic-related adverse effects in 4 case reports.1,24,43,53 The potential for sorbitol related adverse events from the unintentional use of repetitive activated charcoal (AC) dosing was emphasized by a survey revealing that 16% of hospitals surveyed only stocked AC premixed with sorbitol.93 The retention of sorbitol after repetitive doses in an aperistaltic gut may lead to significant morbidity due to the gas formation and abdominal distension as a result of the digestive action of gut bacteria.43

Mechanism

of

Action

The effects of saline cathartics are largely attributed to their relatively nonabsorbable ions that establish an osmotic gradient and draw water into the gut. The increased water leads to increased intestinal pressure and a subsequent increase in intestinal motility.17 Magnesium ion also releases cholecystokinin from the duodenal mucosa, which stimulates intestinal motor activity and alters fluid movement, contributing to its effect.12,79 The hyperosmotic laxatives, including sorbitol, lactulose, and glycerin, also draw water into the gut and produce diarrhea. Polyethylene glycol is a nonabsorbable, isoosmotic indigestible agent that remains in the colon and together with the water diluent is evacuated, resulting in WBI without producing flatus and cramps. Electrolytes are added to limit the ensuing electrolyte and fluid shifts. Many studies of WBI using PEG-ELS demonstrate patient acceptance, effectiveness, and safety when used for bowel preparation.3,10,18,20,22,68,84,87 Promotility agents such as metoclopramide and erythromycin stimulate gut motor function. Metoclopramide does this through gastrointestinal 5HT4 receptor agonist and D2 receptor antagonist activity that together increase acetylcholine release and gastrointestinal motility. Erythromycin also stimulates gut motor function but via direct stimulation of gastrointestinal motilin receptors.66 P.136

Gastrointestinal Management

Evacuation

and

Poison

Although recommended for basic poison management for many years, cathartics should not be used routinely in the management of overdosed patients.5 Intuitively, the advantages of cathartics appear to result from their ability to decrease the potential for constipation or obstruction from AC and hasten the delivery of AC

to the small intestine. However, these theoretical advantages have never been demonstrated clinically. Studies demonstrate that when administered alone, cathartics such as sorbitol or sodium sulfate may decrease peak and/or total absorption of some drugs, but no study has achieved results comparable to that of AC alone.2,16,52,67,91 When comparing the efficacy of a single dose of AC alone with that of AC plus a single dose of cathartic, studies suggest the combination to be equal to,2,56,65,67,75 slightly better than,16,34 or slightly worse than AC alone.52,91 WBI with PEG-ELS is currently advocated to hasten the elimination of poorly absorbed xenobiotics or sustained-release medications before they can be absorbed. This approach is theoretically sound, and does not produce the fluid and electrolyte complications associated with cathartics. Unfortunately, evidence of efficacy is limited to anecdotal case reports and volunteer studies. Although animal models suggest WBI may enhance systemic clearance via gastrointestinal dialysis, much like multiple-dose activated charcoal (MDAC),42 low flow rates, the typical delay in administering WBI in actual clinical situations, and the inconvenience of this procedure make it highly unlikely that enhanced systemic clearance can be achieved in humans. In human volunteer studies, WBI was more effective than singledose AC or MDAC for acetylsalicylic acid (ASA), 35 decreased peak lithium (Li) and Li AUC (area under the [plasma drug concentration versus time] curve) compared to control,77 decreased the bioavailability of two sustained-release medications,15,40 and propelled radiopaque markers through the gut more efficiently than control.46 Not unexpectedly, WBI was inferior to AC with regard to prevention of absorption when administered following 650 mg of immediate-release aspirin.73 Additionally, once aspirin was

absorbed, WBI was unable to enhance systemic clearance.51 There are reports of successful use of WBI in the management of overdoses of iron,23,48,82,83 sustained-release theophylline,32 sustained-release verapamil,13 zinc sulfate,14 lead,55,57,63,72 mercuric oxide powder,45 arsenic-containing herbicide,41 delayedrelease fenfluramine,58 and for body packers.29,85,89 Although some clinicians express enthusiasm for the use of WBI for a variety of ingestions, others question its efficacy.14,74,81 Wholebowel irrigation for 5 hours following ingestion of 10 fluorescent coffee beans by each of 7 volunteers removed an average of only 4 beans (range, 1–8).74 Similar failures were reported with jequirity beans81 and button batteries.82 It can be argued that because of their physical characteristics (density, solubility, size), these agents might not be representative of substances amenable to whole-bowel irrigation. Additionally, the experience of the editors of this text in caring for body packers demonstrates that whole-bowel irrigation may not always evacuate all of the drug packets because of inadequate dosing, partial obstruction, or the nature of the procedure. As a result of these failures, promotility agents were successfully added to WBI to enhance bowel evacuation in two body packers suspected of having ingested wellconstructed

drug

packets.86

Adverse Effects of WBI Adverse effects resulting from the use of WBI with PEG-ELS include vomiting, particularly following rapid administration, abdominal bloating, fullness, cramping, flatulence, and pruritus ani. Typically, the patient will need to remain on a commode for 4–6 hours to complete the procedure. Slow or low-volume administration of PEG-ELS results in sodium absorption. If a total of 500 mL of PEG-ELS were used instead of multiple liters, potentially 1.5 g of sodium may be absorbed.21 This adverse effect may have resulted in the exacerbation of congestive heart failure

in an unstable patient with cardiac and renal dysfunction. 26 An unusual complication of WBI is colonic perforation, which occurred in a patient with severe diverticulitis.39 Other adverse effects noted by the manufacturer include isolated reports of upper GI bleeding from a Mallory-Weiss tear, esophageal perforation, aspiration pneumonitis after vomiting, and acute lung injury. Unfortunately, administration of PEG-ELS by other than the enteral route has occurred. A 4-year-old child inadvertently received 390 mL of PEG-ELS intravenously with no obvious adverse result.71 In contrast, acute lung injury developed in an 11-year-old child administered PEG-ELS through a nasogastric tube inadvertently inserted in the trachea.64

Interaction of AC and WBI Several in vitro studies demonstrate that the addition of PEG-ELS to AC significantly decreases the adsorptive capacity of AC.8,28,47 Some interactions were affected by pH and magnified by high ratios of PEG-ELS to AC.7,36,47 The most likely explanation is competition with the AC surface for solute adsorption. Additionally, in an animal model, whole-bowel irrigation appeared to have an adverse effect by washing the AC away from the sustained-release theophylline.15

Contraindications Contraindications to whole-bowel irrigation include prior, current or anticipated diarrhea; volume depletion; significant gastrointestinal pathology or dysfunction such as ileus, perforation, colitis, toxic megacolon, hemorrhage, and obstruction; an unprotected or compromised airway; and hemodynamic instability.4,82

Dos i n g

The recommended dose of WBI with PEG-ELS solutions is 0.5 L/h or 25 mL/kg/h for small children and 1.5–2 L/h or 20–30 mL/min for adolescents and adults. WBI solution may be administered orally or through a nasogastric tube for 4–6 hours or until the rectal effluent becomes clear. If the xenobiotic being removed is radiopaque, a diagnostic imaging technique demonstrating the xenobiotic's absence may serve as a reasonable clinical end point. An antiemetic such as metoclopramide or a serotonin antagonist may be required for the treatment of nausea or vomiting. Whole-bowel irrigation P.137 with large volumes of fluid was used successfully in 2 pregnant women at 38 and 26 weeks of gestation.88,90

Available Forms of PEG-ELS for WBI The original WBI solution was GoLYTELY from Braintree. This solution contained PEG with electrolytes and sodium sulfate as an added laxative. Colyte is manufactured by Schwartz Pharma and is very similar to GoLYTELY. Braintree later introduced NuLYTELY, a PEG formulation with 52% less total salt than GoLYTELY and no added sodium sulfate. These changes in formulation decreased the salty taste and the chances for fluid or electrolyte abnormalities.54 NuLYTELY is available in flavors. The following lists the composition of the 3 available PEG-ELS products. All are prepared by filling the container to the 4-L mark with water and shaking vigorously several times to ensure dissolution. Lukewarm water facilitates dissolution but chilling afterward improves palatability. Chilled solutions, however, are not recommended for infants because of the risk of hypothermia. The product is stable with refrigeration for 48 hours after reconstitution. GoLYTELY contains 236 g (17.6 mmol/L) polyethylene glycol 3350, 22.74 g sodium sulfate (anhydrous) (sulfate 40 mmol/L), 6.74 g sodium bicarbonate (bicarbonate 20 mmol/L), 5.86 g sodium

chloride (total sodium 125 mmol/L), and 2.97 g potassium chloride (potassium 10 mmol/L and total chloride 35 mmol/L). Colyte contains 240 g (18 mmol/L) polyethylene glycol 3350, 22.72g sodium sulfate (anhydrous) (40 mmol/L sulfate), 6.72 g sodium bicarbonate (20 mmol/L bicarbonate), 5.84 g sodium chloride (total sodium 125 mmol/L), and 2.98 g potassium chloride (potassium 10 mmol/L and total chloride 35 mmol/L). NuLYTELY contains 420 g polyethylene glycol 3350, 5.72 g sodium bicarbonate, 11.2 g sodium chloride, and 1.48 g potassium chloride. MiraLax by Braintree (prescription only) contains PEG 3350 powder meant for oral administration after dissolution in water, juice, or soda. It is indicated for occasional constipation, with a recommended dose of 1 heaping teaspoon (17 g) in 240 mL liquid per day. For MiraLax to be useful in WBI, it would need to be administered at a dose of 2 L/h (8 heaping teaspoons in 2 L of water/h) in adults. This is not recommended for WBI because it does not contain any added electrolytes and may result in an electrolyte imbalance.

Summary Cathartics should never be considered part of routine management of poisoning and overdose in either children or adults. Cathartics should never be used as an AC substitute when xenobiotics known to be adsorbed to AC are involved. Moreover, when total xenobiotic absorption is evaluated, a single dose of a cathartic given with AC appears to be only about as efficacious as AC given alone. Although investigators have also studied the rapidity of stools resulting from the use of various cathartics, promotility agents, and WBI, administering a cathartic just to produce a faster onset of charcoal stools has never been shown to produce a better clinical outcome. In adults, when large amounts of xenobiotics

have been ingested or when desorption from charcoal may be an important consideration (such as with aspirin), a single dose of a cathartic, preferably magnesium citrate or sorbitol, may be given with the AC. When MDAC is being administered, if a cathartic is used at all, it should only be given with the first dose. Sufficient oral fluids should always be administered with a cathartic to avoid inspissation and dehydration. Unless contraindicated, WBI is preferable to repetitive dose cathartics for evacuation of sustained-release or poorly soluble xenobiotics not adsorbed to AC. The precise role of WBI and the interactions between AC and PEGELS in the overdosed patient remain to be defined. There have been no controlled clinical studies assessing outcome, although theoretically, ingestions of sustained-release xenobiotics (theophylline, glyburide XL, verapamil), xenobiotics not adsorbed by charcoal (iron, lead, lithium), and drug packets (in body packers) may be amenable to the use of WBI. An added advantage of using PEG-ELS WBI is that should the patient require endoscopy, diagnostic imaging, or surgery, the gastrointestinal tract may be more easily visualized, facilitating the intervention or procedure. Activated charcoal should be given to those patients for whom it is indicated, and a comparable dose of AC prevent or overcome the possible further systemic

if WBI is being performed in conjunction, should be given following the WBI to potential xenobiotic desorption and absorption of the xenobiotic.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part A - The General Approach to Medical Toxicology > Chapter 9 - Pharmacokinetic and Toxicokinetic Principles

Chapter 9 Pharmacokinetic and Toxicokinetic Principles Mary Ann Howland Xenobiotics are foreign to the body and include natural or synthetic chemicals, drugs, pesticides, environmental agents, and industrial agents. 43 Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of xenobiotics. Mathematical models and equations are used to describe and to predict this behavior. Pharmacodynamics is the term used to describe an investigation of the relationship of xenobiotic concentration to clinical effect. Toxicokinetics, which is analogous to pharmacokinetics, is the study of the absorption, distribution, metabolism, and excretion of a xenobiotic under circumstances that produce toxicity or excessive exposure. Toxicodynamics, which is analogous to pharmacodynamics, is the study of the relationship of toxic concentrations of xenobiotics to clinical effect. Humans with overdoses provide many challenges to the mathematical precision of toxicokinetics and toxicodynamics because many of the variables (eg, dose, time of ingestion, presence of vomiting) that

affect the result are often unknown. In contrast to the therapeutic setting, atypical solubility characteristics are noted and saturation of enzymatic processes occurs. Alterations in enzymatic saturation and protein binding may lead to enhanced absorption (decreased firstpass effect), more free drug available in the serum because of saturation of plasma protein binding, or prolonged elimination because of saturation of hepatic enzymes or active renal tubular secretion. In addition, age, obesity, gender, genetics, chronopharmacokinetics (diurnal variations), and the effects of critical illness and compromised organ perfusion all further inhibit attempts to achieve precise analyses.3,15,35,40,61,65 In addition, various treatments may alter one or more kinetic parameters. There are numerous approaches to recognizing these variables, such as obtaining historical information from the patient's family and friends, performing pill counts, procuring sequential serum concentrations during the phases of toxicity, and occasionally repeating a pharmacokinetic evaluation during therapeutic dosing of that same agent to obtain comparative data. Despite all of the confounding and individual variability, toxicokinetic principles can, nonetheless, be applied to facilitate our understanding and to make certain predictions. These principles can be used to help evaluate whether a certain antidote or extracorporeal removal method is appropriate for use, when the serum concentration might be expected to drop into the therapeutic range (if one exists), what ingested dose might be considered potentially toxic, what the onset and duration of toxicity might be, and what the importance is of a serum concentration. While considering all of these factors, the clinical status of the patient is paramount, and mathematical formulas and equations can never substitute for evaluating the patient. This chapter explains the principles, presents the mathematics in a “user-friendly― fashion,72 and demonstrates the application of these principles and mathematical approaches by example and case illustration.

Absorption Absorption is the process by which a xenobiotic enters the body. For an agent to cause a systemic effect, it must reach the bloodstream and then be distributed to the site or sites of action. Both the rate ( ka ) and extent of absorption (F) are measurable and important determinants of toxicity. The rate of absorption often predicts the onset of action and relies on dosage form, while the extent of absorption (bioavailability) often predicts the intensity of the effect and depends in part on first-pass effects.32,33 Figure 9-1 depicts how changes in the rate of absorption may affect toxicity when the bioavailability is held constant versus how toxicity may be affected by changes in bioavailability when the rate of absorption is held constant. The route by which the xenobiotic enters the body significantly affects both the rate and extent of absorption. As an approximation, the rate of absorption proceeds in the following order from fastest to slowest: intravenous, inhalation > intramuscular, subcutaneous, intranasal, oral > cutaneous, rectal. Following the oral intake of 200 mg of cocaine hydrochloride, the onset of action is 20 minutes, with an average peak concentration of 200 ng/mL.64 In marked contrast, smoking 200 mg of cocaine freebase results in an onset of action of 8 seconds and a peak level of 640 ng/mL, or when administered intravenously as 200 mg cocaine hydrochloride, which then has an onset of action of 30 seconds and a peak level of 1000 ng/mL.64 A xenobiotic must diffuse through a number of membranes before it can reach its site of action. Figure 9-2 shows the number of membranes through which a xenobiotic typically diffuses. Membranes are predominantly composed of phospholipids and cholesterol in addition to other lipid compounds.48 A phospholipid is composed of a polar head and a fatty acid tail, which are arranged P.141 in membranes so that the fatty acid tails are inside and the polar heads face outward in a mirror image.52 Proteins (in a 1:5 ratio with

lipids) are found on both sides of the membranes and may traverse the membrane.48 These proteins may function as receptors and channels. Pores are found throughout the membranes. The principles relating to diffusion apply to absorption, distribution, certain aspects of elimination, and to each instance when a xenobiotic is transported through a membrane.

Figure 9-1. Effects of changes in ka (rate of absorption) and F (bioavailability) on the blood concentration time graph and achieving a toxic threshold. In curves A, B, and C, F is constant as ka is decreased. In curves G, H, and I, k a is constant as F is increased. (Reprinted, with permission, from Riviere JE: Absorption and distribution. In: Hodgson E, Levi P, eds: Introduction to Biochemical Toxicology. Norwalk, CT, Appleton & Lange, 1994, p. 22.)

Transport through membranes occurs via passive diffusion through the membrane, filtration (bulk flow is the major mechanism of transport which occurs with water directly through water pores [aquapores] for small molecules with a molecular weight [MW] < 100), carrier-mediated active or facilitated transport, and, rarely, endocytosis (Fig. 9-3). Most xenobiotics traverse membranes via

simple passive diffusion. The rate of diffusion is determined by the Fick Law of Diffusion (Eq. 9-1) .

The driving force for passive diffusion is the difference in concentration of the xenobiotic on both sides of the membrane. D is a constant for each xenobiotic and is derived when the difference in concentrations between the two sides of the membrane is 1. The larger the surface area A, the higher the rate of diffusion. Most ingested xenobiotics are absorbed more rapidly in the small intestine than in the stomach because of the tremendous increase in surface area created by the presence of microvilli. The partition coefficient K represents the lipid-to-water partitioning of the xenobiotic. To a substantial degree, the more lipid soluble a xenobiotic easily it crosses membranes. Membrane thickness (h) proportional to the rate at which a xenobiotic diffuses membrane. Xenobiotics that are uncharged, nonpolar,

is, the more is inversely through the of low

molecular weight, and of the appropriate lipid solubility have the highest rates of diffusion.

Figure 9-2. Illustration of the number of membranes encountered by a xenobiotic in the processes of absorption and distribution. (Adapted from Riviere JE: Absorption and distribution. In: Hodgson E, Levi P, eds: Introduction to Biochemical Toxicology. Norwalk, CT, Appleton & Lange, 1994, p. 12.)

The extent of ionization of weak electrolytes (weak acids and weak bases) affects their rate of passive diffusion. Nonpolar and uncharged molecules penetrate faster. The Henderson-Hasselbalch relationship is used to determine the degree of ionization. An acid (HA), by definition, gives up a hydrogen ion and a base (B), accepts a hydrogen ion. RCOOH (HA) (ie, aspirin, phenobarbital) and RNH3 + (BH+) are acids and RCOO- (A- ) and RNH2 (B) (amphetamines, tricyclic antidepressants [TCAs]) are bases. The equilibrium dissociation constant Ka can then be described by Equations 9-2A and 9-2B.

To work with these numbers in a more comfortable fashion, the negative log of both sides is determined and results in Equations 3 A and 9-3B.

9-

Figure 9-3. Illustration of transport mechanisms involved in the

passage of xenobiotics across membranes. (Adapted from Gram TE: Drug absorption and distribution. In: Craig CR, Stitzel RE, eds: Modern Pharmacology with Clinical Applications. Boston, Little, Brown, 1997, p. 17.)

P.142 By definition, the negative log of [H+] is expressed as pH and the negative log of Ka is pKa . Rearranging the equations gives the familiar forms of the Henderson-Hasselbalch equations as shown in Equations 9-4A, 9-4B, and 9-4C.

Because noncharged molecules traverse membranes more rapidly, it is understood that weak acids cross membranes more rapidly in an acidic environment and weak bases move more rapidly in a basic environment. When the pH equals the pKa , half of the xenobiotic is charged and half is noncharged. An acid with a low pKa is a strong acid while a base with a low pKa is a weak base. For an acid, a pH less than the pKa favors the protonated or noncharged species facilitating membrane diffusion, whereas for a base, a pH greater than the pKa achieves the same result. Table 9-1 lists the pH of selected body fluids and Figure 9-4 illustrates the extent of charged versus noncharged xenobiotic at different pH and pKa values. Lipid solubility and ionization each have a distinct influence on absorption. Figure 9-5 demonstrates these characteristics for three different xenobiotics. Although the three xenobiotics have similar pKa values, their different partition coefficients result in different degrees of absorption from the stomach.

Specialized transport mechanisms either require energy (adenosine triphosphate [ATP] dependent) to transport xenobiotics against a concentration gradient (active transport), or they can be energy independent (ATP independent) and lack the ability to transport against a concentration gradient (facilitated transport). These transport mechanisms are of importance in numerous parts of the body including the intestines, liver, lungs, kidneys, and the biliary systems. These same principles apply to a small number of lipidinsoluble molecules that resemble essential endogenous agents.24,57 For example, 5-fluorouracil resembles pyrimidine and is transported by the same system, whereas thallium and lead are actively absorbed by the endogenous transport mechanisms that absorb and transport potassium and calcium, respectively.

TABLE 9-1. pH of Selected Body Fluids

Fluids

pH

Cerebrospinal

7.3

Eye

7–8

Gastric

Large

secretions

intestinal

secretions

1–3

8

Plasma

7.4

Rectal fluid: infants and children

7.2–12

Saliva

6.4–7.2

Small

intestinal

secretions:

duodenum

5–6

Small

intestinal

secretions:

ileum

8

Urine

Vaginal

4–8

secretions

3.8–4.5

Adapted from Brody TM: Absorption, distribution, metabolism and elimination. In: Brody TM, Larner J, Minneman KP, Neu HC, eds: Human Pharmacology: Molecular to Clinical, 2nd ed. St. Louis, Mosby, 1994, p. 51.

P.143 P-glycoprotein is a transmembrane protein that is an example of a carrier used for carrier-mediated, active (ATP-dependent) transport. P-glycoprotein is being extensively investigated because of its role in controlling xenobiotic entry into the body and because of its contribution to drug interactions.18,28,66 The discovery of Pglycoprotein resulted from an investigation into why certain tumors exhibit multidrug resistance to many cancer chemotherapy agents. Pglycoprotein is an efflux transporter located in the intestines, renal proximal tubule, hepatic bile canaliculi, and blood–brain barrier that is responsible for transporting compounds from inside to outside the cell.14 First-generation transport inhibitors such as amiodarone, ketoconazole, quinidine, and verapamil are responsible for increasing body levels of P-glycoprotein substrates such as digoxin, the protease inhibitors, vinca alkaloids, and paclitaxel. St. John's wort is a transport inducer, and lowers serum concentrations of these same

agents. Second- and third-generation agents that will affect transport with a higher affinity and specificity are in development.58 Many of the same agents that affect cytochrome P450 (CYP) 3A4 also affect P-glycoprotein.

Figure 9-4. Effect of pH on the ionization of aspirin (pKa = 3.5) and methamphetamine (pKa = 10).

Figure 9-5. Influence of increasing lipid solubility on the amount of xenobiotic absorbed from the stomach for three xenobiotics with similar pKa values. The number above each column is the oil/water equilibrium partition coefficient. (Reprinted, with permission, from Brody T: Absorption, distribution, metabolism and elimination. In: Brody TM, Larner J, Minneman KP, Neu HP, eds: Human Pharmacology: Molecular to Clinical, 2nd ed. St. Louis, Mosby, 1994, p. 50.)

Filtration is generally considered to be of limited importance in the absorption of most xenobiotics, but is substantially more important with regard to elimination. Endocytosis, which describes the encircling of a xenobiotic by a cellular membrane, is responsible for the absorption of large macromolecules such as the oral Sabin polio vaccine.57 Gastrointestinal absorption is affected by xenobiotic-related characteristics such as dosage form, degree of ionization, partition

coefficient, and patient factors such as gastrointestinal blood flow, gastrointestinal motility, and the presence or absence of food, ethanol, or other interfering substances (Fig. 9-6) . The formulation of a xenobiotic is extremely important in predicting GI absorption. Disintegration and dissolution must precede absorption. Controlled-release, extended-release, and sustainedrelease formulations are designed to release the xenobiotic over a prolonged period of time in order to simulate the blood concentrations achieved with the use of a constant intravenous infusion. These formulations minimize blood level fluctuations, reduce peak-related side effects, reduce dosing frequency, and improve patient compliance. A variety of products employ different pharmaceutical strategies, including dissolution control (encapsulation or matrix; Feosol), diffusion control (membrane or matrix; Slow K, Plendil ER), erosion (Sinemet CR), osmotic pump systems (Procardia XL, Glucotrol XL), and ion exchange resins (MS Contin suspension). Overdoses with controlled-release formulations result in a prolonged absorption phase, a delay to peak concentrations, and a prolonged duration of effect.7 Enteric-coated (acetylsalicylic acid [ASA], divalproex sodium) formulations resist disintegration and delay the time to onset of effect.6 Dissolution is affected by ionization, solubility, and the partition coefficient, as noted earlier. In the overdose setting, the formation of poorly soluble or adherent masses such as concretions (meprobamate) and bezoars (bromide) significantly delays the time to onset of toxicity (Table 9-2) .4,9,25,26 Most ingested xenobiotics are primarily absorbed in the small intestine as a result of the large surface area and extensive blood flow of the small intestines.53 Critically ill patients who are hypotensive, have a reduced cardiac output, or are receiving vasoconstrictors such P.144 as norepinephrine, have a decreased perfusion of vital organs, including the GI tract, kidneys, and liver.3 Not only is absorption

delayed, but elimination is also diminished.51 Extremely short gastrointestinal transit times reduce absorption. This change in transit time is the unproven rationale for our prior substantial use of cathartics and current use of whole-bowel irrigation. Delays in emptying of the stomach impair absorption as a result of the delay in delivery to the small intestine. Delays in gastric emptying occur as a result of the presence of food, especially fatty meals; agents with anticholinergic, opioid, or antiserotonergic properties; ethanol; and any agent that results in pylorospasm (salicylates, iron).

Figure 9-6. Determinants of absorption.

Bioavailability is a measure of the amount of xenobiotic that reaches the systemic circulation unchanged (Eq. 9-5) .34 The fractional absorption (F) of a xenobiotic is defined by the area under the plasma drug concentration versus time curve (AUC) of the designated route of absorption as compared to the AUC of the intravenous route. The AUC for each route represents the amount absorbed.

Gastric emptying and activated charcoal are used to decrease the bioavailability of ingested xenobiotics. The oral administration of certain chelators (deferoxamine, D-penicillamine) actually enhances the bioavailability of the complexed xenobiotic. The net effect of some chelators, such as succimer, is a reduction in body burden via enhanced urinary elimination even though absorption is enhanced.27 Historically, the enteral administration of sodium bicarbonate was used to theoretically reduce the solubility of iron salts; unfortunately, this approach was ineffective.13 Presystemic metabolism may decrease or increase the bioavailability of a xenobiotic or a metabolite.47 The GI tract contains microbial organisms that can metabolize or degrade xenobiotics such as digoxin and oral contraceptives, and enzymes such as peptidases that metabolize insulin.48 However, in rare cases, gastrointestinal hydrolysis can convert a xenobiotic into a toxic metabolite, as occurs when amygdalin is enzymatically hydrolyzed to produce cyanide, a metabolic step that is not produced following intravenous amygdalin administration.23 Xenobiotic metabolizing enzymes and Pglycoprotein can also affect bioavailability. Xenobiotic metabolizing enzymes are found in the lumen of the small intestine and can substantially decrease the absorption of a xenobiotic.39,66 Some of the xenobiotic that enters the cell can then be removed by the Pglycoprotein transporter out of the cell and back into the lumen to be exposed again to the metabolizing enzymes.39,66 Venous drainage from the stomach and intestine delivers orally (and intraperitoneally) administered xenobiotics to the liver via the portal vein and avoids direct delivery to the systemic circulation. This venous drainage allows hepatic metabolism to occur before the xenobiotic reaches the blood and is referred to as the first-pass effect. 2,69 The hepatic extraction ratio is the percentage of xenobiotic metabolized in one pass of blood through the liver.42 Drugs that undergo significant first-pass metabolism (eg, propranolol, verapamil) are used at much lower IV doses than oral doses. Some drugs are not administered by the oral route at all because of significant first-pass effect (eg,

lidocaine, nitroglycerin).4 Instead, sublingual or rectal administration of agents such as nitroglycerin is used to bypass the portal circulation and avoid first-pass metabolism. In the overdose setting, presystemic metabolism may be saturated, leading to an increased bioavailability of xenobiotics such as cyclic antidepressants, phenothiazines, opioids, and many β-adrenergic antagonists.50 Hepatic metabolism usually transforms the xenobiotic into a lessactive metabolite, but occasionally results in the formation of a more toxic agent such as occurs with the transformation of parathion to paraoxon.45 Biliary excretion into the small intestine usually occurs for these transformed xenobiotics of molecular weights >350 daltons and may result in a xenobiotic appearing in the feces, even though it had not been administered orally.30,48,60 Hepatic conjugated metabolites such as glucuronides may be hydrolyzed in the intestines to the parent form or to another active metabolite that can be reabsorbed by the enterohepatic circulation.36,43,46,48 The enterohepatic circulation may be responsible for what is termed a double-peak phenomenon following the administration of certain xenobiotics.57 The double-peak phenomenon is characterized as a serum concentration which falls and then rises again as xenobiotic is reabsorbed from the GI tract. P.145 Other causes include variability in stomach emptying, presence of food, or failure of a tablet dosage form.57

TABLE 9-2. Xenobiotics that Form Concretions or Bezoars, Delay Gastric Emptying, and/or Result in Pylorospasm

Anticholinergics

Meprobamate

Barbiturates

Methaqualone

Bromides

Opioids

Enteric-coated

tablets

Phenytoin

Glutethimide

Salicylates

Iron

Verapamil

Distribution After the xenobiotic reaches the systemic circulation or central compartment, it is available for transport to peripheral tissue compartments. Both the rate and extent of distribution depend on many of the same principles discussed with regard to diffusion. Additional factors include affinity of the xenobiotic for plasma and tissue proteins, acid–base status of the patient (which affects ionization), and physiologic barriers to distribution (blood–brain barrier, placental transfer, blood–testis barrier).20,31,52 Blood flow accounts for the initial phase of distribution, whereas xenobiotic affinities determine the final distribution pattern. Hypoperfusion of the various organs in the critically ill affects absorption, distribution, and elimination.67 Plasma and serum concentrations are terms often used

interchangeably by medical personnel. When a reference or calculation is made with regard to a concentration in the body, it is actually a plasma concentration. When concentrations are measured in the laboratory, a serum concentration (clotted and centrifuged blood) is often determined. In reality, the laboratory measurements of most xenobiotics in serum or plasma are nearly equivalent. Frequently, this is not the case for whole-blood determination if the xenobiotic distributes into the erythrocyte, such as lead and most other heavy metals. Volume

of

distribution (Vd) is the proportionality term used to relate

the dose of the xenobiotic that the individual receives and the resultant plasma concentration. Vd is an apparent or theoretic volume into which a xenobiotic distributes. It is a measure of how much xenobiotic is located inside and outside of the plasma compartment, because only the plasma compartment is routinely assayed. In a 70-kg adult male, the total body fluid (TBF) is 60% of total body weight or 42 L, with two-thirds (28 L) of the fluid accounted for by intracellular fluid. Of the 14 L of extracellular fluid, 8 L are considered interstitial or between the cells; 3 L, or 0.04 L/kg, is plasma; and 6 L, or 0.08 L/kg, is blood. If 42 g of a xenobiotic is administered and remains in the plasma compartment (Vd = 0.04 L/kg), the concentration would be 15 g/L. If the distribution of the 42 g of xenobiotic approximated TBF (methanol; 0.6 L/kg), the concentration would be 100 mg/dL. These calculations can be performed by using Equation 9-6, where S equals the percent pure drug if a salt form is used.

Experimental determination of a Vd involves administering an IV dose of the xenobiotic and extrapolating the plasma concentration time curve back to time zero (C0 ). If the determination takes place after steady state has been achieved, the volume of distribution is then referred to as the Vdss. For many xenobiotics the Vd is known and

readily available in the literature (Table 9-3). When the Vd and the dose ingested are known, a maximum predicted plasma concentration can be calculated, after assuming all of the xenobiotic is absorbed and no elimination occurred. This assumption usually overestimates the plasma concentration. Distribution is complex, and differential affinities for various storage sites (plasma proteins, liver, kidney, fat, and bone) in the body determine where a xenobiotic ultimately resides. For the purposes of determining the utility of extracorporeal removal of a xenobiotic, a low Vd is often considered to be 1 L/kg), it is unlikely that hemodialysis, hemoperfusion, or exchange transfusion would be effective because most of the xenobiotic is outside of the plasma compartment. Plasma protein binding also influences this decision. If the xenobiotic is more tightly bound to plasma proteins than to activated charcoal, then hemoperfusion is unlikely to be beneficial even if the Vd of the xenobiotic is small. In addition, high plasma protein binding limits the effectiveness of hemodialysis, because only unbound xenobiotic will freely cross the dialysis membrane. Exchange transfusion can be effective for a xenobiotic with a small Vd and substantial plasma protein binding, because both bound and free xenobiotic are removed simultaneously.

Elimination Removal of a parent compound from the body (elimination) begins as soon as the xenobiotic is delivered to clearance organs such as the liver, kidneys, and lungs. Elimination begins immediately, but may not be the predominant kinetic process until absorption and distribution are substantially completed. As expected, the functional integrity of the major organ systems (cardiovascular, lungs, renal, hepatic) are major determinants of the efficiency of xenobiotic removal and of therapeutically administered antidotes. The xenobiotics themselves may cause renal or hepatic failure (acetaminophen), subsequently compromising their own elimination. Other factors influencing elimination include age (enzyme

maturation), competition or inhibition of elimination processes by interacting xenobiotics, saturation of enzymatic processes, gender, genetics, and the physicochemical properties of the xenobiotic.41 Elimination can be accomplished by biotransformation to one or more metabolites, or by excretion from the body of unchanged xenobiotic. Excretion can occur via the kidneys, lungs, GI tract, and body secretions (sweat, tears, milk). Hydrophilic (polar) or charged xenobiotics and their metabolites, because of their water solubility, are generally excreted via the kidney. The majority of xenobiotic metabolism occurs in the liver but it also commonly occurs in the blood, skin, GI tract, placenta, or kidneys. Lipophilic (noncharged or nonpolar) xenobiotics are usually metabolized in the liver to hydrophilic metabolites, which are then excreted by the kidneys.21,45 These metabolites are generally inactive, but if active, may contribute to toxicity. Examples include the metabolism of amitriptyline to nortriptyline, procainamide to N-acetylprocainamide, and meperidine to normeperidine (Table 9-4) . Metabolic reactions catalyzed by enzymes (categorized as either phase I or phase II) generally result in pharmacologically active P.148 metabolites; frequently, the latter have different toxicities than the parent compounds. Phase I, or preparative metabolism, which may or may not precede phase II, is responsible for introducing polar groups onto nonpolar xenobiotics by oxidation, reduction, and hydrolysis or dealkylation. The result of phase I metabolism is commonly to add or expose polar groups.19,43 Phase II, or synthetic reactions, conjugate the polar group with a glucuronide, sulfate or acetate (often a lesspolar metabolite, which is reabsorbed), methyl groups, glutathione (mercapturic acid synthesis), and amino acids (glycine, taurine, and glutamic acid).12,19,43

TABLE 9-4. Examples of Xenobiotics Activated by Human P450

CYP1A1

Benzene

Benzo[a]pyrene and other polycyclic aromatic hydrocarbons

Carbon tetrachloride Chloroform

CYP1A2

Dichloromethane

Acetaminophen

Ethylene

dibromide

NNK

Ethylene

dichloride

CYP2A6

Ethyl

NNK

N-Nitrosodimethylamine

CYP2B6

CYP2C

None

CYP2D6

NNK

carbamate

Trichloroethylene

8,9,18,19

Vinyl

chloride

known

CYP3A4

Acetaminophen

Aflatoxin B and G

CYP2E1

Acetaminophen

Cyclophosphamide

Ifosphamide

Acrylonitrile

NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-/-butanone, a tobacco-specific nitrosamine. Adapted from Guengerich, FP: Reactions and significance of cytochrome P450 enzymes. J Biol Chem 1991;266:10019–10022. Adapted, with permission, from Parkinson A: Biotransformation of xenobiotics. In: Klaassen C, ed: Casarett & Doull's Toxicology: The Basic Science of Poisons, 5th ed. New York. McGraw-Hill, 1996, p. 154.

Comparatively, phase II reactions produce a much larger increase in hydrophilicity than phase I reactions. The enzymes involved in these reactions have low substrate specificity, and those in the liver are usually localized to either the endoplasmic reticulum (microsomes) or the soluble fraction of the cytoplasm (cytosol).43 The location of the enzymes becomes important if they form reactive metabolites which then concentrate at the site of metabolism and cause toxicity (Table 9-5). For example, acetaminophen causes centrilobular necrosis because the cytochrome P450 2E1 isoenzymes, which form N-acetylp-benzoquinoneimine (NAPQI), the toxic metabolite, are located in their highest concentration in that zone of the liver. The enzymes that metabolize the largest variety of xenobiotics are heme-containing proteins referred to as CYP monooxygenase enzymes. 24,43 This group of enzymes, formerly called the mixed function oxidase system, is found in abundance in the microsomal

endoplasmic reticulum of the liver. These enzymes primarily catalyze the oxidation of xenobiotics. However, cytochrome P450 in a reduced state (Fe2 +) binds carbon monoxide. Its discovery and initial name resulted from spectral identification of the CO-bound cytochrome P450, which absorbs light maximally at 450 nm. The cytochrome P450 system is composed of many enzymes grouped into gene families and subfamilies, of which approximately 57 of these functional human genes have been sequenced. Members of a gene family have >40% similarity of their amino acid sequencing and subfamilies have >55% similarity. Toxicity may result from induction or inhibition of cytochrome P450 isoenzymes by another xenobiotic, resulting in a consequential drug interaction (Table 9-6). Many of these interactions are predictable based on the known xenobiotic affinities and their capability to induce or inhibit the P450 system.10,37,43,44,59 However, polymorphism (individual genetic expression of isoenzymes),1 stereoisomer variability68 (enantiomers with different potencies and isoenzyme affinities), and the capability to metabolize a xenobiotic by alternate pathways, contribute to unexpected metabolic outcomes. The pharmaceutical industry is now exploiting the concept of chiral switching (marketing a single enantiomer instead of the racemic mixture) to alter efficacy or sideeffect profiles. Enantiomers are named either according to the direction in which they rotate polarized light (l or – for levorotatory, and d or + for dextrorotatory), or according to the absolute spatial orientation of the groups at the chiral center (S or R). Chiral means “hand― in Greek, and the latter designations refer to either sinister (left-handed) or rectus (right-handed). There is no direct correlation between levorotatory or dextrorotatory and S and R.63

TABLE 9-5. General Pathways of Xenobiotic Biotransformation and Their Major Subcellular Location

Reaction

Enzyme

Localization

Phase 1

Hydrolysis

Reduction

Carboxylesterase

Microsomes,

Peptidase

Blood,

Epoxide

Microsomes,

lysosomes

Azo- and nitro-

Microflora,

reduction

microsomes,

Carbonyl

reduction

Cytosol

Disulfide

reduction

Cytosol

Sulfoxide

Quinone

Oxidation

hydrolase

reduction

reduction

cytosol

Cytosol

Cytosol, microsomes

Reductive dehalogenation

Microsomes

Alcohol dehydrogenase

Cytosol

Aldehyde dehydrogenase

Mitochondria, cytosol

cytosol

cytosol

Aldehyde

oxidase

Cytosol

Xanthine

oxidase

Cytosol

Monoamine

Diamine

oxidase

oxidase

Prostaglandin synthase

H

Mitochondria

Cytosol

Microsomes

Flavinmonooxygenases

Microsomes

Cytochrome

Microsomes

P450

Phase II

Glucuronide

Microsomes

conjugation

Sulfate

conjugation

Cytosol

Glutathione conjugation

Cytosol, microsomes

Amino acid conjugation

Mitochondria, microsomes

Acylation

Mitochondria, cytosol

Methylation

Cytosol

Reprinted, with permission, from Parkinson A: Biotransformation of xenobiotics. In: Klaassen CD, ed: Casarett & Doull's Toxicology: The Basic Science of Poisons, 5th ed. New York, McGraw-Hill, 1996, p. 114.

Excretion is primarily accomplished by the kidneys, although, as mentioned earlier, biliary, pulmonary, and body fluid secretions contribute to lesser degrees. Urinary excretion occurs through glomerular filtration, tubular secretion, and passive tubular reabsorption. The glomerulus filters unbound xenobiotics of a particular size and shape in a manner that is not saturable, subject to renal blood flow and perfusion. Passive tubular reabsorption accounts for the reabsorption of noncharged, lipid-soluble xenobiotics, and is therefore influenced by the pH of the urine and the pKa of the xenobiotic. The principles of diffusion discussed earlier permit, for example, the ion trapping of salicylate (pK a = 3.5) in the urine through urinary alkalinization. Tubular secretion is an active process subject to saturation and drug interactions (Table 9-7) . Tubular secretion is often less developed in the neonate.

Classical Versus Physiologic Compartment Toxicokinetics Models exist to study and describe the movement of xenobiotics in the body with mathematical equations. Traditional compartmental models (one or two compartments) are data-based and assume that changes in plasma concentrations represent tissue concentrations

(Fig. 9-7) . 42 Advances in computer technology facilitate the use of the classic concepts developed in the late 1930s.62 Physiologic models consider the movement of xenobiotics based on known or theorized biologic processes and are unique for each xenobiotic. This allows the prediction of tissue concentrations, while incorporating the effects of changing physiologic parameters, and affording better extrapolation from laboratory animals.72 Unfortunately, physiologic modeling is still in its infancy and the mathematical modeling it entails is often very complex.16 Regardless, the most commonly used mathematical equations are based on traditional compartmental modeling. P.149 P.150 P.151 The one-compartment model is the simplest for analytic purposes and is applied to xenobiotics that rapidly enter and distribute throughout the body. This model assumes that changes in plasma concentrations will result in, and reflect proportional changes in tissue concentrations. Many xenobiotics, such as digoxin, lithium, and lidocaine, do not instantaneously equilibrate with the tissues and are better described by a two-compartment model. In the twocompartment model, a xenobiotic is distributed instantaneously to highly perfused tissues (central compartment) and then is secondarily, and more slowly, distributed to a peripheral compartment. Elimination is assumed to take place from the central compartment.

TABLE 9-6. Cytochrome P450 isozymes and P-glycoprotein: Selected inducers, Inhibitors, and Substratesa

TABLE 9-7. Xenobiotics Secreted by Renal Tubules

Organic

Anion

Transport

Organic

Cation

Acetazolamide

Acetylcholine

Bile salts

Amiodarone

Cephalosporins

Atropine

Indomethacin

Cimetidine

Hydrochlorothiazide

Digoxin

Furosemide

Diltiazem

Methotrexate

Dopamine

Penicillin

Epinephrine

G

Probenecid

Morphine

Prostaglandins

Neostigmine

Salicylate

Procainamide

Quinidine

Transport

Quinine

Triamterene

Trimethoprim

Verapamil

Figure 9-7. Various classical compartmental models. k =

pharmacokinetic rate constants; 1 = plasma or central compartment; 2 = tissue compartment; k12 = rate constant into tissue from plasma; k21 = rate constant into plasma from tissue; k a = absorption rate constant. (Reprinted, with permission, from Shargel L, Yu A: Introduction to Pharmacokinetics: Applied Biopharmaceutics and Pharmacokinetics, 3rd ed. Norwalk, CT, Appleton & Lange, 1993, p. 40.)

If the rate of a reaction is directly proportional to the concentration of xenobiotic, it is termed first order or linear. Processes that are capacity limited or saturable are termed nonlinear (not proportional to the concentration of xenobiotic) and are described by the Michaelis-Menten equation, which is derived from enzyme kinetics. Calculus is used to derive the first-order equation, as done by Yang and Andersen.72 Rate is directly proportional to concentration of xenobiotic as in Equation 9-8.

An infinitesimal change in concentration of a xenobiotic (dC) with respect to an infinitesimal change in time (dt) is directly proportional to the concentration (C) of the xenobiotic as in Equation 9-9.

The proportionality constant k is added to the right side of the expression to mathematically allow the introduction of an equal sign. The constant k represents all of the bodily factors, such as metabolism and excretion, that contribute to the determination of concentration (Eq. 9-10) .

Introducing a negative sign to the left-hand side of the equation

describes the (Eq. 9-11) .

“decay―

or

decreasing

xenobiotic

concentration

This equation is impractical because of the difficulty of measuring infinitesimal changes in C or t. Therefore, the use of calculus allows the integration or summing of all of the changes from one concentration to another beginning at time zero and terminating at time t. This relationship is mathematically represented by the integration sign (∫). ∫ means to integrate the term from concentration at time zero (C 0 ) to concentration at a given time t (C t ). ∫ means the same with respect to time, where t 0 = zero. Prior to this application, the previous equation is first rearranged (Eq. 9-12) .

The integration of dC divided by C is the natural logarithm of C (ln C) and the integration of dt is t (Eq. 9-13) .

The vertical straight lines proscribe the evaluation of the terms between those two limits. The following series of manipulations are then performed (Eq. 9-14A-D) .

P.152 Equation 9-14D can be recognized as taking the form of an equation of a straight line (Eq. 9-15), where the slope is equal to the rate constant k and the intercept is C 0 .

Instead of working with natural logarithms, an exponential form (the antilog)

of Equation

9-14D may be used (Eq. 9-16) .

Graphing the ln (natural logarithm) of the concentration of the xenobiotic at various times for a first-order reaction is a straight line. Equation 9-16 describes the events when only one first-order process occurs. This is appropriate for a one-compartment model (Fig. 9-8) . In this model, regardless of the concentration of the xenobiotic, the rate (percentage) of decline is constant. The absolute amount of xenobiotic eliminated changes continuously while the percent eliminated remains constant. k is reported in h- 1. A k of 0.10 h- 1 means that the xenobiotic is being processed (eliminated) at a rate of 10% per hour. k is often designated as ke and referred to as the elimination rate constant. The time necessary for the xenobiotic concentration to be reduced by 50% is called the half-life. The halflife is determined by a rearrangement of Equation 9-14D whereby C2 becomes C at time t2 and C1 becomes C at t1 , and by rearrangement giving Equation 9-17.

Substitution of 2 for C 1 and 1 for C 2 or 100 for C 1 and 50 for C 2 gives Equations 9-18A and 9-18B.

Figure 9-8. A one-compartment pharmacokinetic model

demonstrating (A) graphical illustration; (B) hypothetical dataset; (C) linear plot; and (D) semilogarithmic plot. (Modified and reprinted, with permission, from Yang R, Andersen M: Pharmacokinetics. In: Hodgson E, Levi P, eds: Introduction to Biochemical Toxicology. Norwalk, CT, Appleton & Lange, 1994, p. 54.)

The use of semilog paper facilitates graphing the first-order equation. However, because semilog paper plots log (not ln) versus time, to retain appropriate mathematical relationships the rate constant or slope (k) must be divided by 2.303 (see Fig. 9-8) . The mathematical modeling becomes more complex when more than one first-order process contributes to the overall elimination process. The equation that incorporates two first-order rates is used for a two-compartment model and is Equation 9-19.

Figure 9-9 demonstrates a two-compartment model where α often represents the distribution phase and β is the elimination phase. The rate of reaction of a saturable process is not linear (not proportional to the concentration of xenobiotic) when saturation occurs (Fig. 9-10). This model is best described by the MichaelisMenten equation used in enzyme kinetics (Eq. 9-20) in which v is the velocity or rate of the enzymatic reaction; C is the concentration of the xenobiotic; V m a x is the maximum velocity of the reaction between the enzyme and the xenobiotic; and K m is the affinity constant between the enzyme and the xenobiotic.72

Application of this equation to toxicokinetics requires v to become the infinitesimal change in concentration of a xenobiotic (dC) with respect to an infinitesimal change in time (dt) as previously

discussed (see Eq. 9-10). V m a x and Km both reflect the influences of diverse biologic processes. The Michaelis-Menten equation then becomes Equation 9-21, in which the negative sign again represents decay.

When the concentration of the xenobiotic is very low (CKm ), the rate becomes fixed at a constant maximal rate regardless of the exact concentration of the xenobiotic, termed a zero-order reaction. Tables 9-8A and 9-8B compare a first-order reaction to a zero-order reaction. In this particular example, zero order is faster, but if the fraction of xenobiotic eliminated in the first-order example were P.153 0.4, then the amount of xenobiotic in the body would fall below 100 before the xenobiotic in the zero-order example. It is inappropriate to perform half-life calculations on a xenobiotic displaying zero-order behavior because the metabolic rates are continuously changing. Following overdoses, enzyme saturation is a common occurrence as the capacity of enzyme systems are overwhelmed.

Figure 9-9. Mathematical and graphical forms of a twocompartment classical pharmacokinetic model. ka represents the absorption rate constant, ke represents the elimination rate constant, α represents the distribution phase, and β the elimination phase. (Reprinted, with permission, from Yang R, Andersen M: Pharmacokinetics. In: Hodgson E, Levi P, eds: Introduction to Biochemical Toxicology. Norwalk, CT, Appleton & Lange, 1994, p. 55.)

Clearance Clearance (Cl) is the relationship between the rate of transfer or elimination of a xenobiotic from a reference fluid (usually plasma) to the plasma concentration of the xenobiotic and is expressed in units of volume per unit time (ie, mL/min) (Eq. 9-23) .22,42,54

Figure 9-10. Concentration versus time curve for a xenobiotic showing nonlinear pharmacokinetics concentrations Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section I - Biochemical and Molecular Basis > Chapter 12 - Chemical Principles

Chapter

12

Chemical

Principles

Stephen J. Traub Lewis S. Nelson Chemistry is the science of matter; it encompasses the structure, physical properties, and reactivities of atoms and their compounds. In many respects, toxicology is the science of the interactions of matter with physiologic entities. Chemistry and toxicology are intimately linked. The study of the principles of inorganic, organic, and biologic chemistry offer important insight into the mechanisms and clinical manifestations of xenobiotics and poisoning, respectively. This chapter reviews many of these tenets and provides relevance to the current practice of medical toxicology.

The Structure of Matter Basic

Structure

Matter includes the substances of which everything is made. Elements are the foundation of matter, and all matter is made from one or more of the known elements. An atom is the smallest quantity

of a given element that retains the properties of that element. Atoms consist of a nucleus, incorporating protons and neutrons, coupled with its orbiting electrons. The atomic number is the number of protons in the nucleus of an atom, and is a whole number that is unique for each element. Thus, elements with 6 protons are always carbon, and all forms of carbon have exactly 6 protons. However, although the vast majority of carbon nuclei have 6 neutrons in addition to the protons, accounting for an atomic mass (ie, protons plus neutrons) of 12 (12C), a small proportion of naturally occurring carbon nuclei, called isotopes, have 8 neutrons and a mass number of 14 (14C). This is the reason that the atomic weight of carbon displayed on the periodic table is 12.011, and not 12, as it actually represents the average atomic masses of all isotopes found in nature weighted by their frequency of occurrence. Moreover, 14C is actually a radioisotope, which is an isotope with an unstable nucleus that emits radiation (particles and/or rays), presumably in an effort to attain a stable state (Chap. 128). The atomic weight, measured in grams/mole (g/mol), also indicates the molar mass of the element. That is, in 1 atomic weight (12.011 g for carbon) there is 1 mole of atoms (6.023 × 1023 atoms). Elements combine chemically to form compounds, which generally have physical and chemical properties that differ from those of the constituent elements. The elements in a compound can only be separated by chemical means that destroy the original compound, as occurs during the burning (ie, oxidation) of a hydrocarbon which releases the carbon as carbon dioxide. This important property differentiates compounds from mixtures, which are combinations of elements or compounds that can be separated by physical means. For example, this occurs during the distillation of petroleum into its hydrocarbon components or the evaporation of sea water to leave sodium chloride. With notable exceptions, such as the elemental forms of many metals or halogens (eg, Cl2 ), most xenobiotics are compounds or mixtures. Dimitri Mendeleev, a Russian chemist in the mid-19th century,

recognized that when all of the known elements were arranged in order of atomic weight, certain patterns of reactivity became apparent. The result of his work was the Periodic Table of the Elements (Fig. 12-1), which, with some minor alterations, is still an essential tool today. All of the currently recognized elements are represented; those heavier than uranium are not known to occur in nature. Many of the symbols used to identify the elements refer to the Latin name of the element. For example, silver is Ag, for argentum, and mercury is Hg, for hydrargyrum, literally “silver water.― The reason for the periodicity of the table relates to the electrons that circle the nucleus in discrete orbitals. Although the details of quantum mechanics and electronic configuration are complex, it is important to review some aspects in order to predict chemical reactivity. Orbitals, or quantum shells, represent the energy levels in which electrons may exist around the nucleus. The orbitals are identified by various schemes, but the maximum number of electrons each orbital may contain is calculated as 2x 2 , where x represents the numerical rank order of the orbital. Thus, the first orbital may contain 2 electrons, the second orbital may contain 8, the third may contain 18, and so on. However, the outermost shell (designated by s, p, d nomenclature) of each orbital may only contain up to 8 electrons. This is irrelevant through element P.186 P.187 20, calcium, because there is no need to fill the third-level or d shells. Even though the third orbital may contain 18 electrons, once 8 are present, the 4s electrons dip below the 3d electrons in energy and this shell begins to fill. This occurs at element 21, scandium, and accounts for its chemical properties and those of the other transition elements. Note that hydrogen and helium are unique in needing only 2 electrons to complete their valence shell; all other elements require 8 to be complete. Also, because the inert gas elements, which are also known as noble gases, have complete outermost

orbitals, they are unreactive under standard conditions. Transition elements are chemically defined as elements which form at least one ion with a partially filled subshell of d electrons.

In general, only electrons in unfilled shells, or valence shells, are involved in chemical reactions. This property relates to the fact that the most stable form of an element occurs when the configuration of its valence shell resembles that of the nearest noble gas, found in

Figure

12-1. The periodic table of the elements.

In general, only electrons in unfilled shells, or valence shells, are involved in chemical reactions. This property relates to the fact that the most stable form of an element occurs when the configuration of its valence shell resembles that of the nearest noble gas, found in group 0 on the periodic table. This state can be obtained through either the gaining, losing, or sharing of electrons with other elements and is the basis for virtually all chemical reactions.

Inorganic The

Chemistry

Periodic

Chemical

Table

Reactivity

Broadly, the periodic table is divided into metals and nonmetals. Metals, in their pure form, are typically malleable solids that conduct electricity, whereas nonmetals are usually dull, fragile, nonconductive compounds (C, N, P, O, S, Se, halogens). The metals are found on the left side of the periodic table, and account for the majority of the elements, whereas the nonmetals are on the right side. Separating the two groups are the metalloids, which fall on a jagged line starting with boron (B, Si, Ge, As, Sb, Te, At). These agents have chemical properties that are intermediate between the metals and the nonmetals. Each column of elements is termed a family or group, and each row is a period. Although conceived and organized in periods, trends in the chemical reactivity, and therefore toxicity, typically exist within the groups. The ability of any particular element to produce toxicologic effects relates directly to one or more of its many physicochemical properties, which may, to some extent, be predicted by their location

on the periodic table. For example, the substitution of arsenate for phosphate in the mitochondrial production of adenosine triphosphate (ATP) creates adenosine diphosphate monoarsenate (Chap. 13) . Because this compound is unstable and not useful as an energy source, energy production by the cell fails; in this manner arsenic “uncouples― oxidative phosphorylation. Similarly, the existence of an interrelationship between Ca2 + and either Mg2 + or Ba2 + is predictable, although the actual effects are not. That is, under most circumstances, Mg2 + is a Ca2 + antagonist, and patients with hypermagnesemia present with neuromuscular weakness caused by blockade of myocyte calcium channels. Alternatively, Ba2 + mimics C a2 + and closes Ca2 +-dependent K+ channels in myocytes, producing life-threatening hypokalemia. Additionally, the physiologic relationship between lithium (Li+ ), potassium (K+), and sodium (Na+) are consistent with their chemical similarities (all alkali metals in Group IA). However, the clinical similarity between thallium (thallous) ion (Tl +) and K+ is not predictable. Other than their monovalent nature (ie, +1 charge), it is difficult to predict the substitution of Tl+ (Group IIIA, Period 6) for K+ (Group IA, Period 4) in membrane ion channel functions, until the similarity of their ionic radii is known (Tl+, 1.47Å; K+ , 1.33Å).

The Alkali (Group IA: Li, Na, K, Rb, Cs, Fr) and Alkaline Earth (Group IIA: Be, Mg, Ca, Sr, Ba, Ra) Metals Alkali metals and hydrogen (not an alkali metal on earth) have a single outer valence electron and lose this electron easily to form compounds with a valence of 1+. The alkaline earth metals (between the alkali and rare earth, Group IIIB) readily lose 2 electrons, and their cations have a 2+ charge. In their metallic form, members of both of these groups react violently with water to liberate strongly basic solutions, accounting for their group names (2Na0 + 2H2 O → 2NaOH + H2 ). The soluble ionic forms of sodium, potassium, or

calcium, which are critical to survival, also produce life-threatening symptoms following excessive intake (Chap. 17). Toxins may interfere with the physiologic role of these key electrolytes. Li+ may mimic potassium and enter neurons through K + channels, following which it serves as a poor substrate for the repolarizing Na + - K+ ATPase. Thus, lithium interferes with cellular potassium homeostasis and alters neuronal repolarization accounting for the neuroexcitability manifesting as tremor. Similarly, as noted previously, the molecular effects of Mg2 + and Ba2 + may supplant those of calcium. More commonly though, the consequential toxicities ascribed to alkali or alkaline earth salts actually relate to the anionic component. In the case of NaOH or Ca(OH)2 , it is a hydroxide anion (not the hydroxyl radical), while it is a CN- anion in patients poisoned with potassium cyanide (KCN).

The Transition Metals (Group IB to VIIIB) Unlike the alkali and alkaline earth metals, most other metallic elements are neither soluble nor reactive. This includes the transition metals, a large group that contains several ubiquitous metals such as iron (Fe) and copper (Cu). These elements, in their metallic form, are widely used both in industrial and household applications because of their high tensile strength, density, and melting point, which is partly a result of their ability to delocalize the electrons in the d orbital throughout the metallic lattice. Transition metals also form brightly colored salts that find widespread applications including pigments for paints or fireworks. However, the ionic forms, unlike the metallic form, of these elements are typically highly reactive and toxicologically important. Transition elements are chemically defined as elements which form at least one ion with a partially filled subshell of d electrons. Because the transition metals have partially filled valence shells, they are capable of obtaining several, usually positive, oxidation states. This important mechanism explains the role of transition metals in redox reactions generally as electron acceptors (see Oxidation-Reduction below). This reactivity is used by

living organisms in various physiologic catalytic and coordination roles, such as at the active sites of enzymes and in hemoglobin, respectively. Expectedly, the substantial reactivity of these transition metal elements is highly associated with cellular injury caused by the generation of reactive oxygen species. For example, manganese ion exposure is implicated in the free radical damage of the basal ganglia causing parkinsonism.

The

Heavy

Metals

Heavy metal is often loosely used to describe all metals of toxicologic significance, but in reality, the term should be reserved to describe only those metals in the lower period of the periodic table, particularly those with atomic masses greater than 200. The chemical properties and toxicologic predilection of this group vary among the agents, but their unifying toxicologic mechanism is electrophilic interference with nucleophilic sulfhydryl-containing enzymes. Some of the heavy metals also participate in the generation of free radicals through Fenton chemistry (Fig. 12-2). The likely determinant of the specific toxicologic P.188 effects produced by each metal is the tropism for various physiologic systems, enzymes, or microenvironments; thus the lipophilicity, water solubility, ionic size, and other physicochemical parameters are undoubtedly critical. Also, because the chemistry of metals varies dramatically based on the chemical form (ie, organic, inorganic, or elemental), as well as the charge on the metal ion, prediction of the clinical effects of a particular metal is often difficult.

Figure 12-2. The Fenton and Haber-Weiss reactions which are the two most important mechanisms to generate hydroxyl radicals are both mediated by transition metals (TM). Iron (Fe2 +) and copper (Cu+) are typical transition metals.

Mercury Elemental mercury (Hg0 ) is unique in that it is the only metal that exists in liquid form at room temperature, and as such is capable of creating solid solutions, or amalgams, with other metals. Although it is relatively innocuous if ingested as a liquid, it is readily volatilized (ie, high vapor pressure) transforming into a physical state that causes significant pulmonary mucosal irritation on inhalation. In addition, this change in the route of exposure raises its systemic bioavailability. Absorbed, or incorporated, Hg0 undergoes biotransformation in the erythrocyte and brain to the mercuric (Hg2 +) form, which has a high affinity for sulfhydryl-containing molecules including proteins. This causes a depletion of glutathione in organs such as the kidney, and also initiates lipid peroxidation. The mercurous form (Hg+) is considerably less toxic than the mercuric form, perhaps because of its reduced water solubility. Organic mercurial compounds, such as methylmercury and

dimethylmercury, are environmentally formed by anaerobic bacteria containing the methylating agent methylcobalamin, a vitamin B12 analog (Chap. 92) .

Thallium Another toxicologically important member of the heavy metal group is thallium. Metallic thallium is used in the production of electronic equipment and is itself minimally toxic. Thallium ions, however, have physicochemical properties that most closely mimic potassium, allowing it to participate in, and potentially alter, the various physiologic activities related to potassium. This property is clinically used during a thallium-stress test to assess for myocardial ischemia or infarction. Because ischemic myocardial cells lack adequate energy for normal Na+- K+ -ATPase function, they cannot exchange sodium for potassium (or in this scenario radioactive thallium) producing a “cold spot― in the ischemic areas on cardiac scintigraphy (Chap. 96) .

Lead Although lead is not very abundant in the earth's crust (only 0.002%), exposure may occur during the smelting process or from one of its diverse commercial applications. Most of the useful lead compounds are inorganic lead (II) (Pb2 +) salts, but lead (IV) (Pb4 +) compounds are also used. The Pb 2 + compounds are typically ionizable, releasing Pb 2 + when dissolved in a solvent, such as water. Lead (II) ions are absorbed in place of Ca2 + ions by the gastrointestinal tract and replace calcium in certain physiologic processes. This mechanism is implicated in the neurotoxic effect of lead ions. Lead (IV) compounds tend to be covalent compounds that do not ionize in water. However, some of the Pb4 + compounds are oxidants. Although elemental lead is not itself toxic, it rapidly develops a coating of toxic lead oxide or lead carbonate upon exposure to air or water (Chap. 91) .

The Metalloids (B, Si, Ge, As, Sb, Te, At) Although the metalloids share many physical properties with the metals, they are differentiated because of their propensity to form compounds with both metals and the nonmetals carbon, nitrogen, or oxygen. Thus, metalloids may be either oxidized or reduced in chemical reactions.

Arsenic Toxicologically important inorganic arsenic compounds exist in either the pentavalent arsenite (As5 +) form or the trivalent arsenate (As3 +) form. The reduced water solubility of the arsenate compounds, such as arsenic pentoxide, accounts for its limited clinical toxicity when compared to trivalent arsenic trioxide. The trivalent form of arsenic is primarily a nucleophilic toxin, binding sulfhydryl groups and interfering with enzymatic function (Chaps. 13 and 8 5) .

The Nonmetals (C, N, P, O, S, Se, Halogens) The nonmetals are highly electronegative and, unlike the metals, may be toxic in either their compounded or their elemental form. The nonmetals with large electronegativity, such as O2 or Cl2 , generally oxidize other elements in chemical reactions. Those with smaller electronegativity, such as C, behave as reducing agents.

The Halogens (F, Cl, Br, I, At) In their highly reactive elemental form, which contains a covalent dimer of halogen atoms, the halogens carry the suffix -ine (eg, Cl2 , chlorine). Halogens require the addition of one electron to complete their valence shell; thus, halogens are strong oxidizing agents. Because they are highly electronegative, they form halides (eg, Cl- , chloride) by abstracting electrons from less electronegative elements. Thus, the halogen ions, in their stable ionic form, generally carry a charge of –1. The halides, although much less reactive than

their respective elemental forms, are reducing agents. The hydrogen halides (eg, HCl, hydrogen chloride) are gases under standard conditions, but they ionize when dissolved in aqueous solution to form the hydrohalidic acids (eg, HCl, hydrochloric acid). All hydrogen halides except HF (hydrogen fluoride) ionize completely in water to release H+ and are considered strong acids. Because of its small ionic radius, lack of charge dispersion, and intense electronegativity, HF ionizes poorly and is a weak acid. This specific property of HF has important toxicologic implications (Chap. 101) .

Group 0: The Inert Gases (He, Ne, Ar, Kr, Xe, Rn) Inert gases, also known as noble gases, maintain completed valence shells and are thus entirely unreactive except under extreme experimental conditions. However, despite their lack of chemical reactivity, the inert gases are toxicologically important as simple asphyxiants. That is, because they displace ambient oxygen from a confined space, consequential hypoxia may occur, and the expected warning P.189 signs may be completely absent (Chap. 119). During highconcentration exposure, inert gases may produce anesthesia, and xenon is used as an anesthetic agent. Radon, although a chemically unreactive gas, is radioactive, and prolonged exposure is associated with the development of lung cancer.

Bonds Electrons are not generally shared evenly between atoms when they form a compound. Instead, unless the bond is between the same elements, as in Cl2 , one of the elements exerts a larger attraction for the shared electrons. The degree to which an element draws the shared electron is determined by the element's electronegativity (Fig. 12-3). The electronegativity of each element was catalogued by Linus

Pauling and relates to the ionic radius, or the distance between the orbiting electron and the nucleus, and the shielding effects of the inner electrons. The electronegativity rises toward the right of the periodic table, corresponding with the expected charge obtained on an element when it forms a bond. Fluoride ion has the highest electronegativity of all elements, which explains many of its serious toxicologic properties. Several types of bonds exist between elements when they form compounds. When one element gains valence electrons and another loses them, the resulting elements are charged and attract one another in an ionic, or electrovalent, bond. An example is NaCl, or table salt, in which the electronegativity difference between the elements is 1.9, or greater than the electronegativity of the sodium (see text below and Fig. 12-3). Thus, the chloride wrests control of the electrons in this bond. In solid form, ionic compounds exist in a crystalline lattice, but when put into solution, as in the serum, the elements may separate and form charged particles, or ions (Na + and Cl2 ). The ions are stable in solution, however, because their valence shells contain 8 electrons and are complete. The properties of ions differ from both the original atom from which the ion is derived and the noble gas with which it shares electronic structure. It is important to recognize that when a mole of a salt, such as NaCl (molecular weight 58.45 g/mol), is put in aqueous solution, 2 moles of particles result. This is because NaCl essentially ionizes fully in water; that is, it produces 1 mole of Na+ (23 g/mol) and 1 mole of Cl- (35.45 g/mol). For salts that do not ionize completely, less than the intrinsic number of moles are released and the actual quantity liberated can be predicted based on the defined solubility of the compound, or the solubility product constant (Ks p). For ions that carry more than a single charge, the term equivalent is often used to denote number of moles of other particles to which one mole of the substance will bind. Thus, an equivalent of calcium ion will typically bind 2 moles (or equivalents) of chloride ions (which are monovalent) because calcium ions are divalent. Alternatively stated, a 10%

calcium chloride (CaCl2 ) aqueous solution contains approximately 1.4 mEq/mL or 0.7 mmol/mL of Ca2 +. Compounds formed by two elements of similar electronegativity have little ionic character because there is little impetus for separation of charge. Instead, these elements share pairs of valence electrons, a process known as covalence. The resultant molecule contains a covalent bond, which is typically very strong and generally requires a high-energy chemical reaction to disrupt it. There is wide variation in the extent to which the electrons are shared between the participants of a covalent bond, and the physicochemical and toxicologic properties of any particular molecule are in part determined by its nature. Rarely is sharing truly symmetric, as in oxygen (O2 ) or chlorine (Cl2 ). If sharing is asymmetric and the electrons thus exist to a greater degree around one of the component atoms, the bond is polar. However, the presence of a polar bond does not mean that the compound is polar. For example, methane contains a carbon atom that shares its valence electrons with 4 hydrogen atoms, in which there is a small charge separation between the elements (electronegativity [EN] difference = 0.40). Furthermore, because the molecule is configured in a tetrahedral formation, there is no notable polarity to the compound; this compound is nonpolar. The lack of polarity suggests that methane molecules have little affinity for other methane molecules and they are held together only by weak intermolecular bonds. This explains why methane is highly volatile under standard conditions.

Figure 12-3. Electronegativity of the common elements. Note that the inert gases are not reactive and thus do not have electronegativity.

Because the electronegativity differences between hydrogen (EN = 2.20) and oxygen (EN = 3.44) are greater (EN difference = 1.24), the electrons in the HO bonds in water are drawn toward the oxygen atom, giving it a partial negative charge and the hydrogens a partial positive charge. Furthermore, because H2 O is angular, not linear or symmetric, water is a polar molecule. Water molecules are held together by hydrogen bonds, which are stronger than intermolecular bonds (also called van der Waals forces, see below). These hydrogen bonds have sufficient energy to open many ionic bonds and solvate the ions. In this process, the polar ends of the water molecule surround the charged particles of the dissolved salt. Thus, because there is little similarity between the nonpolar methane and the polar water molecules, methane is not water soluble. Similarly, salts cannot be solvated by nonpolar compounds, and thus a salt, such as sodium chloride, cannot dissolve in a nonpolar solvent, such as

carbon

tetrachloride.

Alternatively, the stability and irreversibility of the bond between an organic phosphorus insecticide and the cholinesterase enzyme are a result of covalent phosphorylation of an amino acid at the active site of the enzyme. The resulting bond is essentially irreversible in the absence of another chemical reaction. Compounds may share multiple pairs of electrons. For example, the two carbon atoms in acetylene (HC[triple bond]CH) share three pairs of double bonds between them, and each shares one pair with its own hydrogen. Carbon and nitrogen share three pairs of electrons in forming cyanide (C[triple bond]N- ) making this bond very stable and accounting for the large number of xenobiotics capable of liberating cyanide. Complex ions are covalently bonded groups of elements that behave as a single element. For example, the hydroxide ion (OH- ) and sulfate ion.

(SO4 2 -) form sodium salts as if they were simply a chloride

P.190 Noncovalent bonds, such as hydrogen or ionic bonds, are important in the interaction between ligands and receptors, and between ion channels and enzymes. These are low-energy bonds and easily reversible. Van der Waals forces, also known as London dispersion forces, are intermolecular forces that arise from induced dipoles as a consequence of nonuniform distribution of the molecular electron cloud. These forces become stronger as the atom (or molecule) becomes larger because of the increased polarizability of the larger, more dispersed electron clouds. This accounts for the fact that under standard temperature and pressure, fluorine and chlorine are gases, whereas bromine is a liquid, and iodine is a solid.

Oxidation-Reduction Reduction-oxidation

(redox) reactions involve the movement of

electrons from one atom or molecule to another, and actually comprise two dependent reactions: reduction and oxidation. Reduction is the gain of electrons by an atom that is thereby reduced. The electrons derive from a reducing agent, which in the process becomes oxidized. Oxidation is the loss of electrons from an agent, which is, accordingly, oxidized. An oxidizing agent accepts electrons, and in the process, is reduced. By definition, these chemical reactions involve a change in the valence of an atom. It is also important to note that acid/base and electrolyte chemical reactions involve electrical charge interactions but no change in valence of any of the involved components. The implications of redox chemistry for medical toxicology are profound. For example, the oxidation of ferrous (Fe2 +) to ferric (Fe3 +) iron within the hemoglobin molecule creates dysfunctional methemoglobin. Also, metallic lead and elemental mercury are both intrinsically harmless metals, but when oxidized to their cationic forms both produce devastating clinical effects. Additionally, the oxidation of methanol to formic acid involves a change in the oxidation state of the molecule. In this case, an enzyme, alcohol dehydrogenase, acting as a catalyst, oxidizes (ie, removes electrons from) the C-O bond and delivers the electrons to oxidized nicotinamide adenine dinucleotide (NAD + ), reducing it to the reduced form (NADH). As in this last example, oxidation is occasionally used to signify the gain of oxygen by a substance. That is, when elemental iron (Fe0 ) undergoes rusting to iron oxide (Fe2 O 3 ), it is said to oxidize. The use of this term is consistent because in the process of oxidation, oxygen derives electrons from the atom to which it is binding.

Reactive

Oxygen

Species

Free radicals are reactive molecules that contain one or more unpaired electrons, and are typically neutral but may be anionic or cationic. However, because certain toxicologically important reactive molecules do not contain unpaired electrons, such as hydrogen

peroxide (H2 O 2 ) and ozone (O3 ), the term reactive species is preferred. The reactivity of these molecules directly relates to their desire to fill their outermost orbitals by receiving an electron; the result is oxidative stress on the biologic system. Molecular oxygen is actually a diradical with two unpaired electrons in the outer orbitals. However, its reactivity is less than that of the other radicals because the unpaired electrons have parallel spins, so catalysts (ie, enzymes or metals) are typically involved in the use of oxygen in biologic processes. Reactive species are continually generated as a consequence of endogenous metabolism and there is an efficient system for their control. Under conditions of either excessive endogenous generation or exposure to exogenous reactive species, the physiologic defense against these toxic products is overwhelmed. When this occurs, reactive species induce direct cellular damage as well as initiate a cascade of oxidative reactions that perpetuate the toxic damage. Intracellular organelles, particularly the mitochondria, may also be disrupted by various reactive oxygen species. This causes further injury to the cell as energy failure occurs. This initial damage is compounded by the activation of the host inflammatory response by chemokines that are released from cells in response to reactive oxygen species-induced damage. This inflammatory response aggravates cellular damage. The resultant membrane dysfunction or damage causes cellular apoptosis or necrosis (Chap. 13) . The most important reactive oxygen species in medical toxicology are derived from oxygen, although those derived from nitrogen are also important. Table 12-1 lists some of the important reactive oxygen and nitrogen species. This biradical nature of oxygen explains both the physiologic and toxicologic importance of oxygen in biologic systems. Physiologically, the majority of oxygen is used by the body to serve as the ultimate electron acceptor in the mitochondrial electron transport chain (Fig. 13-3). In this situation, four electrons are added to each molecule of

oxygen to form two water molecules (O2 + 4 H+ + 4 e- → 2 H2 O). Superoxide is generated within neutrophil and macrophage lysosomes as part of the oxidative burst, a method of eliminating infectious agents and damaged cells. Superoxide may subsequently be enzymatically converted, or dismutated, into hydrogen peroxide by superoxide dismutase (SOD). Hydrogen peroxide may be subsequently converted into hypochlorous acid by the enzymatic addition of chloride by myeloperoxidase. Both hydrogen peroxide and hypochlorite ion are more potent reactive oxygen species than superoxide. However, this lysosomal protective system may also be responsible for tissue damage following poisoning as the innate inflammatory response attacks toxin-damaged cells. Examples include acetaminophen-induced hepatotoxicity (Chap. 34), carbon monoxide neurotoxicity (Chap. 120), and chlorine-induced P.191 pulmonary toxicity (Chap. 119), each of which may be altered, at least in experimental systems, by the addition of scavengers of reactive oxygen species.

TABLE 12-1. Structure of Important Reactive Oxygen and Nitrogen

Species

Although superoxide and hydrogen peroxide are reactive oxygen species, it is their conversion into the hydroxyl radical (OH·) that accounts for their most consequential effects. The hydroxyl radical is generated by the Fenton reaction (Fig. 12-2), in which hydrogen peroxide is decomposed in the presence of a transition metal. This catalysis typically involves Fe2 +, Cu+, Cd2 +, Cr5 -, Ni2 +, or Mn2 +. The Haber-Weiss reaction (Fig. 12-2), in which a transition metal catalyzes the combination of superoxide and hydrogen peroxide, is the other important means of generating the hydroxyl radical. Superoxide dismutase, within the erythrocyte, contains an atom of C u2 + that participates in the catalytic dismutation (reduction) of superoxide to hydrogen peroxide (SOD was originally called

erythrocuprein) and the subsequent detoxification of hydrogen peroxide by glutathione peroxidase or catalase. Transition metal cations may bind to the cellular nucleus where they locally generate reactive oxygen species, most importantly hydroxyl radical. This results in DNA strand breaks and modification, accounting for the promutagenic effects of many transition metals.2 In addition to the important role that transition metal chemistry plays following iron or copper salt poisoning, the long-term consequences of chronic transition metal poisoning are exemplified by asbestos. The iron contained in asbestos is the origin of the Fenton-generated hydroxyl radicals that are responsible for the pulmonary fibrosis and cancers associated with long-term exposure.2 The most consequential toxicologic effects of reactive oxygen species occur on the cell membrane, and are caused by the initiation by hydroxyl radical of the lipid peroxidative cascade. The alteration of these lipid membranes ultimately causes membrane destruction. Identification of released oxidative products such as malondialdehyde is a common method of assessing lipid peroxidation. Under normal conditions, there is a delicate balance between the formation and immediate endogenous detoxification of reactive oxygen species. For example, the conversion of superoxide radical to hydrogen peroxide via SOD is rapidly followed by the transformation of hydrogen peroxide to water by glutathione peroxidase or catalase. Furthermore, transition metals cannot be unattended in biologic systems and exist in “free― form in only minute quantities, presumably to minimize the formation of hydroxyl radicals through Fenton reactions. Thus, cells have developed extensive systems by which transition metal ions can be sequestered and rendered harmless. Ferritin (binds iron), ceruloplasmin (binds copper), and metallothionein (binds cadmium) are specialized proteins that safely sequester transition metal ions. Certain proteins and enzymes that contain transition metals at their active sites, such as hemoglobin or SOD, harness the activity of transition metal ions in a controlled

fashion. Detoxification of certain reactive species is difficult because of their extreme reactivity. Widespread antioxidant systems exist to trap reactive species before they can damage tissues. An example is the availability of glutathione, a reducing agent and nucleophile, to prevent both exogenous oxidants from producing hemolysis and the acetaminophen metabolite N-acetyl-p-benzoquinoneimine (NAPQI) from damaging the hepatocyte. The key reactive nitrogen species is nitric oxide. At typical physiologic concentrations, this radical is responsible for vascular endothelial relaxation through stimulation of guanylate cyclase. However, during oxidative burst, high concentrations of nitric oxide are formed from L-arginine. At these concentrations, nitric oxide has primarily both damaging effects and reacts with superoxide radical to generate the peroxynitrite anion. This is particularly important because peroxynitrite may spontaneously degrade to form the hydroxyl radical. Peroxynitrite ion is implicated in both the delayed neurologic effects of carbon monoxide poisoning and the hepatic injury from acetaminophen.

Redox

Cycling

Although transition metals are an important source of reactive species, certain xenobiotics are also capable of independently generating reactive species. Most do so through a process called redox cycling, in which a molecule accepts an electron from a reducing agent and subsequently transfers that electron to oxygen, generating the superoxide radical. At the same time, this second reaction regenerates the parent molecule, which itself can gain another electron and restart the process. The toxicity of paraquat is selectively localized to pulmonary endothelial cells. Its pulmonary toxicity results from redox cycling generation of reactive oxygen species (Fig. 111-1). A similar process, localized to the heart, occurs with anthracycline antineoplastic agents such as doxorubicin.

Acid–Base

Chemistry

Water is amphoteric, which implies that water can function as either an acid or a base, much the same way as the bicarbonate ion (HCO3 ). In fact, because of the amphoteric nature of water, H+, despite the nomenclature, does not ever actually exist in aqueous solution; rather, it is covalently bound to a molecule of water to form the hydronium ion (H3 O +). However, the term H+, or proton, is used for convenience. Even in neutral solution, a tiny proportion of water is always undergoing ionization to form both H+ and OH+ in exactly equal amounts. It is, however, the quantity of H+ that is of concern, and this is the basis of using the pH to characterize a solution. In a perfect system at equilibrium, the concentration of H+ ions in water is precisely 0.0000001, or 10- 7, moles per liter and that of OH- is the same. The number of H+ ions increases when an acid is added to the solution and falls when an alkali is added. In an attempt to make this quantity more practical, the negative log of the H+ concentration is calculated, which defines the p H. Thus, the negative log of 10- 7 is 7, and the pH of a neutral aqueous solution is 7. In actuality, the pH of water is approximately 6 because of dissolution of ambient carbon dioxide to form carbonic acid (H2 O + CO2 → H2 C O3 ), which ionizes to form H+ and bicarbonate (HCO3 - ) . There are many definitions of acid and base. The three commonly used definitions are those advanced by (a) Arrhenius, (b) BrønstedLowry, and (c) Lewis. Because the focus is on physiologic systems, which are aqueous, the original definition by the Swedish chemist Arrhenius is the most practical. In this view, an acid is any xenobiotic that releases hydrogen ions, or protons (H+), in water. Similarly, a base is a xenobiotic that produces hydroxyl ions (OH- ) in water. Thus, hydrogen chloride (HCl), a neutral gas under standard conditions, dissolves in water to liberate H+, and is therefore an acid.

For nonaqueous solutions the Brønsted-Lowry definition is preferable. An acid, in this schema, is a substance that donates a proton and a base is one that accepts a proton. Thus, any molecule that has a hydrogen in the 1+ oxidation state is technically an acid, and any molecule with an unbound pair of valence electrons is a base. Because most of the acids or bases of toxicologic interest P.192 have ionizable protons or available electrons, respectively, the Brønsted-Lowry definition is most often considered when discussing acid-base chemistry (ie, HA + H2 O → H3 O + + A- ; B- + H2 O → HB + O H- ). However, this is not a defining property of all acids or bases. Thus, Lewis offered the least-restrictive definition of such substances. A Lewis acid is an electron acceptor and a Lewis base is an electron donor. Simplistically, acids are sour and turn litmus paper red, whereas bases are slippery and bitter and turn litmus paper blue. Because acidity and alkalinity are determined by the number of available H+ ions, it is useful to classify chemicals by their effect on the H+ concentration. Strong acids ionize completely in aqueous solution and very little of the parent compound remains. Thus, 0.001 (or 10- 3) mole of HCl, a strong acid, added to 1 L of water produces a solution with a pH of 3. Weak acids, on the other hand, obtain an equilibrium between parent and ionized forms, and thus do not alter the pH to the same degree as a similar quantity of a strong acid. This chemical notation defines the strength or weakness of an acid and should not be confused with the concentration of the acid. Thus, the pH of a dilute strong acid solution may be substantially less than that of a concentrated weak acid (Table 12-2) . The degree of ionization of a weak acid is determined by the pKa , or the negative log of the ionization constant, which represents the pH at which an acid is half dissociated in solution. The same relationship applies to the pKb of an alkali, although by convention the pKb is expressed as the pKa (pKa = 14 – pKb ). The lower the pKa , the stronger the acid; the converse is true for bases. Knowledge of the

p Ka does not itself denote whether a substance is an acid or an alkali. To some extent, this quality may be predicted by its chemical structure or reactivity, or obtained through direct measurement or from a reference source. The pK of a strong acid is clinically irrelevant because it is fully ionized under all but the most extreme acid conditions. Because only uncharged compounds cross lipid membranes spontaneously, the pKa has clinical relevance. Salicylic acid, a weak acid with a pKa of 3, is nonionized in the stomach (pH 2) and passive absorption occurs (Fig. 9-4). Because it is predominantly in the ionized form (ie, salicylate) in blood, which the ionized bloodborne salicylate passively However, because in overdose the serum considerably, enough enters the tissue to

has a pH of 7.4, little of enters the tissues. salicylate rises have devastating clinical

effects. Salicylate, a conjugate base of a weak acid and thus a strong base, equilibrates within the various tissues across the outer mitochondrial membrane. In this intermembrane space (between the inner and outer mitochondrial membrane) abundant protons exist, which are transported there via the electron transport chain of this organelle (Chap. 13). Because salicylate is a strong base, it protonates easily in this environment. In this nonionized form, some of the salicylic acid may pass through the inner mitochondrial membrane, into the mitochondrial matrix, and again establish equilibrium by losing a proton. The process just described uncouples oxidative phosphorylation, by dispersing the highly concentrated protons in the intermembrane space that are normally used to generate adenosine triphosphate (Chap. 13). Uncoupling in the skeletal muscle, for example, produces a metabolic acidosis, and this shifts the blood equilibrium of salicylate toward the nonionized, protonated form, enabling salicylic acid to cross the blood–brain barrier. Presumably, once in the brain, the salicylate uncouples the metabolic activity of neurons with the subsequent development of cerebral edema. This is the rationale for serum alkalinization in patients with aspirin overdose (Chap. 35) .

TABLE 12-2. pH of 0.10 M Solutions of Common Acids and Bases Represents the Strength of the Acid or Base

Acid Base HCl

(hydrochloric

acid)

pH 1.1

H 2 SO4 (sulfuric acid)

1.2

H 2 SO3 (sulfurous acid)

1.5

H 3 P O4 (phosphoric acid)

1.5

HF

acid)

2.1

C H3 C O2 H (acetic acid)

2.9

H 2 C O3 (carbonic acid)

3.8

H 2 S (hydrogen sulfide)

4.1

N H4 Cl

4.6

HCN

(hydrofluoric

(ammonium

(hydrocyanic

NaHCO3

(sodium

chloride)

acid)

5.1

bicarbonate)

8.3

NaCH3 C O2 (sodium acetate)

8.9

N a2 HPO4 (sodium hydrogen phosphate)

9.3

N a2 SO3 (sodium sulfite)

9.8

NaCN

11.0

(sodium

cyanide)

N H4 OH (aqueous ammonia)

11.1

N a2 C O3 (sodium carbonate)

11.6

N a3 P O4 (sodium phosphate)

12.0

NaOH

13.0

(sodium

hydroxide)

In a similar manner, alkalinization of the patient's urine prevents reabsorption by ionization of the urinary salicylate. Conversely, because tricyclic antidepressants are organic bases, alkalinization of the urine reduces their ionization and actually decreases the drug's urinary elimination. However, in the management of cyclic antidepressant poisoning, because the other beneficial effects of sodium bicarbonate on the sodium channel outweigh the negative effect on drug elimination, serum alkalinization is recommended.

Organic

Chemistry

The study of carbon-based chemistry and the interaction of inorganic molecules with carbon-containing compounds is called organic chemistry, because the chemistry of living organisms is carbon based. Biochemistry (Chap. 13) is a subdivision of organic chemistry; it is the study of organic chemistry within biologic systems. This section reviews many of the salient points of organic chemistry,

focusing on those with the most applicability to medicine and the study of toxicology: nomenclature, bonding, nucleophiles and electrophiles, stereochemistry, and functional groups.

Chemical

Properties

of

Carbon

Carbon, atomic number 6, has a molecular weight of 12.011 g/mol. With few exceptions (notably cyanide ion and carbon monoxide), carbon forms 4 bonds in stable organic molecules. In organic compounds, carbon is commonly bonded to other carbon atoms, as well as to hydrogen, oxygen, nitrogen, or halide (ie, fluorine, bromine, or iodine) atoms. Under certain circumstances, carbon can be bonded to metals, as is the case with methylmercury.

Nomenclature The most rigorous method to name organic compounds is in accordance with standards adopted by the International Union of P.193 Pure and Applied Chemistry (IUPAC); these names are infrequently used, especially for larger molecules, and alternative chemical names are common. Alternative chemical names are those based on the structure of a molecule, but which do not adhere completely to IUPAC rules. The complete details of the IUPAC naming system are beyond the scope of this text and can be reviewed elsewhere (http://www.iupac.org), but a brief description of the fundamentals of this system is included here. The carbon backbone serves as the basis of the chemical name. Once the carbon backbone has been identified and named, substituents (atoms or groups of atoms that substitute for hydrogen atoms) are identified, named, and numbered. The number refers to the carbon to which the substituent is attached. Some of the common substituents in organic chemistry are –OH (hydroxy), –NH2 (amino), –Br (bromo), –Cl (chloro), and –F (fluoro). Substituents are then

alphabetized and placed as prefixes to the carbon chain. As an example, consider the molecule 2-bromo-2-chloro-1,1,1trifluoroethane. The molecule has a 2-carbon backbone (ethane), 3 fluoride atoms on the first carbon, a bromine atom on the second carbon, and a chlorine atom on the second carbon (Fig. 12-4A). A basic understanding of a few simple rules of nomenclature thus allows one to quickly generate the molecular structure of a familiar compound, halothane, from what initially appeared to be an intimidating name. Although the above-mentioned rules suffice to name simple structures, they are inadequate to describe many others, such as molecules with complex branching or ring structures. The IUPAC rules for naming compounds such as [1R-(exo,exo)]-3-(benzoyloxy)8-methyl-8-azabicyclo[3,2,1]octane-2-carboxylic acid methyl ester, for example, are too complex to include here. Fortunately, many compounds with complex chemical names have simpler names for day-to-day use; as an example, this molecule is commonly referred to as cocaine (Fig. 12-4B) . Cocaine is an example of a common or trivial name, that is, one without a rigorous scientific basis, but which is generally accepted as an alternative to frequently unwieldy proper chemical names. Common names may refer to the origin of the substance; for example, cocaine is derived from the coca leaf, and wood alcohol (methanol) can be prepared from wood. Alternatively, a common name may refer to the way in which a compound is used; “rubbing alcohol― is a common name for isopropanol. Common names are often imprecise and may generate some confusion, however, as evidenced by the fact that “rubbing alcohol,― when commercially marketed, may be ethanol or isopropanol. An even less precise system of nomenclature is the use of street names. A street name is a slang term for a drug of abuse, such as “blow― (cocaine), “weed― (marijuana), or “smack― (heroin). The street name ecstasy refers to the stimulant 3,4-

methylenedioxymethamphetamine (MDMA), which is most frequently consumed in pill form. It would stand to reason that liquid ecstasy might refer to a solution of MDMA, but street names are not necessarily logical. Instead, liquid ecstasy refers to the drug γhydroxybutyrate (GHB), a sedative-hypnotic agent with a completely different pharmacologic and toxicologic profile. Furthermore, there are no standards for the content of ecstasy and many street pills contain other chemicals or no chemicals at all.

Figure 12-4. Nomenclature. A . 2-Bromo-2-chloro-1,1,1trifluoroethane, or halothane. B . [1R-(exo,exo)]-3-(Benzoyloxy)8-methyl-8-azabicyclo-[3,2,1]-octane-2-carboxylic acid methyl ester, or cocaine.

A final consideration must be given to product names. Product names are “trade names― under which a given compound might be marketed, and are frequently different from both the chemical name and common name. Thus, the inhalational anesthetic in Figure 12-4A with the chemical name 2-bromo-2-chloro-1,1,1-trifluoroethane has the common name halothane and the trade name Fluothane.

Bonding

in

Organic

Chemistry

Whereas much of the bonding in inorganic chemistry is ionic or electrovalent, the vast majority of bonding in organic molecules is covalent. Whereas electrons in ionic bonds are described as “belonging― to one atom or another, electrons in covalent bonds are shared between two atoms; this type of bonding occurs when the difference in electronegativity between two atoms is insufficient for one atom to wrest control of an electron from another. Single bonds are represented by 1, double bonds by 2, and triple bonds by 3 lines between the atoms.

Nucleophiles

and

Electrophiles

Many organic reactions of toxicologic importance can be described as the reactions of nucleophiles with electrophiles. Nucleophiles (literally, nucleus-loving) are species with increased electron density, frequently in the form of a lone pair of electrons (as in the cases of cyanide ion and carbon monoxide). Nucleophiles, by virtue of this increased electron density, have an affinity for atoms or molecules which are electron deficient; such moieties are called electrophiles (literally, electron-loving). The electron deficiency of electrophiles can be described as absolute or relative. Absolute electron deficiency occurs when an electrophile is charged, as is the case with cations such as Pb2 + and Hg2 +. Relative electron deficiency occurs when one atom or group of atoms shifts electrons away from a second atom, making the second atom relatively electron deficient. This is the case for the neurotoxin 2,5-hexanedione (Fig. 12-5); the electronegative oxygen of the carbon-oxygen double bond pulls electron density away from the second and fifth carbon atoms of this molecule, making these carbon atoms electrophilic. The reaction of a nucleophile with an electrophile involves the movement of electrons, by forming and/or breaking bonds. This movement of electrons is frequently denoted by the use of curved arrows, which better demonstrates how the nucleophile and electrophile

P.194 interact. The interaction of acetylcholinesterase with acetylcholine, organic phosphorus pesticides, and pralidoxime hydrochloride provides an excellent example of the way in which nucleophiles and electrophiles interact, and of how the use of curved arrow notation can lead to better understanding of the reactions involved.

Figure

12-5. Chemical properties of 2,5-hexanedione. Arrows

designate the electrophilic carbon atoms.

Under normal circumstances, the action of acetylcholine is terminated when the serine residue in the active site of acetylcholinesterase attacks this neurotransmitter, forming a transient serine–acetyl complex and liberating choline; this serine–acetyl complex is then rapidly hydrolyzed, producing an acetic acid molecule and regenerating the serine residue for another round of the reaction (Fig. 12-6A). In the presence of an organic phosphorus agent, however, this serine residue attacks the electrophilic phosphate atom, forming a stable serine–phosphate bond, which is not hydrolyzed (Fig. 12-6B). The enzyme, thus inactivated, can no longer break down acetylcholine, leading to an increase of this neurotransmitter in the synapse, and possibly to a

cholinergic

crisis.

The enzyme can be reactivated, however, by the use of another nucleophile. Pralidoxime hydrochloride (2-PAM) is referred to as a site-directed nucleophile. Because part of its chemical structure (the charged nitrogen atom) is similar to the choline portion of acetylcholine, this antidote is directed to the active site of acetylcholinesterase. Once in position, the nucleophilic oxime moiety (–NOH) of 2-PAM attacks the electrophilic phosphate atom; this displaces the serine residue, regenerating the enzyme (Fig. 12-6C) . For a further discussion of organic phosphorus compound toxicity and the use of 2-PAM, see Chap. 109 and Antidotes in Depth: Pralidoxime. A second toxicologically important electrophile is NAPQI (Fig. 12-7) . NAPQI is formed when the endogenous detoxification pathways of acetaminophen metabolism (glucuronidation and sulfation) are overwhelmed (Chap. 34). As a result of the electron configuration of NAPQI, the carbon atoms adjacent to the carbonyl carbon (a carbonyl carbon is one that is double-bonded to an oxygen) are very electrophilic; the sulfur groups of cysteine residues of hepatocyte proteins react with NAPQI to form a characteristic adduct, 3-(cysteinS-yl)acetaminophen in a multistep process (an adduct is formed when one compound is added to another). These adducts are released as hepatocytes die, and can be found in the blood of patients with acetaminophen-related liver toxicity. Figure 12-7 diagrams the mechanism of the protein–NAPQI reaction (Chap. 3 4) .

Figure 12-6. The reactions of acetylcholinesterase (AChE), organic phosphorus compounds, and pralidoxime hydrochloride (2-PAM). Curved arrows represent the movement of electrons as bonds are formed or broken. A . Normal hydrolysis of acetylcholine by acetylcholinesterase. B . Inactivation (phosphorylation) of acetylcholinesterase by organic phosphorus compound. C . Reactivation by 2-PAM of functional acetylcholinesterase.

Figure 12-7. The reaction of cysteine residues on hepatocyte proteins with NAPQI to form the characteristic adducts 3(cystein-S-yl) APAP.

P.195 Nucleophiles can be described by their strength; strength is related to the rate at which they react with a reference electrophile CH3 I. Of more use in pharmacology and toxicology, however, are the descriptive terms “hard― and “soft.― Although imprecise, the designations “hard― and “soft― help to predict, on a qualitative level, how nucleophiles and electrophiles interact with one another. “Hard― species have a charge (or partial charge) that is highly localized; that is, their charge to radius ratio is high. Hard nucleophiles are molecules in which the electron density or lone pair is tightly held; fluoride, a small atom that cannot spread its electron density over a large area, is an example. Similarly, hard electrophiles are species in which the positive charge cannot be spread over a large area; ionized calcium, a small ion, is a hard electrophile.

“Soft― nucleophiles and electrophiles, on the other hand, are capable of delocalizing their charge over a larger area. In this case the charge to mass ratio is low, either because the atom is large or because the charge can be spread over a number of atoms within a given molecule. Sulfur is the prototypical example of a soft nucleophile and the lead ion, Pb2 +, is a typical soft electrophile. The utility of this classification lies in the observation that hard nucleophiles tend to react with hard electrophiles, and soft nucleophiles with soft electrophiles. For example, a principal toxicity of fluoride ion poisoning (Chap. 101) is hypocalcemia; this is because the fluoride ions (hard nucleophiles) readily react with calcium ions (hard electrophiles). On the other hand, the soft nucleophile lead is effectively chelated by soft electrophiles such as the sulfur atoms in the chelating agents dimercaprol (Antidotes in Depth: Dimercaprol [British Anti-Lewisite or BAL]) and succimer (Antidotes in depth: Succimer [2,3-Dimercaptosuccinic Acid]) .

Isomerism Isomerism describes the different ways in which molecules with the same chemical formula (ie, the same number and types of atoms) can be arranged to form different compounds. These different compounds are called isomers. Isomers always have the same chemical formula, but differ either in the way that atoms are bonded to each other (constitutional isomers) or in the spatial arrangement of these atoms (geometric isomers or stereoisomers) .

Figure 12-8. Two molecules with chemical formula C2 H 6 O. A . Dimethylether. B . Ethanol (ethyl alcohol).

Constitutional isomers are conceptually the easiest to understand, because a quick glance shows them to be very different molecules. The chemical formula C2 H 6 O, for example, can refer to either dimethyl ether or ethanol (Fig. 12-8). These molecules have very different physical and chemical characteristics, and have little in common other than the number and type of their atomic constituents. Stereoisomerism, also referred to as geometric

isomerism, refers to

the different ways in which atoms of a given molecule, with the same number and types of bonds, might be arranged. The most important type of stereoisomerism in pharmacology and toxicology is the stereochemistry around a chiral carbon, a carbon atom to which four different substituents are bonded. Consider the two representations of halothane shown in Figure 12-9. In this figure the straight solid lines and the atoms to which they are bonded exist in the plane of the paper, the solid triangle and the atom to which it is bonded are coming out of the paper, and the dashed triangle and the atom to which it is bonded are receding into

the paper. It is clear that, for the molecules in Figure 12-9A and B, no amount of rotation or manipulation will make these molecules superimposable. They are, therefore, different compounds. The molecules in Figure 12-9A and B are enantiomers or optical isomers. They differ only in the way in which their atoms are bonded to the chiral carbon. It is important to define the stereochemical configuration of these two molecules, which can be done in one of two ways. In the first classification—the D(+)/L(–) system—molecules are named empirically based on the direction in which they rotate plane-polarized light. Each enantiomer will rotate plane-polarized light in one direction; the enantiomer that rotates light clockwise (to the right) is referred to as D(+), or P.196 dextrorotatory; the L(–), or levorotatory enantiomer rotates planepolarized light in a counterclockwise fashion (to the left).

Figure 12-9. The graphic representation of the enantiomers of halothane.

Alternatively, enantiomers can be named using an elaborate and formal set of rules known as Cahn-Ingold-Prelog. These rules establish priority for substituents, based primarily upon molecular

weight, and then use the arrangement of substituents to assign a configuration. To correctly assign configuration in this system, the molecule is rotated into a projection in which the chiral carbon is in the plane of the page, the lowest priority substituent is directly behind the chiral carbon (and therefore behind the plane of the page), and the other three substituents are arranged around the chiral carbon. Figure 12-10 assigns Cahn-Ingold-Prelog priority to the halothane enantiomers of Figure 12-9, and rearranges the molecules in the appropriate projections. If the priority of the substituents increases as one moves clockwise (to the right), the enantiomer is named R (Latin, rectus = right); if it increases as one moves counterclockwise, the enantiomer is named S (Latin, sinister = left). Thus, Figure 12-10A is the R enantiomer of halothane and Figure 12-10B is the S enantiomer. Enantiomers have identical physical properties, such as boiling point, melting point, and solubility in different solvents; they differ from each other in only two significant ways. The first, as mentioned above, is that enantiomers rotate plane-polarized light in opposite directions; this point has no practical toxicologic importance. The second is that enantiomers may interact in very different ways with other three-dimensional structures (such as proteins and other cell receptors), which is of both pharmacologic and toxicologic significance. Perhaps the best analogy to explain the toxicologic and pharmacologic importance of stereochemistry is that of the way a hand (analogous to a molecule of drug or toxin) fits into a glove (analogous to the biologic site of activity). Consider the left hand as the S enantiomer and the right hand as the R enantiomer. There are, qualitatively, three different ways in which the hand can fit into (interact with) a glove. First, if the glove is very pliable (such as a disposable latex glove), it can accept either the left hand or the right hand without difficulty; this is the case for halothane, whose R and S enantiomers possess

equal activity. Second, if a glove is constructed with greater (but imperfect) specificity, one hand will fit well and the other poorly; this is the case for many substances, such as epinephrine and norepinephrine, whose naturally occurring levorotatory enantiomers are 10-fold more potent than the synthetic dextrorotatory enantiomers. Finally, a glove can be made with exquisite precision, such that one hand fits perfectly, while the other hand does not fit at all. This is the case for physostigmine, in which the (–) enantiomer is biologically active, whereas the (+) enantiomer is inactive.

Figure 12-10. R and S enantiomers of halothane. A . The substituents increase in a clockwise fashion, so the configuration is R. B . The substituents increase in a counterclockwise fashion, so the configuration is S. In this projection, hydrogen atoms are directly behind the carbon atoms.

The above analogy is oversimplified, however, as one enantiomer of

a drug can be an agonist, while the other enantiomer is an antagonist. Dobutamine, for example, has one chiral carbon and thus two enantiomers. At the α1 receptor, l-dobutamine is a potent agonist and d-dobutamine is a potent antagonist. Because dobutamine is marketed as a racemic mixture (a racemic mixture is a 1:1 mixture of enantiomers), however, these effects cancel each other out. Interestingly, at the β1 receptor, d- and l-dobutamine have unequal agonist effects, with d-dobutamine approximately 10 times more potent than l-dobutamine.

Functional

Groups

There is perhaps no concept in organic chemistry as powerful as that of the functional group. Functional groups are atoms or groups of atoms that confer similar reactivity on a molecule; of less importance is the molecule to which it is attached. Some representative functional groups in organic chemistry and toxicology are the hydrocarbons (alkanes and alkenes), alcohols, carboxylic acids, and thiols. These groups are discussed here because they illustrate important principles, not because this represents an exhaustive list of important functional groups in toxicology. Hydrocarbons, as their name implies, consist of only carbon and hydrogen. Alkanes are hydrocarbons that contain no multiple bonds; they may be straight chain, usually designated by the prefix n- (Fig. 12-11A), or branched (isobutane, Fig. 12-11B). Alkenes contain carbon-carbon double bonds. Alkynes, which contain carbon-carbon triple bonds, are of limited toxicologic importance. Butane (lighter fluid) is an alkane, and gasoline is a mixture of alkanes. Hydrocarbons are of toxicologic importance for two reasons: they are widely abused as inhalational drugs for their central nervous system depressant effects, and they can cause profound toxicity when aspirated. Although these effects are physiologically disparate, they are readily understood in the context of the chemical characteristics of the hydrocarbon functional group.

Hydrocarbons do not contain polar groups, or groups that introduce full or partial charges into the molecule; as such, they interact readily with other nonpolar substances, such as lipids or lipophilic substances. Hydrocarbons readily interact with the myelin of the CNS, disrupting normal ion channel function and P.197 causing CNS depression. When aspirated, hydrocarbons interact with the fatty acid tail of surfactant, dissolving this protective substance and contributing to acute lung injury (Chaps. 79 and 102) .

Figure 12-11. Two isomers of the 4 carbon alkane, butane. A . n-Butane. B . Isobutane.

Figure

12-12. Reaction of cocaine with ethanol (A) to form

cocaethylene and methanol (B) .

Alcohols possess the hydroxyl (–OH) functional group, which adds polarity to the molecule and makes alcohols highly soluble in other polar substances, such as water. For example, ethane gas (CH3 C H3 ) has negligible solubility in water, whereas ethanol (CH3 C H2 OH) is miscible, or infinitely soluble, in water. In biologic systems, alcohols are generally CNS depressants, but they can also act as nucleophiles. Ethanol may react with cocaine to form cocaethylene, a longer-acting and more vasoactive substance than cocaine itself (Fig. 12-12; see Chap. 74 for clinical details).

Alcohols can be primary, secondary, or tertiary, in which the reference carbon is bonded to 1, 2, or 3 carbons in addition to the hydroxyl group. Methanol, in which the reference carbon is bonded to no other carbons, is also a primary alcohol. The difference between primary, secondary, and tertiary structures is important, because although the alcohol functional group imparts many qualities to the molecule, the degree of substitution can affect the chemical reactivity. Primary alcohols can undergo multistep oxidation to form carboxylic acids, whereas secondary alcohols generally undergo onestep metabolism to form ketones, and tertiary alcohols do not readily undergo oxidation. This is a point of significant toxicologic importance, and is discussed in more detail later. Alcohols can be named in many ways; the most common is to add -o l or -yl alcohol to the appropriate prefix. If the alcohol group is bonded to an interior carbon, the number to which the carbon is bonded precedes the suffix. Carboxylic acids contain the functional group –COOH. As their name implies, they are acidic, and the pKa of carboxylic acids are generally 4 or 5, depending on the substitution of the molecule. Carboxylic acids are capable of producing a significant anion gap metabolic acidosis, which is true whether the acids are endogenous or exogenous. Examples of endogenous acids are β-hydroxybutyric acid and lactic acid; examples of exogenous acids are formic acid (produced by the metabolism of methanol) and glycolic, glyoxylic, and oxalic acids (produced by the metabolism of ethylene glycol). Carboxylic acids are named by adding -oic acid to the appropriate prefix; the four-carbon straight-chain carboxylic acid is thus butanoic acid. Thiols contain a sulfur atom, which usually functions as a nucleophile. The sulfur atom of N-acetylcysteine can regenerate glutathione reductase, and can also react directly with NAPQI to detoxify this electrophile. The sulfur atom of many chelating agents, such as dimercaprol and succimer, are nucleophiles that are very

effective at chelating electrophiles such as heavy metals. Thiols are generally named by adding the word thiol to the appropriate base. Thus, a 2-carbon thiol is ethane thiol. As noted above, molecules with a given functional group often have more in common with molecules within the same functional group than they have in common with the molecules from which they were derived. The alkanes methane, ethane, and propane are straight chain hydrocarbons with similar properties. All are gases at room temperature, have almost no solubility in water, and have similar melting and boiling points. When these molecules are substituted with one or more hydroxide functional groups, they become alcohols: examples are methanol, ethanol, ethylene glycol (a glycol is a molecule that contains two alcohol functional groups), the primary alcohol 1-propanol, and the secondary alcohol 2-propanol (isopropanol). Each of these alcohols is a liquid at room temperature, and all are very water soluble. All have boiling points that are markedly different from the alkane from which they were derived, and quite close to each other. In addition to conferring different physical properties on the molecule, the addition of the alcohol functional group also confers different chemical properties and reactivities. For example, methane, ethane, and propane are virtually incapable of undergoing oxidation in biologic systems. The alcohols formed by the addition of one or more hydroxyl groups, however, are readily oxidized by alcohol dehydrogenase (Fig. 12-13) .

Figure

12-13. Oxidative metabolism of (A) methanol, (B)

ethanol, and (C) isopropanol. Note that acetone does not undergo further oxidation in vivo. ADH = alcohol dehydrogenase; ALDH = aldehyde dehydrogenase.

P.198 As Figure 12-13 indicates, the oxidation of the primary alcohols methanol and ethanol results in the formation of aldehydes (an aldehyde is a functional group in which a carbon atom contains a double bond to oxygen and a single bond to hydrogen), whereas the oxidation of the secondary alcohol isopropanol resulted in the formation of a ketone (a ketone is a functional group in which a carbon is double-bonded to an oxygen atom and single-bonded to two separate carbon atoms). Although both aldehydes and ketones contain the carbonyl group (a carbon-oxygen double bond),

aldehydes and ketones are distinctly different functional groups, and have different reactivity patterns. For instance, aldehydes can undergo enzymatic oxidation to carboxylic acids (Fig. 12-13A and B) , whereas ketones cannot (Fig. 12-13C) . It is here that recognition of functional groups helps to understand the potential toxicity of an alcohol. Methanol, ethanol, and isopropanol are all alcohols; as such, their toxicity before metabolism is expected to be (and in fact is) similar to that of ethanol, producing CNS sedation. Because these toxins are primary and secondary alcohols, all three can be metabolized to a carbonyl compound, either an aldehyde or a ketone. Here, however, the functional groups on the molecules have changed; whereas aldehydes can be metabolized to carboxylic acids (which can, in turn, cause an anion gap acidosis), ketones cannot. It is for this reason that methanol and ethylene glycol can cause an anion gap acidosis, and isopropanol cannot (Chap. 103) . The concept of functional groups, however useful, has limitations. For example, although both formic acid and oxalic acid are organic acids, they cause different patterns of organ system toxicity. Formic acid is a mitochondrial toxin, and exerts effects primarily in areas (such as the retina or basal ganglia) that poorly tolerate an interruption in the energy supplied by oxidative phosphorylation. Conversely, oxalic acid readily precipitates calcium and is toxic to renal tubular cells, which accounts for the hypocalcemia and nephrotoxicity that are characteristic of severe ethylene glycol poisoning. The concept of the functional group is thus an aid to understanding chemical reactivity, but not a substitute for a working knowledge of the toxicokinetic or toxicodynamic effects of xenobiotics in living systems.

Summary Understanding key principles in inorganic and organic chemistry

provides insight into the mechanisms by which xenobiotics act. The periodic table forms the basis for inorganic chemistry and provides insight into the expected reactivity, and to a large extent the clinical effects, of any element. A growing understanding of how reactive species are formed and how they interfere with physiologic processes has led to new insights in the pathogenesis and treatment of toxinmediated diseases. Organic chemistry forms the basis of life, and is essential to an understanding of biochemistry and pharmacology. Because many xenobiotics are organic compounds there is direct relevance to medical toxicology.

References 1. Bailey PS, Bailey CA: Organic Chemistry: A Brief Survey of Concepts and Applications, 5th ed. Englewood Cliffs, NJ, PrenticeHall, 1995. 2. Bergendi L, Benes L, Durackova Z, Ferencik M: Chemistry, physiology and pathology of free radicals. Life Sci 1999;65:1865–1874. 3. Kasprzak KS: Possible role of oxidative damage in metalinduced carcinogenesis. Cancer Invest 1995;13:411–430. 4. Loudon GM: Organic Chemistry, 3rd ed. Redwood City, CA, Benjamin/Cummings Publishing, 1995. 5. Manahan SE: Toxicologic Chemistry. Boca Raton, FL, Lewis Publishers, 1992. 6. McMurry J, Castellion ME: General, Organic, and Biological Chemistry, 2nd ed. Upper Saddle River, NJ, Prentice Hall, 1996.

7. Oulette RJ, Rawn JD: Organic Chemistry. Upper Saddle River, NJ, Prentice-Hall, 1996. 8. van der Vliet A, Cross CE: Oxidants, nitrosants, and the lung. Am J Med 2000;109:398–421.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section I - Biochemical and Molecular Basis > Chapter 13 - Biochemical and Metabolic Principles

Chapter

13

Biochemical Principles

and

Metabolic

Kathleen A. Delaney Xenobiotics are compounds that are foreign to a living system. Xenobiotic toxins injure living organisms by interfering with critical metabolic processes, by causing structural damage to cells, or by altering the cellular genetic material. The specific biochemical sites of actions that disrupt metabolic processes are well characterized for many xenobiotics although mechanisms of cellular injury are not. This chapter focuses on those general biochemical principles that are relevant to an understanding of the injurious effects of toxic xenobiotics. It also reviews the current understanding of the biotransformation enzymes and their clinical implications. The capacity of a xenobiotic to produce injury in a living organism is affected by many factors that include its absorption, distribution, elimination, site of activation or detoxification, site of action, and capability to cross membranes to access a particular organ. Sites of action include the active sites of enzymes or receptor binding sites, DNA, and lipid membranes. The route of

exposure to a toxin may confine damage primarily to one organ: for example pulmonary injury that follows inhalation; GI injury that follows a caustic ingestion; or injury to the skin following dermal exposure. Hepatocellular injury results when a toxic xenobiotic is delivered to the liver, either by the portal venous system following ingestion, or by the hepatic artery that carries blood with xenobiotics absorbed from other sites of exposure. Various factors affect the ability of a toxin to access a particular organ. For example, many potentially toxic xenobiotics fail to produce injury because they cannot cross the blood–brain barrier. The negligible CNS effects of the mercuric salts when compared with organic mercury compounds are related to their inability to penetrate the CNS. Two potent biologic toxins—ricin (from Ricinus communis ) and α-amanitin (from Amanita phalloides )—block protein synthesis through the inhibition of RNA polymerase. Their very different clinical effects are related to tissue accessibility. Ricin has a special binding protein that enables it to gain access to the endoplasmic reticulum in GI mucosal cells, where it inhibits cellular protein synthesis and causes severe diarrhea.48 α-Amanitin is transported into hepatocytes by bile salt transport systems, where inhibition of protein synthesis results in cell death.43 , 50 The electrical charge on a toxin also affects its ability to enter a cell. Unlike the ionized (charged) form of a xenobiotic, the uncharged form is lipophilic and passes easily through lipid cell membranes to enter the systemic circulation. The p Ka of an acidic xenobiotic (HA → A- + H+ ) is the pH at which 50% of the molecules are charged (A- form) and 50% are uncharged (HA form). A xenobiotic with a high pKa is more likely to be absorbed in an acidic environment where the uncharged form predominates. Hence, the site of absorption of a toxin in the gastrointestinal tract; the acidic environment of the stomach or the alkaline environment of the small intestine; is affected by its p Ka . See Chap. 9 for a more extensive discussion of basic principles of pharmacokinetics.

General

Enzyme

Concepts

The capability to detoxify and eliminate both endogenous toxins and exogenous xenobiotics is crucial to the maintenance of physiologic homeostasis and normal metabolic functions for all organisms. A simple example is the detoxification of cyanide, a potent cellular poison that is ubiquitous in the environment and is also a product of normal metabolism. Mammals have evolved the enzyme rhodanese, which combines cyanide with thiosulfate to create the less toxic, renally excreted compound thiocyanate.85 The majority of xenobiotics have lipophilic properties that facilitate absorption across cell membranes in organs that are portals of entry to the body: the skin, GI tract, and lungs. The liver has the highest concentration of enzymes that metabolize xenobiotics. Enzymes found in the liquid matrix of hepatocytes that are specific for alcohols, aldehydes, esters, or amines act on many different substrates within these broad classes. Enzymes that act on more lipophilic xenobiotics, including the CYP (formerly cytochrome P450) enzymes, are embedded in the lipid membranes of the endoplasmic reticulum. When cells are mechanically disrupted and centrifuged, these membrane-bound enzymes are found in the pellet, or microsomal fraction; hence, they are called microsomal enzymes. Enzymes located in the liquid matrix of cells are called cytosolic enzymes and are found in the supernatant when disrupted cells are centrifuged. Cytosolic enzymes are present in all tissues.42

Biotransformation

Overview

The term biotransformation refers to the alteration of a xenobiotic as a result of enzyme action.51 Biotransformation usually results in “detoxification,― a reduction in the toxicity of a substance and its removal from the body. In some cases, however, the metabolites produced may be more toxic than the parent

xenobiotic. In this case, the biotransformation results in “toxication― or “metabolic activation.― 82 A single xenobiotic may be a substrate for biotransformation by P.200 several metabolic pathways, some resulting in detoxification and others in metabolic activation. The predominant pathway for the biotransformation of an individual toxin is determined by many factors that include the availability of cofactors, the effect of substrate concentration on the rate of substrate metabolism (reflected by the Km [Michaelis-Menten dissociation constant] of the biotransformation enzyme and by saturation effects), changes in the concentration of the enzyme caused by induction, and the presence of inhibitors.82 The production of toxic metabolites by a given biotransformation process is also affected by the concentration of protective agents such as glutathione. The likelihood that a xenobiotic will undergo biotransformation depends on its chemical nature. Ionized compounds such as carboxylic acids are less likely to cross a lipid membrane to enter the body. When they do, the kidneys rapidly eliminate them. Very volatile compounds, such as dichloromethane, are expelled promptly via the lungs. Neither of these groups of xenobiotics undergo significant enzymatic metabolism. Nonpolar, lipophilic xenobiotics that are less soluble in aqueous fluids require biotransformation to more water-soluble compounds before they can be excreted.51 Most biotransformation reactions have two sequential phases. Phase I reactions add functional groups to lipophilic xenobiotics, converting them into more chemically reactive metabolites. This is usually followed by phase II reactions that conjugate the reactive products of phase I with other molecules that render them more water soluble, detoxifying the xenobiotic and facilitating its elimination. Some xenobiotics undergo only a phase I or a phase II reaction.

Oxidation

Overview

Much of the activity that occurs during biotransformation or within critical metabolic pathways results in the oxidation or reduction of carbon. Oxidation involves the transfer of electrons from a substrate molecule to an electron-seeking (electrophilic) molecule, leading to reduction of the electrophilic molecule and oxidation of the substrate. These oxidation-reduction reactions are often coupled to the cyclical oxidation and reduction of a cofactor, such as the pyridine nucleotides, NADPH/NADP+ (nicotinamide adenine dinucleotide phosphate) or NADH/NAD+ (nicotinamide adenine dinucleotide). These nucleotides alternate between their reduced (NADPH, NADH) and oxidized (NADP+ , NADH+ ) forms. The terminal transfer of electrons to oxygen also provides a mechanism for oxidation of substrates. Electrons resulting from the catabolism of energy sources are extracted by NAD+ , forming NADH. NADH transports the electrons into the mitochondria where they enter the cytochrome-mediated electron transport system. This results in the production of adenosine triphosphate (ATP), the reduction of molecular oxygen, and the regeneration of NAD+ , a process that is critical to the maintenance of oxidative metabolism. NADPH serves primarily to carry electrons from the oxidative reactions of catabolism to the synthetic (anabolic) reactions of biosynthesis. NADPH is also coupled to the reduction of glutathione, which plays an important role in the protection of cells from oxidative damage. The main source of NADPH is the pentose phosphate pathway (also called the hexose-monophosphate shunt), an alternative pathway for the oxidation of glucose. The oxidation state of a specific carbon atom can be determined by counting the number of carbon and hydrogen atoms to which the carbon atom is connected. The more reduced a carbon, the higher the number of carbon-hydrogen bonds. For example, the carbon in methanol (CH3 OH) has three carbon-hydrogen bonds

and is more reduced than the carbon in formaldehyde (H2 C = O), which has two. Carbon-carbon double bonds count as one bond.

Figure 13-1. A common oxidation reaction catalyzed by CYP enzymes: the hydroxylation of Drug-H to Drug-OH.

Phase

I

Biotransformation

Reactions

Phase I reactions are predominantly oxidation reactions that add functional groups suitable for conjugation during phase II. These include hydroxyl (-OH), sulfhydryl (-SH), amino (-NH2 ), aldehyde (-COH), or carboxyl (-COOH) moieties.42 Elements such as nitrogen, sulfur, and phosphorus that do not contain carbon are also oxidized in phase I reactions. Other phase I reactions result in hydrolysis, hydration, and dehalogenation.82 The CYP enzymes are cytochromes bound to the lipid membranes of the endoplasmic reticulum that use a cyclical transfer of electrons between oxidized (Fe3 + ) or reduced (Fe2 + ) forms of iron. They are responsible for the majority of phase I oxidative biotransformation reactions. Membrane-bound flavin monooxygenase (FMO), another NADPH-dependent oxidase located in the endoplasmic reticulum, makes an important contribution to the oxidation of amines and other compounds containing nitrogen, sulfur, or phosphorus.51 A common oxidation reaction catalyzed by CYP enzymes is illustrated by the hydroxylation or monooxidation of a foreign compound R-H to R-OH (Fig. 13-1 ). 46 The alcohol, aldehyde, and ketone oxidation systems are predominantly cytosolic enzymes that catalyze phase I oxidationreduction reactions using NADH/NAD+ .30 , 44 , 49 , 82 Two classic phase I oxidation reactions are the metabolism of ethanol to

acetaldehyde by alcohol dehydrogenase (ADH) followed by the metabolism of acetaldehyde to acetic acid by aldehyde dehydrogenase (ALDH) (Fig. 13-2 ). Alcohol dehydrogenase, which oxidizes many different alcohols, is found in the liver, lungs, kidney, and gastric mucosa.2 , 49 Females have less ADH in their gastric mucosa than males. This results in decreased first-pass metabolism of alcohol and increased alcohol absorption. Some populations, particularly Asians, are deficient in ALDH, resulting in increased acetaldehyde levels and symptoms of the acetaldehyde syndrome.2 , 49

Figure

13-2. Conversion of ethanol to acetaldehyde by CYP2E1

that uses reduced NADPH and oxygen and by alcohol dehydrogenase that uses oxidized NAD- . This illustrates how NAD and NADP can function in oxidation reactions in both their oxidized and reduced forms. Alcohol dehydrogenase has a low Km for ethanol and is the predominant metabolic enzyme in moderate drinkers.

P.201

Overview of the CYP Enzymes The most numerous and important of the enzymes involved in phase I oxidation reactions are the CYP enzymes. This nomenclature derives from the complex cytochrome protein structure that is the basic unit of the enzyme and the spectrophotometric characteristics of its associated heme molecule. When bound to carbon monoxide, the maximal absorption spectrum of the reduced CYP (Fe2 + ) enzyme occurs at 450 nm.59 , 62 CYP enzymes, which incorporate 1 atom of oxygen

into the substrate and 1 atom into water, were once called “mixed-function oxidases.― This activity is now referred to as a “microsomal monooxygenation reaction.― 59 , 82 These biotransformation CYP enzymes, bound to the lipid membranes of the smooth endoplasmic reticulum, are distinct from the cytochromes that comprise the mitochondrial electron transport chain.59 Although most of the CYP isozymes are found in the liver, high levels can be found in extrahepatic tissues, particularly the gastrointestinal tract.19 The lungs,54 , 59 heart,63 and brain63 also have discernible amounts of CYP isozymes. Each tissue has a unique profile of CYP enzymes that determines its sensitivity to different xenobiotics.19 The CYP enzymes in the enterocytes of the small intestine actually contribute significantly to “firstpass― metabolism of some xenobiotics.41 , 59 Corrected for tissue mass, the CYP enzyme system in the kidneys is as active as that in the liver. The activity of the renal CYP enzymes is decreased in patients with chronic renal failure, with relative sparing of CYP1A2, 2C19, and 2D6 compared with 3A4 and 2C9.13 More than 2500 different genes coding for CYP enzymes have been identified.59 , 60 CYP enzymes are categorized according to the similarities of their amino acid sequences. They are in the same “family― if they are more than 40% similar, and same “subfamily― if they are more than 55% similar. Families are designated by an Arabic numeral, subfamilies by a capital letter, and each individual enzyme (or isozyme) by another numeral, resulting in the nomenclature CYPnXm for each isozyme. For example, CYP3A4 is an isozyme of the CYP3 family and of the CYP3A subfamily.27 , 58 CYP enzymes catalyze a diverse number of reactions that include both biosynthetic and xenobiotic biotransformation. Most xenobiotic metabolism is done by the CYP1, CYP2, and CYP3 families, with a small amount done by the CYP4 family.13 , 84 It is estimated that the total number of exogenous CYP enzyme substrates may exceed 200,000

chemicals.47 Nearly 90% of oxidative transformation of xenobiotics is accomplished by 6 CYP enzymes: 1A2, 2C9, C19, 2D6, 2E1, and 34A (Table 13-1 ).59 , 75 The approximate amounts of liver CYP enzymes are 3A4 (40–55%), 2D6 (30%), 2C9 and 2C19 (10–20%), 2E1 (7%), and 1A2 (2%).46 , 62 Percent of liver CYPs 2% 10–20% 30% 7% 40–55% Contribution to enterocyte CYPs Minor Minor Minor Minor Minor 70% Percent of metabolism of typically used drugs 2–15% 10% 25–30% 50–60% Organs other than liver with isozyme Lung, intestine, stomach Nasal mucosa, stomach, heart, intestine Nasal mucosa, heart, intestine Lung, heart, intestine Lung, intestine

Nasal mucosa, lung, stomach, intestine Polymorphisma No Yes Yes Yes No No Poor metabolizer African American 1–2% 20% 2–8%

Asian 1–2% 15–20% Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section I - Biochemical and Molecular Basis > Chapter 14 - Neurotransmitters and Neuromodulators

Chapter

14

Neurotransmitters Neuromodulators

and

Steven C. Curry Kirk C. Mills Anne-Michelle

Ruha

Many poisonous substances produce their primary toxic effects by affecting neurotransmission. This chapter reviews the normal physiology of neurotransmission, the molecular action and biochemistry of several major neurotransmitters and their receptors, and the toxicologic mechanisms by which numerous substances act at the molecular level. Acetylcholine, norepinephrine, epinephrine, dopamine, serotonin, γ-aminobutyric acid (GABA), γhydroxybutyrate (GHB), glycine, glutamate, and adenosine are the neurotransmitters and neuromodulators of toxicologic interest that are discussed in this chapter. When examining molecular actions of drugs and toxins on neurotransmitter systems, it is apparent that substances rarely possess single pharmacologic actions. For example, doxepin, in part, antagonizes voltage-gated sodium channels, histaminic H 1 and H2

receptors, α-adrenoceptors, muscarinic acetylcholine receptors, dopamine D2 receptors, and GABAA receptors; prevents potassium efflux; and inhibits norepinephrine, serotonin, and adenosine uptake. For obvious reasons, then, this chapter cannot include every action of every drug or toxin on the nervous system. Nor is it meant to be a complete discussion of toxic syndromes produced by various agents, as these are discussed in specific chapters. Rather, this chapter provides a general and basic understanding of the mechanisms of action of various toxic agents affecting neurotransmitter function and receptors, especially in the central nervous system. With this focus, the clinical effects produced by various toxins are more easily understood and predicted, and specific treatments aimed at reversing pharmacologic effects of the offending agents can be rationally undertaken. Given the complexity of the nervous system and the numerous actions of a given drug, it is not always clear which neurotransmitter system is producing an observed effect during a particular toxicity. Therefore, pharmacologic agents discussed in this chapter may be found in several sections. An attempt is made to note what appears to be a drug or toxin's main mechanism of action, although other actions are noted when possible.

Neuron Physiology and Neurotransmission Membrane Potentials, Nerve Conduction

Ion

Channels,

and

Membrane-bound sodium-potassium adenosine triphosphatase (ATPase) moves three sodium ions (Na+ ) from inside the cell to the interstitial space while pumping two potassium ions (K+) into the cell. Because the cell membrane is not freely permeable to large, negatively charged molecules on the inside of the cell, such as

proteins, an equilibrium results in which the inside of the neuron is negative with respect to the outside. This typical neuronal resting membrane potential is –65 mV. Sodium, calcium (Ca2 +), K+ , and chloride (Cl- ) ions move into and out of neurons through ion channels. Ions always move passively down electrochemical gradients through ion channels, which are long polypeptides comprising several subunits that span the plasma membrane several times. Many different ion channels are structurally comparable, sharing similar amino acid sequences.17 Channels for a specific ion can also vary in structure, depending on the specific subunits that have combined to form the channel. Because of structural similarity of different channels, it is not surprising that many drugs or toxins are able to bind to more than one type of ion channel. More than 40 different ion channels have been described in various nerve terminals,99 and it is estimated that a human being contains hundreds of different varieties of ion channels for Na+ , Cl- , Ca2 +, and K+ . Most ion channels fall into two general classes: voltagegated (voltage-dependent) ion channels and ligand-gated ion channels.99 Voltage-gated channels open or close in response to changes in membrane potential. Ligand-gated channels open or close when a ligand (eg, neurotransmitter) binds to the channel to change its configuration. A commonly accepted model describes voltage-gated Na+ channels and some other voltage-gated ion channels in three possible states. Using Na+ channels as an example, the Na+ channel is closed at rest and impermeable to sodium, preventing Na+ from moving into the cell. When the channel undergoes activation, the channel opens, allowing Na+ to move intracellularly, down its electrochemical gradient. The channel then undergoes a third conformational change by becoming inactivated, preventing further influx of Na+. The term recovery describes the conversion of inactive channels back to the resting state, a process that requires repolarization of the cell

membrane. Depolarization of a neuron usually results from an initial inward flux of cations (Na+ or Ca2 +), or prevention of K+ efflux. The fall in membrane potential (movement toward 0 mV) results in further activation of these voltage-dependent Na+ channels, allowing yet a greater influx of cations. When the membrane P.215 potential falls to threshold, Na+ channels are activated en masse, and there is a large influx of Na+ . Depolarization of a segment of the neurolemma causes the adjacent neuronal membrane to reach threshold, resulting in the propagation of an action potential down the neuron. Sodium channel activation is quickly followed by inactivation. Over the short-term, repolarization of the neuron occurring after inactivation of Na+ channels mainly results from efflux of K+ and some influx of Cl- .

Neurotransmitter

Release

Neurotransmitters are chemicals that are released from nerve endings into the synapse, where they produce effects by binding to receptors on postsynaptic and/or presynaptic cell membranes. The receptors may be on other neurons or effector organs such as smooth muscle. Concentrations of neurotransmitters in cytoplasm are usually low because of rapid degradation by various enzymes and because they diffuse out of the nerve ending. To provide a source of neurotransmitters that is protected from degradation and that can be rapidly released, neurotransmitters are concentrated and stored within vesicles in the axonal nerve terminal for release. As a wave of depolarization from Na+ influx reaches the nerve ending, the membrane depolarization causes voltage-gated Ca2 + channels to open, allowing Ca2 + to move rapidly into the cell. This influx of Ca2 + triggers exocytosis of vesicle contents into the synapse. The voltagegated Ca2 + channels responsible for inward Ca2 + currents that trigger neurotransmitter release are mainly of the N and P

subtypes.103,121 Calcium channel blockers used in clinical practice (eg, verapamil, nifedipine) do not block these subtypes of voltagedependent Ca2 + channels, but rather block the L-type. However, Lsubtype Ca2 + channels reside elsewhere on neurons, which explains the ability of traditional Ca2 + channel blockers to affect some neurologic functions.

Vesicle

Transport

of

Neurotransmitters

The pH inside neurotransmitter vesicles is about 5.5, lower than that in the cytoplasm. A vacuolar adenosine triphosphatase (V-ATPase) in the vesicular membrane is responsible for movement of protons into the vesicular lumen at the expense of adenosine triphosphate (ATP) hydrolysis. Vesicular uptake pumps that move neurotransmitters or their precursors from the cytoplasm into the vesicle lumen, in turn, are powered by the electrochemical H+ gradient; that is, the movement of an H+ out of the vesicle into the cytoplasm is coupled to the movement of a neurotransmitter from the cytoplasm into the vesicle. This is particularly true for vesicular transporters of GABA, glycine, dopamine, norepinephrine, and serotonin. At least four unique vesicular

transporters

for

neurotransmitters

have been sequenced to date. VGAT transports GABA and glycine. VMAT2 transports all three monoamines, dopamine, norepinephrine, and serotonin (VMAT1 transports monoamines into nonneuronal vesicles). VAChT is responsible for acetylcholine (ACh) transport, and VGluT1 transports glutamate. Neurotransmitters are confined within the vesicle, to a great extent, by ion trapping, as they are more ionized and less able to diffuse back out of the vesicle at the lower pH. Anything that causes a decrease in the pH gradient across the vesicle membrane results in the movement of neurotransmitters into the cytoplasm.149 For example, amphetamines move into vesicles, where they buffer protons, causing the movement of monoamine neurotransmitters out of vesicles, and raising cytoplasmic concentrations of

neurotransmitters.149,150

Neurotransmitter

Uptake

Although acetylcholine is inactivated in the synapse by enzymatic degradation, most neurotransmitters have their synaptic effects terminated by active uptake into neurons and/or glial cells. These plasma membrane neurotransmitter transporters are distinct from those transporters responsible for movement of neurotransmitters into vesicles within the cytoplasm. Cell membrane transporters (uptake pumps) for different neurotransmitters are Na+-dependent transport proteins, during which the uptake of neurotransmitters is accompanied by the movement of Na+ across the synaptic membrane.2 Neurotransmitter uptake transporters have been subdivided into two main families.2 One family includes structurally similar uptake pumps for γ-aminobutyric acid, glycine, norepinephrine, dopamine, and serotonin. They generally comprise 600–700 amino acids and form loops spanning the plasma membrane 12 times. GAT-1 transports GABA into neurons, while GAT-2, GAT-3 and GAT-4 transport GABA into glial cells and, possibly, into postsynaptic neurons. DAT, SERT, and NET are responsible for uptake of dopamine, serotonin, and norepinephrine, respectively. GLYT-1 (at least three isoforms) transports glycine into neurons and astrocytes, while GLYT-2 transports glycine into glycinergic neurons. The second family comprises 5 glutamate uptake transporters (excitatory amino acid transporters), which appear to traverse the plasma membrane 10 times. EAAT1 resides in cerebellar glial cells; EAAT2 in forebrain glia; EAAT3 in cortical neurons; EEAT4 in cerebellar Purkinje cells; and EAAT5 in the retina. Each time a glutamate moves into a neuron or glial cell, it is accompanied by 3 N a+ and 1 proton. At the same time, a K+ is extruded with each cycle.

Several properties make transporter proteins of particular toxicologic significance. First, they are capable of moving neurotransmitters in either direction; when cytoplasmic neurotransmitter concentrations are significantly elevated, neurotransmitters can be transported back into the synapse. Second, these transporters are not always completely specific for a particular substance. For instance, the uptake transporter for norepinephrine can pump dopamine and other biogenic amines into the neuron. Third, a drug or toxin that acts at the level of the membrane transporter may affect functions of several different neurotransmitters, depending on its specificity for a particular transporter. As an example, fluoxetine is fairly specific at inhibiting uptake of serotonin, whereas cocaine inhibits the uptake of serotonin, norepinephrine, and dopamine.

Neurotransmitter Channel

Receptors

Receptors

The first general class of neurotransmitter receptors comprise ligandgated ion channels (channel receptors or ionotropic receptors) in which the receptor for the neurotransmitter is part of an ion channel. These channels comprise multiple subunits which combine in various combinations to create channels that vary in their response to a given neurotransmitter or other agonist/antagonist. By binding to its receptor, the neurotransmitter allosterically changes the configuration of the ion channel so that ions can more easily traverse the channel and enter or leave the cell. As an example, the acetylcholine nicotinic receptor at the neuromuscular junction is a ligand-gated Na+ channel. When P.216 acetylcholine binds to the nicotinic receptor, the channel's configuration changes, allowing Na+ to move into the cell and trigger an action potential. (The action potential then propagates down muscle via voltage-gated Na+ channels.) Table 14-1 lists other

examples of channel receptors.

TABLE 14-1. Types of Neurotransmitter and Neuromodulator Receptors

Ion ACh

Channel

nicotinic

Linked to G Protein ACh

muscarinic

GABAA , GABAC

GABAB

Glycine

Dopamine

(inhibitory)

Glutamate

AMPA

Norepinephrine

Glutamate

NMDA

5-HT1,2,4–7

Glutamate

kainate

Adenosine

5-HT3

Glutamate

metabotropic

ACh = acetylcholine; AMPA = amino-3-hydroxy-5-methyI-4isoxazole propionate; GABA = γ-aminobutyric acid; 5-HT = 5-hydroxytryptamine (serotonin); NMDA = N-methyl-Daspartate.

G

Protein

Receptors

The second general class of neurotransmitter receptors are linked to

G proteins, which are part of a superfamily of proteins with guanosine triphosphatase (GTPase) activity responsible for signal transduction across plasma membranes.140 G proteins comprise 3 polypeptide subunits: α, β, and γ chains. These chains span the plasma membrane several times, and they associate with a separately transcribed neurotransmitter receptor that spans the cell membrane 7 times, with an external binding site for neurotransmitters. Some receptors (eg, GABAB receptor) coupled to G proteins are dimers comprising two separate proteins, both of which must be present for activity. Both the α subunit and the βγ subunit of a G protein may account for activity resulting from a neurotransmitter binding to its receptor. The α chain normally binds guanosine diphosphate (GDP) in the cytoplasm and is inactive. When a neurotransmitter binds to its receptor on the outside of the cell membrane, GDP dissociates from the α chain and guanosine triphosphate (GTP) binds in its place, activating the α subunit. The activated α chain then dissociates from receptor and from the β and γ chains. Both the activated α subunit and βγ subunits modulate effectors in the plasma membrane.140 The effector influenced by α or βγ subunits may be an enzyme that the subunits stimulate or inhibit (eg, adenylate cyclase) or an ion channel that is opened or closed directly or through other chemical reactions (eg, channel phosphorylation).30 Intrinsic GTPase activity in the α chain eventually converts the GTP to GDP, inactivating the α subunit and allowing it to reassociate with the β and γ chains and the neurotransmitter receptor, terminating the action of the subunits.140

Figure 14-1. Common mechanisms of postsynaptic excitation and inhibition. A . An excitatory neurotransmitter (ENT) binds to receptors linked to G proteins to prevent K+ efflux [1] or to allow N a+ influx [2], producing membrane depolarization. An ENT may bind to and activate a cation channel [3] to allow Na+ and/or C a2 + influx with resultant membrane depolarization. B . An inhibitory neurotransmitter (INT) hyperpolarizes the membrane (makes membrane potential more negative) by binding to receptors linked to G proteins to enhance K+ efflux [4], or to Clchannels to allow Cl- influx [5]. Some chloride channels are regulated by G proteins as well. G = G protein.

G proteins are mainly categorized by the type of α chain they contain. The three main families of G proteins coupled to neurotransmitter receptors are Gs (containing the α subunit α s ) , G i / o (containing αi or αo ), and Gq (containing αq ). Gs is a positive allosteric effector of membrane-bound adenylate cyclase; activation of a neurotransmitter receptor coupled to Gs causes a rise in intracellular 3′, 5′-cyclic adenosine monophosphate (cAMP) concentration.89 Neurotransmitter receptors activating Gi may inhibit adenylate cyclase or modulate K+ and Ca2 + channels. Receptors coupled to Gq/11 act through membrane-bound phospholipase C to

increase

intracellular

calcium

concentrations.

Table 14-1 lists the neurotransmitter receptors coupled to G proteins. A given neurotransmitter can activate different classes of receptors (eg, channel and G protein) or different types of receptors in the same class. For example, GABAA receptors are Cl- channels, whereas GABAB receptors are coupled to G proteins. Dopamine D1 receptors are linked to Gs , whereas D2 receptors are linked to Gi or Go .

Neuronal

Excitation

and

Inhibition

Excitatory neurotransmitters usually act postsynaptically by N a+ or Ca2 + influx, or by preventing K+ efflux, triggering

causing

depolarization and an action potential (Fig. 14-1). These effects may be mediated by channel or G protein-coupled receptors. Postsynaptic inhibition can be mediated by channel receptors or by receptors coupled to G proteins (Fig. 14-1). Inhibition is usually accomplished by movement of Cl- into the neuron or by movement of K + out of the neuron. Both processes hyperpolarize the neuron and move membrane potential farther away from P.217 threshold, making it more difficult for a given stimulus to depolarize the membrane to threshold voltage. Presynaptic inhibition, the prevention of neurotransmitter release, is usually mediated by receptors coupled to G proteins. When a neurotransmitter released from a neuron binds to a receptor on that same neuron to limit further neurotransmitter release, the receptor is termed an autoreceptor.133 Autoreceptors reside on dendrites, cell bodies, axons, and presynaptic terminals. Autoreceptors on dendrites and cell bodies (somatodendritic autoreceptors) usually inhibit further neurotransmitter release by increasing K+ efflux, hyperpolarizing the neuron away from threshold (Fig. 14-2) . However, activation of autoreceptors found on presynaptic terminals

(terminal autoreceptors) usually limits increases in intracellular Ca2 + concentration by limiting Ca2 + influx or preventing release from intracellular Ca2 + stores, impairing exocytosis of neurotransmitter vesicles (Fig. 14-2). Types of neurotransmitter receptors that serve as autoreceptors also usually reside postsynaptically, where they may mediate different physiologic effects. Presynaptic nerve terminal inhibition of neurotransmitter release is not limited to actions by autoreceptors. Presynaptic terminal inhibitory receptors for various neurotransmitters may be found on a single neuron (heteroreceptors). For example, not only does stimulation of an α2 autoreceptor on a noradrenergic nerve limit norepinephrine release, but stimulation of presynaptic α2 receptors found on postganglionic parasympathetic nerve terminals prevents acetylcholine release. Finally, stimulation of receptors on presynaptic nerve endings may enhance, rather than inhibit, neurotransmitter release. Such receptors also are usually coupled to G proteins. For example, stimulation of a β 2 receptor on an adrenergic nerve terminal enhances norepinephrine release.

Figure 14-2. Common mechanisms of presynaptic inhibition (the inhibition of neurotransmitter [NT] release). A . Neuron A releases NT, which returns to activate receptors on the cell body or dendrites (somatodendritic autoreceptors), or on the axonal terminal (terminal autoreceptors). Such activation limits further release of NT by completing a negative feedback loop. B . At somatodendritic autoreceptors, NT binding produces activation of G proteins, which promote either K+ efflux or Cl- influx; both processes hyperpolarize the neuron away from threshold. C . At terminal autoreceptors, NT binding activates G proteins, which, through various mechanisms, lower intracellular Ca2 + concentrations to prevent exocytosis of NT vesicles, despite depolarization. Presynaptic inhibitory receptors for other types of

NTs (heteroreceptors) are illustrated in C. Excitatory axonal terminal autoreceptors and heteroreceptors that serve to enhance (not inhibit) neurotransmitter release are not shown. G = G protein.

Acetylcholine ACh is a neurotransmitter of the central and peripheral nervous system. Centrally, it is found in both brain and spinal cord; cholinergic fibers project diffusely to the cerebral cortex. Peripherally, ACh serves as a neurotransmitter in autonomic and somatic motor fibers (Fig. 14-3) .

Synthesis,

Release,

and

Inactivation

Acetylcholine is synthesized from acetylcoenzyme A and choline. Acetylcholine moves into synaptic vesicles via the vesicular membrane transporter VAChT, where it is stored before release into the synapse by Ca2 +-dependent exocytosis. Acetylcholine undergoes degradation in the synapse to choline and acetic acid by acetylcholinesterase. An Na+-dependent transporter in the neuronal membrane then pumps choline back into the cytoplasm to be used again as a substrate for ACh synthesis (Fig. 14-4) . Pseudocholinesterase (plasma cholinesterase) is made in the liver and P.218 plays no role in the degradation of synaptic ACh. However, it does metabolize some drugs, including cocaine and succinylcholine.

Figure

14-3. Diagram of the cholinergic nervous system,

including adrenergic involvement in the autonomic nervous system. ACh binds to CNS, ganglionic, and adrenal neuronal nicotinic receptors (nnAChRs) and to neuromuscular junction nicotinic receptors (NMJ nAChRs). ACh also binds to various subtypes of muscarinic (M) receptors in the CNS and on effector organs innervated by postsynaptic parasympathetic neurons and to most sweat glands. NE and/or EPI released in response to ganglionic ACh stimulation of nnAChRs activates α- and βadrenoceptors. ACh =acetylcholine; ANS = autonomic nervous system; CNS =central nervous system; EPI =epinephrine; NE =norepinephrine.

Acetylcholine Nicotinic

Receptors

Receptors

After release from cholinergic nerve endings, ACh activates two main types of receptors: nicotinic and muscarinic.85 Nicotinic receptors (nAChRs) reside in CNS (mainly in spinal cord), on postganglionic autonomic neurons (both sympathetic and parasympathetic), and at skeletal neuromuscular junctions, where they mediate muscle contraction (Fig. 14-3) . Nicotinic receptors at neuromuscular junctions (NMJ nAChRs) are part of an Na+ channel made of five protein subunits and are thus channel receptors. Stimulation of these receptors by ACh results mainly in Na+ influx, depolarization of the endplate, and triggering of an action potential that is propagated down muscle by voltage-gated N a+ channels. Nicotinic receptors on central or peripheral neurons or in the adrenal gland are termed neuronal nAChRs. Neuronal nAChRs are also ion channels, although in some cases Ca2 + influx through the receptor may be more important than Na+ influx. Neuronal nAChRs also comprise five protein subunits.

Muscarinic

Receptors

Muscarinic receptors reside in the CNS (mainly in the brain), on end organs innervated by postganglionic parasympathetic nerve endings, and at most postganglionic sympathetically innervated sweat glands (Fig. 14-4). At least five subtypes of muscarinic receptors, M1–5, are recognized and linked to several G proteins. For example, in the heart, ACh released from the vagus nerve binds to M2 receptors linked to Gi. Gi opens K+ channels, allowing efflux of K+ down its concentration gradient, which makes the inside of the cell more negative and more difficult to depolarize, slowing heart rate. Different subtypes of muscarinic receptors also act as autoreceptors in various locations, M 1 being the most common.

Chemical

Agents

Table 14-2 provides examples of agents that affect cholinergic neurotransmission.

Modulators

of

Acetylcholine

Release

Figure 14-4 illustrates sites of actions of numerous agents that influence the cholinergic nervous system. Botulinum toxins, some neurotoxins from pit vipers, and elapid β-neurotoxins prevent release of ACh from peripheral nerve endings.61 This results in ptosis, other cranial nerve signs, weakness, and respiratory failure. Hypermagnesemia also inhibits acetylcholine release, probably by inhibiting Ca2 + influx into the nerve endings.85 Guanidine, aminopyridines, and black widow spider venom enhance the release of ACh from nerve endings. Guanidine has been unsuccessfully tried as a treatment for botulism. Aminopyridines block voltage-gated K+ channels to prevent K+ efflux; the resultant action potential widening (delayed repolarization) causes prolongation of Ca2 + channel activation, enhancing influx of Ca2 + and promoting neurotransmitter release. Aminopyridines have been used therapeutically in Lambert-Eaton syndrome, myasthenia gravis, and multiple sclerosis, and experimentally in calcium channel blocker overdose. P.219 Black widow spider venom causes acetylcholine release with resultant muscle cramping and diaphoresis.6 Carbachol, a nicotinic and muscarinic agonist, also probably causes ACh release.

Figure 14-4. Cholinergic nerve ending. Activation of postsynaptic muscarinic receptors hyperpolarizes the postsynaptic membrane through G-protein-mediated enhancement of K+ efflux. Several subtypes of muscarinic receptors coupled to various G proteins exist—a muscarinic receptor coupled to a G protein that opens K+ channels is shown only as an example. Postsynaptic nicotinic receptor activation causes Na + influx and membrane depolarization. Importantly, C a2 + influx appears to be the main cation involved with some neuronal nicotinic receptors. Presynaptic muscarinic and α2 -

adrenoceptor activation prevents ACh release through lowering of intracellular Ca2 + concentrations. The agents listed in Table 14-2 may act to enhance or prevent release of ACh [1]; activate or antagonize postsynaptic muscarinic (M) receptors [2]; activate or antagonize nicotinic (N) receptors [3]; inhibit acetylcholinesterase [4]; prevent ACh release by stimulating presynaptic muscarinic autoreceptors [5] or α2 -adrenergic heteroreceptors [6]; or enhance ACh release by antagonizing presynaptic autoreceptors [5] or by antagonizing presynaptic Î ±2 -adrenergic heteroreceptors [6] (on parasympathetic postganglionic terminals). ACh =acetylcholine; G = G protein; NE =norepinephrine; VAChT = vesicular transporter for ACh.

Nicotinic Receptor Antagonists

Agonists

and

Agents that bind to and activate nicotinic receptors may stimulate postganglionic sympathetic and parasympathetic neurons, skeletal muscle endplates, and neurons within the CNS (Fig. 14-3). Prolonged depolarization at the receptor eventually causes blockade of nicotinic receptors.113 For example, poisoning by nicotine, both a neuronal and NMJ nAChR agonist, produces hypertension, tachycardia, vomiting, diarrhea, muscle fasciculations, and convulsions (excitation), followed by hypotension, bradydysrhythmias, paralysis, and coma (blockade). Nicotinic agonists include nicotine alkaloids (eg, nicotine, coniine, lobeline), carbachol (mainly muscarinic effects), and methacholine (slight effect). Succinylcholine is a neuromuscular blocking agent that initially stimulates and then blocks NMJ nAChRs.

TABLE 14-2. Examples of Xenobiotics That Affect Cholinergic Neurotransmission

Cholinomimetics Cause ACH release

Cholinolytics Direct nicotinic antagonists α-Bungarotoxinc

α2 -Adrenergic antagonistsa

Aminopyridines

Coniine

Black widow spider venom

Cytisine

Carbachol

Gallamine

Guanidine

Hexamethonium

Lobeline

Anticholinesterases

Echothiophate

Edrophonium

Galantamine

iodide

Mecamylamine

Nicotine

Nondepolarizing

muscular agents

neuro-

blocking

N-methylcarbamate insecticides

Metrifonate

Succinylcholineb

Trimethaphan

Neostigmine

Organic phosphorus insecticides

Physostigmine

Indirect

neuronal

antagonists

Pyridostigmine

Physostigmine

Rivastigmine

Tacrine

Tacrine

Galantamine

Direct

nicotinic

agonists

Direct

muscarinic

antagonists

Carbachol

Amantadine

Coniine

Antihistamines

Cytisine

Atropine

Lobeline

Benztropine

nicotinic

Nicotine

Carbamazepine

Succinylcholine

(initial)b

Clozapine

Cyclobenzaprine

Indirect agonists

neuronal

nicotinic

Disopyramide

Chlorpromazine

Glutethimide

Corticosteroids

Orphenadrine

Ethanol

Phenothiazines

Ketamine

Procainamide

Local

anesthetics

Quinidine

Phencyclidine

Volatile

Scopolamine

anesthetics

Tricyclic

antidepressants

Trihexyphenidyl

Direct

muscarinic

Arecoline

agonists

Inhibit

ACh

release

Bethanechol

α2 -Adrenergic agonistsd

Carbachol

Botulinum

toxins

Methacholine

Crotalidae

venoms

Muscarine

Elapidae

Pilocarpine

β-neurotoxins

Hypermagnesemia

ACh = acetylcholine a Antagonism of α -adrenoceptors enhances ACh release from 2 parasympathetic nerve endings. b Depolarizing neuromuscular blocking agent. c α-Bungarotoxin exemplifies many elapid α-neurotoxins that produce paralysis and death from respiratory failure. d Stimulation

of presynaptic α2 -adrenoceptors on parasympathetic nerve endings prevents ACh release.

Agents that block NMJ nAChRs without stimulation at skeletal neuromuscular junctions produce weakness and paralysis. Examples include curare and atracurium. α-Neurotoxins from elapids (eg, αbungarotoxin) directly antagonize NMJ nAChRs, P.220 producing ptosis, weakness, and respiratory failure from paralysis.164 Chemicals blocking peripheral neuronal nAChRs produce autonomic ganglionic blockade. Trimethaphan is used as a pharmacologic ganglionic blocker; however, trimethaphan is not entirely specific for neuronal nAChRs. Occasional patients develop weakness and

paralysis from NMJ nAChR blockade. Recent studies demonstrate that the function of neuronal nAChRs can be modulated by a variety of compounds that do not bind to the ACh binding site, but bind instead to a number of distinct allosteric sites on the neuronal nAChR. For example, aside from their ability to inhibit acetylcholinesterase, physostigmine, tacrine, and galantamine bind to a noncompetitive allosteric activator site on neuronal nAChRs to enhance channel opening and ion conductance (there is evidence suggesting that serotonin may bind here as well). Furthermore, a diverse range of compounds, including chlorpromazine, phencyclidine, ketamine, local anesthetics, and ethanol bind to a noncompetitive negative allosteric site(s) to inhibit inward ion fluxes without directly affecting ACh binding. Steroids can desensitize neuronal nAChRs by binding to yet an additional allosteric site. Finally, a dihydropyridine calcium channel blocker binding site has been described, but remains poorly understood.115

Muscarinic Receptor Antagonists Peripheral

muscarinic

agonists

Agonists produce

and

bradycardia,

miosis,

salivation, lacrimation, vomiting, diarrhea, bronchospasm, bronchorrhea, and micturition. Central muscarinic agonists produce sedation, extrapyramidal dystonias and rigidity, coma, and convulsions. Examples of direct muscarinic agonists include muscarine (from mushrooms), bethanechol, pilocarpine, carbachol, arecoline, and methacholine. Anticholinergic poisoning syndrome results from blockade of muscarinic receptors and is more appropriately referred to as antimuscarinic poisoning syndrome.136 Central nervous system muscarinic blockade produces confusion, agitation, myoclonus, tremor, picking movements, abnormal speech, hallucinations, and coma. Peripheral antimuscarinic effects include mydriasis, anhidrosis, tachycardia, and urinary retention. Muscarinic antagonists number in

the

hundreds; Table 14-2 lists examples.

Acetylcholinesterase

Inhibition

Agents inhibiting acetylcholinesterase raise ACh concentrations at both nicotinic and muscarinic receptors, producing a variety of CNS, sympathetic, parasympathetic, and skeletal muscle signs and symptoms.32 Anticholinesterases include organic phosphorus compounds and N-methylcarbamates. Organic phosphorus compounds are usually encountered as insecticides, although topical medicinal organic phosphorus compounds are used for the treatment of glaucoma and lice. N-methylcarbamates are found as insecticides and pharmaceutics. Medicinal N-methylcarbamates include physostigmine, pyridostigmine, rivastigmine, and neostigmine. Edrophonium, galantamine, tacrine, anticholinesterases.

and

Î ±2 -Adrenoceptor

metrifonate

are

Agonists

noncarbamate,

and

reversible

Antagonists

Agonists and antagonists of α2 -adrenoceptors are discussed in detail below. Briefly, stimulation of presynaptic α2 -adrenoceptors on postganglionic parasympathetic nerve endings decreases ACh release. Conversely, presynaptic α2 antagonism increases ACh release (Fig. 14-4) .

Norepinephrine

and

Epinephrine

Norepinephrine (NE), epinephrine (EPI), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT) have historically been referred to as biogenic amines, and their neurotransmitter systems are similar in many respects. Neurotransmitter synthesis, vesicle transport and storage, uptake, and degradation share many enzymes and structurally similar transport proteins. Cocaine, reserpine, amphetamines, and monoamine oxidase inhibitors (MAOIs) affect all four types of neurons. In addition, these agents produce several

different effects in the same system. For example, in the noradrenergic neuron, amphetamines work mainly by causing the release of cytoplasmic norepinephrine, but they also inhibit norepinephrine uptake, and their metabolites inhibit monoamine oxidase. Actions of drugs that affect all biogenic amine neurotransmitters are described in the most detail for noradrenergic neurons. For the sake of brevity, similar mechanisms of action are simply noted in discussions of dopaminergic and serotonergic neurotransmission. Norepinephrine

is

released

from

postganglionic

sympathetic

(Fig. 14-3) and is also found in the CNS. The adrenal a modified sympathetic ganglion, releases epinephrine amounts of norepinephrine in response to stimulation nAChRs. Epinephrine-containing neurons also reside in

fibers

gland, acting as and lesser of neuronal the

brainstem. The locus ceruleus is the main noradrenergic nucleus in the brain, comprising about 12,500 neurons in the floor of the fourth ventricle on each side of the pons. Axons radiate from this nucleus out to all layers of the cerebral cortex, to the cerebellum, and to other structures. Norepinephrine demonstrates both excitatory and inhibitory actions in the CNS. Norepinephrine released from locus ceruleus projections in the hippocampus increases cortical neuron activity through β-adrenoceptor activation and G protein-mediated inhibition of K+ efflux. Norepinephrine released in outer cortical areas produces inhibitory effects mediated by α-adrenoceptor agonism. At this level, norepinephrine produces slow cortical neuron hyperpolarization and decreased rates of spontaneous firing. Consistent with this, norepinephrine demonstrates anticonvulsant actions in animals. Carbamazepine's anticonvulsant action may be partly a result of inhibition of norepinephrine uptake. 45 Despite antagonistic actions on different cortical neurons, electrical stimulation of the locus ceruleus produces widespread cortical activation and excitation. This overall effect probably explains a great deal of the hyperattentiveness and lack of fatigue that

accompanies use of agents that mimic or increase noradrenergic activity in the brain. Locus ceruleus neuronal firing increases during waking and dramatically falls during sleep.

Synthesis,

Release,

and

Uptake

Figure 14-5 is a representation of a noradrenergic neuron. Tyrosine hydroxylase is the rate-limiting enzyme in norepinephrine synthesis and is sensitive to negative feedback by norepinephrine. This enzyme requires Fe2 + as a cofactor and exists as a homotetramer and is upregulated by chronic exposure to caffeine and nicotine. Under normal dietary conditions tyrosine hydroxylase is completely saturated by tyrosine, and increasing dietary tyrosine intake does not appreciably increase dopa synthesis. Dopa undergoes decarboxylation by L-amino acid decarboxylase to dopamine. L-Amino acid decarboxylase (dopa decarboxylase) is not specific for dopa. For example, it also catalyzes the formation of serotonin from 5hydroxytryptophan. P.221 About one-half of cytoplasmic dopa is actively pumped into vesicles containing the enzyme dopamine-β-hydroxylase by VMAT2. The remaining dopamine is quickly deaminated.

Figure 14-5. Noradrenergic nerve ending. The postsynaptic membrane may represent an end organ or another neuron in the CNS. Brief examples of effects resulting from postsynaptic receptor activation are shown. Agents in Tables 14-4 and 14-5 produce effects by inhibiting transport of dopamine (DA) or norepinephrine (NE) into vesicles through VMA2 [1]; causing movement of NE from vesicles into the cytoplasm [2]; activating or antagonizing postsynaptic α- and β-adrenoceptors [3–5]; modulating NE release by activating or antagonizing presynaptic Î ±2 -autoreceptors [6], dopamine2 (D2 ) heteroreceptors [10], or Î ²2 -autoreceptors [11]; blocking uptake of NE (NET inhibition) [7]; causing reverse transport of NE from the cytoplasm into the synapse via NET by raising cytoplasmic NE concentrations [8]; inhibiting monoamine oxidase (MAO) to prevent NE degradation

[9]; or inhibiting COMT to prevent NE degradation [12]. COMT is not found in neurons in large amounts. AADC =aromatic L-amino acid decarboxylase; ATP =adenosine triphosphate; DA-OHase = dopamine-β-hydroxylase; COMT = catechol-Omethyltransferase; CNS =central nervous system; DOPGAL = 3,4-dihydroxyphenylglycoaldehyde; G = G protein; NET =membrane NE uptake transporter; NME = normetanephrine; Tyr-OHase = tyrosine hydroxylase; VMA2 =vesicle uptake transporter for NE.

In the vesicle, dopamine is converted to norepinephrine by dopamine-β-hydroxylase, an enzyme requiring Cu2 + and ascorbic acid. Vesicles isolated from peripheral nerve endings contain dopamine, norepinephrine, dopamine-β-hydroxylase, and ATP, and all of these substances are released into the synapse during Ca2 +dependent exocytosis triggered by neuronal firing. (Whether dopamine-β-hydroxylase is released into CNS synapses has not been determined.) In neurons containing epinephrine as a neurotransmitter, norepinephrine is released from vesicles into the cytoplasm, where it is converted to epinephrine by phenylethanolamine-N-methyl-transferase. Epinephrine is then transported back into vesicles before synaptic release.85 Norepinephrine is removed from the synapse mainly by uptake into the presynaptic neuron by the norepinephrine transporter (NET). Although this transporter has great affinity for norepinephrine, it also transports other amines, including dopamine, tyramine, MAOIs, and amphetamines. Once pumped back into the cytoplasm, norepinephrine can either be transported back into vesicles for further storage and release, or can be quickly enzymatically degraded by monoamine oxidase (MAO), an enzyme expressed on the outer mitochondrial membrane. MAO resides in sympathetic postganglionic neurons, intestinal mucosa, liver, kidney, lung, and brain, but also extracellularly. It

exists as two isozymes, MAO-A and MAO-B,98 each with relatively separate affinities for various substrates (Table 14-3). Neuronal MAO degrades cytoplasmic amines, including neurotransmitters, to P.222 prevent elevated cytoplasmic concentrations of biogenic amines. Hepatic and intestinal MAO prevent large quantities of dietary bioactive amines from entering the circulation and producing systemic effects.

TABLE 14-3. Characteristics of Monoamine Oxidase (MAO) Isozymes

MAO

Isozymes

MAO-A

MAO-B

Location

Brain

+

+++

Intestine

+++

+

Liver

++

++

Platelets

0

++++

Placenta

++++

0

Substrates

Norepinephrine

++++

+

Epinephrine

++

++

Dopamine

++

++

Serotonin

++++

+

Tyramine

++

+++

Catechol-O-methyltransferase (COMT), found in the synaptic cleft, also metabolizes norepinephrine and epinephrine. In other tissue, COMT metabolizes catecholamines, including those that have entered the systemic circulation.

Adrenergic

Receptors

The two main types of adrenoceptors are α-adrenoceptors and βadrenoceptors. All adrenoceptors are linked to G proteins.

β-Adrenoceptors β-Adrenoceptors are divided into three major subtypes (β1 , β2 , and Î ²3 ), depending on their affinity for various agonists and antagonists.28,66,68,89 β1 - and β2 -adrenoceptors are linked to Gs , and their stimulation raises cAMP concentration and/or activates protein kinase A, which, in turn, produces several effects, including regulation of ion channels. At least some β3 -adrenoceptors may be coupled not only to Gs , but also to receptors for Gi / o proteins. The β-adrenoceptors are polymorphic, with genetic variation in the human population.26 Polymorphism influences response to medications, regulation of receptors, and clinical course of

disease.26,68,89 In general, peripheral β1 -adrenoceptors are found mainly in the heart (along with β2 receptors), whereas peripheral Î ²2 -adrenoceptors also mediate additional adrenergic effects.68 Presynaptic β2 -adrenoceptor activation causes release of norepinephrine from nerve endings (positive feedback). β3 Adrenoceptors reside mainly in fat, but they also reside in skeletal muscle, gallbladder, and colon where they regulate metabolic processes. Activation of cardiac β3 -adrenoceptors might produce negative inotropic effects in some circumstances. β3 -Adrenoceptors' polymorphism may contribute to clinical expressions of non–insulin-dependent diabetes and obesity.26,148,165

Î ±-A drenoc epto r s α-Adrenoceptors are linked to G proteins that inhibit adenylate cyclase and lower cAMP levels, affect ion channels, increase intracellular calcium through inositol triphosphate and diacylglycerol production, or produce other actions. These receptors are divided into two main types, α 1 and α2 , and at least six subtypes, α1 A, Î ±1 B, α1 D, α2 A, α2 B, and α2 C. 39,66 Most α1 adrenoceptors are coupled to Gq , whereas most α2 adrenoceptors are coupled to Gi. In peripheral tissue, α1 -adrenoceptors reside on the postsynaptic membrane in continuity with the synaptic cleft. Stimulation of these receptors on blood vessels commonly results in vasoconstriction. Most α1 receptors are coupled to Gq . Î ±2 -Adrenoceptors reside on both sides of the synapse. Presynaptic Î ±2 -adrenoceptor activation mediates negative feedback, limiting further release of norepinephrine (Fig. 14-5). Postganglionic parasympathetic neurons (cholinergic) also contain presynaptic α2 adrenoceptors that, when stimulated, prevent release of ACh (Fig. 14-4) . Postsynaptic α 2 -adrenoceptors on vasculature also can mediate vasoconstriction. Initially, it was suggested that postsynaptic α2 adrenoceptors resided mainly outside of the synapse and mediated

vasoconstrictive responses to circulating α agonists such as norepinephrine, whereas postsynaptic α1 -adrenoceptors responded to norepinephrine released from nerve endings. However, it has been demonstrated that in at least some tissues (eg, saphenous vein), norepinephrine released following nerve stimulation produces vasoconstriction through action at α2 -adrenoceptors, making the previous differentiation not as distinct.39,74 Because both α1 - and Î ±2 -adrenoceptors on noncerebral vasculature mediate vasoconstriction, a patient with hypertension from high concentrations of circulating catecholamine (eg, pheochromocytoma or clonidine withdrawal) or from extravasation of norepinephrine from an intravenous line commonly needs both α1 - and α2 adrenoceptor blockade to vasodilate adequately (eg, phentolamine). Stimulation of postsynaptic α2 -adrenoceptors in the brainstem inhibits sympathetic output and produces sedation (Fig. 14-6). In fact, dexmedetomidine, an imidazole and potent α2 A-adrenergic agonist, is used for sedation in intensive care patients, although hypotension and bradycardia occur as expected side effects.13

Figure 14-6. Central action of agents that activate α2 adrenoceptors or that bind to type 1 imidazoline binding sites ( I1 ). There are poorly understood interactions between

imidazoline binding sites and α2 -adrenoceptors that make delineation of specific effects difficult to attribute to specific receptor activation. BP = blood pressure; HR = heart rate; LC =locus ceruleus; NTS = nucleus tractus solitarius; VLM =ventrolateral medulla.

Chemical

Agents

Chemicals producing pharmacologic effects that result in or mimic increased activity of the adrenergic nervous system are sympathomimetics (Table 14-4). Those with the opposite effect are sympatholytics (Table 14-5) .

Sym pathom imet ic s Direct-Acting

Agents

Drugs or chemicals whose sympathomimetic actions result from direct binding to α- or β-adrenoceptors are called direct-acting sympathomimetics. Most of these drugs do not cross the blood–brain

barrier

Indirect-Acting

in

significant

quantities.

Agents

Agents that produce sympathomimetic effects by causing the release of cytoplasmic norepinephrine from the nerve ending in the absence of vesicle exocytosis are called indirect-acting sympathomimetics. Amphetamine is the prototype of indirect-acting agents and is used for the discussion of what is known about their mechanism of action. In general, mechanisms of indirect release of norepinephrine by amphetamines, cocaine, phencyclidine, MAOIs, and mixed-acting agents noted in Table 14-4 are similar in that their actions depend on their ability to produce elevated cytoplasmic norepinephrine concentrations.

Amphetamine and structurally similar indirect-acting agents move into the neuron mainly by the membrane transporter that pumps norepinephrine into the neuron. (Lipophilic indirect-acting P.223 agents move into the neuron by diffusion.) From the cytoplasm, amphetamines are transported into neurotransmitter vesicles, where they buffer hydrogen ions to raise intravesicle pH. As noted earlier, much of the vesicle's ability to concentrate norepinephrine (and other neurotransmitters) is a result of ion trapping of norepinephrine at the lower pH. The rise in intravesicle pH produced by amphetamines causes norepinephrine to leave the vesicle and move into the cytoplasm.149,150 Such movement may be caused by diffusion and/or reverse transport of norepinephrine by VMAT2. In the cytoplasm, amphetamines also compete with norepinephrine and dopamine for transport into vesicles, which further contributes to elevated cytoplasmic norepinephrine concentrations. In the case of amphetamine, the rise in cytoplasmic concentrations of norepinephrine may be enhanced by the ability of amphetamine metabolites to inhibit MAO, which impairs norepinephrine degradation.

TABLE 14-4. Examples of Sympathomimetics

Direct acting β-Adrenoceptor agonists Albuterol Dobutamine Epinephrine Isoproterenol Metaproterenol Norepinephrine Ritodrine

Terbutaline α-Adrenoceptor agonists Dobutamine Epinephrine Ergot alkaloids Methoxamine Norepinephrine Phenylephrine Indirect acting Amphetamines Cocaine Fenfluramine MAOIs Methylphenidate Pemoline Phencyclidine Phenmetrazine Propylhexedrine Tyramine Mixed acting Dopamine Ephedrine Mephentermine Phenylpropanolamine Pseudoephedrine Selective α2 -adrenoceptor antagonists Idazoxan Yohimbine Imidazoline binding-site antagonists Idazoxan MAOIs Amphetamine metabolites a Clorgyline Isocarboxazid

Linezolid Moclobemidea Pargyline Phenelzine Selegilineb Tranylcypromine Inhibit NE Uptake Amphetamines Atomoxetine Benztropine Bupropion Carbamazepine Cocaine Diphenhydramine Duloxetine Orphenadrine Pemoline Reboxetine Tramadol Tricyclic antidepressants Trihexyphenidyl Venlafaxine

MAOIs = monoamine oxidase inhibitors; NE = norepinephrine. a Mainly inhibit MAO-A at low doses. b Mainly inhibit MAO-B at low doses.

Every time the Na+ -dependent uptake transporter, NET, moves, a bioactive amine (eg, tyramine) into the neuron where it is released, a binding site for norepinephrine on NET transiently faces inward and becomes available for reverse transport of norepinephrine out of the neuron. The normally low concentration of cytoplasmic norepinephrine prevents significant reverse transport. In the face of

elevated cytoplasmic norepinephrine concentrations produced by indirect-acting agents as described earlier, NET moves norepinephrine out of the neuron and back into the synapse, where the neurotransmitter stimulates adrenoceptors (indirect action). This process is sometimes referred to as facilitated exchange diffusion, or displacement, of norepinephrine from the nerve ending. Evidence supporting reverse transport produced by amphetamines is that inhibitors of the transporter (eg, tricyclic antidepressants) prevent amphetamine-induced norepinephrine release. While all indirect-acting agents cause reverse norepinephrine transport by increasing cytoplasmic norepinephrine concentrations, those that move into the neuron by the membrane transporter (eg, amphetamines, MAOIs, dopamine, tyramine) further enhance reverse transport because their uptake may cause more norepinephrine binding sites on NET to face inward per unit time. Although cocaine does inhibit NET, it also causes some norepinephrine release. In fact, cocaine similarly lessens pH gradients across vesicle membranes150 to raise cytoplasmic concentrations of P.224 norepinephrine.

That

cocaine

produces

less

norepinephrine

release

than amphetamines is partly explained by cocaine-induced inhibition of the membrane transporter and by the fact that cocaine does not move into the neuron by active uptake (ie, does not increase the number of norepinephrine binding sites facing inward), but diffuses into the neuron. (Most of cocaine's severe sympathomimetic effects probably result from cocaine's action on the brain rather than peripheral nerve endings.155)

TABLE 14-5. Examples of Sympatholytics

α-Adrenoceptor

antagonists

Penbutolola

Clozapine

Pindolola

Doxazosin

Practolola

Droperidol

Propranolol

Ergot

Sotalol

alkaloids

Labetalol

Timolol

Olanzapine

Phenothiazines

Phenoxybenzamine

Prevent NE release with

depolarization

Phentolamine

Bretyliumb

Prazosin

Reserpineb

Quinidine

Risperidone

Terazosin

α2-Adrenoceptor agonistsd α-Methyldopac

Tolazoline

Brimonidine

Trazodone

Clonidine

Tricyclic

antidepressants

Urapidil

Dexmedetomidine

Guanabenz

Guanfacine

Inhibit dopamine-βhydroxylase

Moxonidine

Diethyldithiocarbamate

Naphazoline

Disulfiram

Oxymetazoline

MAOIs

Rilmenidine

Tetrahydralazine

β-Adrenoceptor

antagonists

Xylometazoline

Acebutolola Alprenolola

Atenolol

Imidazoline agonistsd

Clonidine

binding-site

Betaxolol

Guanabenz

Bisoprolol

Guanfacine

Carteolol

Moxonidine

Carvedilol

Naphazoline

Esmolol

Oxymetazoline

Labetalol

Rilmenidine

Metipranolola

Metoprolol

Inhibitors of vesicle uptake

Nadolol

Reserpineb

Oxprenolol a

Tetrabenazine

NE = norepinephrine; MAOIs = monoamine oxidase inhibitors. a Partial β-agonist. b Causes transient NE release after initial dose. c Metabolized to α-methylnorepinephrine, which activates Î ±2 -receptors. d Agents in these categories vary in their relative selectivity for α2 -adrenoceptors or imidazoline binding sites.

Phencyclidine (PCP) is a hallucinogen that possesses multiple pharmacologic actions. Like toxicity from many hallucinogens, PCP

toxicity is accompanied by increased adrenergic activity, which results, in part, from PCP-induced decreases in pH gradients across the vesicle membrane150 and indirect release of norepinephrine. Like cocaine, PCP moves into the neuron by diffusion rather than uptake through the membrane transporter, at least partly explaining less PCP-induced norepinephrine release than is typically seen in amphetamine poisoning. Reserpine, guanethidine, and bretylium cause neurotransmitter release either with initial doses or early in overdose before their primary sympatholytic effects are observed. Presumably this is a result of transient rises in cytoplasmic norepinephrine concentrations. In addition to causing ACh release, black widow spider venom causes vesicle exocytosis of norepinephrine, producing hypertension and diaphoresis over the palms, soles, upper lip, and nose. All of the aforementioned indirectly acting agents, except black widow spider venom, enter the CNS.

Mixed-Acting

Agents

Mixed-acting sympathomimetics act directly and indirectly. For example, large doses of phenylpropanolamine indirectly cause norepinephrine release and act directly as α-adrenoceptor agonists. Intravenously administered dopamine indirectly causes norepinephrine release, explaining most of its vasoconstricting activity, but also directly stimulates dopaminergic and βadrenoceptors. Direct α-agonism occurs at high doses. Except for dopamine, these agents also cross the blood–brain barrier to produce central effects.

Uptake

Inhibitors

Inhibitors of norepinephrine uptake raise concentrations of norepinephrine in the synapse to produce excessive stimulation of

adrenoceptors. There are two main mechanisms of action for inhibitors of biogenic amine uptake: competitive and noncompetitive. Noncompetitive inhibitors, such as cyclic antidepressants, carbamazepine, venlafaxine, methylphenidate, and cocaine, bind at or near the carrier site on NET to prevent NET from moving norepinephrine and other agents into or out of the neuron. These inhibitors are not transported into the neuron by this mechanism; lipophilic agents diffuse into the neuron. Various drugs used for their antimuscarinic effects also block NET noncompetitively. These include benztropine, diphenhydramine, trihexyphenidyl, orphenadrine.105

atomoxetine,

and

The second mechanism, competitive inhibition of NET, characterizes most indirect-acting agents, including amphetamines and structurally similar compounds (eg, mixed-acting agents, MAOIs). These agents prevent norepinephrine uptake by competing with synaptic norepinephrine for binding to the carrier site on NET, the mechanism by which these agents move into the neuron. In fact, an additional adrenergic action of amphetamines, mixed-acting agents, MAOIs, and tyramine is to raise synaptic norepinephrine concentrations by competing with norepinephrine for uptake, thereby compounding their indirect and/or direct actions.

MAOIs MAOIs are transported by NET into the neuron, where they act through several mechanisms.98 Inhibition of MAO, their main pharmacologic effect, results in increased cytoplasmic concentrations of norepinephrine and some indirect release of neurotransmitter into the synapse. As a minor effect they also may displace norepinephrine from vesicles by raising pH in a manner similar to amphetamines. These actions explain the initial hyperadrenergic findings following MAOI overdose and probably also account for occasional and unpredictable adrenergic crises in patients taking these agents,

despite the patients' compliance with diet. Nonspecific MAOIs inhibit both isozymes of MAO, preventing intestinal and hepatic degradation of bioactive amines as well. A person taking such an MAOI who then ingests food or receives drugs containing indirect-acting sympathomimetics (eg, tyramine, phenylpropanolamine, dopamine, amphetamines) has a much larger cytoplasmic concentration of norepinephrine to transport into the synapse and may therefore develop central and peripheral hyperadrenergic findings. Although MAOIs specific for the MAO-B isozyme are less likely to predispose to food or drug interactions by maintaining significant hepatic MAO activity, isozyme specificity is lost as the dose of the MAOI is increased. In fact, selegiline, currently marketed as a selective MAO-B inhibitor, partially inhibits MAO-A activity at therapeutic doses. Specificity may lack importance when indirect-acting agents are administered systemically (eg, intravenous dopamine or amphetamines). Several amphetamine metabolites are capable of inhibiting MAO, contributing to their sympathomimetic activity. Linezolid is an antibiotic that produces weak MAO inhibition. Occasionally,

patients

suffering

from

refractory

depression

respond

to a combination of MAOIs and tricyclic antidepressants. This combination therapy is usually unaccompanied by excessive adrenergic activity because the inhibition of the membrane uptake transporter by the tricyclic antidepressant attenuates excessive reverse transport of elevated cytoplasmic norepinephrine concentrations produced by MAOIs. In animals, tricyclic antidepressants that prevent norepinephrine uptake or cocaine, also an norepinephrine uptake inhibitor, protect against drug and food interactions with MAOIs by inhibiting the uptake transporter, thus inhibiting reverse transport.

COMT

Inhibitors

Inhibitors of COMT are administered in the treatment of Parkinson

disease to prevent the catabolism of concomitantly administered Ldopa. Entacapone only acts peripherally, whereas tolcapone also crosses the blood–brain barrier.

Î ±2 -Adrenoceptor

Antagonists

Yohimbine blocks α2 -adrenoceptors to produce a mixed clinical picture. Peripheral postsynaptic α2 blockade produces vasodilatation. Blockade of presynaptic α2 -adrenoceptors on cholinergic nerve endings (Fig. 14-4) enhances ACh release, occasionally producing bronchospasm82 and contributing to diaphoresis. Similar presynaptic actions on peripheral noradrenergic nerves enhance catecholamine release (Fig. 14-5). Blockade of central α2 -adrenoceptors in the locus ceruleus results in CNS stimulation, whereas blockade of postsynaptic α2 -adrenoceptors in the nucleus tractus solitarius may enhance sympathetic output (Fig. 14-6). The final result includes hypertension, tachycardia, anxiety, fear, agitation, mania, mydriasis, diaphoresis, and bronchospasm.90 Yohimbine does not block P.225 imidazoline receptors (see Imidazoline and α2 -Adrenoceptor Agonists below). One action of the antidepressant mirtazapine is α2 adrenoceptor blockade.

Sympatholytics Direct

Antagonists

Direct α- and β-adrenoceptor antagonists are noted in Table 14-5. In overdose, and sometimes at therapeutic doses, any βadrenoceptor selectivity becomes insignificant. Some β-adrenoceptor antagonists also are partial agonists.

Drugs

That

Prevent

Norepinephrine

Release

Drugs that prevent the release of norepinephrine, despite membrane depolarization, include guanethidine and bretylium. Both drugs initially cause release of norepinephrine and can produce transient sympathomimetic effects. Drugs that block the vesicle uptake transporter prevent the movement of norepinephrine into vesicles and deplete the nerve ending of this neurotransmitter, also preventing norepinephrine release after depolarization. Examples include rauwolfia alkaloids (reserpine), tetrabenazine, and guanethidine (in part). Reserpine and ketanserin inhibit both VMAT1 and VMAT2, whereas tetrabenazine only inhibits VMAT2. Like guanethidine, reserpine causes transient norepinephrine release with initial dose or early in overdose. β-Adrenoceptor antagonists block presynaptic β2 -adrenoceptors to limit catecholamine release from nerve endings, although this does not appear to be their main mechanism of action.

Imidazoline

and

α2 -Adrenoceptor

Agonists

Numerous imidazoline derivatives (eg, clonidine) and structurally similar compounds are used as centrally acting antihypertensive agents or long-acting topical vasoconstrictors. These agents are currently divided into first-generation agents (eg, clonidine) that are thought to act at both α2 A-adrenoceptor and imidazoline binding sites, and second-generation agents (eg, rilmenidine) that express much greater affinity for imidazoline binding sites than for α2 Aadrenergic receptors. The ventromedial (depressor) and the rostral-ventrolateral (pressor) areas of the ventrolateral medulla (VLM) are responsible for the central regulation of cardiovascular tone and blood pressure. They receive afferent fibers from the carotid and aortic baroreceptors, which form the tractus solitarius via the nucleus tractus solitarius (NTS).73 The hypotensive actions of α2 -adrenoceptor agonists were previously attributed entirely to brainstem α2 -adrenoceptor

activation, because stimulation of postsynaptic α2 -adrenoceptors in the NTS decreased sympathetic output (Fig. 14-6) .22 The discovery of imidazoline binding sites, however, led to a more complicated analysis. It was discovered that imidazolines and related substances produced hypotension when applied to the VLM, whereas catecholamines capable of activating α2 -adrenoceptors were claimed to be incapable of producing effects at this site. This led to the hypothesis that receptors specific for imidazoline-like compounds, different from α2 A-adrenoceptors, must exist. Decreased sympathetic output could result from activation of imidazoline binding sites in the VLM and from α2 -adrenoceptor activation in the NTS; sedation and respiratory depression were attributed to α 2 adrenoceptor activation in the locus ceruleus.47 Imidazoline binding sites have been characterized and subdivided into I1 , I2 (with subtypes), and I3 . 42 I1 binding sites reside on neuronal plasma membranes and are involved in controlling systemic blood pressure. I2 sites are allosteric sites found on the external membrane of mitochondria and modulate MAO-A and MAO-B.22,42 The putative I3 sites are thought to modulate insulin secretion via ATPsensitive potassium channels in β-islet cells. The molecular structure of the imidazoline binding sites has not been identified and it is unclear whether these sites act through ion channels, through G proteins, or through some other mechanism. An endogenous ligand for these binding sites has been discovered. Agmatine, originally identified as a clonidine-displacing substance, is synthesized by decarboxylation of arginine. It appears to function as a neurotransmitter, and it binds all subclasses of both α2 adrenoreceptors and I-binding sites, as well as block N-methyl-Daspartate (NMDA) glutamate receptors. Other physiologic functions of agmatine continue to be investigated.10,124 Functional studies suggested that the hypotensive effects of clonidine-like drugs involved imidazoline binding sites, while most of the side effects involved α2 A-adrenoceptors.47 Consequently, drugs

such as rilmenidine, possessing much greater activity at imidazoline binding sites than at α2 A-adrenoceptors, were developed. However, functional evidence suggests that there is significant interaction between the imidazoline sites and α2 A-adrenoceptors, and that this interaction is necessary to trigger hypotensive effects.21,47 As examples, there appears to be a close relationship between “presynaptic― imidazoline sites and “downstream― α2 Aadrenoceptors in the VLM mediating hypotension;62 α2 Aadrenoceptors in the VLM appear to be activated as a consequence of imidazoline site activation. Although second-generation agents (rilmenidine and moxonidine) preferentially act via imidazoline binding sites, and although α2 A-adrenoceptors are important for the hypotension produced by first-generation agents (clonidine and αmethyldopa), hypotension produced by all of these agents is dependent on central noradrenergic pathways.21,62 Some studies report that yohimbine, an α2 -adrenoceptor antagonist, reverses the hypotensive effect of both clonidine and rilmenidine-like drugs, when given at high doses. Thus, it appears that there is significant interaction between imidazoline sites and α2 A-adrenoceptors, and that centrally acting antihypertensive agents with relatively high affinity for imidazoline binding sites may require both imidazolinespecific sites and functional α2 A-adrenoceptors to produce their hypotensive actions. Ingestions of agents that activate α2 A-adrenoceptors and imidazoline binding sites (Table 14-5) produce a mixed picture. Peripheral postsynaptic α2 -adrenoceptor stimulation produces vasoconstriction, pallor, and hypertension, often with reflex bradycardia (Fig. 14-5). Peripheral presynaptic α2 -adrenoceptor stimulation prevents norepinephrine release (Fig. 14-5), whereas central α2 -adrenoceptor stimulation in the locus ceruleus accounts for CNS and respiratory depression (Fig. 14-6). Stimulation of postsynaptic α2 -adrenoceptors in the NTS and, with some agents, of central I 1 receptors in the VLM are thought to inhibit sympathetic output and enhance parasympathetic tone, explaining hypotension

with bradycardia (Fig. 14-6) .73 Both first- and second-generation agents produce dry mouth.22,42

Dopamine-β-Hydroxylase

Inhibition

Inhibition of dopamine-β-hydroxylase (Fig. 14-5) prevents the conversion of dopamine to norepinephrine, resulting in less norepinephrine release and less α- and β-adrenoceptor stimulation with neuronal firing. Disulfiram produces such inhibition.44 Because norepinephrine release mediates most of dopamine's ability to cause vasoconstriction, norepinephrine is the vasopressor of choice in a hypotensive patient taking disulfiram. Diethyldithiocarbamate, used in metal P.226 chelation and by some AIDS patients, is a disulfiram metabolite that produces similar actions. MAOIs and α-methyldopa also inhibit dopamine-β-hydroxylase, although this is not their main mechanism of action.98 Dopamine is relatively contraindicated in hypotensive patients who have overdosed on MAOIs. First, dopamine acts indirectly and its administration might produce excessive adrenergic activity and exaggerated rises in blood pressure. Second, even if an adrenergic storm does not occur, most of dopamine's α-mediated vasoconstriction is secondary to norepinephrine release. In the presence of MAOIs, norepinephrine synthesis may be impaired from concomitant dopamine-β-hydroxylase inhibition, and dopamine may not reliably raise blood pressure if cytoplasmic and vesicular stores have been depleted. In the presence of impaired norepinephrine release or α-adrenoceptor blockade by any cause, unopposed dopamine-induced vasodilatation from action on peripheral dopamine and β-adrenoceptors may paradoxically lower blood pressure further. Norepinephrine and epinephrine can be used to support blood pressure relatively safely in patients taking MAOIs, because these vasopressors have little or no indirect action and are

metabolized by COMT when given intravenously.

Dopamine Because dopamine is the direct precursor of norepinephrine, noradrenergic vesicles contain dopamine. The release of norepinephrine from peripheral sympathetic nerves, therefore, always results in release of some dopamine (Fig. 14-5), as does the release of norepinephrine and epinephrine from the adrenal gland, explaining the normal presence of dopamine in blood. In peripheral tissues, activation of dopamine receptors cause vasodilatation of mesenteric, and coronary vascular beds. Dopamine can also stimulate β-adrenoceptors and, at high doses, can directly stimulate α-adrenoceptors. When dopamine is administered intravenously, most vasoconstriction release.

is

caused

by

dopamine-induced

norepinephrine

Dopamine accounts for about one-half of all catecholamines in the brain and is present in greater quantities than norepinephrine or 5HT. In contrast to the diffuse projections of noradrenergic neurons, dopaminergic neurons and receptors are highly organized and concentrated in several areas, especially in the basal ganglia and limbic

system.81,135

Excessive dopaminergic activity in the neostriatum and/or other areas from any cause (eg, increased release, impaired uptake, increased receptor sensitivity) can produce acute choreoathetosis75 and acute Gilles de la Tourette syndrome, with tics, spitting, and cursing. Excessive dopaminergic activity in the limbic system and, perhaps, in other areas, produces paranoid psychosis that is indistinguishable from paranoid schizophrenia and is thought responsible for much of the drug craving and addictive behavior in patients abusing sympathomimetic drugs. Diminished dopaminergic tone (eg, impaired release, receptor blockade) in the neostriatum produces various extrapyramidal disorders such as acute dystonias and parkinsonism.123,145,158

Synthesis,

Release,

and

Uptake

The steps of dopamine synthesis and vesicle storage are the same as those for norepinephrine, except that dopamine is not converted to norepinephrine after transport into vesicles (Fig. 14-7). Dopamine is removed from the synapse via uptake by DAT, the membrane-bound dopamine transporter. DAT and NET exhibit 66% homology in their amino acid sequences. Like NET, DAT is not completely specific for dopamine, but transports drugs such as amphetamines and other structurally similar sympathomimetics. Cytoplasmic dopamine has a fate similar to norepinephrine. It is pumped back into vesicles by VMAT2 (brain) and VMAT1 (neuroendocrine tissue, adrenal glands) or degraded by MAO and COMT.

Dopamine

Receptors

All dopamine receptors are coupled to G proteins and are divided into two main groups, depending on whether they raise or lower cAMP concentrations. Dopamine D1 -like receptors (D1 and D5 ) are expressed as various subtypes and are linked to Gs to stimulate adenylate cyclase and to raise cAMP concentrations.81 Dopamine is 5–10 times more potent at D5 receptors than it is at D1 receptors. D 2 -like receptors (D2 , D3 , D4 ) are linked to Gi / o, to produce several actions, including inhibition of adenylate cyclase and the lowering of cAMP levels. Again, numerous subtypes of receptors exist (eg, D2 s, D 2L ). D2 receptors are concentrated in the basal ganglia and limbic system. Some D2 receptors also reside on presynaptic membranes, where their activation limits neurotransmitter release, including the peripheral release of norepinephrine (Figs. 14-5 and 14-7). D3 receptors are concentrated in the hypothalamic and limbic nuclei, whereas D4 receptors are concentrated in the frontal cortex and limbic nuclei (rather than basal ganglia nuclei). Most agonists bind to

the D3 receptors with higher affinity than to D2 receptors, whereas most antagonists bind preferentially to D2 receptors.81,135 Most agonists and antagonists express a lower affinity for D 4 receptors than they express for D2 receptors; a notable exception is clozapine.

Chemical

Agents

Table 14-6 provides examples of chemical agents that affect dopaminergic neurotransmission.

Dopamine Indirect-

Agonism and

Mixed-Acting

Agents

Most indirect- and mixed-acting sympathomimetics cause dopamine release. The mechanism of action is similar to that causing norepinephrine release. These agents diffuse into the neuron or undergo uptake by DAT before being transported into vesicles by VMAT2 where they buffer protons and displace dopamine into the cytoplasm for reverse transport by DAT into the synapse. Benztropine, diphenhydramine, trihexyphenidyl, and orphenadrine also cause dopamine release, perhaps contributing to their abuse potential, which is noted below.105 Excessive dopaminergic activity following therapeutic doses or overdoses of decongestants (eg, pseudoephedrine), amphetamines, methylphenidate, and pemoline can produce acute choreoathetosis and Tourette syndrome.24,91 Parkinsonian patients ingesting excessive doses of L-dopa (which is converted to dopamine) may present with similar symptoms.

Direct

Agonists

Bromocriptine is an ergot derivative that directly activates dopamine receptors (mainly D 2 ). Toxic effects include those described above for indirect-acting agents. Apomorphine directly activates D2 receptors. Such action at the chemoreceptive triggering zone

produces vomiting, whereas agonism in the basal ganglia explains apomorphine's use in the treatment of Parkinson disease. Fenoldopam is a D1 agonist used as a vasodilator in the treatment of hypertensive emergencies. P.227 D 1 and D2 -like receptor activation is the predominant mediator of locomotor effects from dopamine agonists. Activation of either D1 - or D 2 -like receptors produces antiparkinsonian effects.63,135 Cabergoline, ropinirole, and pramipexole are D2 -like agonists used to treat Parkinson disease.8,42,60 Dihydrexidine is a D1 -like agonist that has been used for the same purpose.

Uptake

Inhibition

Agents inhibiting DAT prevent dopamine uptake and include cocaine, amphetamines, methylphenidate, and probably amantadine. Increased dopaminergic activity from cocaine toxicity may produce choreoathetosis (“crack dancing―) and Tourette syndrome. In general, antidepressants are not strong dopamine uptake blockers. However, bupropion appears to be more active in this regard.131 As noted earlier, much of the drug craving and addiction produced by sympathomimetics probably results from excessive dopaminergic activity in the mesolimbic system.145 Interestingly, the anticholinergic drugs benztropine, diphenhydramine, trihexyphenidyl, and orphenadrine are also dopamine uptake inhibitors, possibly explaining their abuse.105,141 In fact, benztropine is one of the most potent dopamine uptake inhibitors known. Amantadine, an antiparkinsonian agent that causes dopamine release and some inhibition of dopamine uptake (as well as being anticholinergic), is also abused.

Figure 14-7. A dopaminergic nerve ending and postsynaptic membrane. Dopamine (DA) released from nerve endings binds to various postsynaptic DA receptors (D) on neurons or peripheral end organs. Stimulation of presynaptic D2 receptors [4] lessens DA release. Agents in Table 14-6 may act to inhibit vesicle uptake [1]; cause DA to leave the vesicle and move into the cytoplasm [2]; activate or antagonize DA receptors [3,4]; inhibit DAT to prevent DA uptake [5]; cause reverse transport of cytoplasmic DA (via DAT) into the synapse by raising cytoplasmic DA concentrations [6]; prevent DA degradation by inhibiting monoamine oxidase (MAO) [7]; prevent DA degradation by inhibiting catechol-O-methyltransferase (COMT) [8]; or prevent

dopa metabolism by inhibiting COMT [9]. Both DA and dopa are substrates for COMT. For purposes of illustration, dopa metabolism is shown presynaptically, and DA metabolism is shown postsynaptically. 3-O-MD =3-O-methyldopa; 3-O-MDA =3O-methyldopamine; AADC = L-aromatic amino acid decarboxylase; DAT =membrane DA uptake transporter; DOPAC =3,4-dihydroxyphenylacetic acid; Tyr-OHase =tyrosine hydroxylase; VMA2 = vesicle membrane uptake transporter.

Increase

of

Receptor

Sensitivity

Several drugs are thought to increase sensitivity of dopamine receptors, resulting in choreoathetosis, even with therapeutic doses (eg, phenytoin). Evidence exists that increased dopamine receptor sensitivity may be responsible for movement disorders resulting from amphetamines. 29 Tardive dyskinesia (discussed below) may also result from increased dopamine receptor sensitivity.

MAO

Inhibition

MAOIs inhibit the breakdown of cytoplasmic dopamine. Part of the food and drug interactions with MAOIs results from excessive release of dopamine from nerve endings.

COMT

Inhibition

Peripheral COMT inhibitors (eg, entacapone, tolcapone) are given with levodopa to patients with Parkinson disease to prevent peripheral degradation of levodopa to 3-O-methyldopa. This allows more levodopa to traverse the blood–brain barrier and to be converted to dopamine by neuronal dopa decarboxylase. Tolcapone also inhibits COMT in the brain.71 Other substrates of COMT include dopa, dopamine, norepinephrine, epinephrine, and P.228

their hydroxylated metabolites. COMT inhibitors might potentiate the effects of these drugs when administered intravenously.71

TABLE 14-6. Examples of Xenobiotics That Affect Dopaminergic Neurotransmission

Dopamine

agonism

Direct stimulation of dopamine receptors

Bupropion

Cocaine

Apomorphine

Diphenhydramine

Bromocriptine

Methylphenidate

Cabergoline

Orphenadrine

L-Dopaa

Pemoline

Fenoldopam

Trihexyphenidyl

Lisuride

Pergolide

Increase dopamine receptor sensitivity

Pramipexole

Ropinirole

Amphetamines

Antipsychotics

Inhibit dopamine metabolism—MAOIs

Clorgyline

Metoclopramide

Phenytoin

Isocarboxazid

Linezolid

Moclobemide

Dopamine

Block

antagonism

dopamine

Pargyline

Amoxapine

Phenelzine

Buspirone

Selegiline

Clozapine

Tranylcypromine

Droperidol

Haloperidol

Inhibit dopamine metabolism—COMTs

Loxapine

Entacapone

Metoclopramide

Tolcapone

Molindone

receptors

Olanzapine

Indirect

acting

Phenothiazines

Amantadine

Pimozide

Amphetamines

Quetiapine

Benztropine

Risperidone

Decongestants

Thioxanthenes

Diphenhydramine

Trazodone

MAOIs

Methylphenidate

Tricyclic antidepressantsb

Ziprasidone

Orphenadrine

Pemoline

Destroy neurons

Phencyclidine

Trihexyphenidyl

MPTP

dopaminergic

Inhibit

dopamine

uptake

Prevent uptake

vesicle

dopamine

Amantadine

Amphetamines

Reserpine

Benztropine

Tetrabenazine

COMTs = catechol-o-methyltransferase inhibitors; MAOIs 5 monoamine oxidase inhibitors; MPTP = 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine. a Metabolized to dopamine, which acts as an agonist. b

Relatively weak D2

Dopamine Direct

receptor

antagonists.

Antagonism

Receptor

Blockade

Blockade of dopamine receptors is the specific aim when using many therapeutic agents. The neuroleptic actions of butyrophenones, phenothiazines, and other antipsychotics mainly correlate with their ability to block D2 -like receptors, probably in the mesolimbic system. Many phenothi-azines block both D 1 -like and D2 -like receptors, whereas haloperidol mainly blocks D2 -like receptors. Unfortunately, antipsychotics and metoclopramide also block dopamine receptors in the striatum, producing various extrapyramidal symptoms, including acute parkinsonism and dystonias. In the last decade, several “atypical― antipsychotics have been marketed that produce fewer extrapyramidal effects and are thought to carry less risk of producing tardive dyskinesia. 127 The relative

affinity of an antipsychotic for 5-HT2 A receptors over D2 receptors has predictive value for atypical agents with a lower risk of extrapyramidal symptoms.118 Such agents include clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. The ratio of muscarinic (M1 ) blockade to D 2 -receptor blockade is also important in limiting extrapyramidal symptoms. Antipsychotic agents exhibiting strong antimuscarinic effects (eg, olanzapine, clozapine, thioridazine) are also less likely to induce extrapyramidal symptoms.127 Buspirone, an antianxiety agent, antagonizes D2 receptors, which explains occasional extrapyramidal reactions. Various cyclic antidepressants, especially amoxapine, block D2 receptors to some extent. The chronic use of dopamine-blocking agents causes upregulation of dopamine receptors. The continued use or, especially, withdrawal of dopamine antagonists (antipsychotics, metoclopramide, and occasionally antidepressants) might result in excessive dopaminergic activity and tardive dyskinesia, characterized by choreiform movements typical of excessive dopaminergic influence in the neostriatum. The blockade of dopamine receptors by numerous agents, including butyrophenones, phenothiazines, and metoclopramide, can produce a poorly understood disorder called neuroleptic malignant syndrome. Neuroleptic malignant syndrome also follows acute withdrawal of dopamine agonists (eg, stopping L-dopa or bromocriptine in a patient prior to surgery). Neuroleptic malignant syndrome is characterized, in part, by mental status changes, autonomic instability, rigidity, and hyperthermia.

Indirect

Antagonism

Reserpine and tetrabenazine inhibit VMAT to prevent transport of dopamine into storage vesicles and deplete nerve endings of

dopamine. In fact, reserpine was used as an antipsychotic agent before the introduction of phenothiazines. 1-Methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), a meperidine analog, undergoes activation by MAO to a metabolite that causes death of dopaminergic neurons. Both MPTP and its metabolite undergo uptake not only by DAT, but also by NET and SET, making their way into all biogenic amine neurons. The reasons that dopaminergic neurons are selectively damaged remains unknown. Both MAOIs and inhibitors of dopamine transporters prevent MPTP-induced destruction of dopaminergic neurons.

Serotonin Serotonin (5-HT, 5-OH-tryptamine) is a ubiquitous indole alkyl-amine found in nature (animals, plants, venoms) that acts as a neurotransmitter centrally, but is also found peripherally. In fact, less than 2% of the body's 5-HT is found within the CNS. In the CNS, several hundred thousand serotonergic neurons lie in or in juxtaposition to numerous midline nuclei in the brainstem (9 raphe nuclei), from which they project to virtually all areas of the brain, including the basal ganglia. Serotonin is involved with mood, personality, affect, appetite, motor function, temperature regulation, sexual activity, pain perception, sleep induction, and other basic functions. Serotonin is not essential for any of these processes but modulates their quality and extent. The serotonergic system is extremely diverse, with 14 types of receptors that act to stimulate or inhibit neurons, including those P.229 of other neurotransmitter systems. Serotonin is also the precursor for the pineal hormone melatonin.50 Peripherally, 5-HT is produced mainly in the enterochromaffin cells of the intestine. Local release contributes to peristalsis. Platelets take up 5-HT while passing through the enteric circulation. Serotonin is released from activated platelets to interact with other platelet

membranes (promote aggregation) and with vascular smooth muscle (vasoconstriction in most vascular beds). Experimentally, 5-HT exhibits diverse effects on the cardiovascular and peripheral nervous systems, although the importance of these actions remains uncertain in the normal physiologic state. Serotonin vasoconstricts (stimulation of 5-HT2 , 5-HT1 B, and 5-HT1 D receptors) most vascular beds except for coronary arteries and skeletal muscle, where it produces vasodilatation in the presence of intact endothelium. 5-HT1 B and 5-HT1 D agonists (eg, sumatriptan) might produce coronary vasoconstriction as an adverse effect to their desired actions on cranial vasculature.59 Centrally, it is particularly difficult to ascribe a specific symptom or physical finding to serotonergic neurons because of the diversity of their physiologic actions. However, 5-HT definitely plays an important role in the action of many hallucinogenic or illusionogenic drugs, which act as partial agonists at cortical 5-HT2 receptors.88 Proserotonergic agents are used to treat depression, whereas agents that antagonize 5-HT receptors (5-HT2 ) have greater importance in the management of schizophrenia. Generally, 5-HT acts in opposition to dopamine. For example, 5-HT serves to increase prolactin, adrenocorticotropic hormone (ACTH), and growth hormone secretion, whereas dopamine decreases prolactin secretion. As another example, activation of basal ganglial 5-HT2 A receptors inhibits dopamine release. However, well-known exceptions exist, such as cortical 5-HT3 receptors, whose activation promotes dopamine release.88

Synthesis,

Release,

and

Uptake

Figure 14-8 illustrates 5-HT synthesis. Tryptophan-5-hydroxylase is the rate-limiting enzyme of 5-HT synthesis and is free from negative feedback influences by the end product, 5-HT. Thus, increases in tryptophan are predictably accompanied by increased 5-HT

production. L-Amino acid decarboxylase (dopa decarboxylase) converts 5-hydroxytryptophan to 5-HT. Cytoplasmic 5-HT is transported into vesicles by VMAT2, where it is concentrated by ion trapping before release by Ca2 +-dependent exocytosis. In contrast to vesicles containing dopamine or norepinephrine, 5-HT vesicles contain almost no ATP. After release into the synapse, a transporter (SERT) in the neuronal membrane transfers 5-HT back into the neuron, where it reenters vesicles or is degraded by MAO. Serotonin is preferentially metabolized by the MAO-A isozyme. Paradoxically, the serotonergic nerve terminal is almost devoid of MAO-A but contains abundant amounts of MAO-B. It has been hypothesized that the large amounts of MAO-B metabolize other agents that might inappropriately promote serotonin release (eg, dopa). However, the small amount of MAO-A found in serotonergic neurons provides adequate degradation of 5-HT.50

Serotonin

Receptors

Most authors identify seven major functioning receptors (5-HT1 through 5-HT7 ) and numerous subtypes.9

5 - H T1

Receptors

Receptors in the 5-HT1 class are coupled to G proteins and commonly increase K+ efflux and decrease cAMP concentrations. Members of the 5-HT1 receptor class express greatest affinity for 5-HT and are thus biologically active under normal physiologic conditions. 5-HT1 A receptors reside predominantly on raphe nuclei, where they act as somatodendritic autoreceptors. Hippocampal 5-HT1 A receptors reside postsynaptically, where they also inhibit through similar mechanisms.83 Central 5-HT1 D and 5-HT1 B receptors primarily act as inhibitory terminal autoreceptors and heteroreceptors. They are found less commonly on postsynaptic membranes. Originally 5-HT1 B receptors

were not believed to exist in humans. However, most of the actions described in older literature regarding 5-HT1 D receptors can now be attributed to 5-HT1 B receptors. Unfortunately, this distinction will continue to lead to confusion for some years to come. Cranial blood vessels (eg, meninges) possess 5-HT1 D and 5-HT1 B receptors, whose activation produces vasoconstriction and decreased inflammation.57,59 5-HT1 E and 5-HT1 F receptors are more recently discovered members of the 5-HT1 receptor class. 5-HT1 F receptors reside on presynaptic membranes and may act in a similar fashion to 5-HT1 D and 5-HT1 B receptors.9

5 - H T2

Receptors

The three subtypes of 5-HT2 receptors are coupled to G proteins, thus serving to decrease K+ efflux and/or increase intracellular Ca2 + concentration by raising concentrations of inositol triphosphate and diacylglycerol.130 The three subtypes of 5-HT 2 receptors are so similar in characterization that investigational agents have great difficulty in distinguishing the subtypes. 5-HT2 A receptors are most concentrated in the cerebral cortex, where they serve as excitatory postsynaptic receptors. Their activation increases glutamate release from pyramidal cells, but also can lead to release of GABA.1,86 5H T2 A receptors also reside on platelets, where their activation produces platelet aggregation. 5-HT2 C receptors (previously 5-HT1 C) reside on the choroid plexus, where they regulate cerebrospinal fluid production. Peripherally, 5-HT2 C activation also promotes penile erection. Activation of 5-HT2 B receptors in the GI tract promotes colonic contraction.86

5 - H T3

Receptors

5-HT3 receptors are isopentameric ligand-gated cation channels that are structurally similar to ACh nicotinic receptors, GABAA Clchannels, and NMDA glutamate receptors.3 They have been localized

to both presynaptic and postsynaptic membranes. Upon activation, they stimulate the neuron by opening the channel to cause depolarization through Na+ and/or Ca2 + influx. In addition, these channels are normally blocked by Mg2 + in a voltage-dependent manner similar to glutamatergic NMDA receptors (see Glutamate below). Centrally, 5-HT3 receptors are expressed diffusely, but are especially concentrated in the chemoreceptive triggering zone, where their activation induces emesis. In the cerebral cortex, their activation leads to increased release of dopamine and decreased release of ACh. Cortical 5-HT3 receptors are frequently identified on GABA interneurons where they increase inhibitory, GABAergic tone. In contrast to cerebral actions, activation of peripheral 5-HT3 receptors on cholinergic nerves in the gut enhances ACh release to increase gastrointestinal motility.9,18

5 - H T4

Receptors

5-HT4 receptors are coupled to G proteins (Gs ). Their activation leads to increased cAMP concentrations. 5-HT4 receptors are scattered diffusely throughout the brain, and their exact role remains undefined. Peripheral 5-HT4 receptors reside in the heart, intestines, and adrenal gland where their activation can be demonstrated to produce tachycardia, aldosterone and cortisol release, and contraction of gut and bladder smooth muscle. Again, P.230 whether these actions are important under normal physiologic conditions is not clear. Both central and peripheral 5-HT4 receptors promote the release of acetylcholine.41

Figure 14-8. A serotonergic nerve ending and postsynaptic membrane. Tryptophan hydroxylase [1] converts tryptophan to 5-hydroxytryptophan (5-OH-tryptophan). Aromatic L-amino acid decarboxylase (AADC) then metabolizes 5-OH-tryptophan to serotonin (5-HT). Serotonin is concentrated within vesicles through uptake by VMA2 before exocytosis [2]. After uptake into the neuron by SERT [7], 5-HT is transported back into vesicles or undergoes degradation by monoamine oxidase (MAO) to an intermediate compound, which is converted to 5hydroxyindoleacetic acid (5-HIAA) [8]. 5-HT1,2,4,6,7 receptors [3,9,10] are coupled to G proteins, while 5-HT3 receptors [4] are ligand-gated cation channels that may conduct Na+ and/or Ca2 +. 5-HT3 cation channels also appear to be blocked by Mg2 + until the cell is depolarized, allowing Mg2 + to dissociate—a mechanism similar to that found at NMDA glutamate receptors. In

addition to residing on postsynaptic membranes, 5-HT1 A, 5-HT1 B, 5HT1 D, and 5-HT1 F receptors serve as presynaptic autoreceptors that, when stimulated, decrease further release of 5-HT [9,10]. Presynaptic 5-HT 1 A receptors mainly serve as somatodendritic autoreceptors, whereas presynaptic 5-HT1 B, 5-HT1 D, and 5-HT1 F receptors serve as terminal autoreceptors. Agents in Table 14-7 act to enhance 5-HT synthesis [1]; inhibit VMA2 to prevent vesicle uptake of 5-HT [2]; raise cytoplasmic concentrations of 5HT, resulting in reverse transport of 5-HT into the synapse by SERT [6] by displacing 5-HT from vesicles [5] or inhibiting MAO [8]; activate or antagonize 5-HT receptors [3,4,9,10]; or by inhibiting 5-HT uptake [7]. G =G protein; SERT =membrane 5-HT uptake transporter; VMA2 =vesicle membrane uptake transporter.

5 - H T5

Receptors

5-HT5 receptors exist in the form of at least two subtypes, one of which may be coupled to Gs . Their mechanism of activation remains unknown. 5-HT5 receptor agonists or antagonists are not readily available.9

5 - H T6 and 5-HT7

Receptors

5-HT6 and 5-HT7 receptors are positively coupled to cAMP formation through G proteins. Their distribution is poorly defined. However, many antidepressant and antipsychotic agents antagonize these receptors. They are currently a source of great interest because of the possibility of avoiding dopamine blockade to achieve antipsychotic activity. The 5-HT7 receptor may be particularly important in regulating circadian rhythms.78

Chemical

Agents

Table 14-7 provides examples of chemical agents that affect serotonergic neurotransmission.

Serotonin

Agonists

The ingestion of tryptophan is thought to increase 5-HT production and was commonly used as an unproved sleep aid until it was associated with the eosinophilia myalgia syndrome. 5Hydroxytryptophan (5-HTP) is the immediate precursor to 5-HT. 5HTP is commonly available without a prescription. The antianxiety agents buspirone, gepirone, and ipsapirone act as partial agonists at somatodendritic and postsynaptic 5-HT1 A receptors.9 Sumatriptan, an antimigraine agent, mainly activates 5-HT 1 D and 5-HT1 B receptors. Sumatriptan's action may result from vasoconstriction of meningeal and other cranial, extracerebral vasculature; no impairment of cerebral blood flow follows the use of this agent. Other members of the triptan class of drugs include rizatriptan, zolmitriptan, and naratriptan.59 Metoclopramide, cisapride, zacopride, renzapride, and tegaserod prokinetic drugs that activate 5-HT4 receptors to increase gut

are

motility.41,60,84 Because 5-HT4 receptors are also found in the heart and urinary bladder detrusor muscle, 5-HT4 agonists occasionally produce bladder incontinence and tachycardia. Numerous indoles and phenylalkylamines, including ergot alkaloids, lysergic acid diethylamide (LSD), psilocybin, and mescaline, exhibit both agonistic and antagonistic properties at multiple 5-HT receptors. Their hallucinogenic/illusionogenic action is best P.231 explained by partial agonism at 5-HT2 A receptors. Some substituted amphetamines (eg, methylenedioxymethamphetamine) directly 1,88 stimulate serotonin receptors.

TABLE 14-7. Examples of Xenobiotics That Affect Serotonergic Neurotransmission

Serotonin

Enhance

agonism

Citalopram

5-HT

Cocaine

synthesis

L-Tryptophan

Dextromethorphan

5-Hydroxytryptophan

Duloxetine

Escitalopram

Direct

5-HT

agonists

Fluoxetine

Buspirone

Fluvoxamine

Cisapride

Lamotrigine

Ergots

and

indolesa

Meperidine

Flesinoxan

Milnacipran

Gepirone

Nefazodone

Hallucinogenic

substituted

amphetamines

Reboxetine

Sertraline

Ipsapirone

Tramadol

mCPP

Trazodone

Mescalinea

Metoclopramide

Tricyclic antidepressantsb

Venlafaxine

Naratriptan

Renzapride

Serotonin

Rizatriptan

Direct

Antagonism

5-HT

antagonists

Sulpiride

Alosetron

Sumatriptan

Amisulpride

Tandospirone

Clozapine

Tegaserod

Cyproheptadine

Urapidil

Dolasetron

Zacopride

Zolmitriptan

Ergots and indoles (eg, LSD) a

Granisetron

Increase

5-HT

release

Haloperidol

Amphetamines

Ketanserin

Cocaine

Mianserin

Codeine

derivatives

Mescalinea

Dexfenfluramine

Methysergide

Dextromethorphan

Metoclopramide

L-Dopa

Mirtazapine

Fenfluramine

Nefazodone

MDMA

Olanzapine

Mirtazapine

Ondansetron

Reserpine

(initial)

Phenothiazines

Phentolamine

Increase 5-HT tone by unknown

Pindolol

mechanism

Lithium

Propranolol

Quetiapine

Risperidone

Inhibit 5-HT (MAOIs)

breakdown

Ritanserin

Clorgyline

Sertindole

Isocarboxazid

Trazodone

Linezolid

Tricyclic

antidepressants

Moclobemide

Tropisetron

Pargyline

Ziprasidone

Phenelzine

Zotepine

Tranylcypromine

Selegiline

Enhance

5-HT

Tianeptine

Inhibit

5-HT

uptake

uptake

Amoxapine

Inhibit

vesicle

uptake

Amphetamines

Reserpine

Atomoxetine

Ketanserin

Carbamazepine

Tetrabenazine

5-HT = serotonin; LSD = lysergic acid diethylamide; MAOIs = monoamine oxidase inhibitors; mCPP = mchlorophenylpiperazine (metabolite of trazodone and nefazodone); MDMA = methylenedioxymethamphetamine. a Indoles and phenylalkylamines activate and antagonize various 5-HT receptors. Their hallucinogenic/illusionogenic effects mainly result from partial agonism at 5-HT 2 receptors. b Clomipramine is the most potent 5-HT uptake inhibitor of the tricyclic antidepressants.

Cocaine and indirect-acting sympathomimetics, especially amphetamines, cause serotonin release as previously described. Other releasing agents are dextromethorphan and codeine derivatives. Centrally, dopamine undergoes uptake into serotonergic neurons to displace 5-HT from the neuron. Ingestion of L-dopa or other agents that increase CNS dopamine concentrations can cause 5-HT release.104 Inhibitors of 5-HT uptake include amphetamines, cocaine, various antidepressants, meperidine, and dextromethorphan.104 Several antidepressants specifically inhibit 5-HT uptake. Examples of selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. The use of SSRIs sometimes produces extrapyramidal side effects5 for reasons that

remain unclear because of the numerous actions of 5-HT in the basal ganglia. Two anticonvulsants, carbamazepine and lamotrigine, appear to inhibit 5-HT uptake.144 Again, reserpine and tetrabenazine prevent 5-HT uptake into vesicles. MAO-A accounts for most 5-HT degradation, and nonspecific MAOIs and MAO-A inhibitors (clorgyline, moclobemide) both raise 5-HT concentrations and, through indirect action, probably cause 5-HT release.53,104

Serotonin

Antagonists

Trazodone and nefazodone act mainly as antagonists at 5-HT2 receptors, but are also weak uptake inhibitors. Both undergo metabolism to m-chlorophenylpiperazine (mCPP), which activates most 5-HT receptors, but is especially active at 5-HT2 C receptors. Ketanserin and ritanserin specifically antagonize 5-HT1 D receptors while methysergide receptors.53,104

and

cyproheptadine

antagonize

5-HT1 and 5-HT2

Mirtazapine exhibits complex actions, including antagonism of 5H T2 A, 5-HT2 C, and 5-HT3 receptors.86 Mirtazapine also indirectly increases 5-HT1 A activity and enhances release of norepinephrine through antagonism of α2 -adrenoceptors. Mirtazapine also demonstrates potent antagonism of histaminic, muscarinic, and αadrenoceptors.53 Most antipsychotics and tricyclic antidepressants antagonize 5-HT2 A and, to a lesser extent, 5-HT2 C receptors. In fact, investigators are interested in developing antipsychotic agents similar to risperidone that possess potent antagonistic properties at 5-HT 2 receptors without accompanying dopamine receptor antagonism in order to limit extrapyramidal side effects. These investigations have resulted in the introduction of olanzapine, sertindole, ziprasidone, zotepine, quetiapine, and amisulpride.16 Ondansetron,

granisetron,

tropisetron,

dolasetron,

and

alosetron

antagonize 5-HT3 receptors. Their antiemetic action is thought to be explained by several mechanisms. Central antagonism at the chemoreceptor triggering zone lessens vomiting. Peripheral 5-HT3 receptor antagonism in the gut prevents ACh release, decreasing gut motility. Finally, antagonism of vagal 5-HT3 receptors decreases afferent stimulatory signals to the vomiting center in the brainstem.9 Ondansetron and other experimental 5-HT3 antagonists are being studied in the treatment of schizophrenia because of their ability to prevent dopamine release. Metoclopramide antagonizes 5-HT3 and D2 receptors. Tianeptine is an antidepressant that enhances 5-HT uptake, thus lowering synaptic 5-HT concentrations.112

Serotonin

Syndrome

Excessive stimulation of 5-HT1 A receptors and, to a lesser extent, 5H T2 receptors, causes serotonin P.232 syndrome.104 Briefly, this disorder is characterized by shivering, myoclonus, tremor, and rigidity (especially of legs), along with hyperthermia, tachycardia, diaphoresis, confusion, agitation, convulsions, and coma. This iatrogenic, idiosyncratic syndrome results most commonly from the combined use of two serotonergic drugs (eg, SSRI and lithium, SSRI and MAOI, MAOI and clomipramine). Reports indicate that serotonin syndrome may occur following the isolated use or overdose of a single seroto-nergic agent (eg, venlafaxine or fluvoxamine). Drugs that act to increase CNS dopamine concentrations, such as levodopa and bromocriptine, have potential to precipitate serotonin syndrome by indirect serotonin release.104 Adverse effects (eg, rigidity, hyperthermia) resulting from interactions between MAOIs and meperidine, dextromethorphan, or codeine may result from excessive serotonergic activity, as well, because all of these agents enhance serotonergic tone (Table 14-7) .

γ-Aminobutyric

Acid

GABA is one of two main inhibitory neurotransmitters of the central nervous system (glycine is discussed below; see Glycine as an Inhibitory Neurotransmitter). Drugs that enhance GABA activity are generally used as anticonvulsants, sedative-hypnotics, and general anesthetics. Agents that antagonize GABA activity typically produce CNS excitation and convulsions. GABA is synthesized from glutamate, the brain's main excitatory neurotransmitter. In general, GABA inhibition predominates in the brain. In the spinal cord, through mono- and polysynaptic reflex pathways, GABA mediates a number of physiologically minor peripheral effects outside the CNS (eg, vasodilatation, bladder relaxation). Spinal cord GABA is important in attenuating skeletal muscle reflex arcs.96

Synthesis,

Release,

and

Uptake

Figure 14-9 illustrates GABA synthesis. Glutamic acid decarboxylase (GAD) requires pyridoxal phosphate (PLP) as a cofactor. Pyridoxal phosphate is synthesized from pyridoxine (vitamin B6 ) by the enzyme pyridoxine kinase (PK).102 VGAT, a vesicle-bound transporter comprising about 130 amino acids and crossing the vesicle membrane about 10 times, transports GABA into vesicles from where it is released through Ca2 +-dependent exocytosis into the synapse.96 Uptake of GABA from the synapse back into the presynaptic neurons is mediated by the Na+ -dependent transporter, GAT-1, whereas uptake into glial cells and possibly postsynaptic neurons is mediated by GAT-2, GAT-3, and GAT-4. Evidence also suggests that GABA is released into the synapse from cytoplasm by reverse transport under some conditions. In glial cells, cytoplasmic GABA can undergo degradation by GABA-transaminase (GABA-T) to succinic semialdehyde (SSA), part of which then undergoes oxidation to succinate. GABA-T also requires PLP as a cofactor.109 The transamination of GABA to SSA by GABA-T results in the conversion of α-ketoglutarate to glutamate, which then moves back into

neurons to be used for resynthesis of GABA.

GABA

Receptors

There are three main types of GABA receptors (Table 14-8) .20 GABAA receptors are Cl- channels that mediate postsynaptic inhibition by allowing Cl - to move into and hyperpolarize the postsynaptic neuron. Situated at various sites in relation to the GABA recognition site on the Cl- channel are sites for exogenous and endogenous modulatory agents (Fig. 14-10) where numerous excitatory and depressant drugs bind, and through which GABAA receptor responsiveness is regulated under normal physiologic conditions. The common denominator for modulation at the GABAA complex is an increase or decrease in inward Cl- current. Throughout the CNS there are regional variations in expressions of multiple subunit genes for the GABAA complex. GABAA receptors exist as pentamers, composed most commonly of 1 to 3 α subunits, 1 to 3 β subunits, and either a γ or δ subunit. The most common combination appears to be 2α-2β-1γ. Multiple subtypes of subunits exist (eg, α1 –α6 ), but within a single receptor, the subtypes of individual subunits appear to be identical. Nevertheless, given the large numbers of subtypes and different combinations of subunits, more than 2000 different GABAA Cl- channels theoretically could form, with different pharmacologic affinities for certain ligands, including anesthetics, benzodiazepines, barbiturates, and for GABA itself.8,139 It appears highly unlikely, however, that this many different types of GABAA receptors are found in mammalian brains. The second type of GABA receptor, GABAB , is found on both pre- and postsynaptic membranes. The GABAB receptors are heterodimers, with companion proteins linked to the receptors, and are coupled to G proteins (probably Gi / o) that mediate both presynaptic and postsynaptic inhibition.23 Presynaptic inhibition results from preventing Ca2 + influx so as to impair exocytosis of neurotransmitter vesicles, including those containing excitatory amino acids (eg,

glutamate). Postsynaptic inhibition is mediated by increasing K+ efflux through K+ channels, resulting in hyperpolarization of the membrane away from threshold. Through presynaptic actions, GABAB receptors also serve as autoreceptors, where their activation in response to synaptic GABA provides feedback inhibition of further neurotransmitter release (Fig. 14-9) . A third GABA receptor, GABAC , is a Cl- channel that, when activated, allows increased Cl- influx. The GABAC receptors are thought to comprise 5 ligand-binding sites, whereas GABAA receptors have 2 ligand-binding sites.20 GABAC receptors are composed of ϕ subunits (ϕ1 –ϕ3 ). ϕ1 subunits are located in the mammalian retina, ϕ2 subunits are present in most brain regions, and ϕ3 subunits are found in the hippocampus. ϕ1 and ϕ2 receptors have also been found outside the CNS.69 GABAC receptors are sensitive to cis-4aminocrotonic acid (CACA), are insensitive to baclofen, bicuculline, benzodiazepines, and barbiturates, and are less sensitive to neuroactive steroids and to picrotoxin (Table 14-8) .69 GABAC receptors are activated at 40-fold lower GABA concentrations than GABAA receptors, are less liable to desensitization, and remain open longer than GABAA Cl- channels.

Chemical

Agents

Table 14-9 provides examples of chemical agents that affect GABAergic neurotransmission.

Modulation of Degradation

GABA

Production

and

Isoniazid (INH) and other hydrazines (eg, monomethylhydrazine from mushrooms) lower CNS GABA concentrations by several mechanisms. Most important, they compete with pyridoxine for binding to PK, impairing PLP production.102 Pyridoxal phosphate binding to the GAD complex is easily reversible.109 The acute decrease in PLP

concentration, then, is rapidly accompanied by impaired GABA synthesis and a decrease in GABA concentration. Lack of normal GABA inhibition produces seizures typical of hydrazine intoxications. Although PLP is also required for GABA degradation by GABA-T, acute decreases in PLP do not affect this enzyme nearly as much, because PLP is more P.233 tightly bound to the GABA-T complex and remains associated with the enzyme.109 To a lesser extent, isoniazid binds to the GAD-PLP complex to prevent GABA formation.

Figure 14-9. GABAergic neurotransmission. GABA (γaminobutyric acid) released from a presynaptic neuron (B) binds to postsynaptic GABAA , GABAB , or GABAC receptors to hyperpolarize and inhibit neuron D [5,6] or to presynaptic GABAB

heteroreceptors on neuron C [7] to inhibit neurotransmitter release by blocking Ca2 + influx (an excitatory glutamatergic neuron is shown as an example). Stimulation of GABAB autoreceptors on neuron B [8] also reduces further release of GABA. Synaptic GABA undergoes uptake into the presynaptic neuron by GAT-1, and uptake into glial cells and possibly postsynaptic neurons by GAT-2, GAT-3, and GAT-4 (GAT-2 is shown mediating uptake into glial cell A as an example.) Acute falls in pyridoxal phosphate (PLP) lead to impaired glutamic acid decarboxylase (GAD) activity and low GABA concentrations. Although GABA-transaminase (GABA-T) also requires PLP, acute falls in PLP do not affect this enzyme as dramatically because of tight PLP binding to the GABA-T complex. Agents in Table 14-9 act to impair PLP formation by inhibiting pyridoxine kinase (PK) [1]; to increase GABA concentrations by either stimulating GAD [2] or inhibiting SSAD [3]; to inhibit GABA uptake [4]; to stimulate or block GABA receptors [5–8]; to cause GABA release [9]; or to inhibit GABA-T [10]. Glutamic-oxaloacetic transaminase (GOT), GABA-T, and SSAD are mitochondrial enzymes. α-KG = α-keto-glutarate; G = G protein; GAT = membrane GABA uptake transporter; SA = succinic acid; SSA = succinic semialdehyde; SSAD = SSA dehydrogenase; VGAT = vesicle membrane GABA uptake transporter.

Cyanide inhibits numerous enzymes besides cytochrome oxidase. Inhibition of GAD with a resultant fall in GABA concentration may partly explain seizures that occur in cyanide-poisoned patients. Domoic acid (see Glutamate below) may inhibit GAD.35

TABLE 14-8. GABA Receptors and Their Characteristics

GABAA

GABAB

GABAC

Receptor

C Ichannel

G-proteincoupled

Clchannel

Bicuculline antagonism

Yes

No

No

Baclofen

No

Yes

No

Benzodiazepine agonism

Yes

No

No

Barbiturate agonism

Yes

No

No

Picrotoxin antagonism

Yes

No

Slight

agonism

The most important mechanism for valproate's anticonvulsant action is unknown. In vitro studies demonstrate its ability to increase brain GABA concentrations either by inhibition of succinic semialdehyde dehydrogenase or by activation of GAD.70 Gabapentin's ability to increase the rate of GABA synthesis in the brain also may result from stimulation of GAD.153 Vigabatrin, an anticonvulsant, acts by irreversibly inhibiting GABA-T.147

G A B AA

Agonism

Figure 14-10 schematically illustrates the GABAA receptor complex. In general, substances that increase GABAA complex activity cause CNS depression, ranging from mild sedation and nystagmus to ataxia, stupor, coma, and even general anesthesia. Most indirect agonists that bind to the GABAA complex have no activity in the absence of GABA. With some exceptions, P.234 their pharmacologic actions receptor and do not result exclusive of GABA binding. additional actions that are

require the binding of GABA to its from a direct effect on Cl - conductance Many of these drugs demonstrate not mediated through the GABAA complex.

Figure 14-10. Representation of the GABA A Cl- channel receptor complex. Benzodiazepines (BENZOs), barbiturates, picrotoxin, steroids, and GABA (γ-aminobutyric acid) clearly bind to different sites on the channel. Although separate circles represent different agents capable of binding to and of modulating Cl- influx through the GABAA receptor complex, it is not always apparent where these agents bind on the channel. For example, general anesthetics and ethanol may produce their

effects by interacting with the steroid binding site. Chloral hydrate undergoes metabolism to trichloroethanol, which interacts with the GABAA receptor complex. Zolpidem, zopiclone, and zaleplon are nonbenzodiazepines that bind to the benzodiazepine site. Given the structural similarity of glutethimide and methyprylon to barbiturates, it is speculated that their action may be mediated at GABAA receptors.

Direct

GABA

Agonists

The main direct GABA agonist of toxicologic interest is muscimol, found in some poisonous mushrooms. Muscimol binds to the GABA receptor on the GABAA complex to mimic the action of GABA.110 Ibotenic acid, a direct glutamate agonist found in the same mushrooms, is decarboxylated to muscimol just as glutamate is decarboxylated to GABA.

Indirect

GABA

Agonists

Benzodiazepines bind to benzodiazepine receptors on GABAA complexes to increase the affinity of GABA for its receptor and to increase the frequency of Cl- channel opening in response to GABA binding.138 The benzodiazepine binding site on the GABAA receptor is located in a pocket between an α subunit and a γ subunit.161 Benzodiazepines also inhibit adenosine uptake apart from GABAA activity (see Adenosine below). Various isoforms of GABAA Cl- channels differ in their affinity for different benzodiazepines. GABAA receptors containing γ2 subunits are more sensitive to benzodiazepines than are GABAA receptors containing γ1 and γ3 subunits. Sensitivity and response to benzodiazepine binding is also highly dependent on the specific α subunit composition of the GABAA receptor. GABAA receptors containing an α4 or α6 subunit are completely insensitive to and

will not bind benzodiazepines, whereas GABAA receptors containing Î ±1 , α2 , α3 , or α5 subunits are sensitive to benzodiazepine binding. In addition, specific α subunits may mediate different effects of benzodiazepines. For example, sedative effects are mediated through binding to α1 subunits while anxiolytic effects appear to be mediated by binding to α2 subunits.49 Zolpidem, an imidazopyridine, and zaleplon, a pyrazolopyrimidine, are nonbenzodiazepine agents that act as agonists at the P.235 benzodiazepine binding site on the GABAA receptor. These agents exhibit a high selectivity for the α1 subunit and low selectivity for Î ±2 , α3 , and α5 subunits.142,161 This selective binding to α1 subunits is thought to account for relatively selective sedative properties of zaleplon and zolpidem at therapeutic doses, as compared to benzodiazepines.

TABLE 14-9. Examples of Xenobiotics That Affect GABAergic Neurotransmission

GABA

agonism

Stimulate

GAD

GABA

Direct

antagonism

GABAA

antagonists

Valproate

Bicuculline

Gabapentin

Cephalosporins

Ciprofloxacin

Direct

GABAA agonists

Enoxacin

Muscimol Progabidea

Imipenem

Nalidixic

acid

Norfloxacin

Indirect

GABAA agonists

Avermectin

Ofloxacin

Penicillins

Barbiturates

Benzodiazepines

Chloral

hydrate

Indirect

GABAA

Aztreonam

Clomethiazole

Clozapine

Ethanol

Flumazenil

Etomidate

Lindane

Felbamate

MAOIs

Ivermectin

Maprotiline

Meprobamate

Organochlorine insecticides

antagonists

Methaqualone

Penicillins

Propofol

Pentylenetetrazol

Steroids

Picrotoxin

Topiramate

Tricyclic

antidepressants

Trichloroethanol

Volatile

anesthetics

Zaleplon

Zolpidem

Zopiclone

Inhibit

GAD

Cyanide

Domoic

acid

Hydrazines

Isoniazid

Direct

GABAB agonists

Baclofen

Direct

GABAB

GHB

Phaclofenb

Progabidea

Saclofenb

antagonists

Inhibit

GABA-T

Inhibit

PK

Hydrazinesc

Vigabatrin

Isoniazidc

Inhibit

GABA

uptake

Guvacine

Tiagabine

Valproate

GABA = γ-aminobutyric acid; GABA-T = GABA transaminase; GAD = glutamic acid decarboxylase; GHB = γ-hydroxybutyric acid; PK = pyridoxine kinase; MAOIs = monoamine oxidase inhibitors. a Directly activate GABA A and GABAB receptors as well as being metabolized to GABA. b

Thought not to cross blood–brain barrier in meaningful amounts. c Major site of action is PK inhibition, though some direct GAD inhibition occurs.

Numerous steroids, such as alphaxalone and naturally occurring analogs, bind to more than one site on the GABAA complex to inhibit or enhance the action of GABA.55,138 The synthesis of neuroactive steroids is partly regulated by benzodiazepine binding to mitochondrial benzodiazepine receptors

(MBRs) apart from the GABAA complex.80,138 These mitochondrial benzodiazepine binding sites are found both within and outside the CNS and were originally called peripheral benzodiazepine receptors. Mitochondrial benzodiazepine binding sites comprise three subunits: a voltage-dependent anion channel; an adenine nucleotide carrier; and a binding site for PK 11195, an isoquinoline carboxamide derivative.54 Benzodiazepines vary in their affinity for mitochondrial binding. On binding, benzodiazepines appear to enhance the movement of cholesterol into mitochondria to begin steroid synthesis. Some of carbamazepine's action may be a result of binding at mitochondrial benzodiazepine receptors.45 Barbiturates bind to the GABAA complex to produce several effects.77,138 All barbiturates enhance the action of GABA by producing more Cl- influx for a given amount of GABA binding by increasing the duration of Cl- channel opening. Whereas phenobarbital does not change the affinity of GABA or benzodiazepines for their binding sites, depressant barbiturates, such as pentobarbital, do increase GABA and benzodiazepine receptor affinities for their ligands, further enhancing inward Cl- currents. At high concentrations, at least some barbiturates directly open Clchannels to cause Cl- influx.77 In addition, barbiturates possess other actions that depress all excitable membranes, including cardiac and smooth muscle. The intravenous anesthetics propofol and etomidate enhance inward GABAA Cl- currents, and at high concentrations they directly open chloride channels in the absence of GABA.7 The anesthetic effects of etomidate are mediated by β3 subunits, while agonism at β2 subunits may contribute to etomidate's sedative effect.111,125,142 Volatile general anesthetics also directly activate GABAA Clchannels. Some of ethanol's action is mediated through binding to the GABAA complex. The degree to which ethanol enhances the effect of GABA on Cl- influx depends on the GABAA receptor subunit composition. For

example, receptors with an α4 or α6 subunit and a δ subunit respond to very low concentrations of ethanol.151,163 Methaqualone produces at least part of its pharmacologic effect through indirect GABAA activity. Little is known of glutethimide's and methyprylon's mechanism of action. Their structural similarities to barbiturates suggest that much or most of them reside at the GABAA receptor. Trichloroethanol, a metabolite of chloral hydrate, and clomethiazole interact at the GABAA complex in a manner similar to barbiturates, although it is not clear whether they are binding to an identical site on the Cl- channel.166 Ivermectin, an antihelminthic, activates GABAA Cl- channels by increasing GABA binding. Meprobamate displays barbiturate-like action at the GABAA receptor, and, at high concentrations, is able to cause Cl- influx in the absence of GABA.126 High concentrations of felbamate also cause inward Clcurrents in the presence of GABA, although this seems unimportant at therapeutic doses.126 Part of topiramate's anticonvulsant action may result from enhanced Cl- influx through binding to GABAA receptors.137

Inhibition

of

GABA

Uptake

Valproate and the anticonvulsants guvacine and tiagabine work, in part, by inhibiting GABA uptake. Although valproate is structurally similar to GABA, its inhibition of the GABA transporter does not appear to be competitive.108

G A B AA

Antagonism

Direct

GABAA

Antagonists

Substances can cause inward Clto prevent bicuculline.

that act by any mechanism to decrease GABAA activity CNS excitation and convulsions by preventing inhibitory currents. Direct antagonists bind to the same site as GABA GABA binding, the prototype being the convulsant Various antibiotics interact with the GABA A receptor to

antagonize the action of GABA. In a dose-dependent manner, both imipenem and cephalosporins appear to directly antagonize GABA binding and can produce seizures at high doses or at therapeutic doses in susceptible individuals.162 Evidence suggests that penicillin may also directly antagonize GABA binding. Electrophysiologic and radioligand binding studies indicate that norfloxacin, ciprofloxacin, ofloxacin, and enoxacin all combine with the GABA binding site to prevent GABA binding.162 Theophylline and at least some nonsteroidal antiinflammatory agents markedly enhance GABA antagonism by some fluoroquinolones in vitro.162 Virol A, from Cicuta virosa, appears to directly antagonize binding of GABA to its receptor on the GABAA complex.156

Indirect

GABAA

Antagonists

Penicillin is well known for producing convulsions at high doses (eg, >20 million units of penicillin per day with renal insufficiency), and both penicillin and aztreonam, a monobactam, appear to block the Clchannel to prevent GABA-mediated inward ClPicrotoxin,

from Anamirta

currents.162

cocculus (fish berries), and the

experimental convulsant pentylenetetrazol bind to the picrotoxin site of the GABAA receptor complex to inhibit the action of GABA. Excessive doses produce CNS excitation and convulsions. Some organochlorine insecticides (eg, lindane) also inhibit the action of GABA by binding to what appears to be the picrotoxin site.92 Convulsions characterize acute poisonings by these agents. Both αthujone, the active component in wormwood oil, and cicutoxin from the water hemlock noncompetitively antagonize GABAA activity.64,157 Flumazenil competitively antagonizes benzodiazepines, zolpidem, zaleplon, and zopiclone at their receptors to reverse their pharmacologic effects.20,139 Paradoxically, large doses of flumazenil exhibit anticonvulsant activity in animals. This is explained by flumazenil's ability to inhibit adenosine uptake, not by partial agonism at the benzodiazepine receptor.117

Cyclic antidepressants, including amoxapine and maprotiline, and at least two MAOIs (isocarboxazid and tranylcypromine) inhibit GABAmediated Cl- influx at GABAA receptors.95,146 Their potency at inhibiting Cl- influx correlates with the frequency of seizures that occur in patients taking therapeutic doses of these medications. Impaired GABA A activity may contribute to or be primarily responsible for seizures seen in patients who overdose on these agents. The exact binding site of these drugs on the GABAA receptor complex is not yet known, although some evidence suggests at least indirect activity at the picrotoxin binding site. Some subtypes of GABAA receptors are susceptible to inhibition by zinc ions.138 What role this plays in normal physiology or toxicology is not established. P.236

G A B AA

Withdrawal

Acute withdrawal from all GABAA direct and indirect agonists appears almost identical except for time course; in all cases, a common denominator is impaired Cl- influx. Withdrawal of all GABAA agonists can cause tremor, hypertension, tachycardia, respiratory alkalosis, diaphoresis, agitation, hallucinations, and convulsions. When GABAA receptors are chronically exposed to an agonist, changes in gene expression of receptor subunits occur which lessens Cl- influx in response to GABA or drug binding, producing tolerance. Importantly, withdrawal of the agonist produces yet further changes in subunit expression. For example, benzodiazepine-insensitive α4 -subunit expression is increased following withdrawal of many GABA agonists, including benzodiazepines, zolpidem, zaleplon, neuro-steroids, and ethanol. (Expression of other subunits, including α1 , γ2 , β2 , and Î ²1 also change in response to exposure and/or withdrawal of GABAA agonists.49) Alterations in GABAA receptor subunit composition following chronic exposure to and withdrawal of an agonist can, therefore, affect the ability to successfully treat withdrawal

symptoms. While any GABAA receptor agonist may be used to treat withdrawal from another, some agents work better than others in different clinical settings. For example, patients experiencing severe alcohol withdrawal may have an increased proportion of GABAA receptors containing benzodiazepine-insensitive α4 subunits, and contain fewer GABAA receptors with benzodiazepine-sensitive α1 subunits.27 Even extremely high doses of benzodiazepines in these patients may not effectively control severe alcohol withdrawal. A better treatment option in such a setting would be GABAA agonists such as propofol or phenobarbital that act either on a different site on the GABAA receptor or directly open the Cl- channel.7,27 Phenytoin and carbamazepine do not stop GABAA withdrawal seizures because their pharmacologic effects are independent of GABAA agonism.

G A B AB

Agonists

The main GABAB receptor agonist of toxicologic significance is baclofen. Coma, hypothermia, hypotension, bradydysrhythmias,

and

seizures characterize its toxicity. The convulsions that occur in patients with baclofen overdose are thought to result from disinhibition (inhibition of inhibitory neurons). Carbamazepine's activation of GABAB receptors has been demonstrated, although this is not thought to explain most of its anticonvulsant action. Some of γ-hydroxybutyrate's actions following pharmacologic doses may be mediated through activation of GABAB receptors.

G A B AB

Withdrawal

Baclofen withdrawal is similar clinically to GABAA withdrawal. Hallucinations, agitation, tremor, increased sympathetic activity, and convulsions are the main characteristics of baclofen withdrawal. Withdrawal from chronic intrathecal baclofen administration may also be accompanied by large swings in autonomic tone (hypotension, hypertension, tachycardia, bradycardia) and transient cardiomyopathy and shock. Reinstitution of oral baclofen therapy

following oral withdrawal, or intrathecal baclofen following intrathecal withdrawal is the definitive treatment of choice.96

γ-Hydroxybutyrate γ-Hydroxybutyrate (GHB; γ-hydroxybutyric acid) exists endogenously but toxicologic interest stems from its use as a drug of abuse and as a treatment for narcolepsy.11,46,87 GHB is rapidly absorbed and freely crosses the blood-brain barrier. Toxicity resulting from ingestion of GHB is explained by GHB receptor and GABAB receptor activation, and comprises agitation, tremor, rapid onset of coma, vomiting, bradycardia, hypotension, hypotonia, and apnea that usually resolve within several hours. Although seizure activity has been noted in experimental animals, it is debated whether GHB causes true convulsive activity in human beings. Human experiments with “therapeutic― doses of GHB have not found EEG changes consistent with seizure activity.87 Some authors have reported “generalized seizures― occurring in patients presenting after GHB overdose. Interestingly, patients with the rare inborn error of metabolism, succinic semialdehyde dehydrogenase (SSAD) deficiency, have elevated GHB concentrations and tend to experience seizures.56 Valproate similarly elevates endogenous GHB concentrations

by

inhibiting

SSAD.

Controversy exists as to whether GHB should be considered a neurotransmitter or simply a neuromodulator because it is unclear whether this substance is concentrated within vesicles for synaptic release. There is evidence demonstrating a sodium-dependent uptake transporter for GHB. GHB receptors appear to be heterogeneously distributed throughout the brain, with highest concentrations in the hippocampus, cortex, limbic areas, and thalamus, as well as in regions innervated by dopaminergic terminals and dopaminergic nuclei. GHB receptors exist on neurons, mainly at the synaptic level, but are absent from glial or peripheral cells.

At least two general GHB receptors have been described thus far, based on binding affinity for GHB and other ligands. High-affinity receptors for GHB do not respond to GABA, GABAergic agonists, γbutyrolactone, or dopamine. Similarly, GHB does not activate GABAA Cl- channels. Flumazenil and baclofen fail to antagonize GHB binding to its binding site.11 Although γ-butyrolactone (GBL) does not express affinity for GHB binding sites, GBL rapidly undergoes hydrolysis to form GHB by peripheral γ-lactonase.11,94 1,4-Butanediol undergoes conversion to GHB via alcohol dehydrogenase and aldehyde dehydrogenase. Several proposed pathways for endogenous GHB formation exist (Fig. 14-11) .11 Evidence exists for GHB's metabolism back to GABA, although this appears minimal at physiologic GHB concentrations.46 However, effects resulting from pharmacologic doses of GHB may result, in part, from secondary GABA formation. Although normal endogenous GHB concentrations are probably not high enough to activate GABAB receptors, such receptor activation may occur with exogenous administration of GHB. Furthermore, there appears to be functional interplay between GHB and GABA B receptors.11 Specific interactions between GHB and dopamine are complex and not fully delineated. Treatment with GHB appears to inhibit dopamine release, probably via stimulation of GABAB receptors.168 GHB also affects the firing rates of dopaminergic neurons, dopamine synthesis, and levels of dopamine and its major metabolites. GHB is thought to affect sleep cycles, temperature regulation, cerebral glucose metabolism and blood flow, memory, and emotional control, and it may be neuroprotective. Although GHB can suppress alcohol withdrawal, GHB is also addictive, and both tolerance and a withdrawal syndrome have been described. Withdrawal is characterized, in part, by insomnia, cramps, paranoia, hallucinations, tremor, and anxiety.

P.237

Glycine as an Inhibitory Neurotransmitter Glycine acts as a postsynaptic inhibitory neurotransmitter in the spinal cord and lower brainstem. In the CNS, serine is converted to glycine by serine hydroxymethyltransferase (SHMT).

Figure 14-11. Potential pathways of GHB (γ-hydroxybutyrate) synthesis and degradation. GABA = γ-aminobutyric acid; GBL = γ-butyrolactone; SSA =succinic semialdehyde; [1] =glutamic acid decarboxylase; [2] = GABA-transaminase; [3] =succinic semialdehyde dehydrogenase; [4] =specific succinic semialdehyde reductase and/or nicotinamide adenine dinucleotide phosphate (NADPH)-dependent aldehyde reductase 2; [5] = mitochondrial β oxidation; [6] =alcohol dehydrogenase and aldehyde dehydrogenase; [7] =GHB dehydrogenase; [8] = γlactonase.

Figure 14-12. Inhibitory glycinergic neurotransmission. Glycine is concentrated within vesicles by uptake via VGAT, the vesicle membrane transporter. Signals from the afferent limb of a reflex arc (neuron C) cause the release of an excitatory neurotransmitter (NT) that crosses the synapse to bind to neuron B in the efferent limb of the reflex arc [1]. To prevent excessive neuronal firing and motor activity, glycine (GLY) released from inhibitory neuron A [2] binds to glycine Cl- channel receptors on neuron B [3] and causes inhibition by hyperpolarization through Cl- influx. Synaptic glycine is transported back into the neuron by at least two subtypes of membrane glycine transporters, GLYT-1 and GLYT-2 [4]. Strychnine (STR) binds to the glycinergic Clchannel to decrease glycine's binding, which prevents Cl- influx. Although strychnine is shown to bind to a separate site from

glycine, there is evidence that these sites may overlap.

Release

and

Uptake

Glycine is transported into storage vesicles by VGAT and C a2 +-dependent exocytosis upon neuronal depolarization 1 2). Glycine is removed from the synapse through uptake dependent transporter into presynaptic neurons and into Two glycine membrane transporters have been cloned,

undergoes (Fig. 14by a Na+glial cells.

P.238 and share homology with GABA uptake transporters. GLYT-1 is found both in astrocytes and neurons, whereas GLYT-2 is localized on axons and terminal boutons of neurons that contain vesicular glycine. Although both transporters are found associated with glycinergic neurons in the brainstem and spinal cord, GLYT-1 is also found in the forebrain in regions devoid of glycinergic neurotransmission. At the latter location, GLYT-1 may regulate extracellular glycine that is available for NMDA receptor activation, and GLYT-1 inhibitors, then, could enhance NMDA responses (see NMDA Receptor Antagonists below). Glycine transporters can also function in reverse, pumping glycine out of the cell when the intracellular sodium concentrations rise.4

Glycine

Receptors

Like GABAA , the glycine receptor is a Cl- channel on the postsynaptic membrane. GABAA Cl- channels and glycinergic Cl- channels share significant amino acid homology. Glycine receptors are pentameric proteins made up of α and β subunits. Four isoforms of the α subunit and one isoform of the β subunit have been described.101 Glycine receptor activation causes an inward Cl- current that hyperpolarizes the membrane. It appears that three glycine molecules must bind to sites on the Cl- channel to produce inhibitory

Cl- influx.

Chemical

Agents

Table 14-10 provides examples of chemical agents that affect inhibitory glycine Cl- channels. The amino acids D-alanine, taurine, Lalanine, L-serine, and proline can activate glycinergic Cl- channels. Both ethanol and propofol potentiate glycine-mediated inward Clcurrents through action at the α subunit of the glycine receptor, just as they do at GABAA Cl- channels.97,101 Clozapine inhibits glycine uptake.67 Strychnine is the main toxicologic agent affecting glycinergic transmission. Strychnine binds to the α subunit of the glycine receptor to prevent glycine's action on Cl- influx,3 at least in part by decreasing glycine's binding to its receptors. This physiologic antagonism of glycine's action produces increased muscle tone, rigidity, opisthotonus, trismus, and death from respiratory failure and rhabdomyolysis. Given the similarity in Cl- channels, it is not surprising that strychnine binds to the GABAA complex in vitro. However, strychnine's affinity for this complex is less than that for glycine receptors, and most of its toxicologic action is a result of physiologic

antagonism

of

glycine's

inhibitory

action.

Picrotoxin binds to the glycine receptor to impair Cl- influx.93 Tetanus toxin produces rigidity and trismus by preventing glycine release from nerve endings in the spinal cord and brainstem.

TABLE 14-10. Examples of Xenobiotics That Affect Inhibitory Glycine Chloride Channels

Glycine

agonists

Glycine

antagonists

Ethanol

Strychnine

Propofol

Picrotoxin

D-Serine

Glycine

uptake

inhibitor

Clozapine Ethanol and propofol enhance Cl - influx through glycine Clchannels, although they do not appear to act as direct agonists. Evidence exists for picrotoxin's direct antagonism at the glycine binding site(s) in contrast to GABAA Cl- channels, where it acts at a site separate from where GABA (γaminobutyric acid) binds.

Glutamate Glutamate is the main excitatory neurotransmitter in the CNS. Up to 66% of all brain energy expenditure is attributed to uptake and recycling of glutamate.67 Aspartate displays similar actions although its exact role as a neurotransmitter is not as well defined because it is only active at certain types of glutamate receptors. Glutamate and aspartate are commonly referred to as excitatory amino acid (EAA) neurotransmitters. Glutamate is essential for memory, learning, perception, and locomotion.38,76

Glutamatergic neurotransmission has been a subject of intense research because of its role in mediating neuronal damage in degenerative neurologic diseases and during times of trauma, ischemia, hypoglycemia, and status epilepticus. Although glutamate receptor stimulation is necessary for normal brain activity, excessive glutamate receptor activation endogenously or by glutamate agonists can produce convulsions, neuronal damage, and death. Conversely, glutamate antagonists demonstrate anticonvulsant activity and neuroprotective action in animal models of brain and spinal cord injury. Glutamate may also play an important role in the development of drug abuse and subsequent withdrawal symptoms. Glutamate antagonists decrease drug craving and withdrawal symptoms in patients addicted to ethanol, benzodiazepines, and opioids.14

Synthesis,

Release,

and

Uptake

Glutamate is a nonessential amino acid that does not cross the blood–brain barrier. It must, therefore, be synthesized from products of glucose metabolism or other precursors that enter neurons. Glutamate is primarily synthesized from glutamine by the enzyme glutaminase located within the mitochondrial compartment. Other amino acids, such as aspartate, also serve as sources for glutamate production. Glutamate stored within vesicles is released into the synapse by Ca- 2-dependent exocytosis.38 Five different EAA uptake transporters have been identified, and glutamate undergoes uptake both by neuronal and glial cells.134 Synaptic glutamate transported into glial cells undergoes conversion back to glutamine by the enzyme glutamine synthase. Glial cells then release glutamine back into the synapse for uptake by neurons and recycling back to glutamate and then into storage vesicles (Fig. 14-13). Reverse transport of glutamate from the cytoplasm into the synapse by the membrane transporter may occur under some circumstances.38 Glutamate also serves as the precursor for GABA's synthesis.

Glutamate

Receptors

The EAA receptor system is the most complex of all neurotransmitters. This complexity is necessary for protection against the devastating effects of uncontrolled excitatory neurotransmission. At present, 11 different glutamate receptors are recognized. Three ionotropic glutamate receptors are cation channels, and 8 metabotropic receptors are linked to G proteins.38 A single neuron may express numerous types of glutamate receptors. Postsynaptic glutamate receptors are usually excitatory, although some inhibitory actions have been demonstrated. Presynaptic terminal glutamate receptors appear mainly to inhibit release of various neurotransmitters, including glutamate (Fig. 14-13) .118

Ionotropic

Glutamate

Receptors

Three ionotropic glutamate receptors have been identified. All allow for excitation through cation P.239 influx. These receptors are further categorized and named by their abilities to be activated or antagonized by various substances: kainate, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate), and NMDA (N-methyl-D-aspartate).

Figure

14-13.

Glutamatergic

neurotransmission.

Glutamic-

oxaloacetic transaminase (GOT) converts α-ketoglutarate (αKG) to glutamate (GT) in mitochondria. GT also forms from glutamine via mitochondrial glutaminase (GA). Glutamate is transported into vesicles [6] by VGlut1 (or possibly other subtypes) for exocytotic release into the synapse. Synaptic glutamate activates four main types of receptors. AMPA [2], kainate [3], and NMDA [4] receptors are cation channels. Membrane depolarization in response to their activation causes neuronal excitation through cation influx. Metabotropic receptors (mGluR) [1,8] are coupled to G proteins and are expressed on pre- and postsynaptic membranes. In addition, some mGluRs reside outside of the synapse. Postsynaptic mGluR excitation in this example [1] results from preventing K+ efflux, but other mechanisms of excitation exist. Presynaptic mGluRs act to inhibit

[8] glutamate (and other neurotransmitter) release through modulating intracellular Ca2 + concentrations. Figure 14-14 provides a more detailed illustration of the NMDA receptor. Excessive influx of Ca2 + through NMDA receptors (and through some AMPA and kainate receptors) causes neuronal damage and cell death. An Mg2 + ion normally blocks the NMDA receptor channel to prevent Ca2 + influx despite glutamate binding. However, depolarization of the neuronal membrane by cation influx resulting from activation of any of the other receptor types causes Mg2 + to dissociate from the NMDA receptor and to allow potentially damaging inward Ca2 + currents. Glutamate undergoes uptake by neurons and glial cells by various subtypes of EEAT, the membrane bound glutamate transporter [5]. In glial cells, GT is converted to glutamine by glutamine synthase (GS), and glutamine is transported out of glial cells by system N-1 (SN1), a N a+ - and H+-dependent pump VGAT, the vesicle membrane moves back into neurons [7] to glutamate. Various agents

that is structurally similar to GABA transporter. Glutamine then where it undergoes conversion back in Table 14-11 affect glutamatergic

neurotransmission, in part, by stimulating or blocking the various glutamate receptors [1–4,8] or by preventing glutamate uptake [5]. G =G protein.

Kainate receptors are named for their affinity for kainic acid found in seaweed and comprise GluR5–7, KA1, and KA2 subunits.72 Activation allows Na+ influx and a small amount of K+ efflux, resulting in neuronal depolarization. Some kainate receptors in the hippocampus also appear to allow Ca2 + influx following activation. Kainate receptors are the only ionotropic glutamate receptors, to date, found presynaptically, although they are much more prevalent on postsynaptic neuronal membranes.52 The AMPA receptor is an ion channel structurally similar to the kainate receptor that also mediates Na + influx (and lesser amounts

of K+ efflux) on postsynaptic membranes, triggering neuronal depolarization. 12 AMPA receptors are composed of GluR1–3 subunits.72 The AMPA receptor is the most common ionotropic glutamate receptor found in the brain and appears to account for most glutamatergic excitation under normal conditions. A subtype of AMPA receptors in the hippocampus may also allow Ca2 + influx after activation.129 The NMDA receptor, the most studied of all glutamate receptors, is a C a2 + channel whose activation allows for inward Ca2 + and Na+ currents (and some K+ efflux), resulting in neuronal depolarization P.240 and excitation (Fig. 14-14). NMDA receptors comprise NR1, NR2A–D, and NR3A–B subunits.72 Excessive stimulation of NMDA receptors by glutamate released during times of ischemia, trauma, hypoglycemia, or convulsions triggers damaging rises in intracellular C a2 + concentrations, activation of numerous enzymes, and free radical formation, all of which incite cell death.76 Antagonists of NMDA Ca2 + channels demonstrate anticonvulsant and neuroprotective activity during times of neuronal insult.

Figure 14-14. Representation of the NMDA glutamate receptor. The NMDA receptor is a voltage-gated and ligand-gated Ca2 + channel. Glutamate (GT) binds to its receptor on the channel [2] to open the Ca2 + channel and to allow Ca2 + and Na+ influx and lesser amounts of K+ efflux. Mg2 + normally blocks the Ca2 + channel, preventing cation influx in response to glutamate binding. Mg2 + leaves the channel when the membrane is depolarized by 20–30 mV. Glycine must also bind to its site on the NMDA receptor complex for successful glutamate agonism. Polyamines bind on the extracellular surface of the receptor [5]. Z n2 + binds [4] to inhibit Ca2 + influx. The phencyclidine (PCP) binding site [3] lies within the channel. Agents in Table 14-11 may antagonize glycine binding [1]; block the Ca2 + channel by binding to the PCP binding site [3]; bind to the polyamine binding site [5]; or directly stimulate the glutamate binding site [2].

The NMDA Ca2 + channel is normally blocked by Mg2 + in a voltagedependent manner, preventing Ca2 + influx despite glutamate binding (Fig. 14-14) .128 Only when the neuronal membrane is depolarized by at least 20–30 mV through some other mechanism (eg, activation of another type of glutamate receptor) will Mg2 + leave the channel and allow Ca2 + influx in response to glutamate binding. Thus, the NMDA glutamate receptor is both a ligand-gated and voltage-gated ion channel. Many neurons express both NMDA and non-NMDA receptors for glutamate. Excessive stimulation of kainate or AMPA receptors by glutamate causes cell damage through Na- (and in some instance, Ca2 +) influx, because the membrane depolarization they produce causes Mg2 + to leave the NMDA receptor and allows for potentially damaging inward Ca2 + currents.38 Calcium ion influx through voltage-gated ion channels (including the L subtype) on cell bodies that open in response to depolarization also contributes to accumulation of intracellular calcium and cell damage. Consequently, excessive activation of any excitatory glutamate receptor has the

potential to produce neuronal cytotoxicity.76 Glutamate alone is incapable of activating NMDA receptors, even after Mg2 + has dissociated from the ion channel. Glycine also must bind to its specific receptor on the NMDA receptor complex for successful glutamate agonism (Fig. 14-14), making glycine an indirect agonist of excitatory neurotransmission.38 Strychnine does not antagonize glycine's excitatory action at NMDA receptors, explaining why glycine NMDA receptors are also known as strychnine-insensitive glycine receptors. Zinc ions normally bind to the NMDA receptor complex to antagonize the action of glutamate. Binding of spermine or spermidine to a polyamine binding site on the extracellular side of the NMDA receptor results in increased affinity of glycine and glutamate for their binding sites. However, polyamine agonism is not essential for glutamate activation of NMDA receptors.65

Metabotropic

Glutamate

Receptors

Metabotropic glutamate receptors (mGluRs) are linked to various G proteins on post- and presynaptic membranes (Fig. 14-13). Eight different receptors have been isolated. In contrast to ionotropic glutamate receptors, mGluRs may excite or inhibit at postsynaptic membranes, and appear mainly to inhibit at presynaptic locations. Postsynaptic excitation most commonly results from prevention of K+ efflux or activation of phospholipase C, which serves to raise intracellular Ca2 + concentration. Postsynaptic inhibition usually results from enhanced K+ efflux.100 Metabotropic glutamate receptors are commonly subdivided into three main groups based on their sequence homology, intracellular signaling mechanisms and response to specific experimental agonists.106 As a general rule, group I receptors (mGlu1, mGlu5) reside postsynaptically; activation produces excitation through blockade of K+ efflux or by activating phospholipase C, producing rises in intracellular Ca2 +. 152 In animal experiments, agonists of

group I receptors produce convulsions, while antagonists display anticonvulsant effects.106 Groups II (mGlu2, mGlu3) and III (mGlu4, mGlu6, mGlu7, mGlu8) receptors most commonly serve as presynaptic autoreceptors and heteroreceptors and, when activated, inhibit adenylate cyclase activity. This, in turn, prevents Ca2 + influx and serves to inhibit release of neurotransmitters, including glutamate, GABA, dopamine, and adenosine. Group II presynaptic autoreceptors may play an especially important role in decreasing further glutamate release during pathologic conditions when the extracellular P.241 concentration of glutamate exceeds normal physiologic levels.152 Agonists of groups II and III metabotropic receptors produce anticonvulsant effects in animals.106

TABLE 14-11. Examples of Xenobiotics That Affect Glutamatergic Neurotransmission

Glutamate

agonism

Direct glutamate agonists

BMAA

receptor

Amantadine

Dextrorphan

BOAA

Domoic

NMDA receptor antagonists

Dizocilpine

acid

Ketamine

(MK801)

Ibotenic

acid

Memantine

Willardine

Orphenadrine

Pentamidine

Glycine agonists

NMDA

receptor

Phencyclidine

Ethanola

D-Cycloserine

Milacemide

NMDA

Glutamate

uptake

inhibitor

Clozapine

glycine

antagonists

Felbamate

Kynurenic

acid

Meprobamate

Glutamate

Prevent

antagonism

glutamate

release

Polyamine

Lamotrigine

Ifenprodil

Nimodipine

Eliprodil

antagonists

Riluzole

BMAA = α-amino-β-methylaminopropionic acid; BOAA = βN-oxalylamino-L-alanine; NMDA 5 N-methyl-D-aspartate. a Ethanol antagonizes glutamate's action at NMDA receptors through an unknown mechanism.

Chemical

Agents

Table 14-11 provides examples of chemical agents that affect glutamatergic neurotransmission.

Glutamate

Agonism

Domoic acid produces amnestic shellfish poisoning, partly characterized by confusion, agitation, convulsions, memory disturbance, neuronal damage, and death.58 The structural similarity between domoic acid and glutamate is thought to explain excessive activation of kainate receptors with secondary NMDA receptor activation and neuronal damage. Investigators hypothesize that other naturally occurring glutamate receptor agonists produce additional neurologic diseases. The neurogenic form of lathyrism results from using chickling peas (Lathyrus sativus) as a food staple. Chickling peas contain β-Noxalylamino-L-alanine (BOAA), an agonist of AMPA receptors.38,79 Neurogenic lathyrism was common in German concentration and prisoner of war camps during World War II and still occurs regularly in some parts of the world. Ibotenic acid, from poisonous mushrooms, activates NMDA and some metabotropic glutamate receptors.38,79 It undergoes decarboxylation to muscimol, a direct agonist at GABA A receptors. Clozapine inhibits glutamate uptake.67 Because noncompetitive NMDA receptor antagonism reproduces many

signs and symptoms of schizophrenia, investigators are directing efforts at increasing glutamate's activity at NMDA channels in an effort to treat the disease. After crossing the blood–brain barrier, milacemide undergoes conversion to glycine, which is required for NMDA receptor activation. D-Cycloserine also crosses the blood–brain barrier to stimulate glycine receptors on NMDA calcium channels.38

Glutamate Prevention

Antagonism of

Glutamate

Release

Riluzole, used for the treatment of amyotrophic lateral sclerosis, indirectly glutamate Blockade to impair

NMDA

prevents release of glutamate. Lamotrigine diminishes release through blockade of voltage-gated Na+ channels. of voltage-gated Ca2 + channels by nimodipine also appears glutamate release.154

Receptor

Antagonists

Although some experimental agents and pharmaceutics antagonize the action of glutamate, most of our knowledge concerns antagonism at NMDA receptors. Phencyclidine and ketamine appear to bind within the ion channel (PCP binding site) to block Ca2 + influx following glutamate binding (Fig. 14-14) .76 Both agents possess other pharmacologic actions and can produce convulsions in overdose. However, in animal models of seizures and neuronal insult, both drugs are neuroprotective and anticonvulsant. Dextromethorphan and its first-pass metabolite, dextrorphan, exhibit anticonvulsant activity in animals. Dextrorphan's anticonvulsant activity results, in part, from blockade of NMDA receptor Ca2 + channels by binding to the PCP binding site. Dextromethorphan does not bind to the NMDA complex but, like dextrorphan, can directly block N- and L-type voltage-dependent Ca2 + channels.29

Dizocilpine (MK-801) is an NMDA receptor antagonist that binds to the PCP binding site in the NMDA Ca2 + channel. Human trials of dizocilpine resulted in adverse effects similar to those produced by phencyclidine, preventing further use in humans as a neuroprotective agent. Amantadine, memantine, and orphenadrine act as low-affinity antagonists at the PCP site but are not associated with psychotomimetic adverse effects. Part of amantadine's effectiveness in the treatment of Parkinson disease may be related to NMDA antagonism. Pentamidine also antagonizes glutamate binding at NMDA channels.154 Ethanol competitively inhibits NMDA receptor stimulation by an unknown mechanism, resulting in upregulation of this glutamatergic system. It does not appear to act through currently recognized binding sites.167 In some animal models of ethanol withdrawal seizures, NMDA receptor antagonists demonstrate anticonvulsant action than GABAA agonists.

Glycine

better

Antagonists

Felbamate's anticonvulsant activity may result, in part, from antagonism of glycine at NMDA receptors.100 Kynurenic acid, a metabolite of L-tryptophan, prevents NMDA activation through glycine antagonism. Meprobamate also antagonizes NMDA glutamate receptors by a yet-to-be-determined mechanism. However, given the structural similarity to felbamate, meprobamate may act by antagonizing the action of glycine.126

Polyamine

Antagonism

Ifenprodil and eliprodil antagonize glutamate's action at NMDA channels by preventing polyamine binding.100

Adenosine The overall action of adenosine throughout the body is to lessen

oxygen requirements and to increase oxygen and substrate delivery. In keeping with the paradigm, adenosine functions in the CNS as an extremely important inhibitory neuromodulator and vasodilator.

Synthesis,

Release,

and

Uptake

Normal intracellular concentrations of adenosine range from 50 to 300 nM. An Na+-dependent purine uptake transporter moves P.242 adenosine into the neuron (Fig. 14-15). During times of adequate oxygen delivery and oxidative phosphorylation, intracellular ATP concentrations are normally many fold greater than those of adenosine. Adenosine begins conversion to ATP by adenosine kinase, but adenosine can also be metabolized to inosine by adenosine deaminase, a less important pathway.25,120 ATP is commonly coreleased with other neurotransmitters (eg, norepinephrine, ACh, glutamate) into the synapse where it can be degraded to adenosine monophosphate (AMP) (Fig. 14-15). When oxygen delivery remains adequate to meet metabolic demands, most synaptic adenosine arises from the extracellular dephosphorylation of AMP by ectosolic 5-nucleotidase.25 During increased cellular catabolism, especially during inadequate oxygen delivery, intracellular adenosine concentrations rapidly rise as phosphorylated adenosine species are degraded to adenosine. The rise in intracellular adenosine concentration results in reverse transport of adenosine into the synapse by the purine uptake transporter (Fig. 14-15). Synaptic adenosine, then, activates adenosine receptors on neuronal and nonneuronal tissue (eg, vasculature). Adenosine's actions are terminated by uptake into glial cells and neurons (Fig. 14-15) .25

Figure 14-15. Adenosine's role in regulating excitatory neurotransmission, using glutamate as an example. In this example, glutamate (GT) excites a postsynaptic neuron by activating glutamate receptors [1]. Adenosine triphosphate (ATP) enters the synapse when glutamate is released. Adenosine formed from metabolism of ATP within the synapse binds to postsynaptic A1 receptors [2], which open K+ channels to inhibit the neuron through hyperpolarization. Adenosine also activates presynaptic A1 receptors [4] to lower intracellular Ca2 + concentrations, thereby impairing further glutamate release. After uptake [5], adenosine is acted upon either by adenosine kinase (AK) [7] to form adenosine monophosphate (AMP), or by adenosine deaminase (ADA) [6] to form inosine. Adenosine also binds to neuronal A2 receptors (especially in the striatum) and to vascular A2 receptors to cause vasodilatation [8]. A3 receptors

[9] are not activated by normal concentrations of adenosine. During times of excessive catabolism (eg, seizures, hypoglycemia, stroke) when intracellular adenosine concentrations rise markedly, adenosine moves into the synapse through reverse transport via the purine uptake transporter [10]. Resultant stimulation of A1 and A2 receptors results in inhibitory actions to decrease oxygen requirements and to increase substrate delivery through vasodilatation as described above. However, the resultant stimulation of A3 receptors [9] may contribute to neuronal damage and death. Agents in Table 14-12 act to inhibit adenosine uptake [5]; to inhibit ADA [6]; to inhibit AK [7]; to increase adenosine release; and to antagonize A1 [2,4] and A2 [8] receptors. ADP = adenosine diphosphate; ATP =adenosine triphosphate; cAMP =cyclic adenosine monophosphate; G =G protein; IP3 =inositol triphosphate.

Exogenously administered adenosine used in the treatment of supraventricular tachycardia does not cross the blood–brain barrier and therefore is centrally inactive. The half-life of adenosine in the blood is less than 10 seconds.

Adenosine

Receptors

The purine P1 receptor family comprises four adenosine receptor subtypes linked to G proteins: A1 , A2 A, A2 B, and A3 . 122 Postsynaptic A1 P.243 K+

K+

stimulation results in channel opening and efflux with subsequent hyperpolarization of the neuron (Fig. 14-15). Evidence suggests that G protein-mediated Cl- influx may explain postsynaptic hyperpolarization by A1 activation in some cases. Presynaptic A1 stimulation modifies voltage-dependent Ca2 + channels, lessening C a2 + influx during depolarization, which limits exocytosis of neurotransmitter. Therefore, activation of A1 receptors prevents

release of neurotransmitters presynaptically and inhibits their response postsynaptically.122,159 In the central and autonomic nervous systems, A1 receptors reside on presynaptic and postsynaptic membranes, where they serve as inhibitory modulators for numerous neurotransmitter systems; they are particularly prevalent in association with glutamatergic neurons in the CNS.159 A1 receptor stimulation also produces sedation and is important in sleep regulation.120 Other functions attributed to A1 receptors include neuroprotection, anxiolysis, temperature reduction, anticonvulsant activity, and spinal analgesia. Peripheral A1 receptor activation produces bronchoconstriction, decreased glomerular filtration, decreased heart rate, slowed atrioventricular conduction, and decreased atrial myocardial contractility.36 In the heart, almost all A1 receptors reside in the atria.19 In the CNS, A2 A receptors demonstrate limited distribution. They are concentrated on cerebral vasculature and produce vasodilatation when stimulated.122,159 Additionally, A2 A receptors are especially prevalent on neurons in the striatum where they inhibit the activity of D2 receptors.48 Striatal A2 A receptors enhancing cholinergic, glycinergic, and neurotransmission.40 Some A2 receptors where they serve to increase glutamate

decrease GABA effects while glutamatergic are found presynaptically release upon activation. 19

A 2 B receptors are expressed diffusely throughout the brain, and are most commonly identified on glial cells. A2 B receptors demonstrate low affinity for adenosine, and little is known of their physiologic role.22 Both A2 A and A2 B receptors are coupled to Gs . The rise in cAMP concentration resulting from A2 A activation on cerebral vasculature and elsewhere explains vasodilatation.122 For example, peripheral A2 receptor activation also results in coronary artery vasodilation.33 A 3 receptors reside diffusely throughout the CNS and express low

affinity for adenosine. A3 receptors act through G proteins to decrease adenylate cyclase activity and increase phospholipase C activity.160 The low concentrations of adenosine found during normal metabolism minimally activate A 3 receptors to produce inhibitory effects. During times of excessive adenosine accumulation (eg, hypoxia, seizures), adenosine accumulates at and activates A3 receptors to produce complex responses that appear to enhance ischemic cellular injury and death, at least in part through disinhibition of presynaptic metabotropic glutamate receptor responses. Thus, A3 receptor antagonists are being examined for neuroprotective actions.160

Adenosine

and

Seizure

Termination

In humans and in animal models of status epilepticus, including those from drugs and toxins, there are two alternating phases of electrical activity noted on electroencephalography. Periods of high-frequency spike activity accompanied by marked increases in cerebral oxygen consumption and metabolic requirements alternate with interictal periods of isolated spike waves during which metabolic demands are less. The high-frequency phase lasts only a few minutes before suddenly terminating, sometimes with a few seconds of electrocerebral silence. A gradual increase in electrical activity during the interictal phase eventually leads to a recurrence of highfrequency spike activity. These periodic spontaneous self-terminations of high-frequency electrical activity initially occur before neurons exhaust oxygen and energy supplies. These punctuations result from adenosine release from depolarizing neurons (and probably glial cells).43 Adenosine acts on presynaptic receptors to prevent further release of excitatory neurotransmitters and acts on postsynaptic receptors to inhibit their actions. Any agent that directly or indirectly enhances adenosine's action at A 1 receptors in the brain will usually exhibit anticonvulsant activity.

Conversely, A1 receptor antagonists lower the seizure threshold and make seizure termination more difficult and less likely to respond to anticonvulsants. Agents that antagonize A2 A receptors produce cerebral vasoconstriction and may limit oxygen delivery during times of increased demand. Antagonism of A2 A receptors in the striatum increases dopamine-mediated motor activity.

Chemical

Agents

Table 14-12 provides examples of chemical agents that affect adenosine receptors.

Direct

Adenosine

Agonists

ADAC (adenosine amine congener) is a direct A1 receptor agonist used in the treatment of Huntington disease.19 Tecadenoson is a selective A1 receptor agonist that is used for treatment of supraventricular tachycardia.19

Indirect

Adenosine

Agonists

Papaverine and dipyridamole inhibit adenosine uptake.116 Like other adenosine agonists, papaverine and dipyridamole demonstrate anticonvulsant activity when injected into the CNS. Such actions are not achievable with safe systemic doses. In addition to their actions at GABAA receptors, benzodiazepines inhibit adenosine uptake.34,117 This may explain observations that methylxanthines, potent adenosine receptor antagonists, reverse benzodiazepine-induced sedation in humans. The potencies of benzodiazepines as inhibitors of adenosine uptake show P.244 good correlation with clinical anxiolytic and anticonflict potencies, suggesting that such inhibition contributes to their action. The anticonvulsant effect of large doses of flumazenil also results from

inhibition of adenosine uptake. Carbamazepine inhibits adenosine uptake, although this is not thought to account for most anticonvulsive action.

TABLE 14-12. Examples of Xenobiotics That Affect Adenosine Receptors

Adenosine

Direct

agonism

Inhibit

agonists

Acadesine

Adenosine

ADAC (adenosine congener)

ADA

Dipyridamole

amine

Pentostatin

Tecadenoson

Inhibit

Inhibit

uptake

AK

Acadesine

Acadesine Acetatea

Benzodiazepines

Increase release

Opioids

adenosine

Calcium

channel

blockers

Carbamazepine

Dipyridamole

Adenosine

antagonism

A1 blockade

Ethanola

Caffeine

Flumazenil

Carbamazepine

Indomethacin

Theophylline

Papaverine

Propentofylline

Tricyclic

antidepressants

A2 blockade Caffeine

Theophylline

ADA = adenosine deaminase; AK = adenosine kinase. a Ethanol is metabolized to acetate, which inhibits adenosine uptake.

Adenosine may mediate many of the acute and chronic motor effects of ethanol on the brain. Ethanol, probably through its metabolite, acetate, prevents adenosine uptake, raising synaptic adenosine concentrations.28 Excessive stimulation of several adenosine receptors in the cerebellum may explain much of the motor impairment from low ethanol concentrations. In fact, animals made

tolerant to ethanol develop cross-tolerance to adenosine agonists. In mice, adenosine receptor agonists increase ethanol-induced incoordination while adenosine antagonists decrease this intoxicating response.37 Numerous other agents are inhibitors of adenosine uptake, including propentofylline, nimodipine, tricyclic antidepressants, and other calcium channel blockers.114,116 A 1 receptors located at the spinal cord level are important modulators of pain transmission by limiting release of substance P .132 Tricyclic antidepressants-induced inhibition of adenosine uptake may explain some of their effectiveness in treating neuropathic pain.132 The analgesic effectiveness of opioids can be partially attributed to their ability to increase the release of adenosine within the spinal cord.143 Dipyridamole

inhibits

adenosine

deaminase,

raising

adenosine

concentrations. During times of elevated adenosine levels that occur with cardiac or cerebral ischemia, acadesine further enhances adenosine's beneficial actions by three mechanisms: inhibition of adenosine kinase (AK), inhibition of adenosine deaminase (ADA), and inhibition of adenosine uptake. 107

Adenosine

Antagonists

The main adenosine antagonists of toxicologic concern are methylxanthines. Theophylline and caffeine are selective P1 antagonists, blocking both A1 and A2 receptors.159 The response to methylxanthines by A3 receptors varies widely depending on the species. Human A3 receptors demonstrate very low affinity for methylxanthines.160 Peripherally, methylxanthines produce excessive release of catecholamines from peripheral nerve endings (and probably the adrenal gland) by blocking presynaptic A1 receptors. In turn, catecholamine-mediated responses are exaggerated by blockade of

inhibitory

postsynaptic

A1 receptors on end organs.51

Centrally, enhanced release and actions of excitatory neurotransmitters (eg, glutamate) and resultant lack of periodicity probably explain convulsions that are frequently refractory to anticonvulsants in methylxanthine poisoning. The reasons why theophylline convulsions carry such a high mortality stem from a lack of self-termination (continual high-frequency spike activity and large metabolic demands) that has resulted from A1 antagonism, compounded by vasoconstriction caused by blockade of A2 receptors.119 GABAA receptor agonism, especially by barbiturates, most effectively prevents and terminates methylxanthine-induced seizures. Phenytoin not only is ineffective in treating theophyllineinduced seizures, but may actually increase the likelihood of seizures and mortality.15 Like phenytoin, carbamazepine's major anticonvulsant effect results from Na+ channel blockade. Unlike phenytoin, carbamazepine appears to antagonize A 1 receptors.31,34 This may explain the higher frequency of seizures after carbamazepine overdose than after phenytoin overdose. The absence of A2 blockade by carbamazepine theoretically allows for increases in cerebral blood flow to meet metabolic demands of the seizing brain.

Summary Neurotransmitter systems share common physiologic features, including neurotransmitter uptake, vesicle membrane pumps, ion trapping of neurotransmitters within vesicles, calcium-dependent exocytosis, and receptors coupled to either G proteins or to ion channels. It is not surprising, then, that a single pharmacologic agent frequently produces effects on several different neurotransmitter systems. As the number of new drugs and toxins encountered by man continues to grow, an understanding of their molecular actions in the

nervous system helps the physician to anticipate and better understand various pharmacologic and adverse effects resulting from therapeutic or toxic doses.

Acknowledgment Kimberly Graeme contributed to this chapter in a previous edition.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section I - Biochemical and Molecular Basis > Chapter 15 - Withdrawal Principles

Chapter

15

Withdrawal

Principles

Richard J. Hamilton In the central nervous system, excitatory neurons fire regularly, and inhibitory neurons inhibit the transmission of these impulses. Whenever action is required, the inhibitory tone diminishes, permitting the excitatory nerve impulses to travel to their end organs. Thus, all action in human neurophysiology is disinhibition.50,95,100 Tonic activity of a xenobiotic produces an adaptive change in the neuron. For example, tonic stimulation of an inhibitory neuron reduces the activity of that neuron so that the baseline level of function is again attained. A withdrawal syndrome occurs when the constant presence of this xenobiotic is removed or reduced and the adaptive changes persist. This produces a dysfunctional state in which there is significantly reduced inhibitory neurotransmission, essentially producing excitation (Fig. 15-1). Every withdrawal syndrome has two characteristics: (a) a preexisting physiologic adaptation to a xenobiotic, the continuous presence of which prevents withdrawal, and (b) decreasing concentrations of that

xenobiotic. In contrast, simple tolerance to a drug is characterized as a physiologic adaptation that shifts the dose–response curve to the right; that is, greater amounts of xenobiotic are required to achieve a given effect. Patients with withdrawal syndromes have often developed tolerance, but tolerance does not require the continued presence of the xenobiotic to prevent withdrawal.38,86 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) provides a helpful and descriptive set of criteria that mesh with our understanding of the pathophysiology of withdrawal syndromes.30 According to DSM-IV, withdrawal is manifested by either of the following: (a) a characteristic withdrawal syndrome for the substance or (b) the same (or a closely related) substance is taken to relieve withdrawal symptoms. Note that either criterion fulfills this definition. Logically, all syndromes have the first criterion, and so it is the presence of the second criterion that is critical to understanding physiology and therapy. For the purposes of defining a unifying pathophysiology of withdrawal syndromes, this chapter considers syndromes in which both features are present. An analysis from this perspective distinguishes xenobiotics that affect the inhibitory neuronal pathways from the effects of those agents that stimulate the excitatory neuronal pathways, such as cocaine. Cocaine does not produce a withdrawal syndrome using this definition, but rather a postintoxication syndrome that often results in lethargy, hypersomnolence, movement disorders, and irritability. This syndrome does not meet the second of the DSM-IV criteria for a withdrawal syndrome because the same (or a closely related) substance is not taken to relieve or avoid withdrawal symptoms. This postintoxication syndrome, the so-called “crack crash― or “washed-out syndrome,― is caused by prolonged use of the drug, and patients return to their premorbid function without intervention.74,87,98 This distinction is important for toxicologists, because (a) withdrawal syndromes that demonstrate both features of the DSM-IV criteria are treated with reinstatement and gradual withdrawal of a xenobiotic that has an effect on the

receptor and (b) withdrawal syndromes that do not demonstrate the second feature require only supportive care and resolve spontaneously. Finally, withdrawal syndromes are best described and treated based on the class of receptors that are affected because this concept also organizes the approach to patient care. For each receptor and its agonists, research has identified genomic and nongenomic effects that produce neuroadaptation and withdrawal syndromes. There appear to be six mechanisms involved: (a) genomic mechanisms via mRNA; (b) second messenger effects via protein kinases, cyclic adenosine monophosphate (cAMP), 43 and calcium ions; (c) receptor endocytosis; (d) expression of various receptor subtypes depending on location within the synapse (synaptic localization); (e) intracellular signaling via effects on other receptors; and (f) neurosteroid modulation. All or some of these mechanisms are already demonstrated in each of the known withdrawal states.51 These mechanisms develop in a surprisingly rapid fashion and modify the receptor and its function in such complex ways as to depend on the continued presence of the substance to prevent dysfunction.49,63,67,69,85,99,103

G A B AA Receptors (Barbiturates, Benzodiazepines, Ethanol, Volatile Solvents) γ-Aminobutyric acid type A (GABAA ) receptors have separate binding sites for GABA, barbiturates, benzodiazepines, and picrotoxin, to name only a few xenobiotics (Chap. 14). Barbiturates and benzodiazepines bind to separate receptor sites and enhance the affinity for GABAA at its receptor site. GABAA receptors are part of a superfamily of ligand-gated ion channels, including nicotinic acetylcholine receptors and glycine receptors, that exist as pentamers arranged around a central ion channel.89 When activated,

they hyperpolarize the postsynaptic neuron by facilitating an inward chloride current (without a G protein messenger), decreasing the likelihood of the neuron firing an action potential.50,80 The GABA receptor is a pentamer comprised of two α subunits, two β subunits and an additional subunit, most commonly γ, which P.250 is a key element in the benzodiazepine binding site. The two GABAbinding sites per receptor are located in a homologous position to the benzodiazepine site between the α and β subunits. Although the mechanism is unclear, benzodiazepines have no direct functional effect without the presence of GABA. Conversely, certain barbiturates, or perhaps all in a dose-dependent manner, can increase the frequency of channel opening producing a net increase in current flow without GABA binding.36,67

Figure 15-1. Alcohol intoxication, tolerance, and withdrawal. Alcohol consumption in alcohol-naive persons produces intoxication and sedation by simultaneous agonism at the γ-

aminobutyric acid (GABA) receptor-chloride channel complex and antagonism at the N-methyl-D-aspartate (NMDA)-glutamate receptor. Continuous alcohol consumption leads to the development of tolerance through changes in both the GABA receptor-chloride channel complex (a subunit shift from α1 to Î ±4 , results in reduced sensitivity to the sedating effects of alcohol) and the NMDA subtype of glutamate receptor (upregulation in number, resulting in enhanced wakefulness). There is conceptually a level at which the tolerant patient may appear clinically normal despite having an elevated blood alcohol concentration. Tolerant patients who are abstinent lose the tonic effects of alcohol on these receptors, resulting in withdrawal.

Recent evidence demonstrates that this prototypical pentameric GABAA receptor assembly is derived from a permutation and combination of two, three, four, or even five different subunits. The subtypes of GABA receptors can even vary on the same cell.67 In fact, GABA receptors are heterogeneous receptors with different subunits and distinct regional distribution. Although the preponderance of subtypes α1 Î ²2 Î ³2 , α2 Î ²3 Î ³2 , and α3 Î ²3 Î ³2 account for 75% of GABA receptors, there are at least 16 others of import.103 The recognition of additional subunits of GABA A receptors, such as ω, has permitted the development of targeted pharmaceuticals.7 For example, the drug zolpidem achieves its effect of hastened onset of sleep by targeting the ω1 receptor subunit of GABAA . 84 Previously, ethanol was thought to have GABA-receptor activity, although a clearly identified binding site was not evident (Chap. 75) . Traditional explanations for this effect included (a) enhanced membrane fluidity and allosteric potentiation (so-called crosscoupling) of the 5 proteins that construct the GABAA receptor; (b) interaction with a portion of the receptor; and/or (c) enhanced GABA release.18,50,52,83 Research with chimeric reconstruction of GABAA

and N-methyl-D-aspartate (NMDA) channels demonstrates highly specific binding sites for high doses of ethanol which enhance GABAA and inhibit NMDA receptor-mediated glutamate neurotransmission.68 However, research has not clarified whether ethanol at low doses is a direct agonist of GABAA receptors or a potentiator of GABAA receptor binding.53,67,73,76 Ethanol exhibits all 6 mechanisms of adaptation to chronic exposure, and is the prototypical substance for studying neuroadaptation and withdrawal.51 These 6 mechanisms appear to apply to benzodiazepines as well.3,48,73,76 The mechanisms are (a) altered GABAA receptor gene expression via alterations in mRNA and peptide concentrations of GABAA receptor subunits in numerous regions of the brain (genomic mechanisms); (b) posttranslational modification through phosphorylation of receptor subunits with protein kinase C (second-messenger effects); (c) subcellular localization by an increased internalization of GABAA receptor α1 -subunit receptors (receptor endocytosis); (d) modification of receptor subtypes with differing affinities for agonists to the synaptic or nonsynaptic sites (synaptic localization); (e) regulation via intracellular signaling by the NMDA, acetylcholine, serotonin, and β-adrenergic receptors; and (f) neurosteroid modulation of GABA-receptor sensitivity and expression.17,31,34,46,52,53,78,101 Intracellular signaling via NMDA subtype of the glutamate receptor appears to explain the “kindling― hypothesis, in which successive withdrawal events become progressively more severe.8,10,12,15,33,55,102 The activity of an excitatory neurotransmission increases the more it fires, a phenomenon known as long-term potentiation, and is the result of increased activity of mRNA and receptor protein expression, a genomic effect of intracellular signaling.38 As P.251 NMDA receptors increase in number and function (upregulation)42 and GABAA receptor activity diminishes, withdrawal becomes more severe.28,55,65,78 The dizocilpine (MK-801) binding site of the NMDA

receptor appears to be the major contributor, and this effect is recognized in neurons that express both NMDA and GABAA receptors.4,101,105 Interestingly, animal models suggest that chronic ethanol use induces alterations in the receptor subunit composition of the GABAA receptor, which may be partly responsible for the development of ethanol tolerance, withdrawal, and kindling. 20,55 In summary, it is an over simplification to view GABAA receptors as a homogenous and static collection of cell-surface proteins that are stimulated by sedatives. GABAA agonists induce modulatory changes in the receptors through genomic and nongenomic mechanisms that ultimately alter their function. In this way, withdrawal symptoms represent the clinical manifestation of a change in GABA-receptorcomplex characteristics.19,44 When alcohol or any xenobiotic with GABA agonist activity is withdrawn, inhibitory control of excitatory neurotransmission, such as that mediated by the now upregulated NMDA receptors, is lost.34,63,81 This results in the clinical syndrome of withdrawal: CNS excitation (tremor, hallucinations, seizures), and autonomic stimulation (tachycardia, hypertension, hyperthermia, diaphoresis) (Chap. 76) .39,50,85 Volatile solvents, such as gasoline, ether, and toluene, are widespread substances of abuse whose effects appear to be mediated by the GABA receptor; all of these solvents have a well-established abuse potential, especially in adolescents. These solvents can produce CNS inhibition and anesthesia at escalating doses via the GABAA receptor. Elaboration of the mechanism specific for solvent abuse awaits further study, although it is logical to assume that they act in a similar fashion as ethanol and other xenobiotics with the GABAA receptor. 9 They also appear to initiate the same dopamine reward system as other drugs of abuse.77,91

G A B AB

Receptors (GHB and Baclofen)

GABAB agonists such as γ-hydroxybutyric (GHB) acid and baclofen have similar clinical characteristics with regard to adaptation and

withdrawal.11,24,37,104 The GABAB receptor is a heterodimer of the GABAB ( 1 ) and GABAB ( 2 ) receptor. Unlike GABAA , the GABAB receptor couples to various effector systems through a signal-transducing G protein. GABAB receptors mediate presynaptic inhibition (by preventing Ca2 + influx) and postsynaptic inhibition (by increasing K+ efflux). The postsynaptic receptors appear to have a similar inhibitory effect as the GABAA receptors. The presynaptic receptors provide feedback inhibition of GABA release. Unlike GABAA receptors, these are mediated through G protein messengers.13,62,104 GHB is a naturally occurring inhibitory neurotransmitter with its own distinct receptor. Physiologic concentrations of GHB activate at least two subtypes of a distinct GHB receptor (antagonist-sensitive and antagonist-insensitive). However, at supraphysiologic concentrations, such as those that occur after overdose and abuse, GHB also binds directly to the GABAB receptor and is also metabolized to GABA (which then activates the GABAB receptor). Endogenous GHB activates a presynaptic GHB receptor to modulate GABA and glutamate release and inhibits dopamine release by the GABAB receptor.6 The GHB withdrawal syndrome clinically resembles the withdrawal syndrome noted from ethanol and benzodiazepines. Distinctive clinical features of GHB withdrawal are the relatively mild and brief autonomic instability with the persistence of psychotic symptoms.97 Baclofen is also a GABAB agonist. The pre- and postsynaptic inhibitory properties of baclofen allow it, paradoxically, to cause seizures in both acute overdose (because of decreased release of presynaptic GABA via autoreceptor stimulation) and withdrawal. Withdrawal is probably a result of the loss of chronic inhibitory effect of baclofen on postsynaptic GABAB receptors. On discontinuation, this produces hyperactivity of neuronal Ca2 + channels (N, P/Q type),27 leading to seizures, hypertension, hallucinations, psychosis, and coma. However, these manifestations may not differ from the withdrawal symptoms of GABAA agonists.79,92

Typically, the development of a baclofen withdrawal syndrome occurs 24–48 hours after discontinuation of baclofen. Case reports highlight the development of seizures, hallucinations, psychosis, dyskinesias, and visual disturbances. The intrathecal baclofen pump has become an effective replacement for oral dosing, but withdrawal can occur following use of this modality as well. Reinstatement of the prior baclofen-dosing schedule appears to resolve these symptoms within 24–48 hours. Benzodiazepines and GABAA agonists (not phenytoin) are the appropriate treatment for seizures induced by baclofen withdrawal.72

Opioid

Receptors

(Opiates

and

Opioids)

Similar to ethanol and GABAA receptors, opioid binding to the opioid receptors result in a series of genomic and nongenomic neuroadaptations, especially via second-messenger effects. When opioids bind to opioid receptors they alleviate pain by inhibiting neurons. They also activate Gs proteins, and stimulate K+ efflux currents. The opioid receptors are also linked to the Gi / o proteins. These act through adenyl cyclase and activate inward Na+ current, thus enhancing the intrinsic excitability of a neuron (Chap. 38) .23 Chronic exposure to opiates and opioids (all drugs with opioidreceptor affinity) results in a decreased efficacy of the receptor to open potassium channels by genomic mechanisms and secondmessenger effects. Following chronic opioid exposure, the expression of adenyl cyclase increases through activation of the transcription factor known as cAMP response element-binding protein (CREB).64,70 (Fig. 15-2) This results in an upregulation of cAMP-mediated responses such as P.252 the inward channels responsible for intrinsic excitability. The net effect is that, only higher levels of opioids result in analgesia and other opioid effects. In the dependent patient, when opioid levels drop, inward Na+ flux occurs unchecked, and the patient experiences Na+

the opioid withdrawal syndrome. The clinical findings associated with this syndrome are largely a result of uninhibited activity at the locus caeruleus.21,49,64,66,70

Figure 15-2. Immediate and long-term effects of opioids. The acute effects of both opioids and α2 -adrenergic agonists are to increase inhibition through enhanced potassium efflux and inhibited sodium influx. Chronic effects alter gene expression to enhance sodium influx and restore hemeostasis. CREB (cAMP response element-binding protein).

Furthermore, opioid receptors and central α2 -adrenergic receptors both exert a similar effect on the potassium channel in the locus ceruleus. Clonidine binds to the central α 2 -adrenergic receptor and stimulates potassium efflux, as do opioids, and produces similar

clinical findings.2 This explains why clonidine has some efficacy in treating the opioid withdrawal syndrome. In addition, the antagonistic effect of naloxone at the opioid receptor seems to reverse the effect of clonidine on this shared potassium efflux channel.2,35,40 Rapid opioid detoxification is a form of iatrogenic withdrawal that uses drugs with antagonist activity to accelerate a return to premorbid receptor states. In theory, inducing opioid withdrawal under general anesthesia with high-dose opioid antagonists permits the transition from drug dependency to naltrexone maintenance without drug withdrawal symptoms.56,57,58 Naltrexone blocks the euphoric effects of continued opioid use and discourages recidivism by blunting drug craving.47,59,60,61 Although the mechanism by which naltrexone blocks drug craving is not entirely clear, the speculation is that mere receptor occupancy by an antagonist is sufficient to blunt cravings. However, withdrawal symptoms may still be intense and persist for up to 1 week after rapid detoxification, suggesting that clinical recovery from the changes induced by chronic opioid use is slow.22,41,84,90,94

Î ±2 -Adrenergic

Receptors

(Clonidine)

Î ±2 -Adrenergic receptors are located in the central and peripheral nervous system. Clonidine is a central and peripheral α2 -adrenergic agonist. Stimulation of central presynaptic α2 -adrenergic receptors inhibits sympathomimetic output and results in bradycardia, and hypotension.32 Within 24 hours after the discontinuation of clonidine, norepinephrine concentrations rise as a result of enhanced efferent sympathetic activity.82 This results in hypertension, tachycardia, anxiety, diaphoresis, and hallucinations.16

Adenosine

(A)

Receptors

(Caffeine)

The release of neurotransmitters is accompanied by passive release

of adenosine as a by-product of adenosine triphosphate (ATP) breakdown. The released adenosine binds to postsynaptic A1 receptors where it typically has inhibitory effects on the postsynaptic neuron. It also binds to presynaptic A1 autoreceptors to limit further release of neurotransmitters. A2 receptors are found on the cerebral vasculature and peripheral vasculature where stimulation promotes vasodilation.26,45 Caffeine and other methylxanthines, such as theophylline, antagonize the inhibitory effect of adenosine, primarily on postsynaptic A1 receptors. As a result, acute exposure results in increases in heart rate, ventilation, gastrointestinal motility, gastric acid secretion, and motor activity. Chronic caffeine exposure results in tolerance to the clinical effects of large, acute doses of caffeine. Chronic caffeine exposure regulates A1 receptors by a variety of mechanisms, including increases in receptor number, increases in receptor affinity, enhancing receptor coupling to the G protein, and increases in G protein-stimulated adenyl cyclase.54 An animal study demonstrates that the adenosine receptor has a 3-fold increase in affinity for adenosine at the height of withdrawal symptoms. This model suggests that chronic caffeine administration results in increase in receptor affinity for adenosine, thus restoring a state of physiologic balance (normal motor inhibitory tone). When caffeine is withdrawn, the enhanced receptor affinity results in a strong adenosine effect and clinical symptoms of withdrawal: headache (cerebral vasodilation), inhibition).69,93,96

Acetylcholine

fatigue,

and

hypersomnia

Receptors

(motor

(Nicotine)

Nicotinic receptors are a type of acetylcholine receptors located in the autonomic ganglia, adrenal medulla, CNS, spinal cord, neuromuscular junction, and carotid and aortic bodies. Nicotinic receptors are fast-response cation channels that are not coupled to G proteins, distinguishing them from muscarinic receptors, which are coupled to G proteins. Nicotinic acetylcholine receptors have both excitatory and inhibitory effects. As in other withdrawal syndromes,

changes brought on by chronic use of nicotinic agonists, such as nicotine in cigarettes, appear to be related to selective upregulation of cAMP. Much remains unknown about these receptors and how they affect addiction and withdrawal.71,99

SSRI

Discontinuation

Syndrome

Upon discontinuation of chronic selective serotonin reuptake inhibitor (SSRI) therapy, patients develop a characteristic syndrome. This syndrome complies with the definition of withdrawal syndromes in that symptoms begin when drug concentrations drop, and the syndrome abates when the drug is reinstated. Headache, nausea, fatigue, dizziness, and dysphoria are commonly described symptoms. The condition appears to be uncomfortable but not life-threatening, rapidly resolves with reinstatement of a drug of the same class, and slowly resolves when the drug is discontinued after a more gradual taper (Chap. 70) .14,24,75

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 16 - Thermoregulatory Principles

Chapter

16

Thermoregulatory

Principles

Susi U. Vassallo Kathleen A. Delaney Despite exposure to wide fluctuations of environmental temperatures, human body temperature is maintained within a narrow range.20,130 Elevation or depression of body temperature occurs when (a) thermoregulatory mechanisms are overwhelmed by exposure to extremes of environmental heat or cold; (b) endogenous heat production is either inadequate, resulting in hypothermia, or exceeds the physiologic capacity for dissipation, resulting in hyperthermia; or (c) disease processes or drug effects interfere with normal thermoregulatory responses to heat or cold exposure.

Methods

of

Heat

Transfer

Heat is transferred to or away from the body through radiation, conduction, convection, and evaporation. Radiation involves the transfer of heat from a body to the environment, and from warm objects in the environment, for example, from the sun to a body.

Conduction involves the transfer of heat to solid or liquid media in direct contact with the body. Water immersion or wet clothing in contact with the body conducts significant amounts of heat away from the body. This effect facilitates cooling in a swimming pool on a hot summer day, or may lead to hypothermia despite moderate ambient temperatures on a rainy day. The amount of heat lost through conduction and radiation depends on the temperature gradient between skin and surroundings, cutaneous blood flow, and insulation such as subcutaneous fat, hair, clothing, or fur in lower animals.144 In the respiratory tract, heat is lost by conduction to water vapor or gas. In animals unable to sweat, this represents the primary method of heat loss. The amount of heat lost through the respiratory tract depends on the temperature gradient between inspired air and the environment, as well as the rate and depth of breathing.144 Convection is the transfer of heat to the air surrounding the body. Wind velocity and ambient air temperature are the major determinants of convective heat loss. Evaporation is the process of vaporization of water, or sweat. Large amounts of heat are dissipated from the skin during this process, resulting in cooling. Ambient temperature, rate of sweating, air velocity, and relative humidity are important factors in determining how much heat is lost through evaporation. On a very humid day, sweat may pour off, rather than evaporate from a person exercising in a hot environment, thereby accomplishing little heat loss. In very warm environments, thermal gradients may be reversed, leading to transfer of heat to the body by radiation, conduction, or convection.159,190

Physiology

of

Thermoregulation

In the normal human, stimulation of peripheral and hypothalamic temperature-sensitive neurons results in autonomic, somatic, and behavioral responses that lead to the dissipation or conservation of heat. Thermoregulation is the complex physiologic process that serves to maintain hypothalamic temperature within a narrow

range of 98.6 ± 0.8°F (37 ± 0.4°C) known as the set point.308 This hypothalamic set point is influenced by factors such as diurnal variation, the menstrual cycle and others. Maintaining, raising, or lowering the set point results in many outwardly visible physiologic manifestations of thermoregulation such as sweating, shivering, flushing, or panting. In the central nervous system, thermosensitive neurons are located predominantly in the preoptic area of the anterior hypothalamus, although some are found in the posterior hypothalamus. These neurons may be divided into those that are warm-sensitive, cold-sensitive, or temperatureinsensitive. Approximately 30% of preoptic neurons are warmsensitive. These increase their firing rate during warming and decrease their firing rate during cooling. 32 Warming of the hypothalamus in conscious animals results in vasodilation, hyperventilation, salivation, and increases in evaporative water loss, as well as a reduction of cold-induced shivering and vasoconstriction.128 Cooling of the hypothalamus in conscious animals causes shivering, vasoconstriction, and increased metabolic rate, even if the environment is hot. 119 How these temperature-sensitive neurons of the hypothalamus detect temperature changes and effect neuronal transmission is unclear. Altered action potential initiation and propagation caused by temperature-dependent changes in membrane potential, changes in P.256 the ratios of Na+ to Ca2 + ions which alter neuronal excitability and neurotransmitter release, or effects on the Na+K +-ATPase (adenosine triphosphatase) pump, may be involved.144 Drugs that increase intracellular cyclic adenosine monophosphate (cAMP) increase the thermosensitivity of warm-sensitive neurons.32 In the brainstem, warm- and cold-sensitive neurons are located in the medullary reticular formation, where information from cutaneous receptors, spinal cord, and preoptic area of the anterior hypothalamus is integrated.24,106,130,134

The spinal cord also manifests thermosensitivity. Heat- and coldsensitive ascending spinal impulses are conducted in the spinothalamic tract. As in the hypothalamus, local heating or cooling of the spinal cord results in thermoregulatory responses.128 In addition to the hypothalamus, brainstem, and spinal cord, there is evidence of thermosensitivity in the deep abdominal viscera.115,128,242 Intra-abdominal heating or cooling results in thermoregulatory responses. Cold- and warm-sensitive afferent impulses can be recorded from the splanchnic nerves in animals.115,244 Finally, the skin also contains heat and cold thermosensitive neurons. Cold receptors are free nerve endings that protrude into the basal epidermis, whereas warm-sensitive receptors protrude into the dermis.127,129 Cutaneous thermoreceptor output is affected by the absolute temperature of the skin, rate of temperature change, and area of stimulation.128 Cutaneous Aδ fibers at 5–30 fibers that

cold receptors are Aδ and C nociceptor afferent fibers. are small-diameter thinly myelinated fibers that conduct m/sec, and C-fibers are small-diameter unmyelinated conduct at 0.5–2 m/sec.122 Afferents from heat

receptors are primarily C fibers. Cutaneous thermoreceptive neurons respond to external temperature change as well as rate of temperature change, sending early warning to the central nervous system (CNS) via afferent impulses, allowing rapid and transient thermoregulatory (Fig. 16-1) .

responses

Vasomotor

and

before

brain

Sweat

temperature

Gland

changes

Function

Vasomotor responses to thermoregulatory input differ according to location. The normal thermoregulatory response to heat stress is mediated primarily by heat-sensitive neurons in the hypothalamus. Increased body-core temperature results in active vasodilation in the extremities and is under noradrenergic control; increasing sympathetic stimulation results in vasoconstriction, and decreasing sympathetic control results in vasodilation. Vasodilation in the

head, trunk, and proximal limbs is not a result of decreased sympathetic tone; instead, it is a result of an active process that is under the influence of cholinergic sudomotor nerves and local effects of temperature on venomotor tone. Sweat glands release local transmitters, such as vasoactive intestinal polypeptide (VIP) or bradykinins, and vasodilation results. Areas of the body such as the forehead, where sweating is most prominent during heat stress, correspond to areas where active vasodilation is greatest. The neurotransmitters involved in the regulation of relationships between vasodilation and sweating as a response to heat stress are not fully elucidated, but animal evidence suggests the presence of specific vasodilator nerves.128 Sweat glands are controlled by sympathetic postganglionic nerve fibers, which are cholinergic, and large amounts of acetylcholinesterase as well as other peptides involved in neural transmission.127,128

Figure 16-1. A representation of the response of cutaneous thermoreceptive neurons to external temperature change as an early warning to the central nervous system.

Neurotransmitters Thermoregulation

and

The neurotransmitters involved in thermoregulation include serotonin, norepinephrine, acetylcholine, dopamine, prostaglandins, β-endorphins, and intrinsic hypothalamic peptides such as arginine vasopressin, adrenocorticotropic hormone, thyrotropin-releasing hormone, and α-melanocyte–stimulating 52,230 hormone. Studies on the effects of individual neurotransmitters in thermoregulation yield contradictory results, depending on the animal species and the route of administration of the exogenous neurotransmitter. Refinements in techniques of microinjection of neurotransmitters into the hypothalamus of animals, rather than intraventricular instillation, have elucidated microanatomic sites where neurotransmitters are active. More research is needed, however, as interspecies variations and theoretical differences in response to exogenous versus endogenous peptides makes this area of study complex. Apomorphine is a mixed dopamine agonist that has been shown to cause hypothermia in animals; studies using selective D 1 - and D2 receptor agonists and antagonists suggest that the hypothermic effect of apomorphine is a result of its effects on D2 receptors, with some modulation by D1 receptors in the hypothalamus.205 Stimulation of D2 receptors appears to mediate the hypothermia induced P.257 sauvagine.35

by the peptide Dopamine D3 receptors undoubtedly play a role, as well; stimulation of D3 by specific agonists caused hypothermia in an animal model.206,207 There appears to be a link between dopamine D2 receptors and norepinephrine receptors in the hypothalamus, perhaps leading to vasodilation and hypothermia. The effect of clozapine in producing hypothermia in the rat was demonstrated to be caused by D1 and D3 stimulation.206,255 Lesser-known peptides appear to be involved in

thermoregulation. For example, neuropeptide Y is an amino acid neurotransmitter that occurs in high concentrations in the preoptic area of the anterior hypothalamus. Administration of neuropeptide Y caused a reduction in core temperature when administered with adrenoceptor antagonists such as prazosin, an α1 -adrenergic antagonist, propranolol, a β-adrenergic antagonist, and clonidine, a central α2 -adrenergic agonist.87,253 The administration of synthetic cannabinoids induces hypothermia in animals, an effect that is antagonized by adrenergic agonists and enhanced by adrenergic antagonists.237 Finally, studies on muscarinic receptors suggest the involvement of muscarinic M2 and M3 receptors in the production of hypothermia when agonists to these receptors are administered centrally.256 Blockers of adenosine triphosphate (ATP)-sensitive K+ channels can reverse the effect of cholinomimetic drugs in producing hypothermia.239

Drug

effects

on

Thermoregulation

Many drugs and toxins have pharmacologic effects that interfere with thermoregulatory responses (Tables 16-1 and 162) .187,191,292 α-Adrenergic agonist agents prevent vasodilation in response to heat stress. Increased endogenous heat production in the setting of increased motor activity also occurs in patients poisoned with cocaine or amphetamines. Life-threatening hyperthermia has been associated with the use of these agents. β-Adrenergic antagonists and calcium channel blockers diminish the cardiac reserve available to compensate for heat-induced vasodilation, whereas diuretics decrease cardiac reserve through their effects on intravascular volume.67 β-Adrenergic antagonists also interfere with the capacity to maintain normothermia under conditions of cold stress, possibly related to their interference with the mobilization of substrates required for thermogenesis.128,191 Opioids, and diverse sedative-hypnotics, depress hypothalamic function and predispose to hypothermia in the overdose setting.89 Carbon monoxide poisoning must also be considered in the

hypothermic patient. Organic phosphorous insecticides and other agents that cause cholinergic stimulation cause hypothermia by stimulation of inappropriate sweating and possibly through depression of the endogenous use of calorigenic substrates.191 Drugs with anticholinergic effects decrease sweating and predispose to hyperthermia during environmental heat exposure or exercise. Phenothiazines appear to interfere with normal response to both heat and cold. Severe hyperthermia associated with the absence of sweating is frequently described in patients using phenothiazines and may be a consequence of their anticholinergic effects.257,310 Effects on cold tolerance are attributed to their βadrenergic antagonist effects, which prevent vasoconstriction in response to cold stress.189 In addition, hyperthermia associated with severe extrapyramidal rigidity may occur in patients on antipsychotic agents.178 This rigidity is attributed to the dopamine-blocking effects of this class of drugs.

TABLE 16-1. Effects of Xenobiotics that Predispose to Hyperthermia

I. Impaired cutaneous heat loss A . Vasoconstriction through α-adrenergic stimulation Amphetamine and derivatives Cocaine Ephedrine Phenylpropanolamine Pseudoephedrine B . Sweat gland dysfunction by anticholinergic effects Antihistamines Belladonna alkaloids Cyclic antidepressants Phenothiazines II. Myocardial depression A.

II. A . Decreased cardiac output Antidysrhythmics β-Adrenergic antagonists Calcium channel blockers B . Reduced cardiac filling by dehydration Diuretics Ethanol III. Hypothalamic depression Antipsychotics IV. Impaired behavioral response Ethanol Opioids Phencyclidine Sedative-hypnotics Cocaine V . Uncoupling of oxidative Pentachlorophenol Dinitrophenol Salicylates

phosphorylation

VI. Increased muscle activity seizures, or rigidity Amphetamine derivatives Caffeine Cocaine Isoniazid Lithium Monoamine oxidase Phencyclidine Strychnine Sympathomimetics VII. Dystonia Butyrophenones Phenothiazines VIII. Withdrawal

inhibitors

through

agitation,

VIII. Dopamine agonists Ethanol Sedative-hypnotics

Ethanol Ethanol is the most common xenobiotic related to the occurrence of hypothermia in an urban setting.64,301 The mechanism by which ethanol predisposes to hypothermia is said to be by virtue of its effects on CNS depression, vasodilation, and blunting of behavioral P.258 responses to cold. However, thermoregulatory dysfunction associated with ethanol intoxication is undoubtedly more complex.

TABLE 16-2. Effects of Xenobiotics that Predispose to Hypothermia

Impaired

nonshivering

thermogenesis

β-Adrenergic antagonists Cholinergics Hypoglycemics Impaired perception of cold Carbon monoxide Ethanol Hypoglycemics Opioids Sedative-hypnotics Impaired shivering Carbon monoxide

by

hypothalamic

depression

Ethanol General anesthetics Opioids Phenothiazines Sedative-hypnotics Impaired vasoconstriction α-Adrenergic antagonists Ethanol Phenothiazines

In animal models, ethanol leads to hypothermia, the extent of which is partly dependent on ambient temperature.224,245,246 In mice, as the dose of ethanol increased, body temperature decreased and the rate of this decline in body temperature was faster at higher ethanol doses.219 The decline in body temperature could be reversed by increasing ambient temperature; increasing ambient temperature to 96.8°F (36°C) caused an immediate rise in the body temperature.219 The poikilothermic effect of ethanol was not a result of hypoglycemia. Poikilothermia is the variation in body temperature greater than ±3.6°F (±2°C) on exposure to environmental temperature changes. Rats treated with equipotent amounts of sodium pentobarbital showed the same effects on body temperature as rats treated with ethanol, suggesting a similar central mechanism of central nervous system depression resulting in altered thermoregulation.219 Numerous mechanisms are involved in the “ethanol-induced depression of central nervous system function.―250 Genetic factors influence the role of ethanol in the production of hypothermia. Mouse strains bred for sleep times differed in sensitivity to the effect of ethanol on temperature.103,210,219 Mice can be selectively bred for genetic sensitivity or insensitivity to acute ethanol-induced hypothermia, and the differences appear to

be mediated by the serotonergic systems.90 Histidyl-proline diketopiperazine (cyclo His-Pro or CHP), another neurotransmitter that is found in many animal species, acts at the preoptic-anterior hypothalamus to modulate body temperature.42,137 Exogenous administration of this neuropeptide produced a dose-dependent decrease in ethanol-induced hypothermia. Attenuation of hypothermia resulted from passive immunization with CHP antibody.42,137 Ethanol effects may be mediated through modulation of endogenous opioid peptides, as high-dose (10 mg/kg) naloxone reverses ethanol-induced hypothermia in animals.234 Pharmacokinetic characteristics of ethanol metabolism change in the presence of hypothermia. Hypothermic piglets infused with ethanol showed slower ethanol metabolism and a smaller volume of distribution and, as a result, higher ethanol levels than normothermic controls. Ethanol elimination and metabolism decreased as temperature fell.165 Tolerance develops to the effect of ethanol in producing hypothermia in all species.92,224 The degree of tolerance is proportional to the dose and duration of treatment with ethanol and is not explained by the increased rate of metabolism with chronic exposure.144 Age is a factor in the development of tolerance; older animals do not display the same degree of tolerance to the hypothermic effects of chronic ethanol administration as do younger animals.216,233,307 The development of tolerance to ethanol-induced hypothermia is affected by genetic factors. Experimentally, tolerance to ethanol-induced hypothermia increases the incorporation of certain amino acids into proteins in the rat brain. The formation of new proteins in ethanol-tolerant rats suggests stimulation of gene expression related to the tolerant state.144,295 Deficits in N-methyl-D-aspartate (NMDA) receptor systems may also be implicated in the development of ethanol tolerance. In addition, altered nicotinamide adenine dinucleotide (NADH) oxidation to NAD+, diminished blood flow to

the liver, or slowing of metabolism through the microsomal enzyme system may be involved.250 Hypothermia alters the breath—ethanol partition in the alveolus, and the temperature of expired breath alters breath-alcohol analysis results. In patients with mild hypothermia, ethanol breath analysis results in lower values by 7.3% per degree centigrade (or 1.8°F) decrease in body temperature.95 Whether breath-alcohol analysis is also affected by hyperthermia in the test subject remains to be studied.95

Disease Processes Thermoregulation

and

Many disease processes interfere with normal thermoregulation, limiting an individual's capacity to prevent hypothermia or hyperthermia. Extensive dermatologic disease or cutaneous burns impair sweating and vasomotor responses to heat stress. 37 Patients with autonomic disturbances such as diabetes or peripheral vascular disease also have altered vasomotor responses that impair vasodilation and sweating.243 Extensive surgical dressings may preclude the evaporation of sweat in an otherwise normal patient. Heat-stressed persons with poor cardiac reserve may not be able to sustain a skin blood flow high enough to maintain normothermia.77,276 Intense motor activity may lead to excessive endogenous heat production in patients with Parkinson disease or hyperthyroidism. Patients with agitated delirium or seizures also have significantly elevated rates of endogenous heat production. Hypothalamic injury caused by cerebrovascular accidents, trauma, or infection may disturb thermoregulation.76,183 Hypothalamic dysfunction can lead to high, unremitting fevers and insufficient stimulation of heat loss mechanisms such as sweating. Hypothalamic damage may predispose to hypothermia by interference with centrally mediated heat conservation.76,183,258,259 Fever, the normal response to

stimulation of the hypothalamus by pyrogens, results in an elevated physiologic temperature set point and is a disadvantage in the heat-stressed individual.128 P.259

Hypothermia Epidemiology Hypothermia is defined as an unintentional lowering of the core body temperature to Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 17 - Fluid, Electrolyte, and Acid–Base Principles

Chapter

17

Fluid, Electrolyte, and Acid–Base Principles Alan N. Charney Robert S. Hoffman A meaningful analysis of fluid, electrolyte, and acid–base abnormalities must be based on the clinical characteristics of each patient. Although a rigorous appraisal of laboratory parameters often yields the correct differential diagnosis, essential information concerning extracellular fluid volume (ECFV), pathophysiology, and treatment may only be gained from the history and physical examination. Thus, the evaluation always begins with an overall assessment of the patient's status.

Initial

Patient

Assessment

History The history should include clinical complaints associated with fluid

and electrolyte abnormalities. Common manifestations of xenobiotic exposure result in fluid losses through the respiratory system (hyperpnea and tachypnea), gastrointestinal tract (vomiting and diarrhea), skin (diaphoresis), and kidneys (polyuria). Patients with ECFV depletion may complain of dizziness, thirst, and occasionally polydipsia, and usually the patients can identify the source of fluid loss. A history of exposures to nonprescription and prescription medications, alternative therapies and other xenobiotics may suggest the most likely electrolyte or acid–base abnormality. In addition, premorbid conditions and the ambient temperature and humidity should always be considered.

Physical

Examination

The vital signs are invariably affected by gross alterations in ECFV. Whereas hypotension and tachycardia may herald life-threatening ECFV depletion, an initial increase of the heart rate and a narrowing of the pulse pressure may be earlier findings. Abnormalities may be recognized through an ongoing dynamic evaluation, realizing that the measurement of a single set of supine vital signs offers useful information only when grossly abnormal. The addition of orthostatic pulse and blood pressure measurements provides a more meaningful determination of functional ECFV status (Chaps. 3 and 2 3) . The respiratory rate and pattern can give clues to the patient's metabolic status. Hyperventilation (manifested by tachypnea, hyperpnea, or both) may be caused by a primary respiratory stimulus (a respiratory alkalosis) or may be a response to the presence of metabolic acidosis. Although hypoventilation (bradypnea or hypopnea or both) is present in patients with metabolic alkalosis, it is rarely clinically significant except in the presence of chronic lung disease. More commonly, it is associated with a primary depression of consciousness and respiration, and

respiratory acidosis. Unless the clinical scenario (eg, nature of the overdose or poisoning, presence of renal or pulmonary disease, findings on physical examination or laboratory testing) is diagnostic, arterial blood gas analysis is required to determine the acid–base disorder associated with a change in ventilation. The skin should be evaluated for turgor, moisture, and the presence or absence of edema. The moisture of the mucous membranes can also provide valuable information. These are nonspecific parameters and may not correlate perfectly with the status of hydration. This dissociation is especially true with xenobiotic exposure, as many xenobiotics alter skin and mucous membrane moisture without necessarily altering ECFV status. For example, antihistamines and anticholinergics commonly dry mucous membranes and skin without producing ECFV depletion. Conversely, patients exposed to sympathomimetic agents (eg, cocaine) or cholinergic agents (eg, organic phosphorus insecticides) may have moist skin and mucous membranes even in the setting of significant fluid losses. These dissociative characteristics further reinforce the need to assess patients meticulously. The physical findings associated with electrolyte abnormalities also are nonspecific. Hyponatremia, hypernatremia, hypercalcemia, and hypermagnesemia all may produce a depressed mental status. Neuromuscular excitability such as tremor and hyperreflexia may occur with hypocalcemia, hypomagnesemia, hyponatremia, and hyperkalemia. Multiple, concurrent electrolyte disorders can produce confusing clinical presentations, or patients may appear normal. Rarer diagnostic findings, such as Chvostek and Trousseau signs (primarily found in hypocalcemia), may be useful in assessing patients with potential xenobiotics exposures.

Rapid

Diagnostic

Tools

The electrocardiogram (ECG) is a useful tool for screening of some

common electrolyte abnormalities (Chap. 5). It is easy to perform, rapid, inexpensive, and routinely available. Unfortunately, P.279 because poor sensitivity (0.43) and moderate specificity (0.86) were demonstrated when ECGs were used to diagnose hyperkalemia, in actuality, the test is of limited diagnostic value.173 However, the ECG is valuable for the evaluation of changes in serum potassium and calcium concentrations ([K+ ] and [Ca2 +]) in a single patient. In many patients, bedside assessment of urine specific gravity by dipstick analysis may provide valuable information about ECFV status. A high urine specific gravity (>1.015) signifies concentrated urine and is often associated with ECFV depletion. However, urine specific gravity may be similarly elevated in states of ECFV excess, such as congestive heart failure or third spacing. Furthermore, when renal impairment is the source of the volume loss, the specific gravity is usually ≤1.010 (known as isosthenuria). Patients with lithium-induced diabetes insipidus excrete dilute urine (specific gravity 1.015) in the presence of a normal to high ECFV status. The urine dipstick is particularly useful for rapidly determining the presence of ketones, which are often associated with specific toxicologic problems and common causes of metabolic acidosis (eg, diabetic ketoacidosis, salicylate poisoning, alcoholic ketoacidosis). The urine ferric chloride test rapidly detects exposure to salicylates with a high sensitivity and specificity (Chap. 35) .

Laboratory

Studies

A simultaneous determination of the venous serum electrolytes,

blood urea nitrogen (BUN), and glucose, and arterial or venous blood gases is adequate to determine the nature of the most common acid–base, fluid, and electrolyte abnormalities. More complex clinical problems may require determinations of urine and serum osmolalities, urine electrolytes, serum ketones, serum lactate and other tests. A systematic approach to common problems is discussed in the following sections.

Acid–Base

Abnormalities

Definitions The terminology of acid–base disorders often leads to confusion and error. The following definitions provide the appropriate frame of reference for the remainder of the chapter. The terms acidosis and alkalosis refer to processes that tend to change pH in a given direction. By definition a patient is said to have: A metabolic

acidosis if the patient's arterial pH is 24

mEq/L. A respiratory alkalosis if the patient's arterial pH is >7.40 and PCO2 is Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 19 - Neurologic Principles

Chapter

19

Neurologic

Principles

Rama B. Rao The central nervous system (CNS) coordinates responses to the fluctuating metabolic requirements of the body and modulates behavior, memory and higher levels of thinking. These functions require a diversity of cells: astrocytes, neurons, ependymal cells, and vascular endothelial cells. Disruption or death of any one cell type can cause critical changes in the function or viability of another. This cellular interdependence along with the high metabolic demands of the central nervous system, make neurons especially vulnerable to injury from both endogenous neurotoxins and xenobiotics. Endogenous neurotoxins like the metals iron, copper and manganese, are substances which may be critical to CNS function, but are harmful when their penetration into the CNS is poorly controlled. The understanding of the normal chemical and molecular functions of the CNS is limited at best. Interestingly normal cellular mechanisms have sometimes been revealed by investigating xenobiotic induced neuronal injuries.167 For example, the

pathophysiology of Parkinson disease, which affects movement and motor tone, was elucidated by the inadvertent exposure of individuals to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The mechanisms of axonal transport were elucidated by investigations of the effects of acrylamide exposures in human and animal models.141 The neurodegenerative changes of amyotrophic lateral sclerosis has a promising xenobiotic model in βmethylamino-L-alanine (BMAA), a neurotoxin found in the cyanobacteria associated with cycad plants ingested by the Chamorro people of Guam.69 There are few minimally invasive methods available to investigate xenobiotic-induced CNS injury. Biomarkers are usually nonspecific and not readily available. Xenobiotic concentrations in blood and urine rarely reflect tissue concentrations of the central nervous system.145 Cerebrospinal fluid may be useful in excluding CNS injury from infection, hemorrhage, and inflammatory processes, but is, with few exceptions, poorly reflective of the mechanisms of neuronal injuries.224 Similarly, electroencephalograms and electromyelograms are useful in only a few types of xenobiotic exposures, and neuroimaging, while progressively evolving,132 is a poor substitute for neuroanatomic evaluations that are usually only available on autopsy. Much of the current study to elucidate the mechanisms of CNS injury uses animal models, cultured astrocytes and other tissue, or postmortem investigations. Less commonly, occupational evaluations, such as the enzyme activity of cholinesterases in pesticide workers, are employed. This is not a comprehensive chapter on all neurotoxic compounds and the status of their associated investigations. Instead, the concept of excitotoxicity is introduced, as are the common mechanisms by which xenobiotics exploit the functional and protective components of the CNS, with a few relevant examples. The multiple factors determining the clinical expression of neurotoxicity are reviewed. Finally, a special section on the delivery and complications of intrathecal xenobiotics is included.

Chap. 14 offers a detailed review of neurotransmitters.

Neurons: Classification, Infrastructure, and Functional Pathways Neurons are the major route of cellular communication in the CNS. Having one of the highest metabolic rates in the body, these cells are especially sensitive to changes in the microenvironment and are dependent on astrocytes, choroidal epithelium, and capillary endothelium to confer protection and deliver glucose and other sources of energy. Although each neuron is capable of receiving information through different neurotransmitters and receptor subtypes at the dendrite, neurons typically produce and release a single type of neurotransmitter at the axonal terminal. This specificity allows for cellular classification of neurons based on the neurotransmitter released, for example, serotonergic, cholinergic, and dopaminergic neurons (Chap. 14 ). Other substances that are less specific to the neuron type, such as adenosine, may also be produced and released. The anatomic structure of neurons facilitates their function. Dendrites located on the cell body are lined with receptors that bind neurotransmitters and affect cellular changes via several mechanisms. The soma, or cell body is responsible for coordination and production of multiple proteins required to carry out normal physiologic functions. This synthesis occurs at a rate several times greater than the liver or kidney. These proteins, organelles, and substrates must then be transported across long distances to the terminal axon. This energy-dependent function is supported by a cytoskeleton comprised of neurofilaments, microfilaments, microtubules, and complex transport proteins. Fast anterograde transport of membrane-bound organelles occurs through kinesin at a rate of 200–400 mm per day. Channel proteins, synaptic

vesicles, mitochondria, Na+ -K+ -adenosine triphosphatase (ATPase), glycolipids, and other substances are transported by kinesin. Slow anterograde transport also occurs at a substantially slower rate (0.5–4 mm/d). The retrograde transport protein dynein is produced in the soma P.308 and delivered to the nerve terminal for the movement of larger vesicles and reusable proteins back to the cell body. In the CNS, groups of neurons are organized into complex functional pathways, with a single class of neuron regulating different functions and clinical effects depending on the brain region affected. As an example, dopaminergic neurons regulate cravings, movement, and resting muscle tone, each of which is determined not only by dopaminergic neurons and receptor subtype, but the part of the cortex or basal ganglia specifically affected (Chap. 14 ). Neurons must be able to respond to changes in the local environment and alter the expression of different receptors in response to signaling from neurotrophic factors, variations in metabolic requirements, and xenobiotic interactions. This “neuroplasticity― accounts for the diversity of clinical responses to substances that induce tolerance to xenobiotics such as ethanol (Chap. 15 ).

Glial

Cells

Astrocytes, Microglia

Oligodendrocytes,

Astrocytes comprise between 25% and 50% of the brain volume.159 In addition to the anatomic contribution to the blood–brain barrier (BBB), astrocytes play a critical role in maintaining neuronal function.4 , 5 , 209 They contribute to three

major areas: homeostasis of the extraneuronal environment, provision of energy substrates, and limitation in oxidative stress. In addition, astrocytes contribute to the “plasticity― of cells and receptor expression in the CNS. For cells of all types to function in the CNS, membrane potentials must be adequately maintained. Astrocytes contribute to this by closely regulating the extracellular pH, free water, and, like brain capillaries, the extracellular potassium concentration. Metallothioneins, which control the entry of heavy metals necessary for CNS function, are produced by astrocytes.62 , 239 T o further support CNS functions, astrocytes release energy substrates such as lactate, citrate, alanine, glutathione and αketoglutarate for use by neurons.25 Astrocytes metabolize glutamate, the main excitatory neurotransmitter in the CNS, and ammonia. These cells also produce superoxide dismutase and glutathione peroxidase to reduce free radical propagation. Glutathione, the major antioxidant for the brain, is predominantly located in the astrocytes. It can be released into the extracellular space or cleaved for neuronal uptake and intracellular reformulation.25 Through the release of complex trophic factors, astrocytes control the expression of endothelial transporters of the BBB and the production of tight junctions in both the blood–cerebrospinal fluid barrier (B-CSFB) and BBB. Angiogenesis is similarly astrocyte regulated, as is detection of neuronal injury, immune mediation, and neurotransmitter production. The growth of neurites, the branches of neuronal cell bodies that eventually become dendrites or axons, are similarly modulated by astrocytes. Oligodendrocytes are a type of glial cell that provide anatomic support, protective insulation, and facilitate rapid neuronal depolarization by the production of myelin. Myelin is the primary constituent of white matter in the CNS. The production of myelin in the peripheral nervous system is performed by the Schwann

cells. Finally, microglial cells, another type of glial cell, modulate immune response, inflammation, and tissue repair from a variety of CNS injuries. Like neurons, microglia are dependent on signaling from astrocytes.

Neuroprotective

Mechanisms

The nervous system has multiple neuroprotective mechanisms. Xenobiotics are prevented from accessing the CNS by the blood–brain and blood–CSF barriers. For xenobiotics that enter the CNS, there are multiple cellular specializations to limit oxidant stress. These protective mechanisms are reviewed in the following sections.

Blood–Brain

Barrier

The BBB confers an anatomic and enzymatic barrier to xenobiotic entry into the CNS. Brain capillaries are surrounded by the foot processes of adjacent astrocytes. The potential spaces between endothelial cells are limited by tight junctions, or zonulae occludens, which are between 50 and 100 times tighter than those found on peripheral capillaries.3 , 4 a n d 5 , 126 This anatomic barrier prevents movement of substances between cells, also known as the paracellular aqueous pathway, as a result of osmotic and oncotic forces.3 , 4 a n d 5 , 126 , 156 Trans-endothelial movement of critical substrates and, potentially, xenobiotics, occurs through three major mechanisms: diffusion, transport proteins, and endocytosis.3 , 4 These routes allow carefully controlled entry of critical substrates and cofactors while limiting the potential for injury from either endogenous or exogenous neurotoxins. Lipophilic substances may move directly across the luminal and abluminal endothelial membranes abutting the central nervous

system. Other substances may enter the endothelium through bidirectional transport proteins on the luminal surface. These proteins may be specific, such as the GLUT-1 protein for uptake of glucose, or less-specific large neutral amino acid transporters (LNAAs) which move amino acids and xenobiotics, such as baclofen, intracellularly. These transporters also line the abluminal surface of the endothelial cell for movement of substrates and xenobiotics into the CNS. The third line of entry for larger proteins is via endocytosis. This can be either adsorptive or mediated through specific receptors such as insulin or transferrin.3 , 4 a n d 5 , 126 , 156 , 239

Endothelial cells have other protective properties including intracellular enzymes to metabolize xenobiotics, and efflux proteins to transport certain xenobiotics back into the capillary lumen. These efflux proteins include energy dependent Pglycoproteins which are adenosine triphosphate (ATP)-binding cassette transporters and are sometimes referred to as multidrugresistant (MDR) proteins. Several hydrophobic xenobiotics are prevented from accumulating in the CNS through these transporters, including vinca alkaloids, digoxin, cyclosporine, and protease inhibitors. Nonsedating antihistamines may have limited sedative properties due, in part, to efflux though P-glyproteins.58 Another type of saturable transporter, know as organic acid transport (OAT) protein, facilitates the efflux of hydrophilic xenobiotics such as valproic acid and baclofen. The expression of each of these transporters may be upregulated under certain conditions such as intermittent disruptions in the BBB from seizures. This expression upregulation is theorized to account for the resistance of anticonvulsant medications in patients with epilepsy. Comprehensive lists of xenobiotics that are substrates for these transporters are available elsewhere.3 , 126

Blood–CSF

Barrier

The ventricles of the brain are lined by the epithelial cells of the choroid. These cells also have tight junctions, but they are not as extensive as those of the BBB. They are, however, rich in glutathione peroxidase and other xenobiotic P.309 metabolizing enzymes in concentrations approximating that of the liver. Similar to brain capillary cells, the choroid contains efflux transporters for organic anions and cations, as well as MDR efflux proteins to limit entry of xenobiotics into the CSF.3 , 5 , 126 , 239

Excitotoxicity Neuronal function is strictly dependent on aerobic metabolism with an adequate supply of substrates and functioning mitochondria for the production of ATP. When energy expenditure exceeds production, cellular dysfunction and ultimately, cell death or apoptosis, results. The specific cascade of molecular events relating to this process is termed excitoxicity .24 , 187 The initial event is traced to an oxidant stress and excessive stimulation of N -methyl-D-aspartate (NMDA) receptors by glutamate, an excitatory amino acid neurotransmitter. An influx of intracellular calcium changes membrane potentials across the cellular and mitochondrial membranes. The mitochondria become progressively more inefficient at ATP production and handling the resulting reactive oxygen species. As membrane damage is propagated, calcium further depolarizes the mitochondria, activating a permeability transition pore across the mitochondrial membrane. Gradients are further disrupted, precipitating more injury, energy failure, and ultimately, cell death. Excitotoxicity is considered a common mechanism of cell death as a consequence of xenobiotic, ischemic, traumatic, infectious, neoplastic, or neurodegenerative injury. It is the subject of study for many therapeutic interventions in central nervous system injury.

Determinants

of

Neurotoxicity

The clinical expression of neurotoxicity is related to many factors, including the chemical properties of the xenobiotic; the dose and route of administration; xenobiotic interactions; and underlying patient characteristics including age, gender, and comorbid conditions (Table 19-1 ).

Chemical

Properties

of

Xenobiotics

An important determinant of neurotoxicity is the capability of a xenobiotic to penetrate the BBB. Water-soluble molecules larger than M r 200–400 (molecular weight ratio, or mass of a molecule relative to the mass of an atom) are unable to bypass the tight junctions.3 Xenobiotics with a high octanol-to-water partition coefficient are more likely to passively penetrate the capillary endothelium, and potentially the BBB, whereas those with a low partition coefficient may require energy-dependent facilitated transport.156 Xenobiotics that are substrates for capillary endothelial efflux mechanisms will have limited penetration regardless of the coefficient.3 , 5 , 126 , 239 Chemical properties of xenobiotics Route of administration Xenobiotic interactions Altered CNS penetration Clinical synergy Enhanced concentration Excessive neurotransmitter availability Patient characteristics Age and gender Comorbidities Alterations in receptor function or expression Conditions affecting BBB integrity

Nutritional status Extraaxial organ dysfunction Enhanced sensitivity to xenobiotics Production of endogenous neurotoxins Undiagnosed diseases TABLE 19-1. Determinants of Neurotoxicity

Route

of

Administration

The route of xenobiotic administration may also be consequential. Whereas most xenobiotics gain access to the nervous system through the circulatory system, aerosolized solvent and heavy metals in industrial and occupational exposures gain CNS access through inhalation, traveling via olfactory and circulatory routes. Alternatively, some agents may move from the peripheral nervous system via retrograde axonal transport to the CNS. Naturally occurring proteins such as tetanospasmin, rabies, polio, and herpes viruses use this mechanism to access the peripheral and central nervous system. 29 , 35 , 112 The toxalbumins ricin and abrin, as well as bismuth salts may also use this mechanism to a limited extent.208 , 230 This understanding may prove beneficial from a therapeutic perspective. For example in one small series of patients experiencing severe pain, doxorubicin was injected into the involved peripheral nerves. Therapeutically, a chemical ganglionectomy occurred through retrograde “suicide― transport of doxorubicin, providing substantial relief in these patients in this experimental therapy.122 Some xenobiotics may be delivered directly into the CSF (intrathecally), the consequences of which are variable. See Special Considerations: Intrathecal Xenobiotic Administration.

Xenobiotic

Interactions

Coadministration of xenobiotics may precipitate neurotoxicity by several mechanisms.110 Extraaxially (outside of the CNS), xenobiotic interactions that increase the blood concentration of one or both agents may overwhelm the protective mechanisms of the BBB.46 Similar effects may occur in the peripheral nervous system (PNS), where elevated blood concentrations may have enhanced clinical effects, resulting in peripheral neuropathies.23 Xenobiotic interactions can be synergistic, acting on the same neuroreceptor with additive effects. Benzodiazepines and ethanol, for example, both stimulate the γ-aminobutyric acid type A (GABAA ) receptor.31 The excessive neuroinhibition can result in deep coma and even respiratory depression when these agents are administered together. In some circumstances, xenobiotic interactions result in excessive neurotransmitter availability. This is demonstrated in patients with the serotonin syndrome, the result, for example, of coadministration of a monoamine oxidase inhibitor and a serotonin reuptake inhibitor or other serotonergic agent (Chap. 70 ). Access to the CNS may be altered by one of the xenobiotics, allowing the other to bypass the BBB. For example, mannitol causes transient opening of the BBB; as a result,127 therapeutic use of mannitol is under investigation for the delivery of antineoplastic agents that might otherwise be unable to access the nervous system.127 Similarly, some xenobiotics, such as verapamil, cyclosporine, and probenecid, are blockers of capillary endothelium efflux. 3 , 239 These theoretically limit efflux of other substrates of P-glycoprotein or OAT. The clinical usefulness of employing such efflux blockers P.310 is under investigation as was done in a study in which primates received intrathecal methotrexate. The CSF clearance was reduced in animals administered intrathecal probenecid.27 , 192

Patient

Characteristics

Age Patient-specific variables may affect either the ability of a xenobiotic to penetrate the BBB and/or the clinical effects of a given exposure. For example, age of the patient at the time of exposure is critical, especially in the fetus and neonates.194 The structural and enzymatic development of the blood–brain barrier is incomplete and synaptogenesis, or formation of intercellular relationships, is especially sensitive to impaired protein synthesis or other excitotoxic events. This is demonstrated classically by maternal exposure to methylmercury. The mother may be minimally affected, but the developing fetus suffers profound neurologic and developmental consequences (Chaps. 30 and 9 2 ). In neonates, immature liver function may lead to the accumulation of circulating bilirubin. Because of incomplete formation of the blood–brain barrier, the bilirubin may access the central nervous system and produce a form of encephalopathy known as kernicterus. Elderly patients may also have increased susceptibility to neurotoxins as a result of relatively impaired circulation or agerelated changes in mitochondrial function that predispose to excitotoxicity. 201 Xenobiotic-induced parkinsonism, or the unmasking of subclinical idiopathic Parkinson disease may occur more readily in older than in younger patients. Animal models also suggest age-related sensitivity, with one study noting increased toxicity to manganese as the animals age. 83

Gender The role of gender in expression of xenobiotic-induced neurologic injury is potentially contributory. In animal models, the presence of estrogen- and progesterone-related compounds may be

neuroprotective for some xenobiotic injuries.159 , 179 In humans, females are more susceptible to some movement disorders, such as drug-induced parkinsonism and tardive dyskinesia, whereas dystonias and bruxism are more prevalent in young male patients.188 The etiologies of these gender-related differences are incompletely understood.

Comorbidities Conditions affecting the integrity of the blood–brain barrier can affect CNS penetration of xenobiotics and endogenous neurotoxins. For example, glutamate concentrations are normally higher in the circulatory system than the CNS.140 Patients with trauma, ischemia, or lupus vasculitis2 may experience neuropsychiatric disorders as a result of increased penetration of glutamate or sensitivity to additional xenobiotics. Similarly, meningitis and encephalitis cause openings in the BBB, which can be exploited to enhance therapy. Intravenous penicillin achieves a higher CSF concentration in animals with meningeal inflammation than in animals without meningitis.193 In some patients, previously undiagnosed diseases become evident on exposure to xenobiotics. This is especially true in patients with peripheral neuropathies. For example, patients being treated with therapeutic doses of vincristine suffered a severe polyneuropathy as a result of unmasking of a previously undiagnosed CharcotMarie-Tooth disease.54 Similarly, patients with diabetes mellitus, which is the most common cause of peripheral neuropathy, or HIV disease may have exacerbation of symptoms in the presence of antiretroviral agents.56 , 181 Patients with myasthenia gravis may have exacerbation of weakness with aminoglycoside administration, which can affect transmission at the neuromuscular junction.235 Chronic exposures to some neuroinhibitory xenobiotics such as ethanol may alter neuronal receptor expression and

“upregulate― or increase the amount of receptors for excitatory amino acids. In addition to receptor augmentation, neurotransmitter concentrations of the excitatory neurotransmitters glutamate and aspartate are increased, as is homocysteine. These changes induce a tolerance to neuroinhibitory xenobiotics acting on the same receptor, and patients require escalating doses to achieve the same clinical effect. In such patients, cessation of ethanol intake results in a relative deficiency of exogenous inhibitory tone. The patient experiences neuroexcitability and the clinical syndrome of withdrawal (Chap. 1 5 ). 38 , 39 Adequate nutritional status is important for the maintenance of normal neurologic function. The BBB may not be adequately maintained in patients with malnutrition. Deficiencies of heavy metal cofactors such as manganese, copper, zinc, and iron can affect neurologic function. In some cases, the deficiencies enhance absorption of other xenobiotics. For example, iron deficiency enhances lead and manganese absorption in the gastrointestinal tract, which can ultimately overwhelm neuroprotective mechanisms. Vitamins serve as enzymatic cofactors in modulating the production of glutamate, homocysteine, and other amino acids. Specific vitamin deficiencies can precipitate neurologic syndromes such as Wernicke encephalopathy in thiamine-depleted patients (see Antidotes in Depth: Thiamine Hydrochloride and Chap. 41 ). The toxicity of xenobiotics may also be enhanced. For example, a relative pyridoxine deficiency in patients with acute isoniazid overdose may result in seizures as a result of a relative excess of excitatory amino acids (see Antidotes in Depth: Pyridoxine and Chap. 55 ). Glucose is a critical energy substrate that can cause profound neurologic impairment when delivery is inadequate (see Antidotes in Depth: Dextrose and Chap. 48 ).

Extraaxial

Organ

Dysfunction

Renal failure may impair metabolism of xenobiotics or endogenous neurotoxins such as urea, rendering it more available to the central nervous system. Hyperglycemia in patients with diabetes mellitus may also increase formation of CNS-reactive oxygen species. Similarly, patients with liver failure may have elevations in CNS manganese. Hepatic encephalopathy illustrates the concept of excitotoxicity from endogenous neurotoxins. Hyperammonemia increases oxidative stress and free radical formation in astrocytes. Ammonia potentially decreases critical metabolic enzymes such as catalases, superoxide dismutase, and glutathione peroxidase. Nitric oxide (NO) production is increased as a result of elevations in NO synthetase. Under these conditions, astrocytes upregulate the expression of the peripheral benzodiazepine receptor (PBR) on the outer mitochondrial membrane. The PBR modulates the production of neurosteroids and, in turn, the GABAA receptor. Continued CNS exposure to ammonia and other endogenous solutes propagates this oxidative and nitrosative stress to the mitochondrial membrane, potentially opening the mitochondrial permeability transition pore (channel). Osmotic swelling of the mitochondrial membrane followed by excitotoxicity results in cerebral edema, which

produces

hepatic

encephalopathy.160 , 161 P.311

Mechanisms

of

Neurotoxicity

Alteration of Endogenous Neurotransmission Xenobiotics can induce neurotoxicity by triggering changes in neurotransmission in either the central or peripheral nervous systems. In some cases, xenobiotics enhance neurotransmission through a specific receptor subtype. This enhanced transmission

can occur through inhibition of presynaptic metabolism (monoamine oxidase inhibitors), stimulation of neurotransmitter release (amphetamines), impairment of neurotransmitter reuptake (cocaine), or inhibition of synaptic degradation (acetylcholinesterase inhibitors). Alternatively, synaptic neurotransmission may be impaired.198 Xenobiotics may inhibit the presynaptic release of neurotransmitters (botulinum toxin), block receptors (antimuscarinics) or alter membrane potentials at the postsynaptic membrane (tetrodotoxin).75 , 78 Patients may present with a clinical syndrome of toxicity associated with altered neurotransmission of the specific receptor (Chap. 3 ).

Direct

Receptor

Interaction

Some xenobiotics are able to directly stimulate receptors. Both kainate and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) are subclasses of the glutamate receptors that are targeted by some naturally occurring xenobiotics.101 An example is β-N -oxalylamino-L-alanine (BOAA) found in the grass pea, Lathyrus sativus. BOAA stimulates the AMPA and inhibits specific mitochondrial enzymes resulting in the spastic paraparesis of lathyrism.169 Domoic acid stimulates the kainate receptor and causes the neuroexcitation associated with neurotoxic shellfish poisoning. Direct inhibition is also possible, as exemplified by phencyclidine, an NMDA (N -methyl-D-aspartate) receptor antagonist.

Enzyme

and

Transporter

Exploitation

The classic example of xenobiotics that exploit endogenous enzymes and/or transporters is MPTP.92 Once MPTP crosses the BBB, it is converted by monoamine oxidase to the neurotoxic compound MPP+ (1-methyl-4-phenylpyridine) in astrocytes. MPP+

is taken up by dopamine transporters into the neurons of the substantia nigra pars compacta. MPP+ inhibits complex I of the mitochondrial electron transport chain resulting in dopaminergic excitotoxicity and the clinical syndrome similar to Parkinson disease (see Disorders of Movement and Tone below and Chap. 38 ).

Altered

Conduction

Demyelinating

Along

Membranes:

Neurotoxins

Aside from xenobiotics that affect neurotransmission at the postsynaptic membrane, some affect the production or maintenance of myelin by oligodendrocytes and Schwann cells.55 , 79 , 90 , 115 In the central nervous system, these are often associated with white matter abnormalities and a leukoencephalopathy.79 Agents such as hexachlorophene, arsenic, inhibitors of tumor necrosis factor-α, neural tissue-derived rabies vaccine, and the act of “chasing the dragon― or inhaling volatilized heroin are associated with a demyelinating neurotoxicity.55 In the peripheral nervous system, nitrous oxide, suramin, and tacrolimus are associated with peripheral demyelination (Table 19-2 ). 111

Inhibition

of

Intracellular

Functions

Some xenobiotics are nonspecific inhibitors of cellular function.64 The neurotoxicity of substances such as carbon monoxide (CO) or cyanide can result in diffuse dysfunction or, depending upon the dose and specific vulnerabilities of an exposed patient, be more focal. For example, patients surviving CO exposure may experience delayed neurologic sequelae that is a diffuse impairment of neuropsychiatric function, or more focally, present with a xenobiotic induced Parkinson syndrome (see below and Chap. 120 ).

Alterations in endogenous neurotransmission Alterations in membrane conduction Direct receptor interactions Exploitation of enzymes and transporters Inhibition of intracellular function Inhibition of neuronal transport Inhibitors of protein production Mitochondrial inhibitors TABLE 19-2. Mechanisms of Neurotoxicity Chemotherapeutic agents can affect the production of critical proteins required for cellular maintenance. These can be very specific, such as the ability of vincristine to impair cytoskeletal transport in the peripheral nervous system (Chap. 52 ).

Clinically Relevant Conditions Alterations

in

Xenobiotic

Mediated

Consciousness

The toxicologic differential diagnosis of xenobiotics that induce alterations in mental status or consciousness is expansive. These xenobiotics can be broadly divided into those agents that produce some form of neuroexcitation, and those that produce neuroinhibition. While some agents, such as phencyclidine, have elements of both, depending on dose, this categorization facilitates a general clinical understanding of neurotoxic alterations in mental status. Xenobiotics resulting in neuroexcitation are agents that enhance neurotransmission of excitatory amino acids (EAAs), or diminish inhibitory input from GABAergic neurons. The clinical presentation of the patient can vary, therefore some patients may be alert and

confused, suffering from an agitated delirium, hallucinations or a seizure. Neuroinhibitory xenobiotics typically enhance GABA-mediated neurotransmission. These patients may be somnolent or in deep coma. Benzodiazepines hyperpolarize cells by increasing inward movement of Cl- ions through the chloride channel of the GABAA receptor complex. This hyperpolarization limits subsequent neurotransmission. Less commonly, neuroinhibition is a result of diminution of EAAs. Patients presenting the day after bingeing on cocaine may be sleepy but arousable and oriented in what is termed cocaine “washout,― theoretically related to depletion of EAAs and dopamine. Xenobiotics that cause diffuse cortical dysfunction through impairment in the delivery or use of oxygen or glucose can also present with depressed or altered consciousness. Clinical evaluation of patients with altered consciousness includes obtaining a complete history, including medications, comorbid conditions, occupation, and suicidal intent, when relevant or available. Patients should have a complete physical examination, with particular attention to vital sign abnormalities or findings that may indicate a toxic syndrome. Assessment and correction of hypoxia or hypoglycemia should be performed. An electrocardiogram may be useful in some circumstances (Chaps. 5 and 2 3 ). P.312

Xenobiotic-Induced

Seizures

Seizures are the most extreme form of neuroexcitation. As with alterations of consciousness, this may be a result of enhanced excitatory amino acid neurotransmission (domoic acid, sympathomimetics) or of inhibition of GABAergic tone (isoniazid). Unlike patients with traumatic or idiopathic seizure disorders who have an identifiable seizure focus, the initiation and propagation of xenobiotic-induced seizures is diffuse. It is for this reason that

most non–sedative-hypnotic anticonvulsants such are unlikely to be effective in seizure termination.

as

phenytoin,

Status epilepticus is variably defined, but involves 2 or more seizures without a lucid interval, or continuous seizure activity for greater than 15 minutes. True xenobiotic-induced status epilepticus is rare. Cicutoxin, the toxin in water hemlock (Cicuta maculata ), is a potent inhibitor of GABAA neurotransmission and may cause status epilepticus. Analgesics and nonprescription Antihistamines Caffeine Mefenamic acid Phenylbutazone Salicylates Prescription medications Antihistamines Bupropion Carbamazepine Chlorambucil Chloroquine Clonidine Digoxin Ergotamines Fenfluramine Isoniazid Lidocaine Methotrexate Phenytoin Procarbazine Quinine (cinchonism) Sulfonylureas Theophylline

(OTC)

preparations

Tramadol Psychopharmacologic medications Antiemetics Antipsychotics Cyclic antidepressants Lithium Methylphenidate Monoamine oxidase inhibitors (esp w/food or drug reaction) Opioids (propoxyphene, meperidine) Pemoline Sedative-hypnotic withdrawal Alcohols and drugs of abuse Amphetamines Cocaine Disulfiram reaction Ethanol withdrawal Ethylene glycol MDMA (methylenedioxymethamphetamine) Methanol Phencyclidine Botanicals Ackee fruit Cicutoxin Coprinus spp (disulfiramlike reaction w/alcohol) Daphne Herbal preparations (Lobelia, jimson weed, Galega , mandrake, passion flower, periwinkle, wormwood) (see Chaps. 43 , 7 7 , 114 ) Nicotine Rhododendron

Heavy metals Arsenic Copper Lead Manganese Nickel Household toxins Boric acid (chronic) Camphor Fluoride Hexachlorophene Phenol Pesticides Organochlorines (lindane) Organic phosphorous compounds Pyrethrins Rodenticides (thallium, sodium monofluoroacetate, zinc phosphide, arsenic) Tetramethylenedisulfotetramine Occupational

and

environmental

strychnine,

(TETS) toxins

Carbon disulfide Carbon monoxide Chlorphenoxy herbicides Cyanide Hydrocarbons Simple asphyxiants (methane, ethane, propane, butane, natural gas) High volatility (benzene, toluene, gasoline, naphtha, mineral spirits, light gas oil) Halogenated (carbon tetrachloride, trichloroethane) Hydrogen sulfide

Methyl bromide Toxic inhalants (simple nitrogen, nitrous oxide) Triazine

asphyxiants

producing

hypoxia—helium,

Toxic envenomation and marine animal ingestion Marine animals (Gymnothorax, saxitoxin [shellfish]) Pit viper Scorpion Tick bite (Rickettsia rickettsii ) TABLE

19-3.

Theophylline

Xenobiotic-Induced

toxicity

precipitates

Seizures

seizures

and

status

epilepticus

through a different mechanism. Normally, endogenous termination of seizures is mediated through presynaptic release of adenosine during the release of the primary neurotransmitter at the terminal axon. Adenosine functions as a feedback inhibitor of the presynaptic neuron, disrupting propagation of excitatory neurotransmission. Theophylline is an adenosine antagonist. Adenosine administration is not a useful therapy for theophyllineinduced seizures as adenosine is unable to cross the BBB. Generally high-dose sedative hypnotics, affecting receptors, are required for seizure control.

GABAA

P.313 Some clinical conditions appear to be centrally mediated tonic–clonic movements, but are caused by glycine inhibition in the spinal cord. Glycine is the major inhibitory neurotransmitter of motor neurons of the spinal cord. Under normal conditions glycine contributes to termination of reflex arcs. Glycine inhibition results in myoclonus, hyperreflexia and opisthotonos, often without alteration in consciousness. Presynaptic glycine inhibition is caused by tetanospasmin, the major neurotoxin from Clostridium tetani. Postsynaptic glycine inhibition is caused by strychnine, the

toxin in Strychnos nux-vomica. Patients with exposures to these agents are often treated in quiet environments where the stimuli to propagate hyperreflexia are minimized (Chap. 108 and Table 19-3 ).

Xenobiotic-Induced

Mood

Disorders

Certain xenobiotics are inconsistently associated with alterations in mood.6 , 40 What predisposes individuals to xenobiotic-induced mood alterations is unclear. In some circumstances, patients with previously undiagnosed bipolar disorder are given a xenobiotic that unmasks their disease. Interestingly antibiotic-induced mania is found in some patients without a previous psychiatric history. The symptoms of mania are usually evident within the first week of therapy, and unlike the mania of purely psychiatric origin, readily abate within 48–72 hours of the last antibiotic dose. Some patients with clarithromycin-induced mania have documented reoccurrence on rechallenge of the antibiotic (Table 19-4 ).6

Disorders of Movement and Tone Most movement disorders, including akathisia, bradykinesia, tics, dystonias, and chorea, are mediated by the complex dopaminergic pathways of the basal ganglia. Different dopamine receptor subtypes, modulated by GABAergic, glutaminergic, and cholinergic neurons are involved (Chap. 14 ). Depression β-Adrenergic antagonists Amiodarone Interferon Isotretinoic acid Ribavirin

Mania Acyclovir Amantadine Caffeine Chloroquine Clarithromycin Corticosteroids Dextromethorphan Dehydroepiandrosterone Efavirenz Fenfluramine Fluoroquinolones Gabapentin Ginseng Interferon-α Isophosphamide Isoniazid L-Dopa Mefloquine Phentermine Phenylpropanolamine Pseudoephedrine Quetiapine St. John's wort Testosterone Tramadol TABLE

19-4.

Xenobiotic-Induced

Mood

Disorders 6 , 1 0 , 1 5

, 1 7 , 4 0 , 4 4 , 5 3 , 8 1 , 9 3 , 102 , 124 , 125 , 138 , 157 , 158 , 162 , 163 , 168 , 172 , 173 , 180 , 183 , 185 , 199 , 223 , 225 , 227 , 228 , 231

Anticholinergics Anticonvulsants

Carbamazepine Phenobarbital Phenytoin Antiparkinsonians Amantadine Bromocriptine Levodopa Pergolide Antipsychotics Carbon monoxide Corticosteroids Ethanol Lithium Manganese Metoclopramide Oral contraceptives Sympathomimetics Thallium Toluene Anticonvulsants Antiemetics Metoclopramide Prochlorperazine Antipsychotics Fluvoxamine Levodopa Antipsychotics Calcium channel blockers Flunarizine Cinnarizine Fluvoxamine Orthopramides and substituted Clebopride Metoclopramide

benzamides

Sulpride Veralipride Antidepressants Selective serotonin reuptake inhibitors Cyclic antidepressants Phenelzine Antiemetics Metoclopramide Prochlorperazine Antipsychotics Calcium channel blockers Flunarizine Cinnarizine Dopamine storage and transport inhibitors α-Methyltyrosine Reserpine Tetrabenzine Chorea

TABLE

Dystonia

19-5.

Dyskinesia

Xenobiotic-Induced

Akathisia

Movement

Disorders P.314

Dopamine receptor antagonists can precipitate acute dystonic reactions. The D2 -receptor antagonists, in conjunction with alterations in muscarinic cholinergic tone, are usually implicated. Animal models suggest possible mediation through σ receptors, the craniofacial distribution of which corresponds to the common clinical manifestations of acute dystonias. 116 Chorea occurs in some cases of carbamazepine overdose, therapeutic oral contraceptive use,74 and after cocaine use when the stimulant effects have subsided.188 Other centrally mediated disorders of tone include serotonin syndrome and neuroleptic malignant syndrome (NMS). Both of

these potentially life-threatening syndromes consist of altered consciousness, hyperthermia, rigidity, and autonomic insufficiency. NMS may occur in patients on dopamine-receptor antagonists such as antipsychotic medications, or in patients with idiopathic Parkinson disease who abruptly stop their dopaminergic therapy. Dopamine receptor agonists such as bromocriptine or restoration of antiparkinson medications are used therapeutically in these circumstances (Chap. 67 ). Flaccid paralysis usually occurs as a result of impaired transmission at the neuromuscular junction (NMJ)31 , 34 or from xenobiotics causing demyelination. Rarely, toxins can enhance transmission at the NMJ. Latrotoxin, the toxic compound in black widow spider (Latrodectus spp), causes enhanced release of acetylcholine at the NMJ with severe, painful muscle contractions (Tables

19-5 , 19-6 , and 19-7 ).

Xenobiotic-Induced Syndrome

Parkinson

Similar to idiopathic Parkinson syndrome, xenobiotic-induced Parkinson syndrome is defined by the clinical syndrome of unstable posture, rigidity, gait disturbance, loss of facial expression and hypokinesis.18 The common neuroanatomic target involves the dopaminergic neurons of the basal ganglia, specifically the substantia nigra. 60 , 214 Metabolic Hepatic failure Hyperosmolarity Hypoosmolarity Postanoxic encephalopathy Renal failure Ventilatory failure

Toxic Anticholinergics Anticonvulsants Benzodiazepines Bismuth Crotaline venom Cyclic antidepressants DDT Ethanol Lead Levodopa Mercury Methylbromide Sedative-hypnotics Modified, with permission, from Fahn S. Marsden CD, Van Woert MH: Definition and classification of myoclonus. Adv Neurol 1986;43:1–5. TABLE 19-6. Toxic-Metabolic Causes of Asterixis and Multifocal Myoclonus

Antidiabetics Amiodarone Amiodarone Calcium-channel blockers Amphetamine Antidiabetics Carbon disulfide Antidiabetics Barbiturates Carbon monoxide Arsenic Benzodiazepines Captopril

β-Adrenergic agonists Carbamazepine Chlorpromazine Caffeine Chloral hydrate Chlorprothixene Carbon disulfide Colistin Clozapine Carbon monoxide Ethanol (chronic) Cyanide Chlorpromazine Glutethimide Droperidol Chlorprothixene Lithium Ethanol (withdrawal) Clozapine Methaqualone Fluphenazine Cocaine Methyl mercury Haloperidol Corticosteroids Phenytoin Lithium Cyclic antidepressants Piperazine Loxapine Droperidol Valproic acid Manganese Ergotamine

Methanol Ethanol Methyldopa Fluphenazine Metoclopramide Haloperidol Mesoridazine Lead Molindone Levodopa MPTPa Lithium Perphenazine Loxapine Phenytoin Pimozide MAOIs (food interaction or drug) Prochlorperazine Mesoridazine Reserpine Methylbromide Tetrabenazine Molindone Thioridazine Monosodium glutamate Thiothixene Perphenazine Trifluoperazine Phencyclidine Phenytoin Pimozide Sedative-hypnotics Theophylline Thioridazine

Thiothixene Trifluoperazine Valproic acid a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Modified with permission from Weiner WJ, Lang AE: Movement Disorders: A Comprehensive Survey. Mt. Kisco, NY, Futura, 1989. Resting

TABLE

Tremor

19-7.

Sustension

Tremor

Xenobiotic-Induced

Kinetic

Tremor

Tremor

In some circumstances, the toxicity is transient and the mechanism inadequately understood. Some xenobiotics, such as MPTP, carbon disulfide, manganese, and the endogenous neurotoxin copper in patients with Wilson disease, produce predictable mitochondrial impairment of the basal ganglia neurons. Viscose rayon workers exposed to carbon with a Parkinson syndrome refractory to , 107 Manganese is a critical substrate for metabolism of several neurotransmitters

disulfide may present L-dopa administration.106 production and including glutamate.

Excessive manganese interferes with normal uptake of glutamate and is critical to the function of superoxide dismutase and glutamine synthetase.72 , 82 Patients with liver failure may accumulate manganese.82 Although copper accumulation in the basal ganglia can produce parkinsonism, sometimes the syndrome is clinically silent until a xenobiotic with antidopaminergic properties is administered. Another example of subclinical Parkinson disease being unmasked occurs in patients with both AIDS and psychosis who are administered antipsychotic agents therapeutically.59 Amlodipine Carbon disulfide Cyclosporine Carbon monoxide

Calcium channel blockers Copper Dopaminergic withdrawal Cyanide Kava kava (with manganese) Heroin Chemotherapeutics (numerous) Manganese Progesterone MPTP Sertraline Valproate Trazodone a Improved with removal of xenobiotic, sometimes requiring persistent administration of dopaminergic therapy. Reversiblea

TABLE

19-8.

Irreversible

Xenobiotic-Induced

Parkinsonism 1 8 , 6 0 , 7 0 ,

9 4 , 109 , 151 , 153 , 214

P.315 Other xenobiotics, such as carbon monoxide and heroin, produce more diffuse tissue hypoxia, which occasionally results in xenobiotic-induced Parkinson syndrome. One study of patients with occupational exposure to pesticides suggested an increased risk of Parkinson disorder with long-term exposure. Specific agents were not clearly causative (Table 19-8 ).80

Cranial

Neuropathies

Xenobiotics are a relatively rare cause of cranial nerve impairment. Some neuropathies are a result of direct delivery of the xenobiotic to the affected cranial nerve. For example, some patients may have optic nerve impairment from intraorbital

installation of silicone oil9 or inadvertent deep space injection of a local anesthetic during dental anesthesia with a resultant abducens palsy.146 In some cases, a xenobiotic is converted into a toxic substance such as formic acid in the retina. The neuromuscular junction of the cranial nerves is sensitive to disruptions in neurotransmission and clinically noticed by the patient during disruptions of conjugate gaze. Botulinum toxin, elapid snake venom, and the cranial neuropathy associated with the organic phosphorus insecticide-induced intermediate syndrome are some examples. Absence of critical substrates such as glucose or thiamine can result in an ophthalmoplegia. In most cases, however, the mechanisms underlying the cranial neuropathy understood, such as chemotherapeutic agents. patients who survive ethylene glycol poisoning transient ophthalmoplegia days after the initial

are poorly Similarly, some experience exposure (Table

19-9 and Chaps. 20 and 2 1 ).134 , 216

Peripheral

Neuropathies

Patients may complain of pain, paresthesias, numbness, or weakness of their extremities. This condition is clinically termed a neuropathy, but the mechanisms of its evolution are variable. Common to most xenobiotic-induced neuropathies is early bilateral involvement of the lower extremities. This may be partly a result of the patient's rapid recognition of impairment during an attempt to ambulate. Additionally, the axons serving the lower extremities are longer. Maintenance and transportation of substrates is more energy dependent and sensitive to xenobiotic-induced disruptions (Fig. 19-1 ). In some cases, the anatomic structure of the nerve is maintained, but the xenobiotic affects neurotransmission. This may be a consequence of direct impairment of specific enzymes at the NMJ,

such as cholinesterase inhibitors.61 Triorthocresyl phosphate (TOCP) is an inhibitor of neuropathic target esterase. Contamination of food and beverages with TOCP resulted in irreversible lower extremity paralysis in several epidemic exposures.171 , 217 Indirectly, the extracellular environment may be altered as in the case of hypermagnesemia, or hypokalemia which can be induced by multiple agents (Chap. 17 ). Ciguatoxin, a sodium channel opener, affects neurotransmission causing paresthesias and the unusual symptom of sensory reversal in which the perception of temperature is reversed to the stimulus. Amiodarone II, III Ammonia II Antidiabetics I

(hypoglycemia)

Antiretrovirals Barbiturates Botulinum III, IV, V Cadmium

toxin

Carboplatin Cisplatin Clioquinol Contrast agents VI Deferoxamine II

(intrathecal

water

soluble)

Dichloroacetylene Diiodohydroxyquin Domoic

acid

Ethambutol Ethylene glycol V, VIIl Hypothalamic-releasing

hormone

Î ±2 -Interferon II, III Lithium VI Local anesthetics VI MDMA VI Methotrexate/radiation Nitroglycerin VI OKT3 (ornithine-ketoacid transaminase) VI Organic phosphorus compounds Oxaliplatin Oxalosis V, VIII Silicone oil

Solvents II, IV, VIII Stibanate IX, X Stilbamidine Thallium III, IV, VI Thiamine deficiency Trichloroethylene Venoms III, IV, VI Elapid Scorpion Vincristine Vitamin A VI a These are reported associations and not intended to be exclusive. Many xenobiotics have unpredictable effects on particular cranial nerves, whereas others appear more selective. Substance

TABLE

Cranial

19-9.

Nerve

Xenobiotic-Induced

Cranial

Neuropathiesa 1 4

, 1 6 , 2 0 , 2 6 , 3 0 , 3 6 , 4 8 , 5 1 , 7 7 , 8 8 , 9 6 , 133 , 154 , 178 , 182 , 196 , 209 , 212 , 216 , 232

Xenobiotics such as amiodarone and tacrolimus induce peripheral demyelination. Patients present with weakness and flaccidity.

Nitrous oxide impairs the production of S -adenosyl-L-methionine essential to the production of myelin and is additive to the nitrous P.316 oxide disruptions of vitamin B12 , which further impair axonal function.222

Figure

19-1. Schematic of a peripheral neuron and its three

prototypic pathologic responses to toxic insults. Neuronopathies produce secondary axonopathic and myelinopathic changes, leading to degeneration of the entire peripheral nerve. Myelinopathies and axonopathies may occur separately or together. When the axon is involved, the prognosis is worse than with demyelination alone. Neuronopathies have the poorest prognosis of the three. (Adapted from Chaudhry V: Multifocal motor neuropathy. Semin Neurol 1998;18:74; and Anthony DC, Montine TJ, Graham DG: Toxic responses of the nervous system. In: Klaassen CD, ed. Casarett and Doull's Toxicology, The Basic Science of Poisons, 5th ed. New York, McGraw Hill, 1996.)

Other xenobiotics affect the structure or intracellular function of the peripheral nerves. Those that induce death of the cell body are termed neuronopathies and they may be clinically indistinguishable

from those that affect the axon, or axonopathies . Peripheral nerve cell death is usually linked to injury at the spinal cord as was demonstrated by the doxorubicin injection of the peripheral nerves.122 Pyridoxine overdose is another cause of neuronopathy. However, neuronopathies are an unusual mechanism of peripheral nerve toxicity. Unlike neuronopathies, axonopathies are potentially reversible and are the most common mechanism of xenobiotic induced peripheral neuropathy. Xenobiotic-induced axonal injuries to the peripheral nerves are usually diffuse and bilateral, with preservation of the proximal cell body. These often target the cytoskeleton and impair the capacity for the microtubule system to deliver functional substrates.52 , 100 Patients with occupational exposure to 2,5hexanedione, a γ diketone metabolite of n -hexane present in certain glues, suffer from a sensorimotor axonopathy because of cross-linking of neurofilaments and impaired substrate transport.164 Progressive neuropathy initial exposure. Vincristine similarly Acrylamide impairs fast anterograde animal models, suggesting effects on

may occur long after the effects axonal transport. and retrograde transport with both kinesin and dynein.

Nucleoside reverse transcriptase inhibitors cause peripheral neuropathy by decreasing the production of mitochondrial DNA (Tables 19-10 , 19-11 , and 19-12 ). Presynaptic action Adrenocorticotropic hormone (ACTH), Azathioprine Botulinum toxins Crotaline venom Elapidae β-neurotoxins Lactrodectus mactans venom Magnesium Tick paralysis

corticosteroids

Verapamil Postsynaptic action D-Penicillamine Neuromuscular blockers Nicotine alkaloids Organic phosphorous compounds, Phenothiazines Trimethaphan

carbamates

Pre- and postsynaptic action Antibiotics Aminoglycosides Clindamycin Polymyxins β-Adrenergic Chloroquine Lithium Phenytoin

antagonists

Procainamide Quinidine TABLE 19-10. Xenobiotics that Alter Transmission at the Neuromuscular Junction (Transmission Neuropathy)

5-Fluorouracil Amiodarone Amphotericin B methyl ester Arsenic Cyclosporine Diethylene glycol Fludarabine Hexachlorophene Interferon-α

Levamisole Methotrexate Neural tissue-derived rabies Nitrous oxide Podophyllin Procainamide Tacrolimus Tumor necrosis factor-α inhibitors L-Tryptophan Trovafloxacin Vincristine Zinc TABLE

19-11.

Xenobiotics

Associated

with

Demyelination

Myopathies Some patients experience local muscle damage as a result of direct injury from extravasation of tissue toxic substances or enzymatic degradation associated with crotalid snake envenomations. Acute toxic neuropathies Pyridoxine (S) Hexacarbons (SMA) Thallium (SM) Triorthocresyl phosphate (SM) Vacor (MA) Arsenic (SM) Diphtheria (SM) Black widow spider Botulism Ciguatoxin Elapid and crotaline venoms

Gymnothoratoxin Nicotine Saxitoxin Scorpion venom Tetrodotoxin Tick paralysis Subacute/chronic toxic neuropathies None convincingly demonstrated Acrylamide (SM) Allyl chloride (SM) Arsenic (SM) Buckthorn (M) Carbon disulfide (SM) Colchicine (S) Disulfiram (SM) Dapsone (M) 2′-3′-Dideoxycytidine Ethanol (M) Ethambutol (S) Ethionamide (S) Ethylene oxide (SM) Glutethimide (S) Gold (SM) Hexacarbons (SM) Hydralazine (SM) Hydroxycholoquine Interferon-α Isoniazid (SM) Linezolid Methyl bromide (SM) Mercury (M) Methanol Metronidazole (SM) Misonidazole (SM)

(ddC),

ddl

Nucleoside analogs Nitrofurantoin (SM) Nitrous oxide (S) Nucleosides (S) Organic phosphorus compounds Oxaliplatin Polychlorinated biphenyls (SM) Phenytoin (SM) Platinum (S) Podophylin (SM) Taxol (S) Thallium (SM) Vincristine (SM) 5-Fluorouracil Amiodarone (SM) Amphotericin B methyl ester Amygdalin Buckthorn Cyclosporine Diethylene glycol Diphtheria (SM) Fludarabine Gold (SM) Hexachlorophene Interferon Levamisole Methotrexate Nitrous oxide Podophyllin Procainamide Tacrolimus Trichlorethylene (SM) Trovafloxacin L-Tryptophan

(SM)

Tumor necrosis Vacor (PNU) Vincristine Zinc

factor-α

A = autonomic; M = motor; S = sensory. Neuronopathy

Axonopathy

Myelinopathy

Transmission Neuropathy

TABLE 19-12. Classification of Selected XenobioticInduced Peripheral Neuropathies P.317 Most xenobiotic-induced muscle injuries or myopathies are more diffuse.97 , 190 , 202 , 215 β-Hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can cause myalgias, cramping, myositis, or rhabdomyolysis. The incidence appears to be higher in patients taking other medications that share the same liver metabolic enzymes. The mechanism underlying the myopathy may be related to impaired cholesterol synthesis in myocytes, or diminished production of regulatory proteins such as ubiquinone and guanosine triphosphate (GTP)-binding proteins required for mitochondrial function. Another myopathy that presents predominantly with weakness is the acute quadriplegic myopathy of intensive care patients. This syndrome was originally described in ventilated patients with asthma who received glucocorticoids and nondepolarizing neuromuscular blockers, but is also reported in other critically ill patients P.318 (Chap. 66 ).21 The mechanisms underlying quadriplegic myopathy, eosinophilia myalgia syndrome, and toxic oil syndrome are poorly described. Table 19-13 lists xenobiotics associated with muscle

injury. Amiodarone Azidothymidine Bothrops asper, Agkistrodon, Acanthophis Chloroquine Cimetidine Clofibrate Clostridium toxin Colchicine Crotaline and other tissue-toxic snake venoms Cyclosporine Doxylamine Epsilon aminocaproic Ethanol Ethchlorvynol Glucocorticoids Heroin HMG-CoA reductase Hydroxychloroquine Ipecac

acid

inhibitors

Loxosceles spider envenomation Niacin Organic phosphorus compounds Penicillin D-Penicillamine Phencyclidine Procainamide Propylthiouracil Rifampin Sulfonamides Suxamethonium Toxic oil syndrome L-Tryptophan Vincristine

Zidovudine TABLE 19-13. Xenobiotics Associated with Muscle Toxicity1 9 , 2 1 , 4 3 , 1 3 1

Special Considerations: Fluid Administration of

Cerebrospinal Xenobiotics

Cerebrospinal fluid (CSF) is produced by the choroid plexus lining the ventricles at a rate of between 15 and 30 mL/h, or roughly 500 mL/d in adults.108 Cerebrospinal fluid flows in a rostral to caudal direction and is resorbed through the arachnoid villi directly into the venous circulation. The estimated total volume of CSF in a healthy adult is between 130 and 150 mL, and 35 mL in infants.108 , 142 , 186

For more than 100 years, a variety of experimental and therapeutic agents have been delivered directly into the CSF.121 , 223 , 233 The most common current indications for intrathecal xenobiotic administration include analgesia, anesthesia, and treatment of spasticity or CNS neoplasms. The clinical advantages of this route of administration include targeted delivery and lower medication dosages with fewer systemic effects. Medications are usually administered via a spinal needle or an indwelling intrathecal catheter. Catheters may be attached to either an external or subcutaneous pump. Less commonly, substances are administered into a reservoir of an intraventricular shunt (Table 19-14 ). The distribution of intrathecal xenobiotics is determined by a variety of factors. Baricity is the ratio of the specific gravity of the xenobiotic to the specific gravity of CSF at 98.6°F (37°C). Hyperbaric agents typically distribute in accordance with gravitational forces.104 Patient position, baricity, and interindividual variations in lumbosacral CSF fluid volume may

affect xenobiotic distribution and may account for the differences in the level of spinal anesthesia among patients administered the same local anesthetic dosages.104 In overdose or administration of agents unintended for intrathecal administration, however, distribution, resorption, and clinical effects might not follow predictable models. Complications can occur from preparation and dosing errors or inadvertent puncture of the CSF during epidural anesthesia or analgesia.67 , 103 Medications intended for intrathecal delivery might P.319 be administered into the wrong port of a pump delivery system, resulting in a massive overdose. Another potentially fatal error involves inadvertent administration of the wrong medication into the CSF.117 This occurs with misidentification or mislabeling of medications during pharmacy preparation, or at the bedside. For patients with indwelling devices, medications intended for intravenous delivery can be misconnected to the intrathecal catheter, which also operates via the Luer-Lock system. Adjuvants Dextrose Elliot B solution Analgesics/anesthetics Anesthetics (local) Clonidine Ketamine Midazolam Neostigmine Octreotide Opioids Ziconotide

Antibiotics Amikacin Amphotericin B Cefotetan Ceftriaxone Gentamicin Penicillin Polymyxin E Vancomycin Antiinflammatory Corticosteroids Antispasmodic Baclofen Chemotherapeutics Cytarabine Methotrexate Vasoactive Epinephrine Papaverine Phenylephrine Other Agents Bethanechol Colistin Leucovorinb Somatostatin Tetanus immunoglobulin a very few of these are FDA approved and many are controversial applications at best. b lntrathecal leucovorin is potentially fatal.

TABLE 19-14. Inadvertently or

Intrathecal Xenobiotics Administered Therapeuticallya 1 , 7 , 3 2 , 3 3 , 4 1 , 4 2 , 5 0 ,

5 7 , 6 8 , 9 1 , 9 9 , 117 , 135 , 147 , 148 , 155 , 170 , 175 , 176 , 177 , 197 , 204 , 211 , 221 , 226 , 236

Several factors affect the clinical toxicity of intrathecal medication errors. The properties of the xenobiotic are important. Ionized xenobiotics are likely to disrupt normal neurotransmission and cause toxicity, as may hyperosmolar or lipophilic substances. The site of administration also might be important. Patients administered the wrong xenobiotic into an Ommaya CSF reservoir may suffer more immediate alterations in mental status depending on the agent administered. Although intrathecal administration of preservatives and excipients are investigated in animal models, the characteristics of these adjuvants in medication errors is unlikely to be of value in predicting clinical effect.105 Patients may present with exaggerated symptoms that are typically associated with the xenobiotic. For example, patients with intrathecal morphine overdose may present with symptoms of opioid toxicity.119 Other manifestations of intrathecal errors, regardless of the substance, include pain and paresthesias, often ascending in nature, autonomic instability, especially with extremes of blood pressure, and hyperreflexic myoclonic spasms similar to those seen in patients with tetanus. Seizures or depressed mental status may also occur. The time of onset of these life-threatening symptoms may be determined by the dose, and characteristics of the xenobiotic. For example, a woman inadvertently administered intrathecal potassium chloride complained immediately of severe back pain. 149 Myoclonic spasms, seizures, and coma followed, and the patient expired within 3 hours despite a normal serum potassium concentration. Patients with inadvertent vincristine exposures can be asymptomatic for many hours and expire within a few days to a few weeks.

Once a medication delivery error is identified, rapid intervention is mandatory, especially for ionic agents, chemotherapeutics, or iodinated water-soluble contrast agents. In cases in which outcome is uncertain or not previously described, the exposure should be treated as potentially fatal. Any existing access to the CSF, ideally of the lumbosacral area, should be maintained.219 Immediate drainage by gravity of CSF, in volumes as high as 75 mL in adults, is indicated. This can be replaced with lactated Ringer solution or 0.9% sodium chloride solution. Some authors recommend that the initial large volume drainage be performed in 20–30-mL aliquots. For children, multiple aliquots of between 5 and 10 mL can be drained and replaced with isotonic fluid. If the patient can tolerate an upright position, cephalad movement of xenobiotics may be limited, but positioning for any critical life support measures should take precedence. Delays to initial CSF drainage should be minimized as the interval between the exposure and CSF drainage may affect xenobiotic recovery. In the interim, a neurosurgical consultation should be obtained to consider the placement of ventricular access for the performance of continuous CSF lavage. This procedure, also known as ventriculolumbar perfusion, involves continuous ventricular instillation of an isotonic solution with CSF drainage through a lumbar site. Another intervention involves placement of an epidural catheter into the intrathecal space at a space above the lumbar drainage site. An isotonic solution can be perfused through the catheter and drained caudally. This serves as a readily available, rapid intervention for patients awaiting placement of an emergent ventriculostomy.152 The CSF replacement fluid is isotonic. Lactated Ringer solution, 0.9% sodium chloride solution, Plasma-Lyte, or a combination of those have been used. Some older cases used Elliot B solution. For ventriculolumbar perfusion, lavage flow rates can be as high as 150 mL/h. Fresh-frozen plasma can be added to the lavage fluid to increase the CSF protein content in accordance with intracranial

pressure monitoring. The ideal lavage fluid, protein components, and infusion rates are not known.98 Table 19-15 describes some previously used protocols. Although artificial CSF formulations exist, their role in such medication errors has not been evaluated.165 Depending on the xenobiotic exposure, specific antidotes or rescue agents can be employed. With most intrathecal exposures, these rescue agents are administered via oral, intramuscular, or intravenous routes. Extreme caution should be used to avoid delivery of antidotes directly into the CSF, unless specific data supports their use.

Xenobiotic

Recovery

from

CSF

Immediate, aggressive CSF removal and lavage resulted in nearly 95% recovery of vincristine in the lavage fluid of a patient with inadvertent exposure. Of the published cases in which xenobiotic recovery is reported, percentages relate to the both the lavage method and quantity of CSF drained. For example, drainage of 10 mL of CSF 45 minutes after a methotrexate overdose in a 4-yearold patient recovered 20% of the initial dose.8 Drainage of 200 mL of CSF in aliquots, 45 minutes after methotrexate overdose in a 9year-old recovered 78% of the initial dose.85 Interestingly, the specific xenobiotic may affect recovery as well. For example a patient underwent drainage of 30 mL of CSF at 18 minutes after an overdose of simultaneously administered lidocaine, epinephrine, and fentanyl. Approximately 39% of lidocaine was recovered, whereas the recovery of fentanyl was only 7%.205

Specific Ionic

Exposures

Contrast

Media

Several different agents have been used historically for contrast

myelography. Many of these agents were abandoned because of their capacity to cause an adhesive arachnoiditis and chronic pain syndromes or other complications (eg, Thorotrast). Low osmolar, nonionic contrast media are currently used, but, unfortunately, other hyperosmolar ionic media are readily available in radiographic suites and sometimes inadvertently administered. Exposed patients become symptomatic between 30 minutes and 6 hours with hyperreflexia and myoclonic spasms on minimal stimulation.189 , 191 , 213 Clinical symptoms typically begin in the lower extremities and move in a cephalad direction, sometimes progressing to opisthotonos. This is likely caused by alterations in inhibitory neurotransmission as seen in patients with tetanus, and has been termed ascending tonic–clonic syndrome (ATCS). In one review, nearly one-third of patients died as a result of their exposures.220 Immediate, large-volume CSF drainage should be performed in 20-mL aliquots with isotonic fluid replacement. Ventriculolumbar perfusion should be considered in severe cases.

Chemotherapeutics Methotrexate is administered intrathecally for the prevention and treatment of leukemic meningitis and other CNS neoplasms. Errors are generally dose related.8 , 84 , 85 , 113 In most reported cases, aggressive drainage of CSF up to 250 mL in aliquots with isotonic fluid replacement was used without ventriculolumbar P.320 P.321 P.322 P.323 perfusion. Experimental treatment of patients with intrathecal carboxypeptidase G2 without obvious adverse events has been described.166 , 229 Leucovorin can be administered intravenously, but intrathecal leucovorin is absolutely contraindicated because it can be fatal.114 , 130 , 218

TABLE 19-15. Table of Adverse Intrathecal Exposures Vincristine is typically administered intravenously and does not cross the blood–brain barrier. There are no therapeutic indications for intrathecal vincristine, and such errors are almost always fatal.11 , 12 , 13 , 37 , 71 , 95 , 128 As soon as the exposure is identified, immediate CSF drainage should be instituted and rapid neurosurgical consultation obtained. The few known survivors with cognitive function underwent early neurosurgical intervention for ventriculolumbar perfusion.12 , 152 One of these patients had an epidural catheter placed intrathecally above the drainage site for lumbolumbar perfusion while awaiting ventriculostomy. This method of intrathecal perfusion should be considered in all patients with intrathecal vincristine exposures until definitive ventriculolumbar perfusion can be established. Other rescue medications are covered in Chap. 52 .

Pump

Malfunctions

and

Errors

Some implantable pumps contain two access sites, one of which is contiguous with the intrathecal space and allows for CSF withdrawal or injection of nonionic contrast media for imaging. The other is a depot port that is intermittently filled with concentrated amounts of drug (usually an opioid analgesic or baclofen) to be delivered through a programmable pump. In some cases, a template must be placed on the skin overlying subcutaneous pumps to ascertain the proper medication port. Errors occur when a concentrated bolus is inadvertently injected into the wrong port resulting in a massive, sometimes fatal, overdose.117 , 175 , 234 Massive intrathecal morphine overdose can have severe rapid symptoms, including hypertensive crises. Either reaccessing the CSF port immediately or placing a spinal needle into the intrathecal space at another site is critical for the withdrawal of CSF. Large-volume drainage with isotonic fluid replacement is

required, along with other supportive measures, such as intravenous naloxone. These patients usually require intubation and care in an intensive care unit. The clinical service which placed the pump should be consulted to assist in further CSF access and perform interrogation of the pump in cases where malfunction is suspected.73 If the consultant is not readily available, then emptying the deport port will automatically cause the pump motor to stop. The other pump problem encountered is sudden, insufficient delivery of either baclofen or opioid pain medication.184 This may occur because of pump malfunction. Alternatively, the intrathecal catheter may kink, migrate, or become obstructed by an inflammatory mass.65 , 66 , 117 , 174 Patients with chronic use of baclofen or morphine may suffer severe withdrawal symptoms when intrathecal delivery is disrupted. Intrathecal doses are between 100 and 1000 times more potent than the equivalent dose administered intravenously.120 Consequently, these patients may require very high oral or intravenous doses to treat withdrawal until intrathecal delivery can be reestablished. The clinical service that implanted the pump should be consulted, and a thorough neurologic examination to evaluate for spinal cord compression symptoms should be performed.117 A n anteroposterior and lateral radiograph can be obtained to assess for kinking or fracture of the catheter. P.324

Conclusions The principles involving xenobiotic-induced neurologic injury are an area of ongoing intensive investigation. With improved understanding of these neurotoxic principles, therapeutic medications can be better delivered to the central nervous system while limiting the entry of potentially toxic substances. Toxicologic models for the investigation of neurodegenerative disorders can be

further developed as can new and creative therapies for mood disorders, hepatic encephalopathy, and injuries from infections, trauma, and ischemia. Elucidation of neurotoxicologic principles shows promise for the treatment of many nervous system disorders, and is an evolving field of investigation. The chemical properties of the xenobiotic and the characteristics of the patient exposed are critical to the clinical expression of neurotoxicity.

Acknowledgment E. John Gallagher contributed to this Chap. in previous editions.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 20 - Ophthalmic Principles

Chapter

20

Ophthalmic Adhi

Principles

Sharma

Martin J. Smilkstein Frederick

W.

Fraunfelder

Xenobiotics can affect the eyes in diverse manners. The eyes may be injured by direct contact with a number of xenobiotics, may provide a portal of entry for systemic toxicity, and may themselves be adversely affected by systemic exposures. The clinician must perform a thorough ophthalmic examination. Examination of the eye not only provides clues to the diagnosis of certain direct toxic exposures, but may also lead to timely detection of lifethreatening indirect effects, such as intracranial hemorrhage. In addition to providing diagnostic clues, the visual system is the target of many xenobiotics that threaten normal vision. Understanding these principles can be lifesaving or sightsaving, and is essential to efficient, systematic patient care.

Ophthalmic

Examination

As a matter of convention, the routine eye examination is

performed in the following sequence: visual acuity, pupillary response, extraocular muscle function, funduscopy, and when indicated, a slit-lamp examination. Examination of the pupillary size and response to light can help determine the presence of a toxic syndrome. Opioid and cholinergic agents may produce miosis, whereas anticholinergic agents may produce mydriasis. Assessment of the extraocular muscles can reveal xenobioticinduced nystagmus. Funduscopy can reveal pink discs characteristic of poisoning by methanol or carbon monoxide. The slit-lamp examination allows for evaluation of toxic exposure to the lids, lacrimal systems, conjunctiva, sclera, cornea and anterior chamber. However, before considering specific toxic exposures in detail, it is important to review the anatomy and physiology of the visual pathways and how alteration of the normal physiology and anatomy correlate with clinical signs and symptoms.

Ocular

Anatomy

The eye is a roughly spherical structure referred to as a globe. The globe is divided into anterior and posterior structures (Fig. 20-1) . The most anterior structures are the cornea, conjunctiva, and sclera. Posterior to the cornea are the iris, the lens, and the ciliary body. The space between the cornea and the iris is the anterior chamber, and the space between the iris and the lens is the posterior chamber. Both chambers contain aqueous humor, which is produced by the ciliary bodies. The fundus is the most posterior structure and includes the retina, retinal vessels, and the head of the optic nerve or disc. The fundus is surrounded by gelatinous vitreous fluid, an important body fluid in forensic toxicology (Chap. 3 3). Xenobiotic-mediated injury to any of these structures can lead to symptoms as mild as chemical conjunctivitis or as severe as permanent blindness.

Visual

Acuity

and

Color

Perception

Normal vision is dependent on light transmission to intact neural elements. Appropriate light transmission requires a clear cornea and aqueous humor, proper pupil size, an unclouded lens and clear vitreous. The neural elements include the retina, optic nerve, and the optic cortex; all of these structures require intact blood circulation for proper function. Decreased acuity can result from abnormalities anywhere in the visual system that affect either light transmission or neural elements.4,16,30 Corneal injury or edema may result in blurring of vision, characteristically described as “halos― around lights. Toxicologic causes of corneal abnormalities include direct exposure to chemicals, failure of corneal protective reflexes because of local anesthetic effects or a profoundly decreased level of consciousness, and incomplete eyelid closure during coma. Mydriasis, secondary to various xenobiotics (Table 20-1), may interfere with the pupillary constriction necessary for accommodation, thereby resulting in decreased acuity for near objects. Lens clouding or cataract formation causes blurred vision and decreased light perception, as does blood (hyphema) or other deposits in the aqueous humor or vitreous humors. Xenobiotic-induced lens abnormalities caused by chronic exposures are well described (Table 20-2) ,23,30,39 but are unimportant in the evaluation of an acute toxicologic emergency. Even if light reaches the retina without distortion, abnormal reception or transmission can result from ischemia or injury to any neural element from the retina to the optic cortex. Direct, acute, visual neurotoxic injury is rare and is caused almost exclusively by methanol or quinine. Indirect injury following xenobiotic-induced central nervous system (CNS) ischemia or hypoxia is far more common. Alterations in color perception generally result from abnormalities in retinal or optic nerve function. Color-vision abnormalities are attributed to hundreds of agents, but unlike those caused by chronic xenobiotic exposure such abnormalities are rare and inconsistent features of acute toxicity.23,30

Pupil

Size

and

Reactivity

Generally, pupils are round and symmetric with an average diameter of 3–4 mm under typical light conditions. Physiologic anisocoria (unequal pupils) is a normal variant and is defined as a difference in pupil size of 1 mm or less. However, in the absence P.330 of a history of physiologic anisocoria, any asymmetry in pupil size should be considered an abnormal finding. Pupils react directly and consensually to light intensity by either constricting or dilating. Constriction is also a component of the near reflex (accommodation) that occurs when the eye focuses on near objects. The iris controls pupil size through a balance of cholinergic innervation of the sphincter (constrictor) muscle by cranial nerve III and sympathetic innervation of the radial (dilator) muscle.16

Figure 20-1. The major xenobiotics and their areas of ophthalmic injury. (Courtesy of the National Eye Institute,

National Institutes of Health, adapted by Joseph Lewey.)

Pupillary dilation (mydriasis) can result from increased sympathetic stimulation by endogenous catecholamines or, from xenobiotics such as cocaine, amphetamines, and other sympathomimetics as well as ophthalmic instillation of sympathomimetic agents such as phenylephrine. Mydriasis can also result from inhibition of muscarinic cholinergic-mediated pupillary constriction secondary to systemic or ophthalmic exposure to anticholinergic agents (Chap. 50). Because pupillary constriction in response to light is a major determinant of normal pupil size, blindness from ocular, retinal, or optic nerve disorders also leads to mydriasis as exemplified by methanol and quinine toxicity. Reactivity of mydriatic pupils to light varies with the etiology of the mydriasis.30 Although often difficult to appreciate, constriction to light can usually be elicited after sympathomimetic exposures because constrictor function is preserved, whereas this is often not the case when mydriasis results from anticholinergic excess. Light reactivity is absent in cases of complete blindness caused by retinal or optic nerve damage, but may be preserved if there is some remaining light perception. Miosis can result from increased cholinergic stimulation such as opioids, pilocarpine, and cholinesterase inhibitors such as organic phosphorus compounds, or inhibition of sympathetic dilation caused by clonidine. There are conflicting reports regarding the pupillary reactions to many xenobiotics. Depending on the stage and severity of toxicity, the presence of coingestants or coexistent hypoxemia, and numerous other factors, many individual substances (eg, phencyclidine and barbiturates) are reported to cause either mydriasis, miosis, or hippus, the fluctuation between miosis and mydriasis.30,40 For some xenobiotics, the pupillary examination provides consistent information (Table 20-1), but many factors are involved and the significance of the pupil size

and reactivity must always be considered in the context of the remainder of the patient evaluation.

Extraocular

Movement,

Diplopia,

and

Nystagmus Maintenance of normal eye position and movement requires a coordinated function of a complex circuit involving bilateral frontal and occipital cortices, multiple brainstem nuclei, cranial nerves, extraocular muscles, and connecting fibers between each.2,16 Because of the many elements necessary for normal function, abnormalities of eye movement can result from several causes and are extremely common.30 Probably the most common abnormality is reversible nystagmus or rhythmic oscillations of the globes (Table 20-1). Xenobiotic-induced nystagmus can take many forms, but is most commonly jerk nystagmus, as opposed to pendular, or horizontal and symmetric. The nystagmus may be evident at rest but is accentuated by visual pursuit and extreme lateral gaze. Although nystagmus with extreme lateral gaze is a normal finding, it extinguishes within 2–5 beats; if nystagmus persists, it is evidence of underlying pathology. Xenobiotic-induced vertical nystagmus occurs with phencyclidine, ketamine, dextromethorphan, or phenytoin toxicity; vertical nystagmus, however, is usually associated with a structural lesion of the CNS. Loss of conjugate gaze commonly results from CNS depression of any cause, typically after a sedative-hypnotic or ethanol overdose. Except after extremely rare exposures to neurotoxins (Table 201), diplopia without a decreased level of consciousness should not be attributed to an acute toxicologic etiology. In addition to the transient effects of some xenobiotics thallium, carbon disulfide, and carbon monoxide, may cause sustained gaze disorders as a consequence of residual cranial nerve and CNS injury.30 Nystagmus and ophthalmoplegia caused by thiamine deficiency usually improves after therapy, but the nystagmus may not

completely

resolve.63

Systemic Absorption Ocular Exposures

and

Toxicity

from

Systemic absorption from ocular exposures has caused serious toxicity, morbidity, or death.20,33 Although the patterns of toxicity are characteristic of the xenobiotics involved, recognition may be P.331 delayed as significant xenobiotics absorption

a result of a failure to appreciate the eye as a route of absorption. Although transcorneal diffusion of are limited, there is substantial nasal mucosal after nasolacrimal drainage, and absorption via

conjunctival capillaries and lymphatics, which is markedly increased during conjunctival inflammation. Unlike the gastrointestinal route of absorption, there is no significant firstpass hepatic removal after ocular absorption; consequently, bioavailability is much greater.20,33,57 If nasolacrimal outflow is normal, up to 80% of instilled drug may be absorbed systemically.20 By the time toxicity is apparent, there is no role for ocular decontamination to prevent further absorption. After instillation of eye drops, absorption is generally complete within 7 minutes.

TABLE 20-1. Ophthalmic Findings Caused by Acute Xenobiotic Exposures

Miosis Increased cholinergic tone Carbachol Cholinesterase inhibitors (carbamates, phosphorus compounds)

organic

Muscarine Nicotine Pilocarpine Decreased sympathetic tone (clonidine, guanabenz, methyldopa, opioids) Coma from sedative-hypnotics (barbiturates, benzodiazepines, ethanol) Mydriasis Decreased cholinergic tone Antihistamines Belladonna alkaloids Cyclic antidepressants (inconsistent finding) Postanoxic encephalopathy Increased sympathetic tone (amphetamines, cocaine, phenylephrine and other sympathomimetics, ethanol and sedative-hypnotic

withdrawal)

Nystagmus Carbamazepine Dextromethorphan Ethanol Ketamine Lithium Monoamine oxidase inhibitors Phencyclidine Phenytoin Sedative-hypnotics Thiamine deficiency Disconjugate gaze Botulism Elapid envenomation Neuromuscular blockers Paralytic shellfish poisoning

Tetrodotoxin Thiamine deficiency Secondary to decreased level of consciousness (many causes) Funduscopic abnormalities Carbon monoxide (red) Cocaine (vasoconstriction) Cyanide (retinal vein arteriolization) Ergot alkaloids (vasoconstriction) IV drug use (embolic) Methanol (disc and retinal pallor or hyperemia) Methemoglobin (cyanotic) Papilledema See causes of pseudotumor cerebri (Table 41-2)

Children appear to be at greatest risk, possibly because of the higher relative drug dose they experience when systemic absorption does occur.20,47,57 Diligent attempts to comply with prescribed dosing in a struggling, crying infant may also result in excessive dosing. As eyedrop size (40–50 µL) exceeds ocular cul-de-sac capacity (30 µL), overflow often occurs and is assumed to represent a failed instillation, which leads to unnecessary reinstillation. Also, as doses of ocular medications are typically not adjusted based on patient weight, the consequences of equivalent degrees of systemic absorption are much greater for an infant than for an adult. Toxicity from eye drops is also a problem among the compromised, probably because of the combination of greater use of potentially toxic ophthalmic medications and the presence of comorbid conditions. Prevention of systemic toxicity from topical ophthalmic medications requires recognition of the risk, a careful history, use

of the lowest effective concentration and dose, and patient education including proper administration instructions. To minimize inadvertent absorption, no more than one drop of any eyedrop solution should be instilled at one time in the superolateral corner of the eye while using gentle finger compression of the medial canthus to limit nasolacrimal drainage.20,33

Mydriatics Mydriatics diagnostic generally risk may

are used almost exclusively to dilate the pupils prior to evaluation of the eyes. This common practice is not considered to be potentially dangerous; however, the be substantial if the precautions outlined are not

considered. Anticholinergic poisoning (Chap. 50), including substantial morbidity and mortality, is well described after ocular use of atropine, cyclopentolate, or scopolamine eyedrops, especially in infants. The use of the α-adrenergic agonist phenylephrine eyedrops in a 10% solution may cause severe hypertension, subarachnoid hemorrhage, ventricular dysrhythmias, and myocardial infarction.22 Fortunately, these effects are rare if the 2.5% ocular phenylephrine is used. Mydriatics can also precipitate acute angle closure glaucoma in susceptible individuals.

Miotics

and

Other

Antiglaucoma

Drugs

Maintaining miosis to prevent angle closure is an important part of glaucoma therapy. Cholinesterase inhibitors used for this purpose, such as echothiophate, can exacerbate asthma, parkinsonism, and cardiac disease. If neuromuscular blockade is required for patients using ocular cholinesterase inhibitors, an agent not metabolized by plasma cholinesterase (eg, atracurium, pancuronium, vecuronium, or tubocurarine) must be used. Succinylcholine and mivacurium

are cleared by plasma cholinesterase and have profoundly prolonged effects when a cholinesterase inhibitor is present.33 Because of their long duration of action and resultant risk of accumulation after repeated dosing, cholinesterase inhibitors are associated with the highest incidence of adverse reactions among susceptible patients. Miosis can also be produced by use of direct cholinergic agonists, such as pilocarpine, which have a much shorter duration of action. Although absorption is limited, nausea and abdominal cramps can occur at recommended doses. After excessive dosing, salivation, diaphoresis, bradycardia, and hypotension may occur. P.332 β-Adrenergic antagonists, such as timolol, levobunolol, metipranolol, carteolol, and betaxolol, are used to lower intraocular pressure but cause a variety of adverse effects, including bradycardia, hypotension, myocardial infarction, syncope, transient ischemic attacks, congestive heart failure, exacerbation of asthma, status asthmaticus, and respiratory arrest. Timolol has exacerbated symptoms in patients with myasthenia gravis and is implicated in both causing and masking symptoms of hypoglycemia in diabetics.61,62 Nonspecific complaints of anorexia, anxiety, depression, fatigue, hallucinations, headache, and nausea are also described after use of timolol eyedrops. Despite the cardioselectivity of betaxolol, respiratory toxicity has been reported.20 Dipivefrin, an esterified epinephrine derivative sometimes used to treat glaucoma, can cause adrenergic systemic effects, although much fewer than those caused by epinephrine. Ophthalmic formulations of highly selective α2 -adrenergic agonists, brimonidine (Alphagan) and apraclonidine (Iopidine) have been introduced to treat glaucoma.20,65 Apraclonidine is expected to have a lower potential for toxicity because of limited CNS absorption. Systemic absorption of brimonidine eye drops in a

child has led consciousness, adrenoceptor through both

to bradycardia, hypotension, and a decreased level of similar to the central effects of other α2 agonists (eg, clonidine),7 apparently mediated α2 -adrenoceptors and imidazoline receptors.11

Antimicrobials Life-threatening reactions to ophthalmic antimicrobials are unusual but do occur. Episodes of aplastic anemia have occurred after prolonged use of chloramphenicol eye preparations,21 and Stevens-Johnson syndrome was reported after short-term use of ophthalmic sulfacetamide in a patient with a history of allergy to sulfa drugs.29

Ocular Caustic Exposures: and Initial Approach

First

AID

The initial approach to all patients with ocular caustic exposures should be immediate decontamination by irrigating with copious amounts of fluids, water being the most often used.12,64 Water, normal saline, lactated Ringer solution, and balanced salt solution (BSS) are all appropriate choices.54 In theory, BSS is ideal, because it is both isotonic and buffered to physiologic pH. Lactated Ringer solution (pH 6–7.5) and 0.9% sodium chloride solution (pH 4.5–7) are also isotonic and therefore theoretically preferable to water.32 The use of an ocular anesthetic is usually required to perform irrigation properly. Irrigation is intended to accomplish at least 4 objectives: immediate dilution of the offending agent; removal of the agent; removal of any foreign body; and in some cases, normalization of anterior chamber pH. As delays of even seconds can dramatically affect outcome,30 there is no justification for waiting for any specific solution if water is the first available agent. Irrigation must include the external and internal palpebral surfaces, as well as the cornea and

bulbar conjunctiva and its recesses. Effective irrigation includes lid retraction and eversion or use of a scleral shell or other irrigating device. After irrigation, visual acuity testing, inspection of the eye, and slit-lamp examination should be performed.

Exposure-Specific

Irrigating

Solutions

Despite theoretical concern, there is probably no toxic exposure for which standard aqueous solutions are contraindicated. Of greatest concern are agents such as white or yellow phosphorus, metallic sodium, metallic potassium, and calcium oxide (cement) that may theoretically react violently in the presence of water, leading to heat or mechanical injury, or resulting in the generation of sodium hydroxide, potassium hydroxide, and calcium hydroxide.30 Although not well-studied, irrigation with large amounts of water probably dissipates the heat of the initial hydration reaction with conjunctival moisture more than it initiates a thermochemical reaction. In addition to removing the offending material, irrigation serves to dilute and remove the alkaline byproducts formed by reaction with conjunctival water. The use of special irrigating solutions for more uncommon exposures, including hydrofluoric acid and phenols, is also debated. A recent animal model of alkaline injury suggests irrigation with amphoteric or buffered solutions rapidly restores anterior chamber pH.55 However, the majority of the published human data have been case reports. Therefore, at this time these solutions are probably best suited for first aid treatment at worksite eyewash stations and are neither practical nor proven in the emergency department setting for prolonged irrigation.

Hydrofluoric

Acid

For hydrofluoric acid exposures (Chap. 101), experimental irrigation with calcium salt solutions was too irritating to the eye, but isotonic magnesium chloride solutions appear effective and not

irritating. 41,42 From a practical standpoint, however, 0.9% sodium chloride solution remains readily available, well studied and effective.

Phenol For phenol exposure, topical low-molecular-weight polyethylene glycol (PEG) solutions are effective for treatment of experimental skin exposure; for eyes, copious water irrigation appears to be as effective as PEG.10 There is, however, a report of superior efficacy of PEG-400 over water in treatment of actual phenol eye burns.35 Although PEG-400 may be readily available at worksites where phenols are used, it is not a realistic option in the emergency department, and there should be no hesitation to use water, 0.9% sodium chloride solution, lactated Ringer solution, or BSS as lavage solutions.

Cyanoacrylate

Adhesives

Ocular exposures to cyanoacrylate adhesives such as Dermabond and Krazy Glue occasionally result in rapid adherence between upper and lower eyelids that may persist for days. Such occurrences may be associated with corneal abrasions,17 but are otherwise relatively harmless. In fact, cyanoacrylate has been safely used for decades to treat corneal perforations.66 Solvents such as acetone or ethanol, which are often effective treatment for dermal-to-dermal adhesions caused by cyanoacrylates, should never be used in or around the eyes. Expectant management is the safest approach as spontaneous rejection of the glue will occur over time. Application of gauze pads soaked with antibiotic ophthalmic ointment may speed recovery.34 A thorough eye examination should be performed once the eyelids can be fully opened. Other xenobiotic-specific treatments have been tried experimentally or clinically,32 but none should be considered prior

to or instead of copious irrigation, most are not advocated, and consideration of such agents should be vanishingly rare.

Duration

of

Irrigation

To accomplish the desired goals of irrigation, the appropriate duration varies with the exposure. Most solvents, for example, do not penetrate deeper than the superficial P.333 cornea, and brief (10–20 minutes) irrigation is generally sufficient.30 After exposure to acids or alkalis, normalization of the conjunctival pH is often suggested as a useful end point. Testing of pH should be done in every case of acid or alkali exposure, but the limitations of testing must be understood. When measured by sensitive experimental methods, normal pH of the conjunctival surface is 6.5–7.6.1 This is highly method-dependent, however, and normal values in the literature range from 5.2 to 8.6.14 When measured by touching pH-sensitive paper to the moist surface of the conjunctival cul-de-sac, normal pH is most often near 8.3 Therefore, after irrigation following alkali burns, pH should not be expected to reach 7 and is more likely to stabilize near 8.30 In this setting, lower pH values may indicate the pH of the irrigant rather than of the ocular surface. Waiting for an interval of several minutes between irrigation and pH testing allows washout of any residual irrigant.15 Choice of testing paper is important, as some are intended for use at extremes of pH and lack sensitivity in the clinically useful range. Despite these limitations, a logical role for pH assessment can be described: Probably a minimum of 500–1000 mL of irrigant should be used for each affected eye before any assessment of pH, and after 7–10 minutes, the pH of the lower fornix conjunctiva should be checked. Thereafter, cycles of 10–15 minutes of irrigation followed by rechecks should be continued until the pH is 7.5–8. This is certainly adequate for exposures to weak acids,

which do not penetrate well, and for alkaline exposures where the pH is less than 12. For strong alkaline, concentrated acid, or for hydrofluoric acid exposures with apparent eye abnormalities, normal surface pH is not an adequate end point (see Alkalis below). After these burns, irrigation should be continued for at least 2–3 hours, regardless of surface pH, in an attempt to correct anterior chamber pH;30,53,64 in addition, immediate ophthalmologic consultation is mandatory. Following this lengthy irrigation, it is important to verify that conjunctival pH has normalized. If not, irrigation must be continued, sometimes for 24–48 hours.

Other

General

Measures

There is a wide array of options for adjunctive therapy of chemical burns of the eye. In all cases in which serious injury is evident, the treatment plan must include consultation with an ophthalmologist. Generally, patients with treated with an ocular topical antibiotic antistaphylococcal and antipseudomonal not only reduce pain from ciliary spasm,

corneal injury should be providing coverage. Cycloplegics but also decrease the

likelihood of posterior synechiae (scar) formation. Topical NSAIDs and systemic analgesics also improve patient comfort. It is never appropriate to dispense topical ophthalmic anesthetic agents, because repeated use of these agents leads to further corneal disruption both by direct chemical effects and by eliminating corneal protective reflex sensation.

Ocular Caustic xenobiotics

Exposures:

specific

The effect of any xenobiotic on the eye depends on the inherent properties as a solvent or detergent; the amount, concentration, and pH of the xenobiotic; and the duration of exposure. The end

result of ocular exposure to these agents depends on the extent of damage to the cornea, particularly the integrity and function of the stroma; penetration into the anterior chamber and the resulting injury to its structures; and resultant inflammatory reaction.30,64 Because similar xenobiotics tend to produce similar reactions, they can be conveniently grouped for discussion into acids, alkalis, and others.

Acids Fortunately, weak acids do not penetrate the cornea well.30,64 The hydrogen ion causes damage by lowering ocular pH, while the anion denatures ocular proteins on contact, causing precipitation and coagulation that actually limits the extent of penetration. The dehydrating effect of some acids, the heat of hydration, and the affinity of each anion for corneal tissues all affect the extent of injury. Intense pain usually results from stimulation of exposed nerve endings in the corneal epithelium. Corneal defects are common, but in many cases the damaged epithelium is swept away, revealing a healthy Bowman layer, over which epithelium resurfaces the cornea. Strong acids can penetrate the stroma, damage deeper tissue and structures of the anterior chamber, and lead to the more serious sequelae, such as those that often occur after alkali burns.30,64 Prolonged exposure to weaker acids may result in significant extension of the injury, making immediate irrigation mandatory. Hydrofluoric acid may cause unexpectedly severe injury because of its ability to penetrate deep into the eye.41,42,52 Damage is generally concentration dependent, with severe injury expected after exposure to 20% solutions or higher, but even dilute formulations have led to persistent abnormalities. On the basis of anecdotal reports, some authors60 advocate repeated instillation of calcium gluconate eye drops to bind free fluoride, but there is no evidence that this is beneficial.5 At this time, we do not

advocate the use of calcium or magnesium solutions for irrigation or instillation after hydrofluoric acid eye exposure.

Alkalis Alkali burns of the eye represent an ophthalmic emergency. A rational approach to care is based on an understanding of the complex pathophysiology of these injuries.64 The hydroxyl ion saponifies lipid membranes, directly disrupting cells, whereas the penetration of the alkali is determined by the cation. Cations react with and hydrate stromal collagen and glycosaminoglycans, causing loss of clarity. For this reason, once the damaged epithelium is swept away, any haziness of the underlying stroma is evidence of alkali penetration and potential serious sequelae. If injury is limited only to destruction and lysis of corneal epithelium, with clear stroma, rapid and complete resolution is expected. Large amounts of concentrated strong bases such as sodium hydroxide, xenobiotics that penetrate rapidly such as ammonium hydroxide, and prolonged exposure all promote deeper injury.30,51,64 Penetration into corneal stroma may destroy keratocytes, alter collagen structure, and damage the endothelium.62 Paradoxically, more extensive burns may be less painful, because of destruction of corneal nerve endings and resultant anesthesia. In addition to indicating an increased depth of the burn, stromal and endothelial injuries often impair the ability of the cornea to regenerate later and to maintain an adequate epithelium. Further penetration can cause the pH of the anterior chamber to rise significantly within 2–3 minutes.48,64 Ammonium hydroxide is especially destructive by this mechanism, as it penetrates far more rapidly than other alkalis. Experimentally, 8.5% ammonium hydroxide increases anterior chamber P.334 pH within 15 seconds.30 As a result, the sequelae of these exposures are severe and may be out of proportion to both pH and

the degree of surface injury. The increase in intraocular pH is injurious to the trabecular meshwork, iris, lens, and ciliary body, and also triggers a sudden contraction of corneal and scleral collagen, leading to increased intraocular pressure and exacerbation of pain. A less dramatic but more sustained increase in intraocular pressure ensues, resulting from intraocular prostaglandin release.64 In addition to these direct effects, further injury results from the inflammatory response to the initial injury. Dysfunction of the normal blood–aqueous humor barrier results in exudation of protein and inflammatory cells into the anterior chamber, leading to a severe fibrinous reaction. Fibrosis, in turn, can lead to permanent angle closure with resultant glaucoma. At the opposite extreme, permanent dysfunction of the ciliary body, which produces the aqueous humor, can result in visual loss as a consequence of collapse of the eye (phthisis bulbi).30,64 The full extent of injury may not be evident for 48–72 hours. In the ensuing days to weeks, outcome is determined by the balance between degradation and repair of the stromal matrix, the quantity and quality of corneal reepithelialization, and the extent of inflammatory cell infiltration. After severe burns, normal repair is distinctly rare and extensive scarring is the rule. The goal of therapy is to prevent corneal ulceration, ocular perforation, and glaucoma while preserving the eye for possible secondary surgical revision or repair. The mainstay of treatment is immediate and copious irrigation following the guidelines discussed. After exposures to calcium hydroxide (lime) from mortar or cement splashes, any adherent material must be found and removed. A sterile cotton-tipped applicator soaked in 0.05 mol/L edetate disodium (Na2 EDTA) may aid this process.30,51,64 Follow up is essential in all cases of alkali eye burns. Emergent consultation with an ophthalmologist should be obtained for all suspected severe burns. For isolated, very

superficial corneal defects this is not necessary; however, if there is pain unrelieved by topical anesthetics, evident corneal opacification, increased intraocular pressure, or any slit-lamp examination evidence of deep corneal burn, corneal edema, or anterior chamber cell or flare, immediate consultation is essential. Not only is comprehensive early evaluation important, but the advisability of several adjunctive treatments should be determined in conjunction with the ophthalmologist. Emergent needle paracentesis and lavage of the anterior chamber removes alkali and returns pH to normal and also decreases intraocular pressure.30,48,64 Animal studies suggest that this technique is useful if performed within minutes, but its benefit is not proven in human exposures, possibly because of delay in patient presentation and limited availability of expertise in the technique. In addition to topical antibiotics, cycloplegics, topical steroids, topical and systemic tetracyclines, and antiglaucoma medications may all be indicated. Early steroid treatment may decrease the inflammatory response, but continued use inhibits fibroblast function and healing.18,64 Ophthalmologists therefore suggest steroids only for the first 7 days. Although well-controlled research in animal models of ocular alkali injury suggest that topical citrate and ascorbate improve healing, a recent long-term study showed no significant benefit in humans and demonstrated delayed healing when used in patients with mild to moderate injury.9,49,50 Tetracyclines, particularly doxycycline, inhibit collagenase activity by chelating zinc, and reduce corneal ulceration.13,56 In addition, they also inhibit leukocyte activity. These treatments have supplanted less-effective earlier collagenase inhibitors (cysteine, acetylcysteine, penicillamine, EDTA), and many other previously used approaches. Investigational agents include fibronectin, epidermal growth factor, hyaluronate, and retinoic acid to promote regrowth of epithelium; and medroxyprogesterone and NSAIDs to limit inflammation without inhibiting stromal repair and collagen formation. Many surgical interventions are investigational and may

be indicated, including limbal stem cell and amniotic membrane transplantation.58,65

Ot he rs Most solvents cause immediate pain and superficial injury because of dissolution of corneal epithelial lipid membranes, but do not penetrate or react significantly with deeper tissue.30 The epithelial defect may be large or complete, but the limited depth of injury usually allows rapid regeneration of normal epithelium. Detergents and surfactants cause variable injury, ranging from minor irritation from soaps to extensive injury from cationic agents such as concentrated benzalkonium chloride.30 Ocular exposure to A-200 Pyrinate pediculicide shampoo causes typical detergent-surfactant injury, leading to extensive loss normal underlying stroma, and days. Lacrimators (tear gases), stimulate corneal nerve endings

of corneal epithelium but with therefore complete healing within such as chloroacetophenone, and cause pain, burning, and

tearing, but produce no structural injury at low concentrations. At high concentrations, these agents can produce significant corneal injury. Pepper spray, often used for self-protection by civilians or law enforcement agents, contains the active ingredient oleoresin capsicum (OC). OC results in rapid depolarization of nociceptors containing substance P, resulting in immediate pain, blepharospasm, tearing, and blurred vision. In general, ocular injury is uncommon, although corneal erosions can occur. The solvent used for the spray can be more injurious to the eye than the OC itself. Although most sprays use a water- or oil-based solvent, some use alcohol, which can result in significant corneal damage.67 Management of pepper spray exposure consist of rapid irrigation and pain control. Corneal erosions can be treated with artificial tears but corneal abrasions should be treated with topical antistaphylococcal antibiotics. Specific information on thousands of

agents is readily available if needed.30

Disposition Disposition of patients with chemical burns of the cornea can be challenging. Patients with extensive burns to other parts of the body should be evaluated for transfer to a burn center. Grading the degree of injury in patients with isolated ocular injury can guide disposition. The most commonly used grading system is the Roper-Hall modification of the Ballen classification system. Injury is graded on a 4-tier scale: Patients with mild conjunctival injection with corneal epithelial loss and minimal corneal haziness are classified as grades 1 and 2 (mild to moderate). These patients can be safely discharged from the emergency department with ophthalmology followup within 24–48 hours. Patients with severe corneal haziness or opacification with significant limbal ischemia are classified as grades 3 or 4 (moderate to severe) and should receive immediate consultation with an ophthalmologist and transfer to a burn unit should be considered. P.335

Toxicity

to

Nonocular

Ocular

Structures

from

Exposures

Ocular toxicity from systemic xenobiotics is almost always the result of chronic exposure, and the manifestations develop over a prolonged period of time. Thousands of substances are implicated, affecting every element of the visual system from the cornea to the optic cortex. Thorough discussion of this topic is beyond the scope of this text, but Table 20-2 lists examples of causative xenobiotics.23,30 Many topical and systemic medications are associated with inflammation of the eye, as well as uveitis. 24 Unlike many other ocular abnormalities caused by xenobiotics, uveitis should prompt immediate ophthalmologic consultation.

Because many etiologies are commonly prescribed medications, adverse drug effects should always be considered when patients present with visual abnormalities or unusual ocular findings on examination.

TABLE 20-2. Examples of Ocular Abnormalities Caused by Chronic Systemic Xenobiotic Exposuresa

Corneal/conjunctival inflammation Cytosine (Ara-C)

arabinoside

Retrobulbar and optic neuropathy Carbon

disulfided

Isotretinoinb

Chloramphenicold

Mercury

Dinitrobenzened

(acrodynia)

Practololc

Dinitrochlorobenzened Dinitrotoluened

Retinal

injury

Carmustinec

Carbon

disulfided

Chloramphenicol c

Disulfiram Ethambutolb Isoniazidc Leadc

Chloroquine

Cinchona (quinine)

alkaloids

Thallium Vincristinec

Deferoxaminec Digitalisc

Cataracts

Ethambutol

Busulfanc

Thallium

Corticosteroidsb

Vigabatrin

Deferoxamine

Vincristinec

Dinitrophenol

(internal

use)d Trinitrotoluened

Uveitis

Bisphosphonates

Cortical

blindness

Pamidronate

Cisplatin

Rifabutin

Cyclosporine

Sulfonamides

Interleukinc

Tacrolimus

Corneal

deposits

Methylmercury

compoundsd

Amiodaroneb

Chloroquine

Lens

deposits

Chlorpromazine

Amiodaroneb

Copperd

Chlorpromazine

Gold

Copperd

Mercuryd

Iron

Retinoids

Mercuryd

Silver

Vitamin

(argyria)d

Silverd

D Myopiac

Acetazolamide

Diuretics thiazides,

(chlorthalidone, spironolactone)

Retinoids

Sulfonamides a

This list includes only selected examples and is not intended to be comprehensive. b Particularly important example. c Reported, but extremely rare from this exposure. d Mostly of historical interest; associated with patterns of use that are no longer common.

TABLE 20-3. Xenobiotics Reported to Cause Visual Loss After Acute Exposures

Direct causes Caustics Methanol Quinine Leada Mercuric chloridea Indirect causesb Amphetamines Cocaine Embolization of foreign material (parenteral injection) Cisplatinum Combined endocrine agents (thyrotropin-releasing hormone with gonadotropin-releasing hormone and glucagon) Ergot alkaloids

Hypotension

(eg,

calcium

channel

blockers)

a

Distinctly rare with these poisonings. Distinctly rare with use of these agents; visual loss often instantaneous, secondary to sudden hypotension, vascular spasm, or embolization. Adapted, with permission, from Smilkstein MJ, Kulig KW, Rumack BH: Acute toxic blindness: Unrecognized quinine poisoning. Ann Emerg Med 1987;16:98–101. b

In the setting of emergency care, xenobiotic-induced disturbances of normal vision from systemic exposures take many forms. Impaired near-vision from mydriasis, and diplopia or nystagmus from interference with normal control of extraocular movements, are examples of common, usually harmless, visual effects. Serious effects generally result from injury or dysfunction of the neural elements from the retina to the cortex. Such toxicity can be direct (neurotoxic) or indirect (hypoxia, ischemia). Many xenobiotics historically reported to cause acute visual loss directly are no longer available.30 Methanol and quinine are currently the most important xenobiotics that cause direct visual toxicity after acute oral poisoning. Many xenobiotics capable of causing vasospasm, hypotension, or embolization also cause acute visual loss (Table 20-3) .59 Blindness and other visual defects are described following recovery from severe toxicity with barbiturates and other sedative-hypnotics, opioids, carbon monoxide, and many others.30

Methanol Formate, the byproduct of methanol metabolism (Chap. 103), is the cause of visual toxicity from methanol poisoning. Although interspecies differences complicate the analysis, it appears that the primary event in ocular toxicity is the metabolism of methanol

by retinal glial cells, which results in local elevation of formate concentration.19,27,28,38,46 The exact effects of formate remain to be defined, but formate is postulated to interfere with mitochondrial cytochrome oxidase and succinate-cytochrome c reductase, and possibly with the Na + - K+ -adenosine triphosphatase (ATPase) system in the fibers of the optic nerve head.37 Although the retina is the likely primary site of toxicity,19,27,28,38,45,46 injury to the retinal ganglion cells and the retrobulbar optic nerve are also described, possibly as secondary effects. The visual signs and symptoms of methanol-induced visual disturbance include blurred or misty vision, “snowfield― vision, spots, central and peripheral scotomata, decreased light perception, and complete blindness. 6 The physical examination is consistent with the mechanism described: Although P.336 in many patients with only mild visual impairment the examination may be normal, the most consistent finding in severe cases is initial hyperemia of the optic nerve head, which later becomes edematous. The extension of the edema to the surrounding retina correlates with central scotomata, which are common. In severe cases, the edema may extend to large areas of the retina. In the most severe cases, when light perception is lost, the pupils may be widely dilated and unreactive. In severe cases, histopathologic examination reveals injury to the retinal ganglion cell layer and extension of the optic nerve injury to the retrobulbar nerve fibers.28 Optic atrophy often follows, and although central scotomata and peripheral visual field constriction are common, more complete visual loss may then occur. Patients with prolonged metabolic acidosis show a tendency towards developing residual visual impairment.36 Additionally, the constellation of severe initial impairment, dilated and unreactive pupils, and widespread retinal edema also implies a particularly poor visual prognosis. The concentration and duration of formate exposure also appears

to be critical to the development of retinal toxicity, but there are not yet reliable estimates or practical methods of determining these variables after human poisoning. Therefore, any patient with acidemia after methanol poisoning is assumed to be at risk for retinal damage. As discussed in Chap. 103, the risk can be reduced by the administration of folate or folinic acid to enhance the elimination of formate and to prevent retinal folate depletion27,28 (see Antidotes in Depth: Leucovorin [Folinic Acid] and Folic Acid and Antidotes in Depth: Sodium Bicarbonate) .

Quinine The mechanism of quinine-induced visual impairment is less-well understood, but it is known to involve neurotoxic injury to the optic nerve and perhaps retinal ganglion cells.31 Visual symptoms can include blurred vision, central and peripheral scotomata, and complete blindness. 8 The onset of visual impairment varies, but sudden visual loss can occur as late as 14 hours or more after overdose.59 Physical examination reveals pupils that are dilated and unreactive in proportion to the degree of visual impairment. Funduscopic examination is often completely normal but may show edema of the optic nerve, retina, or both, and retinal arteriolar constriction.30 Retinal vasoconstriction was previously thought to be the cause of visual injury, and therapies such as vasodilators and stellate ganglion block were used in an attempt to reverse the vasospasm. Further study clearly shows both complete blindness with normal vessels, and recovery in patients with vasospasm.26,59 Thus, retinal vasoconstriction is no longer thought to be of primary importance, although there is still speculation that vasospasm may have a modifying effect on outcome. Currently, there is no role for vasodilator therapy in these cases. Recovery is often very rapid, but residual impairment is common in severe cases. In a study of 225 cases of quinine poisoning, 70 patients developed visual impairment. Of 31 patients whose worst

ocular manifestation was blurred vision, all had complete visual recovery. However, of 39 patients who developed complete blindness, only 17 had full recovery.8 The most common residual effects are peripheral field defects and central scotomata. Impaired color vision and complete blindness may also persist, but this is less common. Varying degrees of visual impairment (quinine amblyopia) have resulted from diverse forms of quinine exposure, but complete blindness is reported only after oral ingestion of large amounts of quinine. It is difficult to predict which patients will develop quinine amblyopia, but it does appear to be dose related. Although it certainly occurs at lower levels, permanent blindness should be expected if quinine serum levels exceed 20 mg/mL in the first 10 hours after ingestion (Chap. 56) .8

Ocular

Complications

of

Drug

Abuse

In addition to the well-known ocular pupillary signs of opioid, cocaine, amphetamine, and phencyclidine toxicity, a number of complications may result from short- or long-term use of these and other agents.43 Quinine amblyopia (see Quinine above) caused by intravenous use of quinine-containing heroin is one of many ocular complications caused by injection of contaminants. Talc retinopathy was first described after prolonged intravenous use of adulterated methylphenidate,25 but has subsequently been noted after intravenous use of heroin, methadone,44 codeine, meperidine, and pentazocine. Talc retinopathy develops only after extensive intravenous drug use. In one study of intravenous methadone abusers, only patients who had injected more than 9000 tablets developed this complication.44 Infectious complications, such as fungal (Candida, Aspergillus) or bacterial (Staphylococcus spp, Bacillus cereus) endophthalmitis, are well known as both direct effects of intravenous drug use and secondary complications of AIDS. In addition to AIDS-related ophthalmic infections such as cytomegalovirus, cryptococcus, toxoplasmosis retinitis, and choroidal Mycobacterium avium-

intracellulare complex (MAC), other disorders include retinal cotton-wool spots, conjunctival Kaposi sarcoma, and ocular motility disorders caused by infectious or neoplastic meningitis. Corneal defects have been noted after smoking cocaine alkaloid (“crack eye―).54 Cocaine that is either volatilized or inadvertently introduced by direct contact, probably results in corneal anesthesia and loss of corneal protective reflex sensation. Minor trauma, such as eye rubbing, then leads to corneal epithelial defects. In addition, there appears to be an increased incidence of infectious keratitis and corneal ulceration in these patients. The ability of local anesthetics to interfere with corneal epithelial adhesion may also play a role.

Summary Both systemic and local toxicologic emergencies occur in the ophthalmic system. This discussion has focused on the research in the treatment of damage to the eye caused by xenobiotics. Although the obvious physical injuries are apparent to the clinician, the more subtle clues to toxicologic mechanisms that involve the ophthalmic and neurologic systems are only made by a meticulous examination of the eye. A careful ophthalmic examination often leads to early recognition of a toxicologic emergency.

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3. Adler IN, Wlodyga RJ, Rope SJ: The effects of pH on contact lens wearing. J Am Optom Assoc 1968;39:1000–1001. 4. Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, 2nd ed. Philadelphia, WB Saunders, 2000. P.337 5. Beiran I, Miller B, Bentur Y: The efficacy of calcium gluconate in ocular hydrofluoric acid burns. Hum Exp Toxicol 1997;16:223–228. 6. Benton CD, Calhoun FP: The ocular effects of methyl alcohol poisoning: Report of a catastrophe involving 320 persons. Am J Ophthalmol 1953;36:1677–1685. 7. Berlin R, Sing K, Lee U, Steiner R: Toxicity from the use of brimonidine ophthalmic solution in an infant and reversal with naloxone [abstract]. J Toxicol Clin Toxicol 1997;35:506. 8. Boland ME, Brennand Roper SM, Henry JA: Complications of quinine

poisoning.

Lancet

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9. Brodovsky SC, McCarty CA, Snibson G, et al: Management of alkali burns: An 11-year retrospective review. Ophthalmology 2000;107:1829–1835. 10. Brown VKH, Box VL, Simpson BJ: Decontamination procedures for skin exposed to phenolic substances. Arch Environ Health 1975;30:1–6. 11. Burke J, Kharlamb A, Shan T, et al: Adrenergic and

imidazoline receptor-mediated responses to UK-14,304-18 (brimonidine) in rabbits and monkeys. A species difference. Ann N Y Acad Sci 1995;763:78–95. 12. Burns FR, Paterson CA: Prompt irrigation of chemical eye injuries may avert severe damage. Occup Health Saf 1989;58:33–36. 13. Burns FR, Stack MS, Gray RD, Paterson CA: Inhibition of purified collagenase from alkali burned rabbit cornea. Invest Ophthalmol Vis Sci 1989;30:1569–1575. 14. Carney LG, Hill RM: Human tear pH: Diurnal variations. Arch Ophthalmol 1976;94:821–824. 15. Chen FS, Maurice DM: The pH in the precorneal tear film and under a contact lens measured with a fluorescent probe. Exp Eye Res 1990;50:251–259. 16. Davson H: Physiology of the Eye, 5th ed. New York, Pergamon Press, 1990. 17. Dean BS, Krenzelok EP: Cyanoacrylates and corneal abrasions. J Toxicol Clin Toxicol 1989;27:169–172. 18. Donshik PC, Berman MB, Dohlman CH, et al: Effect of topical corticosteroids on ulceration in alkali-burned corneas. Arch Ophthalmol 1978;96:2117–2120. 19. Eells JT, Salzman MM, Lewandowski MF, Murray TG: Formate-induced alterations in retinal function in methanolintoxicated rats. Toxicol Appl Pharmacol 1996;140:58–69.

20. Flach AJ: Systemic toxicity associated with topical ophthalmic medications. J Fla Med Assoc 1994;81:256–260. 21. Fraunfelder FT, Bagby GC, Kelly DJ: Fatal aplastic anemia following topical administration of ophthalmic chloramphenicol. Am J Ophthalmol 1982;93:356–360. 22. Fraunfelder FT, Fraunfelder FW, Jensvold B: Adverse systemic effects from pledgets of topical ocular phenylephrine 10%. Am J Ophthalmol 2002;134:624–625. 23. Fraunfelder FT, Fraunfelder FW, eds: Drug-Induced Ocular Side Effects, 5th ed. Boston, Butterworth Heinemann, 2001. 24. Fraunfelder FW, Rosenbaum JT: Drug-induced uveitis incidence, prevention and treatment. Drug Saf 1997;17:197–207. 25. Friberg TR, Gragoudas ES, Regan CDJ: Talc emboli and macular ischemia in intravenous drug abuse. Arch Ophthalmol 1979;97:1089–1091. 26. Friedman L, Rothkoff L, Zaks U: Clinical observations on quinine toxicity. Ann Ophthalmol 1980;12:640–642. 27. Garner CD, Lee EW, Terzo TS, Louis-Ferdinand RT: Role of retinal metabolism in methanol-induced retinal toxicity. J Toxicol Environ Health 1995;44:43–56. 28. Garner CD, Lee EW, Louis-Ferdinand RT: Muller cell involvement in methanol-induced retinal toxicity. Toxicol Appl

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1995;130:101–107.

29. Gottschalk HR, Stone Orville J: Stevens-Johnson syndrome from ophthalmic sulfonamides. Arch Dermatol 1976;112:513–514. 30. Grant WM, Schuman JS: Toxicology of the Eye, 4th ed. Springfield, IL, Charles C. Thomas, 1993, p. 1531. 31. Grant WM: The peripheral visual system as a target. In: Spencer PS, Schaumberg HH, eds: Experimental and Clinical Neurotoxicology. Baltimore, Williams & Wilkins, 1980, pp. 77–91. 32. Herr RD, White GL, Bernhisel K, et al: Clinical comparison of ocular irrigation fluids following chemical injury. Am J Emerg Med

1991;9:228–231.

33. Hugues FC, Le Jeunne C: Systemic and local tolerability of ophthalmic drug formulations. An update. Drug Saf 1993;8:365–380. 34. Kimbrough RL, Okereke PC, Stewart RH: Conservative management of cyanoacrylate ankyloblepharon: A case report. Ophthalmic Surg 1986;17:176–177. 35. Lang K: Treatment of phenol burns of the eye with polyethyleneglycol-400. Z Arztl Fortbild (Jena) 1969;63:705–708. 36. Liu JJ, Daya MR, Carrasquillo O, Kales SN: Prognostic factors in patients with methanol poisoning. J Toxicol Clin

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37. Martin-Amat G, Tephly TR, McMartin KE, et al: Methyl alcohol poisoning: II. Development of a model for ocular toxicity in methyl alcohol poisoning using the Rhesus monkey. Arch Ophthalmol 1977;95:1847–1850. 38. Martinasevic MK, Green MD, Baron J, Tephly TR: Folate and 10-formyltetrahydrofolate dehydrogenase in human and rat retina: Relation to methanol toxicity. Toxicol Appl Pharmacol 1996;141:373–381. 39. Mattox C: Table of toxicology. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, 2nd ed. Philadelphia, WB Saunders, 2000, pp. 496–507. 40. McCarron MM, Schulze BW, Thompson GA, et al: Acute phencyclidine toxicity: Incidence of clinical findings in 1,000 cases. Ann Emerg Med 1981;10:237–242. 41. McCulley JP: Ocular hydrofluoric acid burns: Animal model, mechanism of injury and therapy. Trans Am Ophthalmol Soc 1990;88:649–684. 42. McCulley JP, Whiting DW, Petitt MG, Lauber SE: Hydrofluoric acid burns of the eye. J Occup Med 1983;25:447–450. 43. McLane NJ, Carroll DM: Ocular manifestations of drug abuse. Surv Ophthalmol 1986;30:298–311. 44. Murphy SB, Jackson WB, Dare JA: Talc retinopathy. Can J

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45. Murray TG, Burton TC, Rajani C, et al: Methanol poisoning: A rodent model with structural and functional evidence of retinal involvement. Arch Ophthalmol 1991;109:1012–1016. 46. Neymeyer VR, Tephly TR: Detection and quantification of 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH) in rat retina, optic nerve, and brain. Life Sci 1994;54:PL395–PL399. 47. Palmer EA: How safe are ocular drugs in pediatrics? Ophthalmology 1986;93:1038–1040. 48. Paterson CA, Pfister RR, Levinson RA: Aqueous humor pH changes after experimental alkali burns. Am J Ophthalmol 1975;79:414–419. 49. Pfister RR, Haddox JL, Yuille-Barr D: The combined effect of citrate/ascorbate therapy in alkali-injured rabbit eyes. Cornea 1991;10:100–104. 50. Pfister RR, Paterson CA, Spiers JW, Hayes SA: The efficacy of ascorbate treatment after severe experimental alkali burns depends on the route of administration. Invest Ophthalmol Vis Sci 1980;19:1526–1529. 51. Rozenbaum D, Baruchin AM, Dafna Z: Chemical burns of the eye with special reference to alkali burns. Burns 1991;17:136–140. 52. Rubenfeld RS, Silbert DI, Arentsen JJ, Laibson PR: Ocular

hydrofluoric acid burns. Am J Ophthalmol 1992;114:420–423. 53. Saari KM, Leinonen J, Aine E: Management of chemical eye injuries with prolonged irrigation. Acta Ophthalmol 1984;161(Suppl 16):52–59. 54. Sachs R, Zagelbaum BM, Hersh PS: Corneal complications associated with the use of crack cocaine. Ophthalmology 1993;100:181–191. 55. Schrage NF, Kompa S, Haller W, Langefeld S: Use of an amphoteric lavage solution for emergency treatment of eye burns. First animal type experimental clinical considerations. Burns

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56. Seedor JA, Perry HD, McNamara TF, et al: Systemic tetracycline treatment of alkali-induced corneal ulceration in rabbits. Arch Ophthalmol 1987;105:268–271. 57. Shell JW: Pharmacokinetics of topically applied ophthalmic drugs. Surv Opthalmol 1982;26:207–217. 58. Shimazaki J, Yang HY, Tsubota K: Amniotic membrane transplantation for ocular surface reconstruction in patients with chemical and thermal burns. Ophthalmology 1997;104:2068–2076. P.338 59. Smilkstein MJ, Kulig KW, Rumack BH: Acute toxic blindness: Unrecognized quinine poisoning. Ann Emerg Med 1987;16:98–101.

60. Trevino MA, Herrmann GH, Sprout WL: Treatment of severe hydrofluoric acid exposures. J Occup Med 1983;25:861–863. 61. Velde TM, Kaiser Fe: Ophthalmic timolol treatment causing altered hypoglycemic response in a diabetic patient. Arch Intern Med 1983;143:1627. 62. Verkijk A: Worsening of myasthenia gravis with timolol maleate eyedrops. Ann Neurol 1985;17:211–212. 63. Victor M, Adams RD: The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1953;32:526–573. 64. Wagoner MD: Chemical injuries of the eye: Current concepts in pathophysiology and therapy. Surv Ophthalmol 1997;41:275–312. 65. Walters TR: Development and use of brimonidine in treating acute and chronic elevations of intraocular pressure: A review of safety, efficacy, dose response, and dosing studies. Surv Ophthalmol 1996;41(Suppl 1):S19–S26. 66. Webster RG, Slansky HH, Refojo MF, et al: The use of adhesive for the closure of corneal perforations: Report of two cases. Arch Ophthalmol 1968;80:705–709. 67. Zollman TM, Bragg RM, Harrison DA: Clinical effects of oleoresin capsicum (pepper spray) on the human cornea and conjunctiva. Ophthalmology 2000;107:2186–2189.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 21 - Otolaryngologic Principles

Chapter

21

Otolaryngologic

Principles

William K. Chiang Many xenobiotics adversely affect the special senses of olfaction, gustation, and cochlear-vestibular functions. These toxic effects are not life-threatening and frequently are not considered to be important. Because of the lack of standardized diagnostic techniques and normal parameters, particularly for olfactory and gustatory functions, it is likely that such adverse effects will be overlooked and dismissed by healthcare providers, despite significant patient distress and dysfunction. This chapter reviews the anatomy and physiology related to these senses; delineates the effects of xenobiotics on these senses; and examines the significant diagnostic information these senses contribute to the detection of xenobiotics. Understanding the effects of xenobiotics on the senses may allow for early detection, which occasionally can be lifesaving.

Olfaction

Anatomy

and

Physiology

Olfactory receptors are bipolar neurons located in the superior nasal turbinates and the adjacent septum. There are 10–20 million cells per nasal chamber, and the receptor portion of the cell undergoes continuous renewal from the olfactory epithelium.111 , 114 Renewed olfactory receptors regenerate neural connections to the olfactory bulb. Olfactory receptor neurons are distinctive in their ability to regenerate. 25 The axons of these cells form small bundles that traverse the fenestrations of the cribriform plate of the ethmoid bone to the dura. Within the dura, these bundles form connections with the olfactory bulb. Neural projections then connect to the olfactory cortex. There are extensive central interconnections to other parts of the brain, such as the hippocampus, thalamus, hypothalamus, and frontal lobe, suggesting effects on other biologic functions. 111 Although primary odor detection is a function of the olfactory cranial nerve (CN I), some irritant odors, such as ammonia and acetone, are transmitted through the trigeminal cranial nerve (CN V) and its receptors.44 , 150 The actual olfactory receptor sites are structurally similar to taste receptors of the mouth and photoreceptors of the retina. The receptor is a single polypeptide chain consisting of approximately 350 amino acids, which folds back and forth on itself to transverse the cellular membrane 7 times. The outer end of the polypeptide contains an amine group (N-terminal) and the cytosol end contains a carboxyl group (C-terminal). The transmembranous portions determine the receptor shape and characteristics of the binding site. When a molecule binds to a specific receptor site, the resultant conformational change leads to the activation of the Gprotein system, and calcium and/or sodium channel activation and neurotransmission.77 Smelling is an extremely sensitive detector of certain substances. Olfactory receptors can detect as little as a few molecules of

certain xenobiotics with a sensitivity that is superior to some of the most sophisticated laboratory detection instruments.69

Limitations

of

the

Olfactory

Senses

A number of problems present the greatest utility of smell as a toxicologic warning system. Human olfaction is a variable trait.5 , 122 , 179 For example, 40–45% of people have specific anosmia (inability or loss of smell) for the bitter almond odor of cyanide.45 , 91 , 122 There are limited data on the inheritance characteristics or genetic basis of these specific forms of anosmia. While some studies suggest that the ability to detect the odor of cyanide is a sex-linked recessive trait,59 other studies yield conflicting results.5 , 20 , 93 Females have a greater ability to detect androsterone, which is also prominent in human underarm secretion.69 Human olfaction usually can distinguish a mixture of no more than 4 xenobiotics,97 and therefore specific odors may be masked by other stimuli. Olfactory fatigue is the process of olfactory adaptation following exposure to a stimulus for a variable period of time. This leads to a temporal diminution of the smell. Unfortunately, this adaptation may lead to a false sense of security with continued exposure to a xenobiotic. For example, hydrogen sulfide, which inhibits cytochrome oxidase, is readily detectable as distinct and offensive at the very low concentration of 0.025 ppm. At the higher and potentially toxic concentration of 50 ppm, the odor is less offensive, and recognition may disappear after 2–15 minutes of exposure.8 , 154 At an even higher concentration, when toxicity is likely, the onset of olfactory fatigue is even more rapid. The combination of the rapid onset of olfactory fatigue and toxicity at high concentrations of hydrogen sulfide exposure has contributed to numerous fatalities (Chap. 121 ). 1 , 27 In industrial settings, it is important to be aware of impaired olfactory function in any worker who may be exposed to chemical

vapors or gases.75 , 159 Such workers are at increased risk for toxic injury. The National Institute for Occupational Safety and Health (NIOSH) requires that an individual using an air-purifying respirator be capable of detecting the odor of a xenobiotic at levels below those producing toxicity.6 , 159 Sensory perception at this level ensures that the individual can detect filter cartridge “breakthrough― or failure at a safe level.159 The odor safety factor refers to the ratio of the time-weighted average (TWA) threshold limit value (TLV) P.340 to the odor threshold for a given xenobiotic. A xenobiotic with a high odor safety factor can be detected despite prolonged exposure.6 Nontoxic xenobiotics, such as ethyl mercaptan, with a very high odor safety factor, can be added to xenobiotics that are odorless with lower safety factors, so that olfactory detection is predictable. This enhanced sensory awareness is the basis for the addition of mercaptans to the odorless natural gases used in the home so as to limit the potential for unrecognized hazardous exposure.

Clinical

Use

of

Odor

Recognition

The recognition of odors has traditionally been considered an important diagnostic skill in clinical medicine. Diseases can be diagnosed solely by recognizable associated odors: diabetic ketoacidosis as fruity; diphtheria as sweet; scurvy as putrid; typhoid fever as fresh-baked brown bread; and scrofula as stale beer.38 Odors are also described for disorders of amino acid and fatty acid metabolism, such as phenylketonuria, maple syrup urine disease, hypermethioninemia, and isovaleric acidemia.38 The recognition of odors continues to be skill for the rapid detection of xenobiotics increase the awareness of odors of toxic bar― of commonly available odors may

an important diagnostic (Table 21-1 ). To xenobiotics, a “sniffing be prepared (Table 21-2

) .64 Nontoxic xenobiotics that simulate the odors of toxic xenobiotics are placed in test tubes, numbered, and inserted in a test tube rack for circulation among staff. The sniffing bar, brief descriptions of clinical presentations, and a table of diagnostic odors (Table 21-1 ), may be used to teach the recognition of odors in medical toxicology.64

Etiology

of

Olfactory

Impairment

There are different types of olfactory dysfunction. Anosmia, the inability to detect certain odors, and hyposmia, a decrease in the perception of certain odors, are the most common forms of olfactory impairment. The etiology of olfactory impairment may be classified as conductive, from anatomic obstruction of inspired air, or perceptive, from dysfunction of the olfactory receptors or signal transmission. Most conductive olfactory dysfunction results in hyposmia, because the obstruction is usually incomplete.111 , 147 Acetone (sweet, fruity) Lacquer, ethanol, isopropanol, paraldehyde, chloral Bitter almond Cyanide Carrots

hydrate,

chloroform,

trichloroethane,

methylbromide

Cicutoxin (water hemlock) Disinfectants Phenol, creosote Eggs (rotten) Hydrogen sulfide, carbon disulfide, mercaptans, acetylcysteine Fish or raw liver (musty) Zinc phosphide, aluminum phosphide Fruit Nitrites (amyl, butyl) Garlic

disulfiram, N -

Phosphorus, tellurium, arsenic, organic phosphorus selenium, thallium, dimethyl sulfoxide (DMSO) Hay Phosgene Mothballs Naphthalene, p -dichlorobenzene, camphor Pepper 0 -chlorobenzylidene malonitrile Rope (burnt) Marijuana, opium Shoe polish Nitrobenzene Tobacco Nicotine Vinegar Acetic acid Vinyl Ethchlorvynol Violets

compounds,

(Placidyl)

Turpentine (metabolites excreted in urine) Wintergreen Methyl salicylate Characteristic

Odor

Potentially

Responsible

Xenobiotic

TABLE 21-1. Diagnostic Odors The most common causes of anosmia and hyposmia are viral infections, trauma, xenobiotics, tumors, and congenital and psychiatric disorders (Table 21-3 ).44 , 133 , 139 , 147 , 150 Viral infections may result in olfactory impairment either by obstructing nasal airflow or by causing damage to the olfactory epithelium.78 Trauma to the head or nose can shear fragile olfactory nerves crossing the cribriform plate. In fact, as many as 5% of patients

with head trauma have subsequent olfactory dysfunction.150 , 169 Chronic exposures to numerous xenobiotics are associated with olfactory dysfunction (Table 21-3 ). The most common toxic mechanism related is perceptive olfactory dysfunction. This may be a result of a direct injury or of a structural alteration of the receptor, or its components such as G proteins, adenylate cyclase, or receptor kinase.76 , 77 Anosmia or hyposmia from hydrocarbons, formaldehyde, heavy metals such as cadmium, and antineoplastic agents such as cytarabine result from direct effects on the receptor sites.48 , 77 , 82 Local effects on the epithelium and the receptors from antibiotic nose drops may lead to temporary anosmia and hyposmia.88 , 178 Inhaled corticosteroids may have local effects on the epithelium, as well as direct effects on both G proteins and adenylate cyclase.79 Cocaine insufflation causes direct local effects, as well as effects on receptor functions.65 , 73 Because of local effects of most xenobiotics and the regenerative ability of the olfactory receptor neurons, most xenobiotic-induced olfactory dysfunction is reversible. Most people with anosmia have congenital anosmia to selected individual molecules, such as hydrogen cyanide, N -butyl mercaptan, trimethylamine, and isovaleric acid.7 , 44 Some extreme forms of congenital anosmia are associated with other abnormalities, such as Kallmann syndrome, a hereditary form of anosmia associated with hypogonadotropic hypogonadism. Agenesis of the olfactory bulbs and incomplete development of the hypothalamus causes this form of anosmia.44 , 150 Dysosmia or parosmia is the distorted perception of smell (Table 21-3 ). Subclassifications of dysosmia include the perception of foul smell or cacosmia, the sensation of smell without a stimulus or phantosmia, and the sensation of the smell of a burnt or metallic material, torqosmia.147 The etiologies are classified as peripheral or central. Peripheral etiologies include abnormalities of the nose, sinuses, and upper respiratory tract. Central etiologies

may be related to disorders such as Addison disease, hypothyroidism, temporal lobe epilepsy, and psychosis, or to conditions such as pregnancy.44 , 111 , 148 How these conditions actually alter the perception of smell is unclear. A number of xenobiotics with similar effects are listed in Table 21-3 . Bromocriptine alters dopaminergic transmission and inhibits adenylate cyclase. Levodopa also affects the dopaminergic transmission and chelates zinc, which is important in the maintenance of normal receptor functions.77 , 79

Evaluation

of

Olfactory

Impairment

General evaluation of olfactory function should include a detailed history, focusing on types, duration, and progression of symptoms, recent illnesses, head and nose trauma, sinus problems, family history, occupational history, hobbies, medications, and drug history.39 , 68 A complete physical examination and detailed examination P.341 of the nasopharynx and sinuses should be performed to assess the potential for inflammation or structural abnormality. A simple set of olfactory stimulants, such as ground coffee, almond extract, peppermint extract, and musk, should be used to test each nostril individually with the patient's eyes closed.68 , 150 Standardized smell tests such as the UPSIT (University of Pennsylvania Smell Identification Test) and the CCCRC (Connecticut Chemosensory Clinical Research Center) tests are now commercially available; a composite score based on a panel of tests can determine the degree of olfactory dysfunction.103 Pungent odors or stimulation associated with ammonia, capsaicin, acetone, and menthol are dependent on the trigeminal nerve (CN V) olfactory function, which is mainly P.342 responsible for tactile pressure, pain, and temperature sensation in the mouth and nasal cavity. A patient who has olfactory nerve

damage should be able to detect these substances; conversely, a person with hysteria may deny detection of these substances that should physiologically be recognized.68 , 150 , 178 If a xenobioticmediated mechanism is suspected, the offending agent should be discontinued. A coronal CT of the sinuses and nose or a CT or a MRI of the brain may be required if structural abnormalities are suspected.150 , 178 Gas chromatographic analysis of the urine may be useful in patients with fish odor syndrome associated with trimethylaminuria.98 , 156 Complicated cases and patients with significant impairment should be referred to an otolaryngologist or neurologist. Tube 1 Tube 7 Case history: A lethargic 28-year-old woman was brought to emergency department with an altered mental status. Case history: A 4-year-old boy was brought to the emergency department with a temperature of 103.5°F (39.7°C), a respiratory rate of 32 breaths/min, and markedly altered mental status. Laboratory tests on admission showed a high-anion-gap metabolic acidosis. The patient smelled like a “wintergreen candy.― Odor: Toxin: Vinyl smell Ethchlorvynol Contents of tube: Liquid contents of Placidyl capsule Tube 2 Case history: A 34-year-old man in cardiopulmonary arrest found in a chemical plant near several gas cylinders. Odor:

Wintergreen Toxin: Methyl salicylate Odor: Bitter almond Contents of tube: Oil of wintergreen or wintergreen candy Toxin: Cyanide Contents of tube: Macerated seeds from inside of peach pit or almond extract. Tube 8 Case history: A 3-year-old boy was brought to the emergency department in considerable pain. On examination the department in considerable pain. On examination the child exhibited dysphagia and dysphonia, the oral mucosa appeared blistered and erythematous. The child's mother stated that he must have gotten into cleaning supplies. Tube 3 Case history: A 27-year-old man was brought to the emergency department with necrotic burns on his oral mucosa after gargling with an unknown liquid germicide. The patient thought it would help his sore throat. The pH of the germicide was 5. Odor: Toxin: Ammonia Ammonia Odor: White paste (glue)

Contents of tube: Ammonia (diluted Toxin: Phenol

household)

Contents of tube: Phenol (liquefied) (5 × 109 /L). Allergic or inflammatory reactions, infections with parasites, and certain malignancies, such as lymphoma, are the most common causes of eosinophilia.150 Two unusual toxicologic outbreaks were characterized by eosinophilia. The first outbreak, named the toxic oil syndrome, took place in central Spain in 1981, when industrial-use rapeseed oil denatured with 2% aniline was fraudulently sold as olive oil by door-to-door salesmen.53 The ingestion of this oil resulted in the acute onset of cough, fever, and pulmonary infiltrates, followed by severe myalgia, neuropathy, and

eosinophilia. The precise causative agent remains uncertain, but may include fatty acid esters of 3-(N-phenylamino)-1,2-propanediol.53 The second outbreak, called the eosinophilia-myalgia syndrome, occurred during 1988 and 1989 in users of L-tryptophan supplements traced back to a single wholesaler in Japan.5 The causative contaminant has not been identified, but is believed to have been present in only trace quantities in the L-tryptophan purified from microbial culture. Both syndromes appear to be mediated by immunologic mechanisms.

Leukemia The leukemias represent the malignant, unregulated proliferation of hematopoietic cells. Although monoclonal in origin, they affect all cell lines derived from the progenitor cell. Acute myeloid leukemia (AML) and the myelodysplastic syndromes are the most common leukemias associated with xenobiotics. The long-recognized association between AML and occupational benzene exposure, radiation, or treatment with alkylating antineoplastic agents has helped to advance understanding of the molecular mechanisms underlying leukemogenesis.14 The necessary events are believed to involve several sequential genetic and epigenetic alterations, as evidenced by a distinct pattern of chromosomal deletions preceding the development of AML.72,73 Other recognized xenobiotics that can cause leukemia include topoisomerase II inhibitors, 1,3-butanediol, styrol, ethylene oxide, and vinyl chloride.82 In many cases, the latency period between exposure and illness is prolonged. For example, leukemia linked to benzene is preceded by several months of anemia, neutropenia, and thrombocytopenia. Benzene or other petroleum products are not believed to cause multiple myeloma.14

TABLE 24-5. Selected Causes of Idiosyncratic Drug-Induced Agranulocytosis

Anticonvulsants Carbamazepine Phenytoin Antiinflammatory agents Aminopyrine Ibuprofen Indomethacin Phenylbutazone Antimicrobials β-Lactams Cephalosporins Chloramphenicol Dapsone Ganciclovir Isoniazid Rifampicin Sulfonamides Vancomycin Antirheumatics Gold Levamisole Penicillamine Antipsychotics Clozapine Phenothiazines Antithyroid agents Methimazole Propylthiouracil Cardiovascular agents Hydralazine Lidocaine Procainamide Quinidine Ticlopidine

Vesnarinone Diuretics Acetazolamide Hydrochlorothiazide Hypoglycemics Chlorpropamide Tolbutamide Sedative-hypnotics Barbiturates Flurazepam

Hemostasis In the absence of pathology, blood remains in a liquid, flowing form with cells in suspension. In response to injury, the processes of coagulation and thrombosis are triggered. The result, including clot formation, retraction, and dissolution involves an interaction between the vessel endothelium, soluble constituents of the coagulation system, and receptors and intracellular proteins contained on the surface of and within platelets. Platelet function is influenced by the physical properties of flowing blood, as well as by the chemical constituents within it. Platelets respond to signals within their immediate environment and from injured components of the distant microcirculation. A dynamic balance must be maintained between coagulation and fibrinolysis to maintain the integrity of the circulatory system (Fig. 24-4) .

Coagulation Two basic pathways are Activation of the intrinsic tissue factor in damaged leukocytes. Tissue factor

involved in the initiation of coagulation. system occurs when blood is exposed to blood vessels or on the surface of activated binds factor VIIa, forming the intrinsic

tenase complex, which activates factors IX and X. Factor IXa binds to the surface of activated platelets together with VIIIa and calcium, forming the extrinsic tenase complex. Factor X, which is activated by extrinsic and intrinsic tenase, binds to factor Va on the surface of activated platelets, forming the prothrombinase complex. The prothrombinase complex activates prothrombin, which results in the generation of thrombin activity. Thrombin P.392 activates platelets, promotes its own generation by activation factors V, VIII, and XI, and converts fibrinogen to fibrin (Chap. 57) .66

Figure 24-4. The relationships between thrombosis, coagulation, and fibrinolysis. Although these pathways are shown independently, they are intricately linked as outlined in the text. Dotted lines indicate inhibition; drugs are shown in italics. ATIII = antithrombin III; PAI = plasminogen activator inhibitor; t-PA = tissue plasminogen activator; rt-PA = recombinant t-PA; [circled plus] = activation of catalytic activity.

Fibrinolysis The coagulation system is opposed by three major inhibitory systems. As with the coagulation cascade, components of the fibrinolytic system circulate as zymogens, activators, inhibitors, and cofactors.46 Plasminogen can be activated to plasmin by an intrinsic pathway involving factor XII, prekallikrein, and high-molecularweight kininogen. This produces the degradation products and fibrin monomers that are found in disseminated intravascular coagulation. The extrinsic pathway involves the release of tissue plasminogen activator (t-PA) from tissues and urokinase plasminogen activator (uPA) from secretions.46 Once activated, plasmin can degrade fibrinogen, fibrin, and coagulation factors V and VIII. The degradation of cross-linked fibrin strands results in the formation of D-dimers. Several inhibitors oppose the fibrinolytic system, including α2 antiplasmin, α 2 -macroglobulin, both of which oppose plasmin activity, and plasminogen activator inhibitor (PAI) types 1 and 2, which oppose t-PA. PAI-1 and -2 are opposed by activated protein C and protein S. Activated protein C is activated by thrombin. Congenital deficiencies of proteins C and S may result in pathologic venous thrombosis. Decreased fibrinolytic activity may result from decreased synthesis, release of t-PA, or from an elevation of the PAI1 level. Both conditions have been observed postoperatively, with the use of oral contraceptives, in the third trimester of pregnancy,

and in obesity. The activity of α 2 -antiplasmin and α2 -macroglobulin are increased in pulmonary fibrosis, malignancy, infection, and myocardial infarction, and in thromboembolic disease.46

Platelets In the resting state, platelets maintain a discoid shape. The platelet membrane is a typical trilaminal membrane with glycoproteins, glycolipids, and cholesterol embedded in a phospholipid bilayer. The plasma membrane is in direct continuity with a series of channels, the surface-connected canalicular system (SCCS), which is sometimes referred to as the open canalicular system. The SCCS provides a route of entry and exit for various molecules, a storage pool for platelet glycoproteins, and an internal reservoir of membrane that may be recruited to increase platelet surface area.129 This facilitates platelet spreading and pseudopod formation during the process of cell adhesion. The glycocalyx, or outer coat, is heavily invested with glycoproteins that serve as receptors for a wide variety of stimuli. The β1 -integrin family includes receptors that mediate interactions between cells and mediators in the extracellular matrix, including collagen, laminin, and fibronectin.163 The β2 -integrin receptors are present in inflammatory cells and platelets and are important in immune activation. The β3 integrin receptors (also known as cytoadhesins) include the glycoprotein (GP) IIb-IIIa fibrinogen receptor, as well as vitronectin.66 Vitronectin has binding sites for other integrins, collagen, heparin, and components of complement. All of the integrins are active in the process of platelet adhesion to surfaces. Platelet aggregation is mediated by the GP IIb-IIIa receptors.66 The submembrane region contains actin filaments that stabilize the platelets' discoid shape and are involved in the formation and stabilization of pseudopods. They also generate the force needed for the movement of receptor-ligand complexes from the outer plasma membrane to the SCCS. These mobile receptors are important in the

spreading of platelets on surfaces, and for binding fibrin strands and other platelets. Platelet cytoplasm contains three types of membrane bound secretory granules.66 The α granules contain βthromboglobulin, which mediates inflammation, binds and inactivates heparin, and blocks the endothelial release of prostacyclin. In addition, platelet factor-4, which inactivates heparin, and fibrinogen are contained within the α granules. Dense granules store adenine nucleotides, serotonin, and calcium, which are secreted during the release reaction. Platelet lysosomes contain hydrolytic enzymes. Stimulation by platelet agonists causes the granules to fuse with the channels of the SCCS, driving the contents out of the platelets and into the surrounding media.

Platelet

Adhesion

In the vessel wall, collagen, von Willebrand factor (vWF), and fibronectin are the adhesive proteins that play the most prominent role in the adhesion of platelets to vascular subendothelium.163 On the exposure of collagen (eg, following a laceration or the rupture of an atherosclerotic plaque), platelet adhesion is triggered. Under conditions of high shear (flowing blood), platelet adhesion is mediated by the binding of GP Ib-IX receptors on platelet membranes to vWF in the vascular subendothelium.66,163 Following adherence of platelets to subendothelial vWF, a conformational change in GP IIb-IIIa on platelet membrane occurs, activating this receptor complex to ligate vWF and fibrinogen. The result is the amplification of platelet adhesion and aggregation. An important interaction occurs between thrombosis and inflammation. Plateletactivating factor is synthesized and coexpressed with P-selectin on P.393 the surface of the endothelium in response to mediators such as histamine or thrombin. Platelet-activating factor interacts with a receptor on the surface of neutrophils that activates the CD11/CD18 adhesion complex, and results in adhesion of neutrophils to endothelium and to platelets. This results in the synthesis of

leukotrienes and other mediators of inflammation.

Platelet

Activation

Thrombin, collagen, and epinephrine can activate platelets. In response to thrombin, α granules fuse with each other and with elements of the SCCS to form secretory vesicles.129 These vesicles are believed to fuse with the surface membrane, releasing their contents into the surrounding medium. The membranes of the secretory granules become incorporated into the platelet surface membrane.

Platelet

Aggregation

Following activation, GP IIb-IIIa is expressed in active form on platelet surface. This receptor binds exogenous calcium and fibrinogen. GP IIb-IIIa ligates fibrinogen along with fibronectin, vitronectin, and vWF, resulting in the binding of platelets to other platelets, and ultimately the formation of the platelet plug. Collageninduced platelet aggregation is mediated by adenosine diphosphate (ADP) and thromboxane A2 . ADP binds to the metabotropic purine receptors P2Y1 and P2Y12, leading to transient and sustained aggregation, respectively.51 Thromboxane A2 is formed from arachidonic acid by the action of cyclooxygenase (COX) 1. It is a potent vasoconstrictor and inducer of platelet aggregation and release reactions.66 Platelets participate in triggering the coagulation cascade by binding coagulation factors II, VII, IX, and X to membrane phospholipid, a calcium-dependent process.

Xenobiotic-Induced Coagulation

Defects

in

Warfarin The recognition of a hemorrhagic disease in cattle in the 1920s and

the isolation of the causative agent dicoumarol from spoiled sweet clover in the 1940s resulted in the development of the warfarin-type anticoagulants (Chap. 57). This group of anticoagulants indirectly inhibits hepatic synthesis of coagulation factors II, VII, IX, X, and proteins C and S.135 Hepatic γ-carboxylation of glutamic acid residues by vitamin K-dependent carboxylase results in the formation of the vitamin K-dependent clotting factors. Vitamin K must be available in its reduced form, vitamin K quinol, to effectively catalyze this reaction. The carboxylation reaction oxidizes vitamin K quinol to vitamin K2 , 3 epoxide, which must be reduced to vitamin K by reductase enzymes. The warfarin anticoagulants inhibit the reductase that is responsible for the regeneration of vitamin K quinone from vitamin K epoxide, impairing the synthesis of the vitamin Kdependent proteins.85,165

Heparin Heparin is a highly sulfated glycosaminoglycan that is normally present in tissues. Commercial unfractionated heparin is either bovine or porcine in origin, and consists of a mixture of polysaccharides with molecular weights ranging from 4000–30,000 daltons. It is used extensively for the prophylaxis and treatment of venous thrombosis and thromboembolism. It is ineffective orally because it cannot cross membranes. This same property makes it safe for use during pregnancy because heparin cannot cross the placenta.151 The anticoagulant activity of heparin is through its catalytic activation of antithrombin III. Antithrombin III is a serine protease that inactivates thrombin and factor X.119

TABLE 24-6. Xenobiotics Associated with Disorders of Fibrinolysis Resulting in Thrombosis

Antineoplastics Anthracyclines L-Asparaginase Mithramycin Aprotinin and other Coagulation factors Cytokines

antifibrinolytics

Erythropoietin Thrombopoietin Hormones

Adapted from Fareed J, Hoppensteadt DZ, Jeske WP, et al: Acquired defects of fibrinolysis associated with thrombosis. Semin Thromb Hemost 1999;25:367–374.

The low-molecular-weight heparins (LMWHs) have a mean molecular weight of 4000–6000 Da.66 The pharmacokinetics and bioavailability of the LMWHs are more predictable, eliminating the need for close monitoring. They exhibit lower protein binding and a longer half-life, making them more convenient to use.119

Xenobiotic-Induced

Defects

in

Fibrinolysis

Table 24-6 lists xenobiotics associated with an acquired defect of fibrinolysis. The antitumor agents may result in a reduction in serine protease inhibitors such as antithrombin. L-Asparaginase is associated with a reduction in circulating t-PA levels. Methotrexate can damage vascular endothelium, which may trigger thrombosis (Chap. 52) .46 Hemostatic drugs used therapeutically include the

synthetic lysine derivatives aminocaproic acid and tranexamic acid, which bind reversibly to plasminogen; the bovine protease inhibitor aprotinin, which inhibits kallikrein; the vasopressin analog desmopressin, which increases plasma concentrations of factor VIII and vWF; and conjugated estrogens, which normalize bleeding times in uremia.105

Antiplatelet

Agents

Aspirin Aspirin inhibits COX by the irreversible acetylation of a serine residue at the active site of the enzyme. Aspirin inhibition of the COX-1 isoform of this enzyme is 100–150 times more potent than its inhibition of the COX-2 isoform. The inhibition of COX-1 results in the irreversible inhibition of thromboxane A2 formation. Because platelet activation by other mechanisms, such as thrombin, remain intact, thrombosis can develop despite aspirin therapy (Chap. 35) .156

Selective

COX-2

Inhibitors

Platelets express primarily COX-1 and use it to produce mostly thromboxane A2 , which leads to platelet aggregation and vasoconstriction. Endothelial cells express COX-2 and use it to produce prostaglandin I2 , an inhibitor of platelet aggregation and a vasodilator. Whereas aspirin and traditional (nonselective) nonsteroidal antiinflammatory medications inhibit the production of thromboxane A2 and prostaglandin I2 at both sites, the selective COX-2 inhibitors do not affect platelet-derived thromboxane A2 , perhaps accounting for the increase in cardiovascular events associated with long-term use of some of these xenobiotics.34,79,89,104,167,180

GP

IIb-IIIa

Antagonists

The GP IIb-IIIa antagonist abciximab is a chimeric human-murine monoclonal antibody that binds the GP IIb-IIIa receptor of platelets and megakaryocytes. Two synthetic GP IIb-IIIa receptor antagonists have been developed: eptifibatide and tirofiban. These agents are used primarily in patients undergoing P.394 percutaneous coronary Reversible thrombocytopenia can occur within hours of initiation of these xenobiotics. interventions.66

Thienopyridines The prodrugs clopidogrel and ticlopidine antagonize ADP-mediated platelet aggregation by noncompetitive inhibition of ADP binding to the P2Y12 receptor.133,142 Both prodrugs are associated with thrombotic thrombocytopenic purpura, as well as neutropenia and aplastic anemia.11,12,130,131,142 Thrombotic thrombocytopenic purpura is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and fluctuating neurologic abnormalities.117 The hallmark is the presence of platelet aggregates throughout the microvasculature, without fibrin clot, and therefore involves a derangement of platelet aggregation. It is believed that drug-induced autoantibodies inactivate a metalloprotein ADAMTS13, thereby blocking its ability to depolymerize large multimers of vWF and leading to platelet clumping.6,7,11,181

Dipyridamole The pyrimidopyrimidine derivative dipyridamole inhibits cyclic nucleotide phosphodiesterase in platelets, resulting in the accumulation of cyclic adenosine monophosphate and perhaps cyclic guanine monophosphate.

Xenobiotic-Induced

Thrombocytopenia

Multiple drugs are reported to cause thrombocytopenia, generally

mediated via the formation of drug-dependent antiplatelet antibodies. Drug-induced platelet antibodies are estimated to occur in 1 in 100,000 drug exposures. Reversible drug binding to platelet epitopes such as GP Ib-IX, GP IIb-IIIa, and platelet–endothelial cell adhesion molecule-1, lead to a structural change that can form or expose a neoepitope target for antibody formation.6,147 The presence of the drug is required for antibody binding and increased platelet destruction, but there is no covalent bond (as occurs in the hapten model of penicillin binding to the erythrocyte membrane). Thrombocytopenia can also occur as a result of heparin-induced thrombocytopenia (discussed in Chap. 57), bone marrow toxicity, and thrombotic thrombocytopenic purpura. After excluding these conditions and nontherapeutic exposures, a systematic literature search updated annually lists more than 1000 cases reported in English involving more than 150 xenobiotics.186 Table 24-7 lists the xenobiotics appearing in multiple cases satisfying criteria for probable to definite causality including drug rechallenge. Nevertheless, a common clinical problem is to distinguish druginduced thrombocytopenia from idiopathic thrombocytopenic purpura in a patient on multiple medications who develops thrombocytopenia. In the absence of validated laboratory assays for drug-dependent platelet antibodies other than heparin, diagnosis still depends on the clinical course following drug discontinuation and perhaps rechallenge. Large databases exist to provide some guidance regarding past reported experience.54,146,186 In patients administered the sensitizing agent de novo, at least 7 days are typically required for the development of the immune response. During rechallenge, thrombocytopenia can develop within 12 hours. Interestingly, the unique ability of GP IIa/IIIb inhibitors such as abciximab to cause thrombocytopenia within hours of first use suggests the presence of preformed antibodies directed against platelet epitopes, perhaps accounting for ex vivo clumping of platelets observed in approximately 0.2% of normal patients having routine automated blood counts. 147 Clinically, fever, chills, pruritus,

and lethargy may occur. The onset of bleeding may be abrupt. Hemorrhagic vesicles may be seen in the oral mucosa.44 Lifethreatening hemorrhage may develop. Laboratory investigations will demonstrate an absence of platelets on peripheral smear, prolongation of the bleeding time, deficient clot retraction, and an abnormal prothrombin consumption test. Bone marrow aspiration will demonstrate normal or increased numbers of megakaryocytes and immature forms. Treatment includes the transfusion of blood products, glucocorticoids, and the withdrawal of the offending agent.

TABLE 24-7. Xenobiotics Reported to Cause Thrombocytopenia as a Result of Antiplatelet Antibodiesa

Abciximab Acetaminophen Aminoglutethimide Aminosalicylic acid Amiodarone Amphotericin B Carbamazepine Cimetidine Danazol Diclofenac Digoxin Eptifibatide Gold Heparin Indinavir Levamisole Meclofenamic acid Methyldopa Nalidixic acid Oxprenolol

Procainamide Quinidine Quinine Rifampin Tirofiban Trimethoprim-sulfamethoxazole Vancomycin a

Xenobiotics reported in at least 2 cases to have definitely caused immune thrombocytopenia, or in at least 5 cases to have probably caused immune thrombocytopenia following therapeutic use. Adapted from George JN, Raskob GE, Shah SR, et al: Druginduced thrombocytopenia: A systematic review of published case reports. Ann Intern Med 1998;129:886–890; Rizvi MA, Kojouri K, George JN: Drug-induced thrombocytopenia: An updated systematic review. Ann Intern Med 2001; 134:346; and WHO Working Group. Glucose-6-phosphate dehydrogenase deficiency. Bull WHO 1989;67:601–611.

Heparin-Induced

Thrombocytopenia

An immune response to heparin, manifested clinically by the development of thrombocytopenia and, at times, venous thrombosis, is now recognized to result from antibodies to a complex of heparin and platelet factor 4. The heparin–platelet factor 4 antibody complex can directly activate platelets, and is believed to be the mechanism for the paradoxical thrombosis associated with this condition. Indeed, although bleeding is uncommon, the thrombotic complications that develop in approximately 20% of patients with heparin-induced thrombocytopenia are associated with a mortality rate of up to 30% (Chap. 57) .4

Summary The mechanisms of toxic injury to the blood are extremely varied and complex. The response to injury may be idiosyncratic, as in many xenobiotic-related causes of agranulocytosis and aplastic anemia, or predictable, as in the case of significant exposures to ionizing radiation or to benzene. Injury may depend on the presence of certain host factors, such as G6PD deficiency. Xenobiotics may directly injure mature cells or the stem cell pool, thus prohibiting the development of mature cells. Toxicity may result from the amplification of a potentially therapeutic intervention, such as occurs with many chemotherapeutic agents and anticoagulants. Finally, a common theme in hematologic toxicity is the perturbation of homeostatic equilibria that exist between cell proliferation and apoptosis, between immune activation and suppression, or between thrombophilia and thrombolysis. It is therefore important to be aware of these complex pathways in order to better understand, diagnose, and treat toxic injury to the blood. P.395

Acknowledgment Dr. Diane Sauter contributed to this chapter in previous editions.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 25 - Gastrointestinal Principles

Chapter

25

Gastrointestinal

Principles

Donald P. Kotler Neal E. Flomenbaum The gastrointestinal (GI) mucosa, like other mucous membranes, occupies a discrete anatomic niche: the interface between a sterile internal environment and a contaminated external, or luminal environment. Humans are continuously in contact with potential xenobiotics, and the GI mucosa forms part of the initial line of defense. Despite this important responsibility, the GI mucosa lacks a strong physical barrier, with the interface between the internal and external environments being the apical cell membranes of epithelial cells. The reason for this seemingly paradoxical situation is that epithelial cells require intimate contact with the luminal environment in order to carry out their primary function—the absorption of nutrients, ions, and water. The need for such intimate contact with the external environment makes the GI tract inherently vulnerable. The task of mucosal defense is confounded by a large surface area, which is an adaptation that maximizes absorptive capacity.

The GI tract may be exposed to a wide variety of potentially toxic xenobiotics, including those with diffuse, nonspecific pathogenic effects, such as caustic agents and ionizing radiation, as well as highly specific xenobiotics and microbial pathogens. The GI tract also is vulnerable to the physical effects of foreign bodies, unlike the situation in most other organ systems. The GI tract, including the liver and pancreas, may be targeted specifically by xenobiotics. Alternatively, the gut may play a permissive role by absorbing xenobiotics with systemic toxicity. Antimicrobial defense in the GI tract is complicated and involves both nonspecific and specific processes. include antiinfective and other factors in endogenous secretions, gastric acid, the epithelial surface, intestinal motility, and

The nonspecific processes saliva and other mucus layer overlying the the endogenous flora. In

addition, specific molecular pumps, as well as biotransforming enzymes within the epithelial cell, may modify potentially toxic xenobiotics. The mucosal immune system of the GI tract is the largest lymphoid compartment in the body.15 Antimicrobial defenses include both innate and adaptive immunity. Innate immunity is an antimicrobial defense system that is based on the recognition of nonspecific, non–self antigens and is mediated through such nonspecific processes as complement activation. In contrast, adaptive immunity is based on the recognition of specific epitopes, and the responses are directed specifically at the invading microbe. This chapter discusses the role of the GI tract as it relates to toxicology. Anatomic, physiologic, and microbiologic principles are discussed, including the role of the GI tract in the metabolism of xenobiotics. Although the liver is the body's major metabolic organ, the intestines also contribute significantly. Examples of specific GI toxicities and their clinical GI manifestations are discussed.

Anatomic

Principles

The luminal GI tract can be divided into 5 distinct structures and luminal environments: oral cavity and hypopharynx; esophagus; stomach; small intestine; and colon. These environments differ in luminal pH, specific epithelial cell receptors, and endogenous flora. The transitional areas between these distinct organs have specialized epithelia and muscular sphincters, with specific functions and vulnerabilities. Knowledge of the anatomy of the transitional areas is particularly important to the localization and management of foreign bodies. The functions of the pancreas and liver are closely integrated with those of the luminal organs, although they are not within the nutrient stream. The liver and its metabolic functions are discussed extensively in Chaps. 13 and 2 6 ; the pancreas is discussed below. The organs of the GI tract are composed of 5 layers: the epithelium, lamina propria, submucosa, muscle layers (circular and longitudinal), and serosa, the latter only in intraperitoneal organs. Some authors combine the epithelial layer, the lamina propria, and the muscularis mucosa Neural tissue is found a neural plexus in the Immunocompetent cells

into a single compartment, the mucosa. diffusely in the intestine, and organized into submucosa and between the muscle layers. also are located in all of the layers, with

the subpopulations in the epithelium and lamina propria being the best studied. The major structural adaptations of the intestine are designed to increase the surface area available for absorption. These adaptations include mucosal folds; the so-called valves of Kerckring, which triple surface area; villus formation, which also increases the surface area by a factor of 10; and microvilli on the apical surface of epithelial cells, which increase surface area by a factor of 20. Because of all these anatomic adaptations, the surface area of the intestine is 600-fold greater than that of a simple tube.103 To provide the cells to cover the surface, cell

proliferation is continuous in the intestinal crypts. Intestinal epithelium is one of the most rapidly proliferating cell compartments in the body, which makes it vulnerable to xenobiotics that affect the cell cycle. The most specialized cell type in the intestine is the epithelial cell. There is a polarity, distinct to epithelia, in which one side of P.400 the cell (basal) faces “self― while the other side (apical) faces “non–self.― To adapt to these different environments and to facilitate the different functions, the apical and basal membranes of the epithelial cell contain different receptors and other surface molecules. The basal layer of the epithelial cell faces the lamina propria and the lamina propria mononuclear cells. In addition to its role as an absorptive organ, the epithelial cell also functions as part of mucosal immune defense, as it communicates with lamina propria cells, both in heralding the presence of microbial pathogens and in downregulating the immune system in the presence of nonpathogenic or probiotic microbes. An elaborate system has evolved to protect the GI tract from pathogens, which is part of a common mucosal immune system.94 Mucosal immunity can be divided into an afferent limb, which recognizes a pathogen and induces the proliferation and differentiation of immunocompetent cells, and an efferent limb, which coordinates and effects the immune response. The afferent and efferent limbs of the mucosal immune system are anatomically separate, but intermingled. The afferent system includes discrete lymphoid follicles, which are overlaid by a follicle-associated epithelium, including microfold, or M cells, that promote transit of particulate and soluble antigens to antigen-presenting cells.69 Once sensitized, immune cells undergo a complicated process of clonal expansion and differentiation, which occurs in mucosal and mesenteric lymphoid follicles, as well as in extraintestinal sites. Immunocompetent cells then return to the intestine and other

mucous membranes, and are scattered diffusely within the epithelial and lamina propria compartments. The function of the muscle layers is integrated with the enteric nervous system to provide for a coordinated movement of luminal contents through the GI tract so as to maximize absorption and minimize bacterial growth. One level of integration provides for an aborad flow of chyme, which requires a coordinated sequence of muscular contractions and relaxations and leads to segmenting and to peristaltic movements. For unidirectional flow to occur, the intestine distal to the contraction of circular muscle must decrease its muscular tone and increase compliance, while the intestine proximal to the contraction must increase muscle tone and decrease compliance. Furthermore, this gradient of muscular tone and compliance must, itself, move down the intestine. This level of neural control is maintained within the intestine, using a variety of neurotransmitters. The various neural circuits also can be affected by external stimuli originating in the central nervous system, or via xenobiotics. Destruction of the neural circuits at the level of the intestine abolishes neuromuscular coordination and leads to stasis, which presents clinically as pseudoobstruction, that is, absence of propulsion of a meal in the absence of an organic, obstructing

lesion.

A second level of neural integration relates to the overall speed of intestinal transit. Digestion and absorption are time-dependent processes and optimal absorption requires adjustment of the luminal environment through secretion of ions and water, to accommodate meals that vary considerably in nutrient composition and density. Osmoreceptors and chemoreceptors in the GI tract fine-tune the digestive and absorptive process by regulating transit and secretion, using a variety of neurocrine, paracrine, and endocrine mechanisms, allowing optimum absorption under a variety of circumstances. For example, hyperosmolar solutions empty more slowly from the stomach than isosmolar solutions.65 Interference with this integrated response may lead to stasis and

bacterial overgrowth, or rapid transit with decreased absorption and the development of diarrhea. A large number of mediators affect motility, including common neurotransmitters, such as acetylcholine and norepinephrine as well as peptidergic nerves, hormones, cytokines, inflammatory compounds, and others; typically, multiple agents affect motility. In general, parasympathetic impulses promote motility, whereas sympathetic impulses inhibit motility. Other transmitters, such as serotonin, promote transit while others, such as dopamine and enkephalins, slow transit. The luminal contents also can be considered an anatomic structure, especially the endogenous flora. There are two subcompartments of endogenous flora. Microbes within the bulk luminal contents play a relative small role in the body's economy, except for possible biotransforming functions. Organisms, predominantly anaerobes, also bind to specific receptors in the mucus layer overlying the epithelial cells and may play a more important, but perhaps a poorly understood role, including effects on epithelial cell gene expression. The importance of the endogenous flora is best illustrated by the result of their unintentional eradication during antibiotic therapy, when the pathogenic or toxigenic bacteria that replace them cause functional alterations and clinical symptoms.7 Differences in the luminal environment in young infants, compared to adults, underlie the endogenous production of botulinum toxin, with the clinical consequence being infant botulism.18

Physiologic Intestinal

Principles Absorption

The microenvironment between the bulk luminal contents and the epithelial cells has special properties. An “unstirred layer― is characteristic of all tubular structures through which fluids flow. 92

Whereas the bulk luminal contents move through the GI tract with a velocity that is dependent primarily upon muscle activity, water molecules immediately adjacent to the epithelial cell membrane do not move at all, and water molecules slightly more distant from the epithelial cell may move with a velocity below that of the bulk luminal contents. The unstirred layer has an estimated thickness of about 35 microns, as compared to the (approximately) 5-cm diameter of the small intestine.57 Although this layer presents little impediment to the diffusion of water-soluble materials, it poses a more substantial problem to the diffusion of lipid-soluble materials. In the stomach, secretion of bicarbonate into the unstirred layer below a mucus layer protects the epithelial cells from gastric acid (pH [congruent] 1).28 The chemical composition of the unstirred layer also may differ from that of the bulk luminal contents, resulting in a pH immediately adjacent to the epithelial cell that is lower than the pH of the bulk luminal contents. Based on the absorption rates of weak acids, an acidic microenvironment is hypothesized to face the small intestinal epithelium.85 The major barrier to the penetration of xenobiotics and microbes is the GI epithelium, a single-cell-thick membrane.24 The cell membrane is a lipid bilayer that contains proteins, which act as aqueous pores through which certain materials can pass, based on size or molecular structure, providing the basis for semipermeability. The membrane is not continuous as it consists of epithelial cells. However, the epithelial cells are attached to one another by structures known as tight junctions, which are located on the lateral surfaces of the cells, near their apical membranes. The tight junctions have a gap of about 8 Ã…, which allows passage only of water, ions, and low-molecular-weight materials. Of all the functions of the intestine, the absorption of nutrients, ions, and water is the most important for survival. Nutrient P.401 absorption is a function of the small intestine, while the colon contributes to the absorption of ions and water, and salvages

some malabsorbed carbohydrates. The role of the other GI organs is to prepare food for absorption and to deliver it to the absorptive surface at a rate promoting optimal absorption. For example, the major digestive functions of the oral cavity are to initiate the mechanical and enzymatic breakdown of foods into a form that is optimal for absorption. This process is continued in the stomach, where the gastric antrum further grind foods to particle sizes less than 0.2 mm, in addition to continuing protein digestion.66 Gastric emptying rates vary in accordance with the chemical and physical characteristics of the meal, and in a manner that optimizes nutrient absorption. Bicarbonate in bile and pancreatic juice neutralize gastric acid. In addition, pancreatic secretions continue the digestive process and yield small molecules that are capable of being hydrolyzed and transported by the intestinal mucosa, while bile salts and lecithin form micelles that maintain products of lipid digestion in solution (emulsion) so that absorption can occur. Ingested food also is diluted with endogenous secretions in order to optimize nutrient absorption. In addition to absorbing ions and water, the colon converts indigestible and unabsorbed materials plus bacteria to solid feces, which are stored and then eliminated. Multiple factors affect absorption from the intestine, transport from the lumen into the body may occur via transcellular or intercellular routes; absorption may occur by passive or active (energy-using) processes. Passive diffusion through the luminal membrane is directly related to the surface area of the membrane, to the concentration or concentration difference on the two sides of the membrane, to the degree of lipid solubility, and to a diffusion constant that varies with each chemical; passive diffusion is inversely related to diffusion distance. Written as an equation, these factors would appear as: Flux = (Diffusion Constant)(Surface Difference)/Diffusion Difference

Area)(Concentration

The diffusion constant, and thus the flux rate, is related to

molecular size. This relationship establishes the principles for clinical permeability tests performed clinically, such as the lactulose-mannitol permeability test, which compares the relative absorption rates of nonmetabolizable monosaccharides and disaccharides.48 Transcellular transport of many nutrients, ions, and xenobiotics—both uptake at the lumen and excretion at the basolateral membranes—occur via carrier-mediated mechanisms.1 These transport processes are subject to multiple controls allowing positive and negative adaptations to optimize absorption and limit toxicity, as described for such diverse nutrients as glucose and iron.67 , 78 Net absorption is a combination of active and passive processes, plus secretion in some situations. The same transport processes may be used both by essential and toxic materials. For example, the absorption of both lead and calcium are increased by vitamin D.31 The chemotherapeutic agent 5-fluorouracil, and the nucleoside reverse transcriptase inhibitor zidovudine, are absorbed by the same transport process used for the absorption of naturally occurring pyrimidines. The pH of the luminal contents is important in modulating the absorption of acids and bases. Many xenobiotics are either weak acids or weak bases and the effect of ambient pH is to affect water versus lipid solubility. For example, acids are ionized at basic pH, but nonionized at acid pH. In contrast, bases are nonionized at basic pH and ionized at acid pH. In general, ionized molecules are more water soluble, whereas nonionized molecules are more lipid soluble. Because the total area of membrane lipid is much greater than that of the membrane's aqueous pores, nonionized xenobiotics typically are absorbed more rapidly than ionized xenobiotics. Thus, one would expect weak acids to be better absorbed in the stomach and weak bases to be better absorbed in the small intestine. This may not always be the case, because surface area is much greater in the intestine than in the stomach.

Salicylate toxicity to the gastric mucosa is a classic example of pH-dependent absorption.81 Acetyl salicylate (aspirin) is a watersoluble salt of the weak acid salicylic acid, which is poorly soluble in water. At gastric pH, aspirin is converted to the nonionized salicylic acid, which facilitates its uptake through the luminal membrane of the gastric epithelial cell. Once intracellular, the acid dissociates, leading to elevated intracellular concentrations of water-soluble salicylate, which is toxic to the cell. The pH in the small intestine and colon are higher than in the stomach, which would be expected to favor the uptake of weak bases. However, there is evidence that the pH at the epithelial microenvironment in the intestine is lower than the pH of the bulk luminal contents as a result of the active secretion of an acidic compound; the lower pH at the cell surface facilitates the absorption of weak acids in the small intestine.85 The actual relationship between nonionized and ionized compounds and pH is specific for each xenobiotic and is related to its ionization constant (pKa ), which is the pH at which 50% of the compound is ionized. Variation in the diffusion of chemicals across the intestinal membrane also may be important in elimination. For example, acidification of colonic contents may occur as a result of lactulose therapy for hepatic encephalopathy, via production of lactic acid and other short-chain fatty acids in the colon which trap ammonia as NH4 + and promote its fecal excretion.19 Such a process also might affect the ability of multiple doses of activated charcoal to promote elimination of already absorbed xenobiotics.10 Other luminal factors affecting absorption include particle size, which is relevant for the ingestion of mercury and other heavy metals. Intestinal transit time can also theoretically modify the absorption of potential xenobiotics, although evidence of efficacy in overdoses is lacking. With respect to the absorption of medications, different types of drug formulations, such as timed release via enteric coating, slowly dissolving matrices, dissolution

control via osmotic pumps, ion exchange resins, pH-sensitive mechanisms, or other mechanisms, can limit bioavailability. In the case of analgesics and other medications with potent CNS effects, the potential for unintentional overdose may be diminished by these formulations, although external manipulation of the product, such as crushing time-release beads prior to ingestion, may circumvent the pharmaceutical design.71 Stimulation of intestinal transit using magnesium salts or other cathartics is an outdated approach to manipulating transit time in attempting to decrease the absorption of xenobiotics. However, apart from the paucity of any reliable data demonstrating beneficial effects, adverse effects on fluid and electrolyte balance were often problematic. The use of whole-bowel irrigation (WBI) with polyethylene glycol electrolyte lavage solution (PEG-ELS) in toxicologic management may be thought of as the modern therapeutic approach to decrease transit time of harmful xenobiotics without interfering with fluid and electrolyte balance. Unfortunately, with the possible exception of its use to ameliorate the effects of intentional or unintentional overdoses with iron tablets, the scientific evidence to substantiate the beneficial effects of WBI is limited. Anticholinergic and other antidiarrheal agents may exacerbate microbial or other luminal xenobiotics by P.402 increasing contact time and absorption, and by preventing the innate response of flushing away noxious material. In fact, the Infectious Disease Society of America guidelines on the management of acute diarrhea strongly recommend avoiding the use of antimotility agents in the management of acute diarrhea.

Xenobiotic

Metabolism

Although the liver is usually identified as the site of xenobiotic metabolism, similar functions also are found in the luminal GI tract. The stomach has long been known to contain alcohol dehydrogenase activity. Biotransformation is a property both of

luminal bacteria and enterocytes. The consequences of metabolism differ for diverse xenobiotics. Metabolism by the intestine affects the amount of orally administered xenobiotic that enters the body and contributes to the first-pass effect, or presystemic disposition. Variations in intestinal metabolism also may influence the pharmacokinetics of a xenobiotic. Metabolism can result in detoxification or the production of xenobiotics, and the rate of metabolism affects the exposure to xenobiotics by the body as a whole and the epithelial cell. Intestinal epithelial cells metabolize xenobiotics by multiple types of reactions such as hydroxylation, sulfation, acetylation, and glucuronidation. Intestinal epithelial cells contain many of the same metabolic enzymes as the liver. In addition, epithelial cells contain export pumps, as do hepatocytes and other cells.101 The responsible agent, P-glycoprotein, is related to the cystic fibrosis transmembrane regulator.98 P-glycoprotein is involved in chloride secretion and the regulation of cell volume, and is encoded by the multidrug-resistance gene. Its function in the enterocyte likely is the secretion of unmetabolized and metabolized xenobiotic agents directly into the intestinal lumen. Intestinal epithelial cells contain many metabolic enzymes, with variable specificities. Clinical studies have been performed using pharmacologic “cocktails― of probe substrates, whose metabolic disposal is well understood. For example, the clearance of caffeine, administered orally, is mediated by cytochrome CYP1A2, whereas the clearance of midazolam is mediated by CYP3A. Providing both xenobiotics would allow understanding of the relative metabolic rates of these two enzymes in a given subject. To further determine the relative contributions of intestine and liver in drug metabolism, the relative clearance rates after oral and intravenous administration can be compared. A greater or lesser clearance after oral administration is evidence of metabolic induction and inhibition, respectively.

There is wide variation in the rates of metabolism of xenobiotics between individuals. Demographic variables, such as age and sex,43 and inherited variables, such as specific polymorphisms, are demonstrated. Metabolism of individual xenobiotics may be affected by foods, herbal products, and other xenobiotics. For example, clinical observations associated the intake of grapefruit juice and Brussels sprouts with xenobiotic toxicity or ineffectiveness. Formal studies then demonstrated the effects of these foods on the pharmacokinetics of certain xenobiotics.6 , 73 Grapefruit juice inhibits intestinal CYP3A and other enzymes, including the P-glycoprotein transporter, which, following ingestion, may lead to exaggerated pharmacologic effects from medications such as calcium channel blockers and statins.25 , 80 One compound in grapefruit juice, 6,7-dihydroxybergamottin, not only directly inhibits CYP3A but also promotes its degradation. 60 The same pharmacokinetic effects were not observed when the some medications were administered intravenously, implying that the effect may be limited to drug metabolism during its transport across the intestinal epithelium, rather than in the liver. This interaction is especially problematic when the grapefruit juice is taken intermittently rather than consistently, as the pattern may be erratic and may consequently go unnoticed. Many interactions between allopathic medications and herbal products also have been described. For example, observational studies demonstrated that plasma levels of indinavir, digoxin, and other drugs are lowered by concomitant long-term use of St. John's wort.47 , 75 The FDA has further reported interactions between St. John's wort and a wide variety of medications, including oral contraceptives, selective serotonin reuptake inhibitors, HIV protease inhibitors, cyclosporine, and sildenafil.17 St. John's wort is associated with breakthrough menstrual bleeding and pregnancies occurring in women using oral contraceptives.83 The interactions of St. John's wort and the intestine are complex, as the xenobiotic has been found to inhibit intestinal CYP3A4 over

the short-term and to induce intestinal CYP3A and P-glycoprotein over the long-term. Thus, the actual effect of St. John's wort on a drug metabolized by CYP3A4 and/or P-glycoprotein will differ when the drug is initiated, when it is continued, and when it is stopped. Echinacea also affects drug-metabolizing enzymes, specifically inhibiting CYP3A4, CYP2C9, and CYP1A2, and inducing CYP3A activities, leading to reported interactions with theophylline, phenytoin, and cyclosporine.37 Drug–drug interactions also may affect the intestine. The interactions may include inhibition or induction. A prominent example is rifampin, which induces CYP3A4 enzymes and Pglycoprotein in both the intestine and liver.82 Both activities would lead to enhanced drug disposition and decreased effectiveness. Rifampin exerts these effects binding to and activating the pregnane X receptor nuclear transcription factor, and promoting transcription of relevant mRNA in the intestinal epithelium and liver.35 On the other hand, ketoconazole inhibits P-glycoprotein transporter, which could lead to higher concentrations than expected of administered drug.

Biotransformation

and

Carcinogenesis

The processes of biotransformation in the intestine are relevant to colonic carcinogenesis. For example, environmental factors, such as diet and tobacco use increase the risk of developing adenomatous polyps or colorectal cancer.68 , 90 Uridine diphosphate glucuronosyltransferase (UDPGT) catalyzes the conjugation of numerous xenobiotics with uridine diphosphate glucuronic acid. Colonic epithelial cells express several UDPGT isoforms, which may be involved in the detoxification of colorectal carcinogens.91 Glucuronidation is a critical detoxification pathway for the two major classes of tobacco smoke carcinogens, as well as heterocyclic amines, which are mutagenic compounds that are abundant in tobacco smoke and in fried and broiled meats. It is

possible that other environmental xenobiotics could have similar effects over a period of years. The activities of these detoxifying enzymes vary greatly in different individuals.89 These differences lead to variable rates of disappearance of the potential carcinogen and, in combination with dose of carcinogen and other factors, could influence the development of carcinoma in an individual.

Microbiologic

Considerations

The endogenous flora in the GI tract includes more than 400 different species of bacteria. The number of bacterial “cells― in the intestinal lumen is greater than the total number of host cells, the mass of bacteria is more metabolically active than the liver, and the bacteria have a greater diversity in genetic material than the host. The P.403 concentration of luminal bacteria varies by site, from lowest in the proximal small bowel to highest in the colon. Endogenous bacteria occupy unique niches related to host physiology, environmental pressures, and microbial interactions, which result in long-term stability.41 There is considerable variation in the composition of the endogenous flora between individuals. The flora may be altered by various insults but returns to baseline once the insults are removed. The endogenous flora affects enterocyte and lamina propria mononuclear cell functions. This is best shown in studies of germ-free animals that are colonized with a single species of bacteria. The intestinal microflora also modifies the intestinal and systemic responses to intestinal injury, as demonstrated by the mild nature of graft-versus-host disease in germ-free animals.8 The endogenous flora has multiple metabolic functions. A primary function in the colon is the salvage of malabsorbed carbohydrates by fermentation and production of short-chain fatty acids, which is a preferred substrate for colonic epithelial cells. Hydrolysis of urea occurs following its passive diffusion into the intestinal lumen,

producing NH3 and a carbon skeleton. Elevated levels of nitrogenous compounds, including ammonia, may result from increased dietary load, or from gastrointestinal hemorrhage, by decreased excretion caused by renal failure, or by decreased clearance, such as occurs in end-stage liver disease with hepatic encephalopathy. Bacterial fermentation of the nonabsorbable disaccharide lactulose in the colonic lumen leads to the production of lactic acid and other short-chain fatty acids, which decrease intraluminal pH and trap nitrogen in the lumen as NH4 + , conditions that are useful in treating patients with hepatic encephalopathy.19 Bacterial metabolism also may affect the disposition of intraluminal compounds. Bacterial metabolism of digoxin contributes to its steady-state concentrations in the body, and antibiotic treatment may reduce or eradicate the intestinal flora, affecting the steady state and predisposing to digoxin toxicity.20 Bacterial contribution to vitamin K metabolism also is demonstrated by changes in the prothrombin time, necessitating adjustments in the therapeutic doses of warfarin after antibiotic therapy. Bacterial metabolism also affects the composition and concentration of various bile acids and steroid hormones. Bacterial enzymes have been incorporated into treatment strategies, for example, as in the treatment of ulcerative colitis. The first effective drug treatment for this disease was developed by linking 5-aminosalicylic acid, an antiinflammatory agent, to sulfapyridine, thus making it nonabsorbable in the small intestine. This medication only becomes active when bacterial azoreductases in the terminal ileum and colon break the azo bonds, making the products absorbable in the colon at the site of inflammation.86 There is considerable evidence that the endogenous flora also might affect carcinogenesis in the intestinal lumen. Because many lipophilic xenobiotics are excreted from the liver after conjugation with glucuronic acid, bacterial β-glucuronidases might lead to reabsorption and recirculation of these compounds. In addition,

bacterial β-glucosidases may activate carcinogens. For example, germ-free animals do not develop tumors when fed cycasin, but in non–germ-free animals bacterial metabolism produces methazoxymethanol, a known carcinogen found in the colon.55 Consumption of a high-beef diet leads to increased fecal bile acid excretion and changes in colonic bacterial metabolism,39 which may convert a bile salt, chenodeoxycholic acid, into a carcinogen. Bacterial sulfatases also are capable of converting dietary cyclamate to cycloheximine, which is a bladder carcinogen.13 The term probiotics connotes live, nonpathogenic bacteria and fungi that are part of the normal flora, and which can be used as prophylactic or therapeutic agents. These bacteria compete for and displace pathogenic bacteria from ecologic niches, they directly modulate intestinal immune function, and they exert a trophic effect on the gut. They are being studied to decrease traveler's diarrhea, suppress recurrent Clostridium difficile toxin-associated diarrhea, and to reduce the inflammation in ileal pouches after colectomy in patients with ulcerative colitis, among other uses.14

An Anatomic Approach to Xenobiotics and the Gastrointestinal Tract An anatomic approach to the effects of xenobiotics on the lips, mouth, and oropharynx (Table 25-1 ), the esophagus (Table 25-2 ), P.404 the stomach (Table 25-3 ), and the small and large intestines (Table 25-4 ) is offered in brief in these tables. Gingivitis, stomatitis (loose Inflammation and irritation Antineoplastics Caustics Ciguatera (tooth pain)

teeth)

Ionizing radiation Metals (arsenic trioxide, mercuric chloride, lead, thallium, zinc chloride) Oxalates Phenol Phenytoin Phosphorous Edema Allergic Penicillin Angioedema Angiotensin-converting enzyme inhibitors Mechanical irritation and injury Caustics Oxalate-containing plants Pain and ulceration Early Caustics Paraquat Delayed Clozapine Antineoplastics Drooling Increased saliva Aminopyridine Cholinergics Nicotine Phencyclidine Dysphagia Foreign bodies (drug packets, batteries) Dry mouth Decreased saliva Direct

Anticholinergics Botulism From hypovolemia Diuresis Diuretics Lithium Insensible loss Salicylates CNS stimulants Decreased fluid intake CNS depressants Increased Gl fluid losses Cathartics Colchicine Tongue discoloration Direct toxic effects Blue—methylene blue Brown—bromide, bismuth Green—vanadium Type of Effect

Mechanism

Example

TABLE 25-1. Toxic Effects on the Lips, Mouth, and Oropharynx

Pain—retrosternal Pain fiber stimulation Alcohol Caustics Increased muscle tension caused by Obstruction Foreign body/drug

packets

Spasm Caustics Mediastinitis/esophageal perforation Caustics Emetics Foreign body Dysphagia/odynophagia Neuromuscular Botulism Diphtheria Paralytic shellfish Strychnine Tetrodotoxin Thallium Mechanical—obstruction Diphtheria Foreign body (drug packets) Large pill size or large number of pills Mechanical—irritation and injury Caustics Iodine Mercuric chloride Paraquat, diqua Type of Effect

Mechanism

Examples

TABLE 25-2. Xenobiotics that Affect the Esophagus

The

Pancreas

and

Pancreatic

Disease

The pancreas lies in the retroperitoneum, in a transverse fashion, between the second portion of the duodenum and the spleen. The gland serves both exocrine and endocrine functions, with the secretion of pancreatic juice and enzymes as exocrine functions,

and the secretion of insulin, glucagon, and other hormones as endocrine functions. The pancreatic acini contain cells producing digestive enzymes, which flow to the duodenum through the pancreatic ducts. Endocrine cells are found in the islets of Langerhans, which are found diffusely throughout the pancreas. Pancreatic exocrine function responds to neural, hormonal, and luminal stimuli. The strongest stimulus is the presence of partially digested food in the duodenum, which leads to the release of cholecystokinin and subsequent stimulation of pancreatic secretion and fluid flow, among other effects. Pancreatic exocrine function is inhibited by hormones derived from the distal intestine. Pancreatic enzyme activities are further regulated by the secretion of inactive precursors, which require activation in the intestinal lumen. This is accomplished by the action of trypsin, after the activation of trypsinogen by enterokinase in the duodenum. In fact, amylase and lipase are the only pancreatic enzymes to be secreted in an active form. Pain Epigastric

pain

fiber

stimulation

Alcohols Antineoplastics Arsenic Caustics Colchicine Iron Mercuric chloride NSAIDs Podophyllin Salicylates Perforation (peritonitis) Caustics Salicylates Pill concretions

Obstruction Bezoars Foreign body NSAIDs Salicylates Vomiting Local stimulation Caustics Colchicine Detergents/soap (strong) Fluoride Metals (iron, mercury, thallium, arsenic) Mushrooms Salicylates Solvents Staphylococcal exotoxin Zinc chloride Central chemoreceptor trigger Cardioactive steroids CO (?) Opioids Nicotine Local and central Methylxanthines Syrup of ipecac Increased intracranial Toxin-induced Amphetamine Cocaine Ephedrine Edema Vitamin A Postanoxic brain

pressure

hemorrhage

injury

zone

Hemorrhage or infarct Hypertension Hypotension Coagulopathy Anticoagulants Crotaline envenomation Hematemesis Direct mucosal injury Alcohols (ethanol, isopropyl) Caustics Metals Plants Radiation Salicylates and NSAIDs Zinc chloride Coagulopathy Anticoagulants Hepatic failure Type of Effect

Mechanism

Examples

TABLE 25-3. Xenobiotics that Affect the Stomach

Pain Increased contraction Local irritation Caustics Colchicine Metals Mushrooms Solanine-containing plants Stimulant cathartics Cholinergic stimulation Cholinergics

Opioid withdrawal Obstruction Foreign body/drug-containing packets Diarrhea Mechanical irritation and injury Bacterial endo- and exotoxins (food poisoning) Cathartic stimulants Caustics Colchicine Metals Mushrooms Solanine-containing plants Failure of mucosal regeneration Colchicine Daunorubicin Etoposide Fluorouracil Ionizing radiation Podophyllin Cholinergic stimulation Cholinergics Nicotine Opioid withdrawal Other mechanisms Methylxanthines Constipation Local effects Fluid and electrolyte depletion Opioids Central effects Anticholinergics Infant botulism CNS depressants Type of Effect

Mechanism

Examples

TABLE 25-4. Xenobiotics that Affect the Small and Large Intestines P.405 Pancreatitis connotes tissue damage and inflammation. Pancreatitis can be categorized clinically as acute or chronic, based upon course and mild or severe, based upon organ function, systemic effect, complications, and recovery time. Pancreatitis also can be categorized pathologically as interstitial or hemorrhagic. Interstitial pancreatitis features edema and inflammation histologically, plus acinar cell necrosis. In contrast, hemorrhagic pancreatitis features more widespread necrosis and widespread tissue hemorrhage and vascular thrombosis. Pathogenically, acute pancreatitis usually involves premature activation of pancreatic enzymes in the acinus. Pathogenic mechanisms include both pancreatic hypersecretion and inhibition of secretion. The activity of the pancreatic proteases and other digestive enzymes is opposed by circulating protease inhibitors, Î ±2 -macroglobulin, α1 -antitrypsin, and others. These latter proteins are acute-phase reactants and are released in response to tissue damage. They act to localize the damage, limit its severity, and prepare for tissue repair, but they respond to the development of pancreatitis and do not play a preventive role. Although there are multiple etiologies underlying acute pancreatitis, alcohol, and gallstones are the most important. The specific effects of alcohol are uncertain, but may include hypersecretion, sphincter of Oddi spasm, and hypertriglyceridemia.36 The delivery of ethanol to the pancreatic interstitium and ductal space results in premature release of free fatty acids, hypertriglyceridemia, and subsequent epithelial damage. Evidence of chronic pancreatitis occurs in the majority, but not all

alcoholic patients with pancreatitis. In contrast, the effect of gallstones in promoting pancreatitis is likely to be physical in nature, that is, an impacted gallstone directly blocks the pancreatic duct. Recent evidence suggests that excess free radicals may exacerbate pancreatitis from many causes. Xenobiotic-induced pancreatitis is a broad topic with multiple agents, whose association with disease can be listed as definite, likely, or possible (Table 25-5 ). The pathogenic mechanism varies with the specific xenobiotic, although some xenobiotics, such as the nucleoside reverse transcriptase 2′,3′-dideoxyinosine, may promote pancreatitis as a result of mitochondrial toxicity.84 Multiple mechanisms account for xenobiotic-induced pancreatitis. Overstimulation is recognized with exposure to cholinesterase inhibitors, such as parathion56 or scorpion venom;76 vasospasm, secondary to ergot alkaloids, is also reported.23 Acute exposure to excessive amounts of dioxin led to acute pancreatitis in an assassination attempt during the 2004 presidential campaign in the Ukraine.49 Of more widespread concern, environmental exposures to dioxins are known to produce pancreatic disease with ultrastructural studies demonstrating evidence of mitochondrial damage.70 , 79

Direct Toxicity to the GI Tract There are several important categories of xenobiotics that are directly toxic to the GI tract. Among them are “traditional agents― such as caustics, ethanol, and other alcohols. In recent years, the potential damage of biologic, chemical, or radiologic weapons to the body in general, and to the GI tract in particular, has become a great concern. Among the biologic agents considered to be potential weapons, botulism, ricin, and staphylococcal enterotoxin B are of particular concern to the GI tract. Exposure to ionizing radiation affects the GI tract to a greater extent than most other areas of the body because of the

rapid cell turnover in the GI tract.

Caustics Caustics are a commonly available, serious source of direct toxicity to the upper GI tract. Alkaline caustics such as sodium hydroxide (NaOH), the main ingredient in lye, drain cleaners, and oven cleaners, produce liquefactive destruction of the mucosa that may involve all layers of the esophagus and stomach. In contrast, hydrogen ions desiccate epithelial cells and denature proteins, producing an eschar and resulting in what is histologically referred to as coagulation necrosis. In some series, both the gastric and esophageal mucosae are equally affected by acids,105 while in others, the esophagus is spared and the stomach is severely injured.38 Although the esophageal lining is well equipped to withstand the effects of brief exposure to pH 1, which is the same concentration of hydrochloric acid as is present in gastric acid, much higher concentrations can be obtained commercially, and the risk of acid damage to the esophagus is most likely related to concentration. Perhaps as a result of the coagulation necrosis produced by acids in that location, the acid damage to the esophagus may not be as great P.406 as the damage caused there by strong alkalis. However, in marked contrast, the damage to the stomach and the resultant systemic effects of acid ingestion may be devastating. Because of its tendency to perforate the stomach, acid ingestion may result in widespread damage to other abdominal organs including the spleen, pancreas, and biliary tract.104 Late effects of acid ingestions include esophageal pseudodiverticula, gastric atony, decreased acid secretion, and gastric outlet obstruction. 53 Both acid and alkali ingestions are linked to the subsequent development of squamous cell carcinoma of the esophagus and

stomach,

particularly

at

the

gastroesophageal

Alcohols Ethanol Methanol Analgesics and NSAIDs Acetaminophen Opioids Salicylatesa Sulindac Antibiotics Pentamidine Rifampin Sulfonamides Tetracycline Anticonvulsants Valproic acid Antihypertensives ACE inhibitors Diazoxidea Methyldopaa Antimitotics Azathioprine L-Asparaginase Mercaptopurine Antivirals for HIV Disease Nucleoside analog Reverse transcriptase inhibitors Didanosine Zalcitabine Zidovudine Diuretics Chlorthalidonea Ethacrynic acida Furosemide

junction.45

Thiazides Hormones Corticosteroids Estrogens Others Organic phosphorous compounds Phenformin Alpha Cells Cobalt salts Decamethylene diguanidine Phenylethylbiguanide Beta Cells Alloxan Androgens Cyclizine Cyproheptadine Diazoxide Dihydromorphanthridine Epinephrine Glucagon Glucocorticoids Growth hormone Pentamidine Streptozocin Sulfonamides Vacor Zinc chelators Delta Cells None known a Based on single or Modified after Riddell RH, ed: Pathology ot Churchill Livingstone,

rare case reports. RH, Strauss FH: The pancreas. In: Riddell Drug-Induced and Toxic Diseases. New York. 1982, pp. 611–629.

Exocrine

Endocrine

Pancreas

(Islets

of

Langerhans)

Pancreas

TABLE 25-5. Xenobiotics Associated with Pancreatitis Endoscopy cannot provide information about the depth of injury and is best at determining whether there is little or no injury. The most serious toxicity is full-thickness ulceration, with esophageal perforation and the development of mediastinitis. When perforation does not occur, healing is characterized by dense scarring, despite steroid or other therapies,42 , 77 with strictures that can be so irregular and severe as to require surgical intervention to allow food intake (see Fig. 6-22 ). For the clinical presentation and treatment of caustic acid and alkali injuries, see Chap. 100 .

Biologics Botulism is an old disease whose presentation has evolved.18 Classically a food-borne disease, it also became recognized as a complication of wounds, and is recognized to occur in infants. In addition, the potential use of botulinum toxin as a weapon has been emphasized. In fact, the toxin has been applied both therapeutically and cosmetically. The toxin is a product of the anaerobic Gram-positive bacterium Clostridium botulinum . In food-borne botulism, the toxin is ingested, whereas in young infants, poorly formed normal flora and other products fail to inhibit the organism's growth. For this reason, in situ production of toxin may occur and lead to neurologic impairment. Rarely, a similar complication may occur in an adult. Ricin is extracted from the seeds of the castor bean, whose

ingestion can be lethal. The toxin is protein in nature and is largely degraded in the GI tract, so that toxicity is 1/100 that of a dose administered parenterally. Ricin and the related compound abrin are dimers. One chain inhibits protein synthesis via an enzymatic effect on the 60 S ribosome subunit. The other chain is a lectin and acts as an agglutinin after being taken up by cells. Clinically, ricin produces a severe inflammatory response resembling, in an experimental mouse model, the hemolytic uremic syndrome.54 Because of its protein composition, protective vaccination is possible and is being investigated. Staphylococcal enterotoxins are exoproteins produced by Staphylococcus aureus . Exposure to these toxins produces a wide range of GI effects, ranging from mild upset to lethal toxic shock. There are multiple types of staphylococcal enterotoxins. Staphylococcal enterotoxin B may produce typical food poisoning, with 12–24 hours of fever, vomiting, diarrhea, and more prolonged anorexia. In addition, the enterotoxin may act as a superantigen and bind directly to major histocompatibility complex class II and T-cell receptors in large numbers of T lymphocytes, leading to massive stimulation and release of huge amounts of proinflammatory cytokines, presenting clinically as toxic shock. The toxin has the ability to bind to a receptor on the apical surface of the intestinal epithelial cell, to be transcytosed intact, and to gain access to the systemic circulation. In experimental animals, lymphoid hyperplasia developed after lethal exposure to the toxin, which is consistent with widespread immune activation.99 I n addition to lymphoid effects, direct toxicity on pulmonary and renal endothelium can be demonstrated. Clinically, a biphasic response occurred, with an early GI syndrome and a later systemic shock syndrome and renal failure.

Radiation The GI tract is a major site of acute and chronic radiation injury

related either to environmental contamination or to radiation applied for medical use. Radiation damage to normal tissues occurs P.407 by the same mechanisms as the damage intended for a targeted neoplasm.26 Electrons ejected by high-energy photons as they pass through the body (Compton effect) damage DNA directly or through the generation of free radicals.59 The result is abnormal cross-linking of the DNA strands (guanine–guanine bonds), which must be excised and repaired, as they interfere with DNA replication and subsequent cell mitosis. The degree of damage is related to the dose of radiation as well as factors intrinsic to individual cells and tissues, such as degree of oxygenation, the cell cycle of the individual cells, and others.27 As damage from radiation and other agents is a normal phenomenon, the cell has the machinery to repair damaged DNA. Excess radiation injury overwhelms the reparative processes and leads to programmed cell death (apoptosis). Individual variation in the efficiency of the DNA repair processes also may influence the fate of radiation injury, especially the buildup of mutations leading to enhanced carcinogenesis.46 Such a process underlies the pathogenic mechanism in several familial cancer syndromes (Chap. 128 ).62 The pathology of radiation injury is related to its effect on DNA and subsequent inhibition of cell replication. The vulnerability to radiation-induced damage is related to cell proliferation rate. As stated above, the intestine is one of the most rapidly proliferating organs of the body. Damage is greatest with alpha particles intermediate with beta particles and least with gamma irradiation. However, gamma radiation may penetrate and produce deep injury. Radiation injury can occur to the whole body or may be localized, and can be divided into acute and chronic forms, with the chronic form subdivided into chronic damage and secondary carcinogenesis of either epithelial or stromal origin. Clinically, acute response to radiation exposure is comprised of

nausea, vomiting, cramps, diarrhea, and dehydration, and may have a neurogenic origin.50 If there has been significant environmental exposure, or the patient has received total-body irradiation sufficient to ablate the bone marrow, this phase is followed within a few days by diffuse destruction of many cell types in the intestine, including lymphocytes, epithelial cells, and vascular endothelial cells. Damage to the intestinal epithelium is enhanced because of its rapid turnover rate under normal situations. The injury persists at higher doses of radiation, leading to diffuse enteropathy, fluid and protein losses through the GI tract, and Gram-negative bacterial and candidal sepsis of presumed enteric source. Healing is associated with neovascularization and dense fibrogenesis, which promotes stricture formation. The clinical manifestations of radiation injury in the GI tract are dependent on the specific part of the tract involved.52 Acute and chronic injury to the esophagus leads to dysphagia from ulcers and edema acutely, and from stricture chronically. Rarely, the injury leads to fistulization. The stomach is relatively radioresistant, although affected in cases of high radiation exposure. In contrast, the small intestine is relatively radiosensitive.95 Radiation injury is very common clinically, and is usually reversible. Although the colon is thought to be relatively radioresistant, it is frequently involved in cases of pelvic irradiation. The situation is worse in segments fixed in the retroperitoneal space, like the rectum, or in segments immobilized by previous surgery. Acute injury is related to epithelial cell injury and is usually reversed within 2 weeks. In contrast, chronic radiation injury is a progressive process with an initiation within a few years of radiation but progressive damage for decades.32 Progressive disease may occur even after resection of severely damaged segments and preservation of “healthy― intestine.63

Ethanol Many studies have documented a wide range of GI toxicity in experimental models of alcohol excess and in people who consume large quantities of ethanol (Table 25-6 ). The toxicities of alcohols other than ethanol, such as methanol and isopropanol, are generally systemic rather than intestinal, but hemorrhagic gastritis or other effects may occur. The major gastrointestinal toxicity of ethanol occurs in the stomach. Alcohol-induced lesions tend to occur after acute ingestions of 8% or higher concentrations in total volume of intake, and alcohol-associated erosive gastritis (sometimes with the concomitant use of aspirin and/or NSAIDs) may be responsible for a majority of cases of upper GI hemorrhage.22 As commonly used, the term alcoholic gastritis describes the gastric erosions and subepithelial hemorrhages, with or without inflammatory cell infiltrates, seen endoscopically in alcoholics. Alcohol stimulates the secretion of gastric acid and reduces the transmucosal potential difference, allowing back diffusion of hydrogen ions and increased mucosal permeability.34 Microscopically, alcohol-induced lesions initially alter cell cytoplasm and nuclei, which is followed by widening of intercellular spaces, focal separation of tight junctions, and disruption of apical membranes. Most studies of small intestinal mucosa show only minimal light microscopic changes induced by alcohol. However, many people who drink large amounts of ethanol, acutely or chronically, note alterations in bowel habits. On investigation, a number of abnormalities in the GI tract are found, including rapid intestinal transit, decreased intestinal disaccharidase activity, decreased bile secretion as a consequence of alcoholic liver disease, and decreased P.408 pancreatic exocrine secretion as a consequence of chronic

pancreatitis. Markedly decreased absorption of fluid and electrolytes together with ileal and colonic fluid malabsorption has been documented in clinically ill subjects, although the role played specifically by alcohol is uncertain. Mouth Nutritional stomatitis Cheilosis Esophagus Esophagitis Diffuse esophageal spasm Mallory-Weiss tear Rupture with mediastinitis Stomach Acute gastritis Chronic hypertrophic Peptic ulcer

(Boerhaave

syndrome)

gastritis

Hematemesis Small and Large Intestines Malabsorption Diarrhea Liver Steatosis Alcoholic hepatitis Cirrhosis Pancreas Acute pancreatitis Chronic pancreatitis Pancreatic pseudocyst Adapted from West LF, Maxwell DS, Noble EP, Solomon DH: Alcoholism. Ann Intern Med 1984;100:412–420. TABLE 25-6. Gastrointestinal Effects of Ethanol

Other gastrointestinal lesions that occur with consumption of large quantities of alcohol include reflux esophagitis associated with reduced lower esophageal sphincter pressure, GI hemorrhage associated with mucosal tears at the gastroesophageal junction (Mallory-Weiss syndrome), and esophageal perforation associated with vomiting (Boerhaave syndrome), as well as acute and chronic pancreatitis, hepatitis, and cirrhosis. In a Scandinavian study of 591 first episodes of acute alcoholic pancreatitis, 260 (46%) of the 562 patients who survived the episode developed recurrent disease. The overwhelming majority of patients were men (503) and 80% of the first relapses occurred within 4 years.74

Iatrogenic Foreign

Diseases

Bodies

For obvious reasons, the esophagus is the site of most foreign bodies, which may be found in the cervical esophagus, at the level of the aortic notch, just above the gastroesophageal junction, or just proximal to an esophageal narrowing.16 Food impaction is a foreign body composed of ingested food and is often found in the presence of some esophageal narrowing. The likelihood that a foreign object will lodge in the esophagus is related to its size and shape. The major symptoms related to foreign objects in the upper GI tract are pain, bleeding, perforation, or obstruction. The general rule is that nonoperative means can be employed for up to 12 hours, after which time surgery should be considered, as the chances of tissue necrosis and perforation increase after this time.12 Foreign bodies also are commonly found in the stomach. Many small foreign bodies will pass through the stomach and the rest of the GI tract without problems, although objects greater than 5 cm in the largest diameter or 2 cm in the smallest diameter may not be able to traverse the duodenum and must be removed

endoscopically33 or

surgically.

Once in the small intestine, the narrowest area and a site for obstruction is the ileocecal valve, whose maximal opening is about 2.5 cm. Probably the most common type of “foreign― body to become impacted at the ileocecal valve is a large gallstone, which gives rise to “gallstone ileus.― Foreign objects in the rectum usually are introduced retrograde and may be low-lying in the rectum, or high-lying, above the rectosigmoid junction.51 Low-lying foreign objects usually can be removed transanally. For more proximally placed objects, the same 12-hour rule can be followed, after which time surgical intervention may be considered.

Gastrointestinal

Therapies

A variety of techniques have been applied to the GI tract over the years to minimize local or systemic damage related to xenobiotics, including the induction of vomiting with ipecac,40 , 88 , 97 , 100 the use of activated charcoal,2 , 10 , 58 prokinetic agents, WBI4 and luminal acidification.19 The literature is large but varied, with a relative lack of randomized, controlled studies and great variability in the clinical material available for treatment and for study.102 I t may be difficult to distinguish complications from the poisoning from those related to therapy, for example, aspiration pneumonitis (Table 25-7 ). 44 There is little evidence that cathartic use alters the outcomes of activated charcoal therapy,64 and repeated use of cathartics may have its own toxicities. WBI with a balanced polyethylene glycol and electrolyte solution, decreases the effectiveness of activated charcoal in both in vitro and in vivo studies. The application of multiple doses of activated charcoal has two rationales: (a) to prevent absorption of xenobiotics, and (b) to speed the elimination of xenobiotics that have already been

absorbed.3 , 29 Many agents promote intestinal evacuation, and are referred to as laxatives, cathartics, purgatives, promotility agents, and evacuants. These descriptions connote varying degrees of activity. Laxatives and cathartics act within the intestinal lumen, while promotility agents are systemic drugs that have effects on neuromuscular activity. Evacuants typically are used to prepare the colon for diagnostic or therapeutic procedures, but also are used in the case of toxic ingestion. In the past, saline cathartics, such as magnesium salts, and hyperosmolar agents, such as nonabsorbable

sugars, P.409

often were used, but there were problems with fluid and electrolyte balances. Currently, bowel evacuation is typically performed using a solution of polyethylene glycol (PEG) with added electrolytes. The PEG is minimally absorbed, and increases the amount of intraluminal water by osmotic means, while the added electrolytes minimize solute fluxes into or out of the intestine. This treatment is ideal for ingestion of sustained-release or entericcoated drugs, drug packets used for illicit smuggling,87 and for xenobiotics that are slowly absorbed, like iron and lead.4 Orogastric lavage Emesis Esophageal tears or perforation (Mallory-Weiss or Boerhaave syndromes) Gastric perforation Hemorrhage Activated charcoal Constipation Diarrhea Intestinal obstruction or pseudo-obstruction (especially after repetitive doses in the setting of dehydration or prior bowel adhesions)

Vomiting and aspiration Cathartics Abdominal cramping (sorbitol) Diarrhea and frequent watery stools (sorbitol) Electrolyte imbalance: increased Mg2 + , decreased K+ and Na+ (also increased PO4 3 - and decreased Ca2 + and K+ from phosphate enemas) Nausea and vomiting Rectal prolapse Volume depletion and consequent metabolic alkalosis Emesis with syrup of ipecac Delayed emesis after loss of gag reflex Diarrhea Electrolyte imbalance with chronic use Esophageal (Mallory-Weiss) tears Gastric rupture or herniation Intractable vomiting and aspiration Whole-bowel irrigation Bloating Colonic perforation (in the presence of severe diverticulitis) Rectal itching (from excessive wiping) Vomiting, especially with rapid administration Procedure

TABLE

Adverse

25-7.

Effect

Gastrointestinal Complications Decontamination Measures

of

Gastric

Saline cathartics, such as magnesium salts, are poorly absorbed, and increase intraluminal osmolality, leading to a flux of water into the intestine, dependent upon the permeability characteristics of the small intestine. Intraluminal magnesium also stimulates the release of cholecystokinin. Among other effects, cholecystokinin stimulates gallbladder emptying and biliary pancreatic flow, as well

as intestinal motor activity.11 Hyperosmotic laxatives include sorbitol (D-Glucitol) and lactulose (Cephulac). Milk is an effective hyperosmotic laxative in people who are lactase deficient, as is any nonabsorbable sugar. By remaining in the lumen, the sugar prevents isosmolar water absorption in the duodenum and jejunum, where carbohydrate and water absorption is maximal. Thus, a larger-than-normal amount of fluid, electrolytes, and solute (sugar) enters the colon. Once in the colon, bacteria ferment the sugars, producing 2-, 3-, and 4carbon compounds that further increase luminal osmolality, as well as hydrogen gas, leading to the production of flatus. Motility also is affected, leading to the symptom of cramping. PEG is a nonabsorbable, nonmetabolizable sugar in polymeric form, that exerts similar osmotic effects as the laxatives mentioned above. However, the addition, the ion or water minor. Many

PEG is inert, so that it is not metabolized. In electrolyte composition is balanced so that significant fluxes do not occur, and symptoms typically are studies document its safety and efficacy.93 , 96

Cathartics have long been recommended for basic poison management but there is little evidence of clinical effectiveness. Bowel evacuation with PEG solutions is currently recommended to speed the elimination of poorly absorbed xenobiotics or sustainedrelease medications, although evidence, once again, is limited. It is unlikely that evidence will ever be developed to support the efficacy of PEG-ELS based on large, randomized clinical trials; in its absence, reliance on case series and volunteer studies will continue. In one study using orally administered radiopaque markers, administration of PEG solution 30 minutes later did not lead to clearance. Abdominal radiographs taken after the administration of the PEG showed that, in 8 of 10 subjects, some radiopaque markers remained in the right colon, whereas the markers were present throughout the intestine in the other 2 subjects.61 Thus, some care in the clinical application of this technique in a variety of circumstances is warranted, especially in

the follow up of treatment in cases where the offending agent can be detected, such as iron tablets and drug packets (see Figs. 6-8 , 40-1 , and 40-2 ). Alterations in fluid and electrolyte balance are the major potential adverse effects of cathartics and other agents, especially when used repetitively. Nausea, vomiting, and cramping are most common, while other problems, such as rectal prolapse, have been reported. Morbidity may be higher in the elderly9 and in young infants. Antiemetics may be used, if needed. While antiemetic therapies are not usually considered in discussions of toxicology, they may play a role in the management of symptoms related to toxic agents. A number of antiemetic agents with differing mechanisms of activity have been developed. Phenothiazines and butyrophenones prevent nausea and vomiting via central nervous system dopamine antagonism. Metoclopramide is a substituted benzamide and procainamide derivative with a variety of central and peripheral effects, predominantly dopamine antagonism, but also 5-hydroxytryptamine type 3 (5-HT3 ) receptor antagonism and cholinomimetic effects. Domperidone is a benzimidazole derivative that blocks peripheral dopamine receptors and is thought not to cross the blood–brain barrier, although it does affect the circumventricular areas where the barrier is incomplete, such as the area postrema. It is not approved for any specific indication by the FDA, but is available in many other countries. Anticholinergics, such as transdermally administered scopolamine, are not antiemetics, but decrease the sensation of nausea, especially related to motion sickness. Based on studies that show that nausea and vomiting may be mediated via 5-HT3 receptors,30 particularly in the area postrema, a number of inhibitors have been developed and are in wide clinical use.

Summary The GI tract is vulnerable to a wide variety of pathogenic agents

with diverse physical, chemical, and biologic forms. Understanding the effects of such xenobiotics on the intestine and the body requires an understanding of the normal anatomy and physiology of the intestine. Except when injured or perforated by agents such as caustics, ionizing radiation, and alcohol, or obstructed by drugcontaining packets or batteries, the GI tract is typically not regarded as a significant site of drug toxicity. Nevertheless, because of both its potential as a site of severe local or systemic effects and the role that GI signs and symptoms play in various diagnostic toxic syndromes, the GI tract is an important consideration in almost any toxicologic emergency.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 26 - Hepatic Principles

Chapter Hepatic

26 Principles

Kathleen A. Delaney

The liver plays an essential role in the maintenance of physiologic homeostasis. include the synthesis, storage, and breakdown of glycogen; the metabolism of l synthesis of albumin, clotting factors, and other important proteins; synthesis o acids necessary for the absorption of lipids and fat-soluble vitamins; the metabo

cholesterol; the excretion of metals, most importantly iron, copper, zinc, mang mercury, and aluminum; and the detoxification of products of metabolism, such and ammonia.28 , 62 , 129 Generalized disruption of these important functions re familiar manifestations of liver failure: hyperbilirubinemia, coagulopathy, hypo

hyperammonemia, and hypoglycemia.40 , 74 Disturbances of more specific funct accumulation of fat, toxic metals, hypercholesterolemia, and fat-soluble vitamin deficiencies.20

The liver is also the primary site of biotransformation and detoxification of xeno contains the highest concentration of enzymes involved in phase I oxidation-re reactions.46 Its interposition between the gut and systemic circulation makes it recipient of xenobiotics absorbed from the gastrointestinal tract into the portal also receives blood from the systemic circulation and participates in the detoxif elimination of xenobiotics that reach the bloodstream through other routes, suc

or cutaneous absorption. Many detoxified xenobiotics are excreted in the urine. the biliary tract provides a second essential route for the elimination of detoxif and products of metabolism.20 , 28

Many xenobiotics are lipophilic, inert substances requiring chemical activation to sufficiently soluble to be eliminated. This is accomplished by conjugation of the products of phase I biotransformation with molecules such as glucuronide that or biliary excretion. Although phase I activation followed by phase II conjugatio results in detoxification of these xenobiotics, it occasionally leads to the produc xenobiotics with increased toxicity, which is often manifest at the site of their 83 Because of its location at the end of the portal system and its substantial co

biotransformation enzymes, the liver is especially vulnerable to toxic injury.37 ( for a more in-depth discussion of the biotransformation reactions.)

Morphology and Function of the Liver

Approximately 75% of the blood supply to the liver is derived from the portal v drains the alimentary tract, spleen, and pancreas. This blood is enriched with n

other absorbed xenobiotics and is poor in oxygen. The remainder of the hepatic comes from the hepatic artery, which delivers well-oxygenated blood from the circulation.20 , 129 Blood from the hepatic artery and portal vein mixes in the s coming in close contact with cords of hepatocytes before it exits through small h

wall of the vein. Oxygen content diminishes several fold as blood flows from the to the central vein, affecting the localization of oxygen-dependent mechanisms , 16 The sinusoidal lining formed by endothelial cells is thin and fenestrated, al of fluid, chylomicrons, and proteins across the space of Disse, an extrasinusoida with microvilli.20 Macrophages (Kupffer cells) within the sinusoids scavenge pa materials and cell debris. When immunologically activated by xenobiotics, Kupff contribute to the generation of oxygen free radicals and may also participate in production of autoimmune injury to hepatocytes. 33 Ito cells found between the cells and hepatocytes are a primary site for the storage of fat and vitamin A.43

Bile acids, organic anions, bilirubin, phospholipids, xenobiotics, and other mole in bile are actively transported across the hepatocyte plasma membrane into th canaliculi at sites that have specificity for acids, bases, and neutral compounds. junctions separate the contents of the bile canaliculi from the sinusoids and he

maintaining a rigid and functionally necessary compartmentalization. Bile acids u transport systems: a sodium-dependent bile salt transporter in the sinusoidal m adenosine triphosphate (ATP)-dependent bile salt carrier in the canalicular mem canalicular membrane transport site driven by the membrane voltage potential. Glucuronidated xenobiotics are substrates for the bile acid transport systems an secreted into bile. Xenobiotics with molecular weights greater than 350 daltons preferentially secreted into bile. Like the transport and concentration of constitu sinusoids and hepatocytes, the flow of bile through the canaliculi is an active p facilitated by ATP-dependent contractions of actin filaments that encircle the c 139 Xenobiotics induce cholestasis by targeting specific mechanisms of bile synt flow.67

The enterohepatic circulation of bile acids and some vitamins plays a crucial role conservation. Unfortunately, this physiologically important process impedes the elimination of some xenobiotics by reabsorbing and returning them back into th

circulation, prolonging their half lives and toxicity. Xenobiotics that are not ioniz intestinal pH and that have low

P.413 molecular weights, such as methyl mercury, phencyclidine, and nortriptyline, are to be reabsorbed.28 , 114

Two basic pathologic concepts are used to describe the appearance and function a structural one represented by the hepatic lobule, and a functional one represe

acinus. The basic morphologic unit of the liver characterized by light microscopy hepatic lobule, a hexagon with the central vein at the center and the portal triad angles. Cords of hepatocytes are oriented radially around the hepatic vein. The “metabolic lobule― is a functional unit of the liver. Located between two it is bisected by terminal branches of the hepatic artery and portal vein that ext bases of the acini toward hepatic venules at the apices. The acinus is subdivided metabolically distinct zones. Zone 1 lies near the portal triad, zone 3 near the and zone 2 is intermediate. Figure 26-1 illustrates the relationship of these stru functional concepts of the liver. The different metabolic functions of these zones cellular location of biotransformation reactions affect the anatomic distribution o produced by xenobiotics. There is useful correlation between these anatomic an conceptualizations of the liver. Hepatocellular injury that occurs near the portal periportal necrosis. This term describes injury in zone 1.20 The terms centrilobu

necrosis refer to injury that surrounds the central vein. Figure necrosis caused by exposure to bromobenzene.

26-2 shows cen

Figure 26-1. The acinus is defined by three functional zones. Specific contribut zone to the biotransformation of xenobiotics reflect the declining oxygen content it flows along sinusoids from the oxygen-rich portal area to the central hepatic

Hepatocytes that form the parenchyma of these three zones also have enzymati metabolic functions that are specific to each of the three zones. The hepatic lob shown) is a structural concept, a hexagon with the central vein at the center su portal areas that contain branches of the hepatic artery, bile duct, and portal ve hepatocytes that is confined to zone 3 is called “centrilobular― because in of the lobule, zone 3 encircles the central vein, which is the center of the hepat (Adapted with permission from Crawford JM: The liver and the biliary tract. In: Fausto N, Abbas A, eds: Robbins and Cotran's Pathologic Basis of Disease, 7th e Philadelphia, Elsevier, 2004, Fig. 18.1 , p. 879.)

Factors

Affecting

the

Localization

of

Hepatic

I

Metabolic characteristics of the three zones of the acinus have important relevan anatomic distribution of toxic liver injury. Zone 1, which begins in the periportal closest to the vascular supply and has a 2-fold higher oxygen content than zone Predictably, hepatic injury that results from the metabolic production of oxygen predominates in zone 1.7 The tendency for centrilobular or zone 3 accumulation patients with alcoholic steatosis is attributed to the effect of relative hypoxia in vein area on the oxidation potential of the hepatocyte.80 The availability of sub detoxification and the localization of enzymes involved in biotransformation also site of injury. Zone 1 has a higher concentration of glutathione, whereas zone 3 capacity for glucuronidation and sulfation.134 Zone 3 has higher levels of alcoho dehydrogenase, which may lead to increased production of toxic acetaldehyde a centrilobular sites.80 , 84 Zone 3 also has high levels of cytochrome oxidase cyt (CYP) 2E1, which converts acetaminophen, nitrosamines, benzene, and carbon (CCl4 ) to reactive intermediates that may cause centrilobular injury. In chronic proliferation of the smooth endoplasmic reticulum in the centrilobular areas is a increased activity of CYP2E1.

P.414 This increases the risk of liver injury in alcoholic patients exposed to xenobiotics metabolized by CYP2E1 (Table 26-1 ).48 , 81 , 99

Figure 26-2. Centrilobular necrosis in a rat liver caused by bromobenzene adm Note the polymorphonuclear leukocyte infiltration surrounded by vacuolated hep

the necrotic area. (Reprinted with permission from Hetu C, Dumont A, Joly JG, e chronic ethanol administration on bromobenzene liver toxicity in the rat. Toxicol 1983;676:166.)

The behavior of free radicals produced by the metabolism of CCl4 has been ext studied in the laboratory. The following steps are proposed to explain the mech hepatic injury by CCl4 . The trichloromethyl free radical (·CCl3 ) is generated f CYP2E1 in a reduced form of nicotinamide adenine dinucleotide (NADPH)-depen reaction.2 , 81 This occurs primarily in zone 3, which has the higher concentratio activity. It can form covalent bonds with cellular proteins, cause lipid peroxidati

spontaneously react with oxygen to form the more highly reactive trichlorometh radical (CCl3 OO·).2 , 33 Low oxygen tension in zone 3 limits synthesis of CCl3 whereas high oxygen tension in zone 1 fosters its formation. The highly reactive that predominates in zone 1 is rapidly detoxified by glutathione; however, the

·CCl3 that predominates in zone 3 is not. Therefore, zone 3 incurs the greater injury. Hyperbaric oxygen increases the oxygen tension throughout the liver an liver injury caused by exposure to CCl4 , possibly by increasing the formation of zone 3, which is then efficiently detoxified by glutathione.16 1 Periportal High oxygen content High glutathione content Oxygen free radical-mediated necrosis 2 Mid-zonal Shared functions, zones 1 and 3 Shared functions, zones 1 and 3 3 Centrilobular Low oxygen content High capacity of glucuronidation and sulfation Necrosis caused by toxic metabolites of CYP2E1 High CYP2E1, alcohol dehydrogenase

Increased Zone

CCl4 and ethanol injury caused by reducing environment

Location

Biochemistry

Types of Injury

TABLE 26-1. Metabolic Zones of the Liver

The observed effects of isoniazid (an inhibitor of the enzyme CYP2E1) and chro intake (an inducer of the CYP2E1 gene) on injury in cell cultures from the perip centrilobular areas exposed to CCl4 support the association of CCl4 injury with of CYP2E1 activity. Acute exposure to isoniazid significantly decreases the injur with exposure of cultured zone 3 cells to CCl4 , whereas chronic treatment with significantly enhances it (see Table 26-1 ). 81

Factors

that

affect

the

Development

of

Hepato

Xenobiotics that produce liver damage in all humans in a predictable and dosemanner, such as acetaminophen, CCl4 , and yellow phosphorous, are called intr hepatotoxins. Those that cause liver damage in a small number of individuals an effect is not apparently dose dependent or predictable are called idiosyncratic

Some cause hepatotoxicity very rarely, whereas others produce it commonly. Th hepatotoxins fall into the category of idiosyncratic xenobiotics.75 , 83 The inhale agent halothane is both an intrinsic and an idiosyncratic hepatotoxin. A mild deg hepatitis occurs in as many as 20% of patients exposed to halothane.32 This for

halothane hepatitis, which can be reliably induced in animals, is likely caused by toxicity.117 A more severe idiosyncratic form appears to be caused by an autoim response induced by halothane that targets liver proteins.13 , 127 , 135

Sporadic unpredicted hepatotoxicity is not really idiosyncratic, but more likely is the combined effects of genetic and other factors that result in the overproducti decreased clearance of toxic metabolites. Idiosyncratic toxicity is related to ind variability in the capacity to metabolize a specific xenobiotic and would be pred than “idiosyncratic,― if the exposed individual's metabolic capabilities cou prospectively defined (Chap. 13 ). An individual's susceptibility to a hepatotoxin numerous factors, including the activity of biotransformation enzymes, the avai substrates, and the immune competence of the individual. In turn, these are aff

sex, diet, underlying diseases, concurrent exposure to other xenobiotics, and g The susceptibility to toxic effects of a drug may be determined by inherited vari enzymes. Many enzymes involved in biotransformation show genetic polymorphi example, approximately 8% of whites are deficient in CYP2D6 (formally called hydroxylase), which is responsible for the metabolism of a number of drugs, in debrisoquine (an antihypertensive first identified as the substrate of this enzym antidepressants and antidysrhythmics, some opioids, and phenformin. 75 Perhexil antianginal agent marketed in Europe in the 1980s, caused severe liver disease peripheral neuropathy in persons with a demonstrated inability to metabolize d The congenital disorder that results in Gilbert syndrome is characterized by imp glucuronyltransferase. These patients demonstrate decreased glucuronidation an bioactivation of acetaminophen during chronic therapeutic dosing, suggesting an risk of hepatic injury following ingestions of acetaminophen.25 P.415

Effects of Other Xenobiotics on Enzyme Functio

Changes in the activities of biotransformation enzymes that result in increased hepatotoxic metabolites increase susceptibility to hepatic injury. Induction of th gene by the chronic ingestion of ethanol results in a 5- to 10-fold increase in C

activity.23 , 80 Chronic administration of isoniazid (INH) to slow acetylators also CYP2E1 activity.145 Anecdotal observations in humans suggest the possibility th toxicity caused by solvents such as CCl4 , dimethylformamide, and bromobenzen

exacerbated by the chronic ingestion of ethanol.6 , 107 Currently, no data suppo contention that using ethanol increases the clinical risk of acetaminophen hepa 103 , 121 , 148

The major studies that describe these xenobiotic interactions were done in exp animals.48 Bromobenzene is a xenobiotic whose metabolism and hepatotoxicity a that of acetaminophen. When administered to rats chronically exposed to ethano of hepatotoxicity occurs more rapidly in study animals, with only a small increas extent of hepatic necrosis. The dose of bromobenzene required for hepatic injury not altered by pretreatment with ethanol.48 Conversely, chronic administration phenobarbital to rats results in a very significant increase in the hepatotoxic eff bromobenzene.109 In other rat studies, prior administration of CYP inhibitors su

cimetidine may protect against acetaminophen-induced hepatic necrosis.128 Cul hepatocytes of ethanol-treated rats show increased in vitro susceptibility to the effects of CCl4 .81

Some xenobiotic combinations increase the possibility of hepatotoxic reactions b xenobiotic alters the metabolism of the other, leading to the production of toxi This is the case with combinations of rifampin and isoniazid; amoxicillin and cla and trimethoprim and sulfamethoxazole.3 , 55 , 72 , 102 , 106

Hyp er s ens i tivity

Immune-mediated liver injury is an idiosyncratic and host-dependent hypersen response to exposure to xenobiotic.83 It is differentiated from liver injury cause autoimmune disorders by the absence of self-perpetuation, that is, the need for

exposure to the xenobiotic to perpetuate the injury.83 Hypersensitivity reactions forms of liver injury that include hepatitis, cholestasis, and mixed disorders. Dr hypersensitivity reactions that typically present with hepatitis include halothane

trimethoprim-sulfamethoxazole, anticonvulsants, and allopurinol.3 , 4 , 86 Drugs present with cholestatic signs and symptoms (pruritus, jaundice, insignificant e aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) include chlorpromazine, erythromycin, penicillins, rifampin, and sulfonamides.27 , 50 , 1

injury typically begin 1–8 weeks following the initiation of the drug, although begin as late as 20 weeks for drugs such as INH or dantrolene.37 The onset of s associated with the oxypenicillins may occur up to 2 weeks after the drug is sto all cases, the onset is earlier when the patient is rechallenged with the drug. A

eosinophilia, atypical lymphocytosis, fever, and rash are common clinical manife hypersensitivity, their absence does not exclude the diagnosis of drug associate injury.63 , 64 , 83 , 86

How the immune response ultimately leads to cell injury is not well defined. De the hepatocyte may be mediated by complement- or antibody-directed lysis; by mediated cytotoxicity; or by an inflammatory response induced by immune com complement.10 , 14 , 59 , 61 , 92 , 118 The covalent binding of a reactive electrop metabolite with a hepatocellular protein resulting in the formation of a neoantige defined first step in the development of xenobiotic-related autoimmune liver inj covalent binding creates an “adduct― that is perceived as foreign by the

system and induces an immune response. In cases where the metabolite is high the electrophilic attack is directed against the CYP enzyme at the site of formati metabolite.13 , 77 , 83 Adducts and associated autoantibodies have been demons acetaminophen,18 minocycline,10 halothane,13 , 127 dihydralazine,14 phenytoin,7 germander.71 The most severe form of idiosyncratic halothane liver injury is ma fulminant hepatic failure associated with formation of adducts of its trifluoroace (TFA) metabolite with numerous hepatoproteins.9 , 135 TFA binds and forms add hepatic enzymes that include pyruvate dehydrogenase. 31 , 59 , 127 It also forms CYP2E1, the enzyme that metabolizes halothane to TFA. Studies demonstrate a against the CYP2E1 enzyme (Chap. 65 ). 13 , 59 , 118 , 135 Autoantibodies specific against CYP enzymes have also been demonstrated for dihydralazine,14 and ph trifluoroacetyl protein adduct similar to that associated with halothane hepatitis in workers who developed hepatic necrosis following exposure to hydrochlorofl Whether autoantibodies stimulated by the xenobiotic-protein adducts are the ac of cell injury is not clear.

Early reports of lymphocyte sensitization in cases of xenobiotic-mediated liver suggested that cell-mediated immunity may play a role.137 Cell-mediated antib cytotoxicity is implicated in the idiosyncratic type of halothane hepatitis.32 Cellautoimmune mechanisms are suspected in an increasing number of models of e xenobiotic-mediated liver injury. Polymorphonucleocyte activation appears to be factor in one experimental rat model, where exposure to α-naphthyl-isothiocya

causes acute cholangitis associated with polymorphonucleocyte (PMN) infiltration exposure to ANIT stimulates the release of cytotoxic lysosomal enzymes and ox radicals by activated PMNs.92 In addition, antibodies directed against circulating decrease the extent of liver damage caused by ANIT.22 Natural killer T cells (NK ubiquitous in the liver, and their possible role in facilitation of cell-mediated au injury is currently being investigated in other models. 21 , 45

Availability

of

Substrates

The availability of substrates for detoxification may significantly affect the likeli hepatic injury. The metabolism of acetaminophen illustrates the effect of glutat concentration on the delicate balance between detoxification and the production metabolites. In healthy adults taking therapeutic amounts of acetaminophen, a

90% of hepatic metabolism results in formation of glucuronidated or sulfated m Most of the remainder undergoes oxidative metabolism to the toxic electrophile benzoquinoneimine (NAPQI) and is rapidly detoxified by conjugation with glutat Glutathione may be depleted during the course of metabolism of acetaminophen normal livers, or it may be decreased by inadequate nutrition or liver disease.73 Excessive amounts of acetaminophen result in increased synthesis of NAPQI, wh absence of glutathione, reacts avidly with hepatocellular macromolecules. The concentration of glutathione correlates inversely with the demonstrable covalent NAPQI to liver cells.18 P.416

Morphologic Injury

and

Biochemical

Manifestations

of

The liver responds to injury in a limited number of ways. Cells may swell (ballo degeneration) and accumulate fat (steatosis) or biliary material. They may necro or undergo the slower process of apoptosis, forming shrunken, nonfunctioning, bodies. Necrosis may be or pan acinar; or it may necrosis.20 , 75 Injury to obstruction to venous or

focal or bridging, linking the periportal or centrilobular be massive. An inflammatory cell response may precede the bile ducts results in cholestasis. Vascular injuries m arterial flow. The variety and spectrum of injury caused

azathioprine illustrates the difficulty in categorizing and characterizing all of the causes of xenobiotic hepatic injury. This single agent is associated with most for including asymptomatic aminotransferase elevations, simple cholestasis, hepatitis injury, and vascular injury.37 All of these manifestations of toxic injury are disc Table 26-2 lists characteristic morphologies of hepatic injury and associated xe

Acute

Hepatocellular

Necrosis

Acute necrosis of a hepatocyte disrupts all aspects of its function. Because there deal of functional reserve in the liver, hepatic function may be preserved despit development of focal necrosis. Extensive necrosis results in functional liver failu processes that lead to cell necrosis are not well known. Cell lysis is preceded by of blebs in the lipid membrane and leakage of cytosolic enzymes, primarily am

and lactate dehydrogenase. Coalescence of blebs leads to rupture of the cellula and acute irreversible cell death, with disintegration of the nucleus and terminat cellular function. Prior to membrane rupture, this injury is reversible by membr processes.20 The release of intracellular constituents, caused by disruption of th membrane, attracts circulating leukocytes and results in an inflammatory respon hepatic parenchyma.37 A proposed mechanism of rapid injury to the cell is the cascading lipid peroxidation reaction following attack by a free radical. The CYP has a significant potential to produce oxygen free radicals, as do activated PMN cells.23 , 33 , 92 Mechanisms such as covalent binding to cellular enzymes and p membrane lipids are not the only causes of cell necrosis. The oxidation of prote phospholipid fatty acyl side chains, and nucleosides also appear to be widesprea Mitochondrial injury and its associated ATP depletion is also associated with ne NAPQI, the reactive metabolite of acetaminophen, may target mitochondrial en xenobiotics known to cause mitochondrial injury include antiviral drugs,79 , 90 t valproic acid,11 hypoglycin, margosa oil, and cerulide.85 , 119 Although the intra calcium ion that precedes the onset of cellular injury accompanies cell death in this simple concept of

P.417 calcium as a final mediator of cell death does not account for all observed proc Acute Hepatocellular Acetaminophena Allopurinol Arsenic Atomoxetine Carbamazepine Carbon tetrachloride a Cyclopeptide-containing Dantrolene Halothane Hydralazine Infliximab Iron Isoniazid Methotrexate a

Necrosis

mushroomsa

Methyldopa Nitrofurantoin Phenytoin Phosphorus (yellow)a Procainamide Propythiouracil Quinine Sulfonamides Tetracycline Troglitazone Steatohepatitis Amiodarone Ethanol Perhexiline Vitamin A Microvesicular Aflatoxin Cerulide

Steatosis

Fialuridine Hypoglycin Margosa oil Nucleoside analogs (antiretrovirals) Tetracycline Valproic acid Granulomatous Hepatitis Allopurinol Aspirin Carbamazepine Diltiazem Halothane Hydralazine

Isoniazid Metolazone Methyldopa Nitrofurantoin Penicillins Phenytoin Procainamide Quinidine Quinine Sulfonamides Sulfonylureas Fibrosis Ethanol Methotrexate Vitamin A Neoplasms Androgens Contraceptive Vinyl

steroids

chloride

Venoocclusive Disease Cyclophosphamide Pyrrozolidine

alkaloids

Cholestasis Allopurinol Amoxacillin/clavulanic acid Androgens Chlorpromazine Chlorpropamide Erythromycin estolate Hydralazine Nitrofurantoin

Oral contraceptives Rifampin Tetracycline Trimethqprim-sulfamethoxazole a Intrinsic hepatotoxin. TABLE 26-2. Morphology of Liver Injury by Common Xenobiotics

Acetaminophen is a common cause of acute hepatic injury, as are herbal remed risks are increasingly recognized.1 , 34 , 51 , 52 , 71 , 97 Many halogenated hydro include carbon tetrachloride, bromobenzene, monochlorobenzene, hydrochloro and halothane also produce hepatocellular necrosis.6 , 48 , 49 A recent study of 11,000 patients exposed to isoniazid during preventive treatment showed that injury occurred in 0.10% of those starting treatment, and in 0.15% of those co

treatment.93 , 94 , 101 Risk factors for the development of hepatotoxicity from I are female sex, increasing age, coadministration with rifampin, and alcoholism.6 discussed extensively in Chap. 55 . The thiazolidinedione agents troglitazone an rosiglitazone, marketed for the treatment of type 2 diabetes, are associated wit

hepatocellular necrosis.5 , 44 The much higher incidence of liver injury attribute troglitazone led to its withdrawal from the market in March 2000.78 Table 26-2 the pharmacologic and toxic xenobiotics that have been reported to cause hepa

Steatosis

Steatosis is the abnormal accumulation of fat in hepatocytes. It occurs in a num metabolic conditions that include responses to xenobiotics. Two forms of steatos described: macrovesicular steatosis, in which the nucleus is displaced by accum intracellular fat, and microvesicular steatosis, which is characterized by fat drop not displace the nucleus. The intracellular fat accumulation reflects abnormal h metabolism and may occur as a result of any one or more of the following mech impaired synthesis of lipoproteins; increased mobilization of peripheral adipose increased uptake of circulating lipids; increased triglyceride production; decreas triglycerides to lipoprotein; decreased release of very-low-density lipoproteins f hepatocytes; and decreased β-oxidation of fatty acids.80 Steatosis is a condition usually well tolerated by hepatocytes and is reversible following withdrawal of

When associated with hepatocellular injury by xenobiotics, it signals the presenc underlying metabolic dysfunction that may lead to cell injury and death. Comm associated with macrovesicular steatosis include ethanol and amiodarone. Ethan the uptake of fatty acids into hepatocytes and decreases lipoprotein secretion. the increased ratio of the reduced form of nicotinamide adenine dinucleotide (NA oxidized form of nicotinamide adenine dinucleotide (NAD+ ), associated with he metabolism of ethanol, decreases oxidation of fatty acids and promotes fatty ac The initial pathologic lesion that occurs in alcoholic liver disease is reversible m steatosis. Mallory bodies, eosinophilic cytoplasmic deposits of keratin filaments degenerating hepatocytes, are also common microscopic findings in alcoholic liv Amiodarone is concentrated in the liver and may account for up to 1% of its we during chronic therapy.37 Amiodarone hepatic toxicity resembles that of alcoho with steatosis, Mallory bodies, and potential for progression to cirrhosis. Lamel intralysosomal phospholipid inclusion bodies were found in all cases in one study be specific for amiodarone toxicity.112 Figure 26-3 shows macrovesicular steato Mallory bodies caused by administration of amiodarone.

Figure 26-3. Macrovesicular steatosis associated with administration of amioda small arrow indicates the presence of Mallory bodies. The large arrow points to intracellular fat. (Note that the nuclei are displaced.) Polymorphonuclear leukocy also present. (Reprinted with permission from Lee WM: Drug-induced hepatotoxic

Med

1995;333:1118.)

Microvesicular steatosis is attributed to impairment of ATP-dependent β-oxidatio acids within hepatocyte mitochondria and is a sign of failure of hepatic mitocho oxidative phosphorylation.42 , 90 , 119 , 122 It is associated with a much more se hepatocellular dysfunction. High doses of tetracycline produce microvesicular s associated with moderate elevations of aminotransferases, markedly prolonged time, and progression to fulminant hepatic failure.122 Recently, microvesicular s been reported in patients taking nucleoside analogs (zidovudine, zalcitabine, an for the treatment of HIV infection.119 , 131 This is attributed to disruption of m DNA synthesis.19 The nucleoside analog deaths during a study of its use in the examinations of liver specimens showed structural injury. In these cases, severe

fialuridine caused severe hepatotoxicity treatment of chronic hepatitis B infectio marked accumulation of fat with minim acidosis with minimal elevation of hep

enzymes and bilirubin, and failure of hepatic synthetic function suggested injury the mitochondria. Mitochondria examined under the electron microscope were abnormal.90 Microvesicular steatosis attributed to mitochondrial failure was repor case of Bacillus cereus food poisoning, where high levels of the bacterial emetic cereulide were found in the bile and liver. In this case, microvesicular steatosis associated with extensive hepatocellular necrosis.85 In all cases, lactic acidosis biochemical manifestation of impaired energy production.42 , 119 In addition to

other xenobiotics associated with mitochondrial failure are hypoglycin, the cause vomiting sickness, aflatoxin, and margosa oil. 119 Figure 26-4 demonstrates mi steatosis in a patient with fialuridine hepatotoxicity.

Sodium valproate causes mild elevations of aminotransferases in approximately patients, usually during the first few months of therapy. The earliest pathologic signals progression of liver injury is microvesicular steatosis, which occurs in th necrosis. A small percentage of patients progress to

P.418 fulminant hepatic failure characterized by centrilobular necrosis.146 The incidenc hepatocellular injury is highest in children, approaching 1 in 800 children younge years.104 Carnitine is an amino acid that has an essential role in the transport o into the mitochondria and their subsequent β-oxidation. An association between carnitine and the development of hyperammonemia is observed in children treat

valproic acid.104 , 136 It is not yet known whether valproic acid causes carnitine that results in hepatic injury, or whether patients with preexisting metabolic err in carnitine deficiency are at greater risk of hepatic injury. A retrospective study patients showed a significant decrease in the mortality rate in patients with val acid–induced hyperammonemia treated with carnitine. 11

Figure 26-4. This figure shows severe microvesicular steatosis in a patient trea fialuridine. Note the central location of the nuclei. (Reprinted with permission fr R, Fried MW, Sallie R, et al: Hepatic failure and lactic acidosis due to fialuridine, investigational nucleoside analogue for chronic hepatitis B. N Engl J Med 1995;

Steatosis is also observed following exposure to the industrial solvent dimethy The mechanism of hepatotoxicity in humans is unknown. Liver biopsies in patien illness show focal hepatocellular necrosis and microvesicular steatosis. More pro symptomatic exposures result in significant macrovesicular steatosis with mild aminotransferase elevations.107 , 108

Cholestasis

Cholestasis results from a number of toxic mechanisms. It may occur with or w associated hepatitis. The development of jaundice following hepatic necrosis is

manifestation of general failure of liver function. More specific mechanisms that postulated to result in cholestasis include (a) impairment of the integrity of tigh junctions that functionally isolate the canaliculus from the hepatocyte and sinus failure of transport of bile components across the hepatocytes; (c) blockade of membrane active transport sites; (d) decreased membrane fluidity resulting in transport; and (e) decreased canalicular contractility resulting in decreased bile 5 ). 67

Figure 26-5. Potential mechanisms of xenobiotic-induced cholestasis. (Reproduc permission from Moslen MT: Toxic responses of the liver. In: Klaassen CD, ed: Doull's Toxicology, The Basic Science of Poisons. New York, McGraw-Hill, 1996,

Estrogens cause intrahepatic cholestasis by altering the composition of the lipid and inhibiting the rate of secretion of bile into the canaliculi.67 , 78 Rifampin imp uptake of bilirubin into hepatocytes. Methyltestosterone and C-17 alkylated ana impair the secretion of bilirubin into canaliculi.78 Exposure to chlorpromazine is with cholestasis and periductal inflammation. This may be caused by inhibition o adenosine triphosphatase (ATPase), which results in decreased canalicular con 116 Cyclosporine inhibits sodium-dependent uptake of bile salts across the sinu membrane, and blocks ATP-dependent bile salt transport across the canalicular Floxacillin causes cholestasis with minimal inflammation or evidence of hepatoc injury.137 Exposure of rats to ANIT causes a specific injury localized to the tigh that separate the hepatocyte from the canaliculi. This results in reflux of bile c the sinusoidal space and increased access of sinusoidal molecules to the biliary

Venoocclusive

Disease

Hepatic venoocclusive disease is caused by toxic injury to the endothelium of t venules that results in intimal thickening, edema, and nonthrombotic obstruction sublobular hepatic veins may also become edematous and fibrosed. There is int sinusoidal dilation in the centrilobular areas associated with liver cell atrophy a The injury is caused by an activated pyrrole derivative produced by the cytochro system.87 , 142 The gross pathologic appearance is that of a “nutmeg― liv

Massive hepatic congestion and ascites ensue.69 , 111 Hepatic venoocclusive dise fatal in

P.419 15–20% of cases. It is also associated with exposure to pyrrolizidine alkaloids many plant species, and with the use of cytotoxic drugs, especially in patients bone marrow transplantation. A rapidly progressive form may follow high-dose cyclophosphamide.89 Hepatic venoocclusive disease is also associated with expo comfrey tea (Symphytum species),140 , 144 and other pyrrolizidine alkaloid-cont preparations that include Heliotrope, Senecio , and Crotalaria species.69 It has epidemic proportions, in South Africa after the ingestion of flour contaminated (Senecio ); in Jamaica after the ingestion of “bush teas― (Crotalaria speci India and Afghanistan when food was contaminated with Heliotropium lasiocarp Crotalaria . 15 , 95 , 124 , 132

Peliosis

Hepatis

Peliosis hepatis is characterized by large blood-filled cavities associated with si dilation (Chap. 44 ). It is most frequently associated with the use of androgenic Although most patients are asymptomatic, occasionally the dilated sinusoids rup cause hemoperitoneum.8

Chronic

Hepatitis

A form of hepatitis that clinically resembles autoimmune hepatitis occurs with t administration of some drugs such as methyldopa, nitrofurantoin, propylthioura dantrolene, and diclofenac.4 , 60 , 88 , 110 , 115 , 123 , 130 Many of these cases a with positive antinuclear antibody (ANA), smooth muscle antibody (SMA), and hyperglobulinemia. Jaundice is prominent and hepatocellular enzymes are elevate

fold. Liver biopsy commonly reveals intrahepatic cholestasis, as well as centrilo inflammation.37 , 83

Granulomatous hepatitis is associated with infiltration of the hepatic parenchym granulomata. As many as 60 drugs are associated with this disorder. Fever and symptoms are common, 25% have splenomegaly. Liver enzymes are mixed, ref variable degrees of cholestasis and hepatocellular injury. Eosinophilia occurs in 3 extrahepatic manifestation of severe form of liver disease. kidney, is a disturbing sign lists some of the xenobiotics

drug hypersensitivity. Continued exposure may res Small vessel vasculitis, which may involve the skin associated with increased mortality. 37 , 75 , 91 , 147 that have been implicated in this disorder.

Cirrhosis

Cirrhosis, which results in irreversible hepatic dysfunction and portal hypertensi by progressive fibrosis and scarring of the liver. Fibrosis is related to increased collagen. In alcoholic cirrhosis, “activated― lipocytes in the centrilobular a play a major role in the production of septal and perivenular collagen that corre collagen deposition in the space of Disse. Acetaldehyde also stimulates collagen lipocytes, as do other aldehydes that are products of lipid peroxidation.80 Alcoho generally precedes cirrhosis, although cirrhosis may develop in its absence.84 C

ingestion of excessive amounts of vitamin A (25,000 U/d for 6 years or 100,000 years) results in cirrhosis. An increase in the fat content of the sinusoidal Ito ce increasing degrees of collagen formation are characteristic lesions that occur ea A toxicity (Chap. 41 ). Portal hypertension may be early and striking.43 Like vita methyldopa and methotrexate also cause a slow progressive development of cir minimal clinical symptoms.76 , 141 Methotrexate-induced hepatic fibrosis is dose Risk factors include associated alcohol intake and preexisting liver disease. Red has largely eliminated the risk of the development of cirrhosis in patients receiv methotrexate.58 , 141

Hepatic

Tumors

There is persuasive evidence that the use of oral contraceptive steroids increase hepatic adenomas.29 , 63 There is also evidence that oral contraceptives increas

risk of hepatocellular carcinoma; however, the number of cases associated with therapy is low. 53 , 70 Anabolic steroids are rarely associated with the developme benign and malignant hepatic tumors.17 , 38 , 56 Angiosarcoma is strongly assoc exposure to vinyl chloride, in addition to arsenic, thorium dioxide, and steroid 37

Hepatic Injury Associated with Plants and Herb

In addition to the venoocclusive disease associated with pyrrolizidine alkaloids above, herbal remedies are increasingly recognized as a cause of acute hepato Numerous plants or plant products are known or suspected to cause hepatic inju and 114 ).1 , 30 , 34 , 51 , 52 , 71 , 97 , 120

Clinical

Presentations

Two general types of clinical patterns occur with hepatic toxins: a chronic indol progression of injury that may elude diagnosis, and a more acute, sometimes f progression of injury that is temporally related to exposure to the xenobiotic.

Chronic injury is associated with an initially asymptomatic or minimally sympto state, with mildly abnormal liver chemistries and slow progression to clinically dysfunction or cirrhosis.37 , 75 , 137 Over a period of time ranging from months

jaundice, coagulopathy, encephalopathy, hepatomegaly, or signs of cirrhosis suc angiomata, ascites, caput medusa, and gynecomastia may be evident. An indol to cirrhosis with minimal symptoms occurs in some patients with chronic exposu A, methotrexate, ethanol, amiodarone, and methyldopa.43 , 75 , 80 , 84 Cholestat manifested primarily by jaundice and pruritus.

Symptoms of acute liver injury include fever, anorexia, nausea, vomiting, and f include coagulopathy, jaundice, percussion tenderness in the right upper quadra encephalopathy. Rapid development of portal hypertension, ascites, and death f onset of some cases of venoocclusive disease.69 Patients with acute, large expo carbon tetrachloride, yellow phosphorus, acetaminophen, and cyclopeptide-con

mushrooms present first with gastrointestinal symptoms. This is followed by a p being (1–3 days), and then signs of acute hepatic and renal failure, with fatig and nausea, followed by profound jaundice, hemorrhage, ascites, hepatic ence and death.74 , 113 Patients with significant acute occupational exposure to dim P.420 present with abdominal pain, anorexia, and disulfiram-type reactions.108 , 138 Subclinical Normal physical examination Subtle impairment of neuromotor function → driving or work injury hazard I

Euphoric, irritable, depressed, fluctuating mild confusion, poor attention, sleep Poor coordination; may have asterixis alone II Impaired memory, cognition, simple mathematical tasks Slurred speech, tremor, ataxia III Difficult to arouse, persistent confusion, incoherent Hyperactive reflexes, clonus, nystagmus IV Coma; may respond to noxious stimuli May have decerebrate posturing; Cheyne-Stokes respirations; pupils are typicall the oculocephalic reflex is intact; may have signs of intracranial pressure

Clinical Stage

Mental

Status

Neuromotor

Function

TABLE 26-3. Stages of Hepatic Encephalopathy

Fulminant hepatic failure (FHF) is defined as liver injury that progresses to enc within 8 weeks of the onset of illness in a patient without preexisting liver disea Complications from FHF include encephalopathy, cerebral edema, coagulopathy, dysfunction, hypoglycemia, hypotension, acute lung injury, sepsis, and death. In a patient may progress from health to death in as little as 2–10 days.74 , 85 , 3 shows the clinical progression of liver failure as hepatic encephalopathy devel prognosis of FHF is related to the time that passes between the onset of jaundic onset of encephalopathy. Perhaps surprisingly, a better prognosis is associated

(2–4 weeks) jaundice-to-encephalopathy intervals.113 Most cases of fulminan failure are caused by xenobiotics or viral hepatitis. Fulminant hepatic failure is associated with extensive necrosis, although it may occur in the absence of de necrosis, as occurs in exposures to xenobiotics that injure mitochondria, such a analogues and Bacillus cereus toxin.85 , 90 , 131 Some xenobiotics that are asso fulminant necrosis are clove oil, bromfenac, amanitin cyclopeptides, acetaminop tetracycline, phosphorus, halogenated hydrocarbons, INH, methyldopa, and valp 41 , 74 , 96

The Evaluation of the Patient with Liver Diseas

The history is critical in establishing the diagnosis of the patient with liver disea medication history should include careful investigation of nonprescription agent acetaminophen and the possible use of herbal therapies. Nearly all chronically u medications should be suspect. An occupational history may indicate exposure t chloride (plastics industry), dimethylformamide (leather industry), or other ind solvents. Table 26-4 lists some of the occupational exposures that result in live Alcohol abuse is a common cause of acute hepatitis and the most common caus in this country.80 , 84 A history of male homosexual contacts, healthcare occupa intravenous drug use indicates the possibility of hepatitis B, whereas recent trav underdeveloped country suggests the possibility of hepatitis A. In patients with

pain, the possibility of cholelithiasis should be considered.

Clinical

Laboratory

Aminotransferases

Laboratory tests are helpful and certain patterns may be suggestive of specific (Table 26-5 ). Elevation of hepatocellular enzymes, especially the AST and ALT, hepatocellular injury, and within a given clinical context, has useful diagnostic Aminotransferases may be increased up to 500 times normal when hepatic necr extensive, such as in severe acute viral or toxic hepatitis.74 The degree of eleva always reflect the severity of injury as concentrations may decline as fulminant progresses. Only moderately elevated, or occasionally normal aminotransferase concentrations occur in some patients with hepatic failure caused by mitochond

cirrhosis, or venoocclusive disease.43 , 69 , 146 Processes associated with intrah cholestasis in the absence of hepatitis also may not lead to significant aminotra elevation.98 , 106 , 147 Patients with acute liver injury caused by dimethylforma demonstrated P.421

aminotransferase concentrations 2–30 times normal, and ALT greater than AS and alkaline phosphatase concentrations were often normal.108 In alcoholic liver contrast to other forms of hepatitis, the AST concentration is typically two to th greater than the ALT. This is attributed to impairment of ALT synthesis because

5′-phosphate deficiency in alcoholics. Elevation of either of these enzymes ab is inconsistent with injury caused by ethanol.129 During acute extrahepatic obstr biliary tract, the AST or ALT may be as high as 1000 IU/L, indicating inflammati reflux of bile acids into the biliary tree.129 The measurement of γ-glutamyl tra (GGTP) is not very useful as it is present throughout the liver and its elevation nonspecific.129 Arsenic Cirrhosis, angiosarcoma Beryllium Granulomatous hepatitis Carbon tetrachloride

Acute necrosis Chlordecone Minor hepatocellular injury Copper salts Granulomatous hepatitis, angiosarcoma Dimethylformamide Steatohepatitis Methylenedianiline Acute cholestasis Phosphorus Acute necrosis Tetrachloroethane Acute, subacute necrosis Tetrachloroethylene Acute necrosis Toluene Steatosis, minor Trichloroethane Steatosis, minor Trinitrotoluene Acute necrosis Vinyl chloride Acute necrosis, Xylene Steatosis,

injury

hepatocellular

injury

fibrosis,

minor

Xenobiotic

hepatocellular

angiosarcoma

hepatocellular

injury

Type of Injury

TABLE 26-4. Occupational Exposures Associated with Liver Injury

Hepatocellular N or ↑ ↑↑↑ N

necrosis,

acute

focal

(hepatitis)

N or ↑ ↑↑ N N Hepatocellular necrosis, acute massive N or ↑ ↑↑↑ N ↑↑ ↑↑↑ ↑↑ ↑ Chronic infiltrative disease (tumor, fatty liver) ↑↑ ↑ N N N N N Microvesicular N or ↑ ↑↑ ↓ ↑↑ ↑ ↑↑ ↑↑↑ Cholelithiasis ↑ ↑ N N N or ↑

steatosis,

acute

N N Cholestatic hepatitis ↑↑ ↑ N N ↑ N N Chronic hepatitis N or ↑ ↑ N or ↓ N N or ↑ N N Cirrhosis N or ↑ ↑ ↓ N or ↑ N or ↑ N or ↑ N ↑ = increase; ↓ = decrease; N = normal. Disorder

Alkaline Phosphatase

AST, ALT

Albumin

Prothrombin Time

TABLE 26-5. Laboratory Tests that Evaluate the Liver

Bilirubin

Amm

Alkaline

Phosphatase

In patients with cholestasis, bile acids stimulate the synthesis of alkaline phosp hepatocytes and biliary epithelium in response to a number of pathologic proces liver. Elevations of the alkaline phosphatase as high as 10-fold may occur with liver diseases, but are most commonly associated with extrahepatic obstruction Although the alkaline phosphatase may be normal or elevated only minimally in injury, it is unusual for obstruction to occur without some elevation of the alkal phosphatase. Elevations of alkaline phosphatase and GGTP parallel each other in the biliary tract.129

Bilirubin

Elevation of conjugated, or direct, bilirubin implies impairment of secretion into elevation of unconjugated, or indirect, bilirubin implies impairment of conjugati

Unconjugated hyperbilirubinemia also occurs during hemolysis and in rare disord conjugation such as Gilbert or Crigler-Najjar syndromes. Except in cases of pure unconjugated hyperbilirubinemia, the fractionation of bilirubin in the case of h disorders does not have any important diagnostic utility, and will not distinguish

parenchymal disorders of the liver from intrinsic or extrinsic cholestatsis.129 The bilirubin in the urine implies elevation of conjugated (direct) bilirubin and obviat for laboratory fractionation. Urobilinogen is produced by the bacterial metabolism of bilirubin in the absorbed and excreted in the urine. Its presence in the urine indicates of bilirubin in bile, while its absence is associated with complete biliary result of more modern methods of detection of complete obstruction of test is mainly of historical interest.

Serum

bowel lu the norm obstruct the bilia

Albumin

Quantitatively, albumin is the most important protein that is made in the liver. of up to 20 days, the albumin is usually normal in the previously healthy patien liver injury. In the absence of other disorders that affect albumin, such as neph syndrome, protein-losing enteropathy, or starvation, a low serum albumin is a for the severity of chronic liver disease.129

Coagulation

Factors

Impairment of coagulation is a marker of the severity of hepatic dysfunction in and chronic liver disease. Unlike the case with serum albumin, with its half-life o the onset of coagulopathy as a consequence of impaired synthesis of the shortK-dependent clotting factors II, VII, IX, and X is rapid. Very acute changes in reflect the concentration of factor VII, which has the shortest half life.57 The e coagulation pathway, as measured by the prothrombin time (PT) or the interna normalized ratio (INR), is affected by reductions in factors II, VII, and X. Elevat or PT in acute hepatitis is associated with a higher risk of fulminant hepatic fail In addition to failure of hepatic synthesis, inadequate levels of factors II, VII, IX also result from ingestion of warfarin anticoagulants or malabsorption of vitamin ) .24

International

Normalized

Ratio

or

Prothrombin

Tim

Because different thromboplastin reagents give different PT values on the same INR was developed to normalize PT measurements in patients treated with war

comparisons of therapeutic outcomes across different care settings and across The INR uses the ISI (International Sensitivity Index) that is derived from a coh patients on stable anticoagulant therapy. It normalizes the responsiveness of a thromboplastin reagent in comparison to a WHO reference standard that is assig

of 1.0.66 There is little controversy regarding the value of the INR when compar ratio for measuring the extent of warfarin-induced anticoagulation. Because fac deficiencies in patients with liver disease are different from those in patients on there is considerable

P.422 controversy regarding which measurement is best for patients with liver disease Although comparison of factor levels in warfarin-treated patients with those with showed no difference in factor VII, there are significant differences in factors II, fibrinogen. Comparison of the PT with INR in the evaluation of test results with thromboplastin reagents showed consistency among the control groups of warf patients, but no consistency among PT or INR measurements using the same t reagents in patients with liver disease.66 Because of a failure to demonstrate a liver specialists who have expressed an opinion support the continued use of the

describe the degree of liver injury, bemoaning the availability of a single reliab that would help predict operative risk. 24 , 26 , 66 In patients with liver disease, u implies a normalized correlation that does not exist and is therefore potentially The implication for toxicologists is that caution should be exercised in relying to published INR values that purportedly predict the severity of illness in patients liver failure.

Ammonia

Severe generalized impairment of hepatic function leads to a rise in the serum concentration as a result of impairment of detoxification of ammonia produced catabolism of proteins. The absolute level of elevation is not clearly associated status alteration.129 Elevations of serum ammonia concentrations occur in only patients with hepatic encephalopathy, suggesting that ammonia may be a marke a primary cause of CNS dysfunction.40

Some patients treated with valproic acid have developed alterations in mental s

associated with elevated ammonia levels, sometimes in the absence of other la indicators of hepatic injury, and without demonstrable toxic levels of valproic ac attributed to selective impairment of urea cycle enzymes ornithine transcarbam carbamyl phosphate synthetase by pentanoic acid metabolites (Chap. 47 ).35 , 1

Other

Serologic studies for the presence of markers of hepatitis A, B, and C should be routinely in patients with hepatitis.

In the patient with severe liver injury, hypoglycemia is a major concern because impairment of glycogen storage and gluconeogenesis. Hyperglycemia also occurs of the liver's inability to handle a large glucose load. The arterial blood-gas valu commonly shows a respiratory alkalosis. Severe lactic acidosis occurs in patient failure caused by mitochondrial injury. Measurements of serum lactate concentra useful in identifying the cause of acidosis in a patient with suspected toxic liver 119

The CT and MRI scans are useful tests for evaluation of parenchymal disease of ultrasound examination reliably demonstrates dilation of the extrahepatic bile d

biopsy may be helpful but is not specifically diagnostic of xenobiotic-induced he

Hepatic

Encephalopathy

Hepatic encephalopathy (HE) is a severe, but potentially fully reversible, manife liver failure, even in cases of deep coma.39 , 40 Table 26-3 describes, in detail, stages of acute HE. Ammonia levels are elevated in patients with nitrogenous HE elevated in nonnitrogenous HE. Conditions associated with nonnitrogenous HE i hypoglycemia, hypoxia, anemia, and exposure to sedative hypnotic agents.40 Ni is precipitated by processes that elevate CNS ammonia concentrations, such as alkalosis, increased muscle wasting, volume depletion, azotemia, or gastrointes bleeding.40 Alkalosis and hypokalemia facilitate conversion of NH4 + to NH3 , w more easily across the blood–brain barrier. The clinical improvement in HE th lowering of serum ammonia levels, continues to be accepted as evidence for an

of ammonia in the pathogenesis of HE.39 The demonstration that ammonia is no many cases suggests that it may be an epiphenomenon, or marker, for other e endogenous toxins. There is evidence that liver failure is associated with the ac substances that stimulate central benzodiazepine receptors, leading to inhibition

transmission. Although it is clear that sedatives that depress γ-aminobutyric ac transmission can make encephalopathy worse, studies of the use of flumazenil i of encephalopathy show conflicting results. There does seem to be a significant improvement in some patients who already have a highly favorable prognosis.

is no clear evidence that all patients will benefit from flumazenil, some individua benefit for a short time. Certainly, the administration of benzodiazepines should The pathophysiologic processes discussed above are not mutually exclusive as t HE is likely multifactorial.

Management

In many cases, toxic liver injury resolves with simple withdrawal of the offendi In cases of severe injury, significant improvement in survival is associated with supportive care in an intensive care environment.74 Early referral to a transplan patients with evidence of severe or rapidly progressive toxic injury is indicated. of indications for the use of N -acetylcysteine and discussion of indications for transplantation, see Antidotes in Depth: N -Acetylcysteine and Chap. 34 .

Summary

The primary role of the liver in the biotransformation of xenobiotics results in a risk of hepatotoxicity. The spectrum of liver injury includes combinations of ch steatosis, and hepatocellular necrosis. Injury may be a result of cellular or ant autoimmune mechanisms; free radical initiation of lipid peroxidation; mitochond formation of adducts with critical cellular enzymes; and other, less-well-defined Disturbances in intracellular calcium concentrations may play a role in the deve hepatocellular injury, although the common “final pathway― role of calcium into question. Xenobiotic-induced liver injury can be dose-dependent and predic idiosyncratic and unpredictable. Idiosyncratic injury is affected by host characte include genetic makeup, concomitant or previous exposure to drugs and toxins, underlying condition of the liver. P.423

Acknowledgment Charles Maltz and Todd Bania contributed to this chapter in a previous edition.

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138. Wang JD, Lai MY, Chen JS, et al: Dimethylformamide-induced liver dama

synthetic

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1991;46:161–166. P.426

139. Watanabe N, Tsukada N, Smith CR, et al: Permeabilized hepatocyte coup Adenosine triphosphate-dependent bile canalicular contractions and a circumf pericanalicular microfilament belt demonstrated. Lab Invest 1991;65:203–2

140. Weston CF, Cooper BT, Davies JD, et al: Veno-occlusive disease of the li secondary to ingestion of comfrey. Br Med J (Clin Res Ed) 1987;295:183.

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142. Williams DE, Reed RL, Kedzierski B, et al: Bioactivation and detoxication pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver. D Dispos 1989;17:387–392.

143. Yeong ML, Clark SP, Waring JM, et al: The effects of comfrey derived py alkaloids on rat liver. Pathology 1991;23:35–38.

144. Yeong ML, Swinburn B, Kennedy M, et al: Hepatic veno-occlusive disease with

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 27 - Renal Principles

Chapter Renal

27 Principles

Donald A. Feinfeld Vincent L. Anthony

Overview Anatomic

of

Renal

Function

Considerations

The kidneys lie in the paravertebral grooves at the level of the T12-L3 vertebrae while the lateral margins are convex, giving the organ a bean-shaped appearanc 10–12 cm in length, 5–7.5 cm in width, and 2.5–3.0 cm in thickness. In t 125–170 g; in the adult female, each kidney weighs 115–155 g.

At its concave surface is the hilum, through which the renal artery, vein, renal lymphatics pass. On the convex surface, the kidney is surrounded by a fibrous c capsule with a fibroareolar capsule (called the renal fascia ), which offers furthe place.

The arterial supply begins with the renal artery, which is a direct branch of the artery subdivides into branches supplying the 5 major segments of each kidney segment, the anteroinferior segment, the posterior segment, and the inferior p within each segment to become lobar arteries. In turn, these vessels give rise t

sharply branching interlobular arteries, which directly supply the glomerular tuf

The cut surface of the kidney reveals a pale outer rim and a dark inner region medulla, respectively. The cortex is 1 cm thick and surrounds the base of each consists of between 8 and 18 cone-shaped areas called medullary pyramids; the containing the ends of the collecting ducts. Urine empties from these ducts into and, subsequently, into the urinary bladder.

The kidneys maintain the constancy of the extracellular fluid by creating an ultr free of cells and larger macromolecules, and then processing that filtrate, reclaim the rest escape as urine. Every 24 hours, an adult's kidneys filter about 180 L o 25–60 L), and 25,000 mEq of sodium (total body Na+ is 1200–2800 mEq). kidneys regulate these two substances independent of each other, depending on 1% of the filtered water and 0.5–1% of the filtered Na+ are excreted.

Renal function begins with filtration at the glomerulus, a highly permeable capil arterioles in series. The relative constriction or dilation of these vessels normal (GFR). Under normal circumstances, approximately 20% of the plasma water in

actually goes through the filter, carrying with it electrolytes, small metabolites and urea, and leaving behind the blood cells and nearly all the larger proteins, filtrate then enters a series of tubules that reabsorb most of it and secrete cert and bases, into the urinary space. The proximal tubule performs bulk reabsorp

of the filtrate. Distal to the proximal tubule are the loop of Henle, which contro urine, and the distal nephron, which does the fine-tuning in the balance betwee Reabsorption of sodium is controlled proximally by hydrostatic and oncotic pres distally by hormones such as aldosterone. Control of water reclamation depends of the loop of Henle, which absorbs solute without water. This produces a dilute makes the medullary interstitium hypertonic. Final regulation of water reabsorptio antidiuretic hormone (ADH), which opens water-reabsorbing channels (aquaporins nephron segments (collecting ducts). The kidneys also regulate balance for potas are influenced by the effect of aldosterone on the distal nephron), and calcium influenced by the blood level of parathormone). Injury to either the glomeruli or the filtration. As the kidneys fail, serum relationship between these levels and levels of these substances denotes a

tubules can lead to renal dysfunction; that levels of the marker substances urea and the level of GFR is hyperbolic, not linear, large decrease in renal function. By the tim

creatinine exceeds the upper limit of normal, GFR is already reduced by more th

Many xenobiotics cause or aggravate renal dysfunction. The kidneys are particul reasons;141 (a) They receive 20–25% of cardiac output yet make up less than metabolically active, and thus vulnerable to xenobiotics that disrupt metabolism;

P.428 remove water from the filtrate and may build up a high concentration of xenobio interstitium are susceptible to attack by the immune system. Many factors, such individual's reaction to a particular nephrotoxin.12 The clinician should be aware alter them to minimize the adverse effect after a toxic exposure.

Functional

Toxic

Renal

Disorders

Although most toxic renal injury results in decreased renal function, there are 3 balance despite normal GFR in anatomically normal kidneys: renal tubular acido secretion of antidiuretic hormone, and nephrogenic diabetes insipidus.

Renal tubular acidosis (RTA) is a loss of ability to reclaim the filtered bicarbona to generate new bicarbonate to replace that lost in buffering the daily acid load nonanion-gap

metabolic

acidosis,

usually

accompanied

by

hypokalemia.

The primary defect in distal RTA involves the decreased secretion of hydrogen (

distal tubule. This most often denotes a defect in the H+ -translocating adenosin luminal surface of these cells. Less frequently occurring mechanisms include a exchanger, which is responsible for returning bicarbonate generated within the c given the voltage dependence of hydrogen secretion, if there is a decrease in t

charge, there will be a decrease in this secretion. Most of this voltage is created on the peritubular capillary side of the adjacent cell. (Note: Cells adjacent to th cells and primarily control K+ secretion.) As this pump malfunctions, less sodium a decreased gradient from the lumen to the cell. Thus, the lumen becomes mo transmembrane potential.

The primary defect in proximal RTA is incompletely understood. Normally, the N membrane, the Na+ -K+ -ATPase in the basolateral membrane, and the enzyme systems necessary for proximal tubular bicarbonate reabsorption. It is proposed become disordered and thereby diminish the resorptive capacity of the proximal part of the Fanconi syndrome , a generalized failure of proximal tubular transp

renal

glycosuria,

and

hyperphosphaturia).

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs wh fall in plasma osmolality, which normally inhibits ADH secretion. ADH primarily increased water reabsorption by increasing the aquaporin channels in this segme altered physiology: there may be altered secretion of ADH, a resetting of the os secretion), or the inability to decrease ADH secretion in the face of a water load serves to augment normal free water retention, which subsequently leads to the concentrated urine (as reflected in a relative increase in urine osmolality) and h Although this most often occurs as a complication of intracranial lesions or from in a diseased lung, many xenobiotics (eg, chlorpropamide, antidepressants, vin

methylenedioxymethamphetamine [MDMA or Ecstasy]) can also cause inappropria Nephrogenic

diabetes

insipidus (NDI) is the reverse of SIADH. It denotes inabilit

stimulation despite severe losses of body water. There are many causes of NDI disease states. Several xenobiotics also cause NDI. Lithium, demeclocycline, fo are noted drugs that can cause this syndrome (Chap. 17 ). Of these, our under described, although the exact mechanism has not been elucidated. After lithium

through the sodium channel, it interferes with ADH-mediated water transport b channels.

Major Toxic Syndromes of the Kidney

Most nephrotoxicity involves histologic renal injury. Although xenobiotics can affe ), there are three major syndromes of toxic renal injury: (a) chronic renal failu

especially, (c) acute renal failure (Table 27-1 ). For purposes of continuity, acu Because nephrotoxins usually affect the tubules, the most metabolically active s nephrotoxicity involves either acute or chronic tubular injury, although glomerul xenobiotics. These processes are not mutually exclusive, and toxic nephropathy m the nephron (eg, nonsteroidal antiinflammatory drug [NSAID]-induced acute ren

Chronic renal failure refers to any disease process that causes progressive declin months to years. There is usually a gradual rise in BUN and serum creatinine falls; often there are no symptoms other than nocturia (indicating loss of urina

The most common lesion of nephrotoxic chronic renal failure is chronic interstiti destruction of tubules over a prolonged period,74 with tubular atrophy,

P.429 fibrosis, and a variable cellular infiltrate (Fig. 27-2 ), sometimes accompanied nephritis may progress to chronic interstitial nephritis, if exposure to xenobiotic insidious and relatively asymptomatic, often presenting as secondary hypertensi The major symptom is nonspecific nocturia. Papillary necrosis may lead to urete ureteral space. There is mild to moderate proteinuria that remains well under t renal disorders, interstitial nephritis is characterized by failure of the diseased tu impairment, resulting in metabolic imbalances such as hyperchloremic metabolic hyperkalemia early in the disease course.70 Injury to erythropoietin-secreting ce anemia. Chronic Renal Failure (slowly increasing azotemia) Chronic interstitial nephritis Papillary necrosis Chronic glomerulosclerosis Nephrotic Syndrome (proteinuria, Minimal glomerular change

hypoalbuminemia,

Membranous nephropathy Focal segmental glomerulosclerosis Acute Renal Failure (rapidly increasing azotemia) Acute prerenal failure Acute Acute Acute Acute

urinary obstruction tubular necrosis interstitial nephritis vasculitis

TABLE 27-1. Major Nephrotoxic Syndromes

edema)

Figure 27-1. Schematic showing the major nephrotoxic processes and the sites affect. ATN = acute tubular necrosis. (Courtesy of the National Institutes of Hea

Nephrotic syndrome is characterized by massive proteinuria (>3 g/d in the ad and the edema that usually prompts the patient to seek medical attention. Alth findings are not completely understood, the underlying event is injury to the g macromolecules from passing from the capillary lumen into the urinary space. A

excretion as a result of renal tubular catabolism of filtered protein. The tubules

P.430 of the extracellular space and edema. The glomerular lesion may progress to re continues. Xenobiotics induce nephrotic syndrome (Table 27-2 ) in 2 ways. Firs the blood, which leads to antigen–antibody complex formation after the immu complexes subsequently deposit in the glomerular basement membrane, thereby Fig. 27-3 ). Second, they can upset the immunoregulatory balance (eg, NSAIDs hypersensitivity vasculitis.

Figure 27-2. Chronic interstitial nephritis (secondary to NSAIDs). Interstitial f tubular atrophy (H&E × 225). (Courtesy of Dr. Rabia Mir.)

Acute renal failure is defined as any abrupt decline in renal function that impair metabolic balance. The 3 main categories of acute renal failure are prerenal, p

Prerenal failure involves impaired renal perfusion, which can occur with volume failure. Hence, toxic events that cause bleeding (overdose of anticoagulants),

or emetics), cardiac dysfunction (β-adrenergic antagonists), or hypotension from failure.66

One important cause of prerenal failure is the extreme renal hypoperfusion caus syndrome. This syndrome is characterized by impaired renal function and marke associated with severe chronic or acute hepatic failure. Many neurohumoral distu systemic hemodynamic changes that occur in the syndrome. Specifically, circula greatly increased in hepatorenal syndrome. Angiotensin, norepinephrine, vasopr all contribute to the extreme cortical vasoconstriction. Furthermore, splanchnic increases in endotoxin, nitrate, nitrite, and glucagon, all decrease mean arteria renal blood flow. That this renal insufficiency is prerenal is best illustrated by the

patient with hepatorenal syndrome is transplanted into a uremic patient, the fun normal. Captopril Drugs of abuse (heroin, cocaine) Metals (gold, mercury) NSAIDs Penicillamine TABLE 27-2. Xenobiotics Commonly Causing Nephrotic Syndrome

Figure

27-3. Membranous glomerulonephropathy (secondary to gold), a cause

thickened glomerular capillaries and interstitial foam cells are seen (H&E × 45

Postrenal

failure , such as urinary tract obstruction, may result from crystalluria

poisoning) or blocked urinary flow (eg, bladder dysfunction from anticholinergic urinary tract obstruction, there are characteristic histologic and pathophysiologic Microscopically, there is tubular dilation, predominantly in the distal nephron se distal tubules). There is initial preservation of the glomerular structure with sub finally,

periglomerular

fibrosis

may

develop.

Pathophysiologically, GFR falls as tubule pressure counteracts the capillary hyd there is a fall in renal perfusion leading to ischemic damage to nephrons. Tubul concentrating ability, potassium secretory function, and urinary acidification mec common nephrotoxic lesions, however, are intrinsic renal injuries , particularly interstitial nephritis (see Table 27-1 ).5

Acute tubular necrosis (Table 27-3 ), the most common nephrotoxic event, is necrosis of tubules, usually the proximal segments (Fig. 27-4 ). This lesion is a processes: direct toxic injury, ischemic injury from renal hypoperfusion, and p

Direct toxicity accounts for approximately 35% of all cases of acute tubular nec

different

P.431 segments of the renal tubules; for example, uranium attacks the proximal tubul (see Fig. 27-1 ). However, the clinical pattern of rapidly declining renal function identical in all forms of tubular necrosis. Poisoning may also lead to ischemic tu failure causes ischemia of nephron segments (proximal straight tubule and inner particularly vulnerable to hypoxia. Acetaminophen Antibacterials Aminoglycosides Amphotericin Pentamidine Polymyxins Antineoplastics Cisplatin Ifosphamide Methotrexate Mithramycin Streptozotocin Fluorinated anesthetics Glycols Ethylene glycol Diethylene glycol Halogenated hydrocarbons Metals Arsenic Bismuth Chromium Mercury Mushrooms Cortinarius spp Amanita smithiana Pigments Myoglobin

Hemoglobin Radiocontrast agents Those that cause hypotension or hypovolemia TABLE 27-3. Xenobiotics that Cause Acute Tubular Necrosis

Figure 27-4. Acute tubular necrosis (secondary to mercury). Proximal tubular associated with interstitial edema (H&E × 450). (Courtesy of Dr. Rabia Mir.)

Pigmenturia refers to either myoglobinuria from rhabdomyolysis (skeletal muscle massive hemolysis.59 Either pigment may cause tubular injury and necrosis by 166 Myoglobinuria follows necrosis of striated muscle. Alcohol can be directly m β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins Xenobiotics that produce hypokalemia (eg, diuretics and laxatives) or predispos cause muscle necrosis on this basis. Most often, poisoning leads to muscle bre prolonged unconsciousness (opioids and sedative-hypnotics), excessive muscle c seizures (alcohol withdrawal, theophylline).82 Pigmenturic acute renal failure ma carbon monoxide, copper sulfate, and zinc phosphate.35 , 124 , 139

Myoglobin is normally excreted without causing toxicity. A study of patients wit concentration of myoglobin in the urine may affect the development of renal fa

tubular lumen because of renal hypoperfusion and high water absorption, it diss environment as H+ is secreted, releasing tubulotoxic hematin.59 This toxicity m production of oxygen free radicals.

Myoglobinuric renal failure is diagnosed when acute renal failure occurs following simultaneous elevation of concentration of serum muscle enzymes such as creat urine orthotolidine test, with no erythrocytes in the sediment, and urine myoglo because primary renal failure may itself cause detectable myoglobinuria that do myoglobin in the urine does not prove the diagnosis.

Myoglobinuric renal failure can be prevented by early volume expansion if renal Alkalinizing the urine may prevent dissociation of myoglobin and minimize tubu rhabdomyolysis can lead to severe hypocalcemia from the release of large amou Alkalemia in this setting can cause tetany or seizures, worsening muscle injury. must be weighed against the benefit.

Hemoglobinuria follows hemolysis, which can be caused by a number of xenobio venoms, cresol, phenol, aniline, arsine, naphthalene, and methylene chloride. S

(hydralazine, quinine) can also cause hemolysis.59 The pathophysiology of hem of myoglobinuria. The pigment deposits in the tubules and dissociates, causing and acidosis precipitate this disorder, so volume expansion and alkalinization m

Although there is controversy as to how a tubular lesion leads to glomerular sh obstruction, back-leak of filtrate across injured epithelium, renal hypoperfusion, surface combine to impair glomerular filtration.215 Recent evidence suggests th

perhaps caused by an imbalance in the production of vasoconstrictors such as e nitric oxide, is important in prolonging the renal dysfunction after the tubular i Allopurinol Anticonvulsants Antibacterials Carbamazepine β-Lactams, especially Phenobarbital Phenytoin Rifampin Captopril

ampicillin,

methicillin,

penicillin

Sulfonamides Diuretics Vancomycin Furosemide Azathioprine Thiazides NSAIDs

More

Common

Less

Common

TABLE 27-4. Xenobiotics that Cause Acute Interstitial Nephritis P.432

Clinically, acute tubular necrosis presents as a rapid deterioration of renal funct Muddy brown casts or renal tubular cells may be seen in the urinary sediment, unusual. Disorders of metabolic balance, such as hyperkalemia and metabolic a tubular sodium reabsorption is decreased, the fall in glomerular filtration usually balance, as renal output of these substances is fixed.147 Acute

interstitial

nephritis (Table 27-4 ) is clinically similar to acute tubular nec

renal biopsy, which shows a cellular infiltrate separating tubular structures nephritis is caused by hypersensitivity.219 In many cases, the renal failure systemic allergy such as fever, rash, or eosinophilia. Finding eosinophils in However, approximately 25% of patients with xenobiotic-induced interstitial

(Fig. is a the nep

Unlike those with tubular necrosis, most patients with acute interstitial nephritis particularly eosinophiluria.12 Secondary fever at the onset of azotemia is commo present. The lesion usually improves once the xenobiotic is removed. Corticoste many physicians use this treatment only if the renal failure does not improve p stopped.

Figure

27-5. Acute interstitial nephritis (secondary to rifampin). Interstitial ede

cell, and eosinophil infiltration occurs without fibrosis. Tubular epithelium show changes and mononuclear cell infiltration (tubulitis) (A , H&E × 112; B , H&E

Differential

Diagnosis

of

Acute

Renal

Failure

Patients who present with acutely deteriorating renal function often represent a

are there 3 major etiologic categories, but each category has several subdivision present. For example, a patient with an opioid overdose may have neurogenic muscle necrosis causing myoglobinuric renal failure (intrinsic renal) and opioid Because renal, prerenal, and postrenal processes are not mutually exclusive an

three should always be considered, even when one appears to be the most obvi

Prerenal failure (renal hypoperfusion) initiates a sequence of events leading to is released, causing production of angiotensin, which both enhances proximal tu stimulates adrenal aldosterone release, thus increasing distal sodium reabsorpti accompanied by low urinary sodium excretion (Table 27-5 ). Release of antidiur retention. Unresolving renal hypoperfusion may cause tubular necrosis.

Xenobiotics may decrease renal blood flow without necessarily causing intrinsic cathartics can decrease blood volume and antihypertensive agents can excessiv

P.433 reduce blood pressure. Some xenobiotics (eg, cyclosporine, amphotericin, meth

vasoconstriction. NSAIDs lower filtration rate by inhibiting production of vasodil arteriole. Finally, cardiotoxins, such as doxorubicin, can cause severe heart failu hypersensitivity vasculitis (Fig. 27-1 ).

TABLE 27-5. Tests of Renal Function

Urinary tract obstruction should always be considered when the kidneys fail ra leads to anuria, partial obstruction, which is more common, is usually associate Continued production of urine in the presence of obstruction leads to distension

blockage. Calyceal dilatation is common. Obstruction of the bladder outlet or ur Anticholinergics Ethylene glycol Antihistamines Fluorinated anesthetics Antidepressants (cyclic) Fluoroquinolones Atropine Heme pigments Scopolamine Indinavir Antipsychotics Methotrexate Butyrophenones Phenylbutazone Phenothiazines Sulfonamides Bromocriptine CNS

depressants

Retroperitoneal Fibrosis Ergotamines (Methysergide) Chinese herbs (Stephania ) Bladder

Dysfunction

Crystal Deposition

TABLE 27-6. Xenobiotics that Cause Urinary Obstruction

Obstruction may be caused by xenobiotics (Table 27-6 ).74 Most do so by impa anticholinergic action (atropine, tricyclic antidepressants). Rarely, certain xeno cause retroperitoneal fibrosis and ureteral constriction. Finally, a few xenobiotic obstruction. Sometimes the xenobiotic itself forms precipitates (sulfonamides,47 excretion of a precipitating chemical such as oxalate (ethylene glycol and fluor

Patient

Evaluation

Evaluation of a patient with suspected toxic renal injury should include extrarena response to xenobiotics is affected by previous renal function, renal blood flow, obstruction that can exert back-pressure on the nephrons, all of which must be

History

A past history of renal disease or conditions that can affect the kidney (eg, d disease) should be noted. Flank pain, hematuria, or any abnormal pattern of ur patient's intravascular volume status affects renal perfusion. Thus, a history of h plasma volume such as vomiting or diarrhea is important. Prior cancer chemothe

methyl-CCNU (methyl-1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) should be not evaluated for potential renal effects, both those with direct and indirect nephro alcohol and drugs of abuse should be explored. A careful occupational history a are crucial, with emphasis on exposure to nephrotoxic xenobiotics.

Physical

Examination

The patient's hemodynamic status should be carefully assessed. Postural changes either engorgement or decreased filling of the neck veins, give important inform The skin should be examined for lesions. Pupillary abnormalities may suggest a reveal evidence of chronic hypertension or diabetes. All aspects of cardiac funct

or absence of edema. Injuries or scars in the suprapubic area or evidence of p may suggest obstruction, as may a palpable or percussible bladder.

Laboratory

Evaluation

Nephrotoxic injury is not always apparent clinically, so the laboratory is exceedi function may be suspected if urine output decreases, but oliguria is not univers renal function is glomerular filtration. Because urea and creatinine are largely ex these substances are used as markers of renal function. However, the blood leve production and excretion. Azotemia—elevation of BUN or creatinine—is a sta However, BUN or creatinine in the normal

P.434 range does not exclude a substantial degree of renal impairment because of th relationship between these parameters and GFR. In addition, decreased producti or creatinine (amputation, muscle wasting) may result in a normal value for BUN significant renal impairment. Conversely, decreased renal perfusion (prerenal fail disproportionate rise in BUN as compared to the rise in creatinine, because urea and water, whose reabsorption is increased when the kidneys are underperfused is suggestive of prerenal failure (Table 27-5 ). Because many nephrotoxic xeno acute renal failure (urine volume >400 mL/d), progressive azotemia without olig drug-related cause. Tubular injury, especially in lead poisoning and myoglobinur decreased tubular secretion of uric acid. Antimony36 +

Arsenic129 ,155 ,224 ,225 +++ +++ ++ + +

Barium 190 ,234 +

Beryllium18

++

Bismuth 22 ,23 ,217 ++

+ + + Cadmium1 ,80 ,118 ,232

+++ +++ Chromium166 ,229 +++

Copper195 + +

Gadolinium87 ,104 ,200 +

Germanium139a ,165

+

Gold8 ,56 ,161 ,222

+

+++ Iron42 ,143 ,221 ++

+

Lead7 ,16 ,21 ,35 ,39 ,45 ,49 ,65 ,111 ,233 + + +++ +++

Lithium 4 ,53 ,78 ,102 ,103 ,130 ,205 +

++ ++

Mercury83 ,166 ,185 +++ +

+ + Platinum ++

(cisplatin)90 ,95 ,192 ,207 ,236

++ ++

Silicon116

+ Silver140 ,143 +

Thallium199 +

+

Uranium166 ,172 +

+++ = common; + = uncommon. Toxic Acute Tubular Necrosis

Shock Acute Tubular Necrosis

Hemolysis

Acute

Chronic

Interstitial Nephritis

Interstitial Nephritis

Tubular Dysfuncti

TABLE 27-7. Nephrotoxic Effects of Metals

Certain xenobiotics alter measured levels of urea and creatinine in the absence most obvious is exogenous creatine taken to build muscle mass. Cefoxitin, nitro the same frequency as the creatinine reaction product, thus artifactually increa a component of rocket model fuel, produces extreme elevation of creatinine thro

renal creatinine secretion, such as cimetidine and trimethoprim, may also increa raised independently of renal function by tetracycline or corticosteroids, which

In patients with chronic renal insufficiency or failure, it is necessary to assess t the patient properly. Clearance measurements are generally used to determine common is endogenous creatinine clearance (see Table 27-5 ).

Determining creatinine clearance in acute renal failure is not helpful, as the accu state. Changing GFR during a clearance time period distorts the resulting estima between changes in kidney function and changes in BUN or creatinine concentra renal failure should be treated as if glomerular filtration were Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section II - Pathophysiologic Basis: Organ Systems > Chapter 28 - Genitourinary Principles

Chapter

28

Genitourinary

Principles

Jason Chu The genitourinary system encompasses two major organ systems: the reproductive and the urinary. Successful reproduction requires interaction between two sexually mature individuals. Xenobiotic exposures to either individual can have an adverse impact on fertility, which is the successful production of children, and fecundity, which is an individual's or a couple's capacity to produce children. However, the role of occupational and environmental exposures in the development of infertility is difficult to define.11 , 49 , 120 , 125 Well-designed and conclusive epidemiologic studies are difficult to accomplish because of the following factors: laboratory tests used to evaluate fertility are relatively unreliable; clinical end points are unclear; xenobiotic exposure is difficult to monitor; and indicators of biologic effects are imprecise. The negative impact on fertility as an adverse effect of xenobiotics is often ignored, but the evaluation of infertility is incomplete without a thorough drug and occupational history. Differences in the toxicity of xenobiotics in individuals may be sexand/or age-related. Xenobiotic-related, primary infertility may be

the result of effects on the hypothalamic–pituitary–gonadal axis or of a direct toxic effect on the gonads.105 Fertility is also affected by exposures that cause abnormal sexual performance. Table 28-1 lists xenobiotics associated with infertility. Aphrodisiacs are used to heighten sexual desire and to counteract sexual dysfunction. Historically, humans have continued to search for the perfect aphrodisiac. Efficacy is variable, and toxic consequences occur commonly. Various treatments have been evaluated for male sexual dysfunction, but the perfect remedy remains a mystery. Whereas many people search for a cure for impotence or infertility, many others explore drugs and plants that can be used as contraceptives and abortifacients. Routes of administration vary from oral to parenteral to intravaginal. Toxicity results not only in the termination of pregnancy but also from the systemic effects of the various xenobiotics. This chapter examines all of these issues, as well as the impact of xenobiotics on the urinary system, specifically, urinary retention and incontinence and abnormalities detected in urine specimens. Renal (Chap. 27 ), teratogenic, and carcinogenic (Chap. 30 ) principles are discussed in further detail elsewhere in this text.

Male

Fertility

The male reproductive system is comprised of the male gonads and the endocrine organs that provide the hormonal controls. Disruption of normal function at any part of the system affects fertility. There are a multitude of xenobiotics that adversely affect spermatogenesis and sexual function.

Spermatogenesis Central to the male reproductive system is the process of spermatogenesis, which occurs in the testes. The bulk of the

testes consist of seminiferous tubules with germinal spermatogonia and Sertoli cells. The remainder of the gonadal tissue is comprised of the interstitium containing blood vessels, lymphatics, supporting cells, and Leydig cells. Spermatogenesis begins with the maturation and differentiation of the germinal spermatogonia. The process is controlled by the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which stimulates the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the development of Sertoli cells in the testes, which are responsible for the maturation of spermatids to spermatozoa. LH promotes production of testosterone by Leydig cells. Testosterone levels must be maintained to ensure the formation of spermatids.27 Both FSH and testosterone are required for initiation of spermatogenesis, but testosterone alone is sufficient to maintain the

process.

Testicular

Xenobiotics

Xenobiotics can affect any part of the male reproductive tract, but, invariably, the end result is decreased sperm production, defined as oligospermia, or absent sperm production, azoospermia. Spermatogenesis is an ongoing process throughout life (as compared to oogenesis in women) and can be inhibited by decreases in FSH and/or LH or Sertoli cell toxicity. Spermatogenic capacity is evaluated by semen analysis, including sperm count, motility, sperm morphology, and penetrating ability. Normal sperm count is above 40 million sperm/mL of semen, and a count below 20 million sperm/mL of semen is indicative of infertility.27 Decreased motility (asthenospermia) below 40% of normal or abnormal morphology (teratospermia) of more than 40% of the total number of sperm also indicates infertility.27 , 140

Antineoplastics

Oligospermia and azoospermia are reported with cyclophosphamide, chlorambucil, and methotrexate when used as single agents.27 , 138 Combination therapies with procarbazine, vinca alkaloids, or any of the above agents also decrease sperm production and fertility with variable recovery rates.27 Anabolic steroids ↓ LH, oligospermia Antineoplastics Gonadal toxicity Androgens Suppress testosterone Cyclophosphamide

production

Ovarian failure Antineoplastics Gonadal toxicity Busulphan Amenorrhea Cyclophosphamide Oligospermia Combination chemotherapy Amenorrhea Chlorambucil Oligospermia (MOPP, MVPP) Methotrexate Oligospermia Diethylstilbestrol Spontaneous abortions Combination chemotherapy (COP, CVP, MOPP, MVPP) Oligospermia Ethylene oxide Spontaneous abortions Lead

Spontaneous abortions, still births Carbon disulfide ↓ FSH, ↓ LH, ↓ spermatogenesis Oral contraceptives Affect hypothalamic–pituitary axis, end-organ hormones, amenorrhea Cimetidine Oligospermia

resistance

to

Chlordecone Asthenospermia, oligospermia Thyroid hormone ↓ Ovulation Dibromochloropropane (DBCP) Azoospermia,

oligospermia

Diethylstilbestrol Testicular

hypoplasia

Ethanol ↓ Testosterone production, oligospermia, teratospermia

Ethylene oxide Asthenospermia (in

Leydig

monkeys),

Ionizing radiation ↓ Spermatogenesis

cell

damage,

oligospermia

asthenospermia,

Opioids ↓ LH, ↓ testosterone

Lead ↓ Spermatogenesis,

asthenospermia,

teratospermia

Nitrofurantoin ↓ Spermatogenesis

Sulfasalazine ↓ Spermatogenesis

Tobacco ↓ Testoterone

Men Xenobiotic

Women Effects

Xenobiotic

Effects

TABLE 28-1. Xenobiotics Associated with Infertility P.443

Hormonals Diethylstilbestrol exposure in utero can lead to testicular hypoplasia in men, but may not lead to infertility or sexual dysfunction.27 , 160 Work-related exposure to estrogens and

progestins in the oral contraceptive industry may result in decreased libido, impotence, and gynecomastia caused by hyperestrogenism.140 Anabolic steroid use can result in decreased libido, azoospermia, and decreased testicular size.

Radiation

Therapy

Treatment of neoplasms with ionizing radiation leads to dosedependent oligospermia and azoospermia. Time to recovery is dependent on dose and duration of exposure.7

Occupational

Exposures

1,2-Dibromo-3-Chloropropane A soil fumigant used in agriculture to control nematodes, 1,2dibromo-3-chloropropane (DBCP) provides the clearest example of occupational exposure resulting in testicular toxicity and human reproductive dysfunction. In one small series, 7 of 10 patients who were exposed to DBCP had decreased or absent spermatogenic activity on testicular biopsy. This correlated with duration of exposure and was most consistently observed after inhalation exposure. A selective decrease or loss of spermatogenic activity was observed without any other consistent testicular defect, and all stages of differentiation were affected. In the most severe cases, the seminiferous tubules were devoid of germ cells.17 The mechanism of toxicity of DBCP is unknown but may be the result of transformation of the parent compound to an alkylating agent. Testosterone levels remain normal, although testicular size is decreased. After removal from exposure, improvement in sperm counts occurred in most oligospermic men, but those who had developed azoospermia showed no recovery of spermatogenic function.159

Lead Painters and artisans are commonly exposed to inorganic lead, which is also a hazard in the smelting and battery industries.89 Lead is a proven spermicide, and lead exposure is associated with decreased libido, asthenospermia, oligospermia, teratospermia, and testicular atrophy. An increase in the frequency of stillbirths and spontaneous abortions results when the male partner is a lead worker.162 Lead levels of 35–50 µg/dL are associated with direct spermatogenic toxicity. Indirect effects result from the inhibition of general metabolic processes by lead (Chaps. 91 ).162

Glycol

Ethers

Glycol ethers are used as fuel, deicers, and as components in paints, varnishes, methoxymethanol azoospermia, and decreased sperm glycol

Male

thinners, and printing inks. Animal studies with and ethoxyethanol show oligospermia, testicular atrophy. One study documents counts in human workers exposed to ethylene

ether.124

Sexual

Dysfunction

Sexual dysfunction can be a result of decreased libido (sexual desire), impotence, diminished ejaculation, and erectile dysfunction. Libido can be decreased by xenobiotics that block dopaminergic pathways or testosterone production, or by xenobiotics that produce dysphoria. Xenobiotics that affect spinal reflexes can cause diminished ejaculation and erectile dysfunction.161 Approximately 30 million men in the United States suffer from erectile dysfunction, with an increased prevalence in older men.70 Erectile dysfunction, as defined by the National Institutes of Health (NIH), is the inability to achieve and/or maintain an erection for a period of time that is long enough to permit satisfactory sexual

intercourse116 and can be divided into the following classifications: psychogenic, vasculogenic, neurologic, endocrinologic, P.444 and xenobiotic-induced. Xenobiotic-induced erectile dysfunction is associated with the following categories of xenobiotics: antidepressants; antipsychotics; centrally and peripherally acting antihypertensives; CNS depressants; anticholinergics; exogenous hormones; antibiotics; and chemotherapeutic agents. 97 , 139 , 161 Treatment of this disorder is varied and includes vacuumconstriction devices, penile prostheses, vascular surgery, and medications (intracavernosal, transdermal, and oral agents). The following section contains a discussion of the physiology of erection followed by a discussion of agents that cause sexual dysfunction in men, agents that are used to treat erectile dysfunction, and priapism.

Physiology

of

Erection

Normal penile erection is a result of both neural and vascular effects leading to smooth muscle relaxation and increased blood flow into the corpora cavernosa sinusoids of the penis. Psychogenic neural stimulation arising from the cerebral cortex is mediated through the thoracolumbar sympathetic and sacral parasympathetic tracts. In animals, dopamine and nitric oxide play a role in erection.111 Reflex stimulation can also occur from the sacral spinal cord. The afferent limb of the reflex arc is supplied by the pudendal nerves and the efferent limb by the nervi erigentes (pelvic splanchnic nerves). The internal pudendal arteries supply blood to the penis via 4 branches. Blood outflow is via multiple emissary veins draining into the dorsal vein of the penis and plexus of Santorini. Within the penis, the corpora cavernosa share vascular supply and drainage as a result of extensive arteriolar, arteriovenous, and sinusoidal anastomoses. 166 When penile blood flow is above

20–50 mL/min, erection occurs. Maintenance of tumescence occurs with flow rates of 12 mL/min. The tunica albuginea limits the absolute size of erection. Penile erection depends on corpus cavernosal smooth muscle relaxation to allow increased blood flow and involves parasympathetic dominance, either by stimulation of parasympathetic receptors or inhibition of the sympathetic axis. Both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) pathways mediate smooth muscle relaxation. Cholinergic nerves release acetylcholine, which stimulates endothelial cells via M3 receptors to produce nitric oxide and prostaglandin E2 (PGE2 ). Prostaglandin E2 and nerves containing vasoactive intestinal peptide (VIP) and calcitonin generelated peptide (CGRP) increase cellular cAMP to potentiate smooth muscle relaxation. Nonadrenergic-noncholinergic nerves and endothelial cells produce nitric oxide, which activates guanylate cyclase conversion of guanosine triphosphate (GTP) to cGMP. Increasing levels of cGMP act as a second messenger, mediating arteriolar and trabecular smooth muscle relaxation to enable increased cavernosal blood flow and penile erection.111 In the flaccid state, sympathetic efferent nerves maintain helicineresistant arteriole constriction primarily through norepinephrineinduced α-adrenergic agonism. α-Adrenergic receptor agonism in the erectile tissues decreases cAMP to produce flaccidity, whereas α-adrenergic antagonism can result in pathologic erection (priapism) as a consequence of parasympathetic dominance.166 Other vasoconstrictors, such as endothelin, prostaglandin F2 a , and thromboxane A2 play a role in maintaining corpus cavernosal smooth muscle tone in contraction, which results in a flaccid state.111

Antihypertensives Erectile dysfunction is reported as an adverse effect with all

antihypertensives and may be caused, in part, by a decrease in hypogastric artery pressure, which impairs blood flow to the pelvis.159 Methyldopa and clonidine both are centrally acting α2 adrenergic agonists that inhibit sympathetic outflow from the brain. Sexual dysfunction is reported in 26% of patients taking methyldopa and in 24% of those patients receiving clonidine.16 , 114 Erectile dysfunction associated with thiazide diuretics may be related to decreased vascular resistance, diverting blood from the penis.29 Spironolactone acts as an antiandrogen by inhibiting the binding of dihydrotestosterone to its receptors. Impotence related to use of β-adrenergic antagonists is well documented1 , 77 , 156 and may be caused by unopposed α-mediated vasoconstriction resulting in reduced penile blood flow.

Ethanol Ethanol is directly toxic to Leydig cells Chronic alcohol abuse causes decreased libido, erectile dysfunction, and testicular atrophy. In alcoholics, liver disease contributes to sexual dysfunction because of decreased testosterone and increased estrogen production. Alcoholics also can have autonomic neuropathies affecting penile nerves and subsequent erection. Alcoholics suffer more erectile dysfunction than do episodic drinkers.158

Psychotropics Individuals who take psychotropics therapeutically have varying levels of sexual dysfunction related to both their underlying disease and their medications. All psychotropic agents are associated with sexual dysfunction to some degree. Monoamine oxidase inhibitors (MAOIs), cyclic antidepressants, antipsychotics, and selective serotonin reuptake inhibitors (SSRIs) are associated with decreased libido and erectile dysfunction in men.39

Thioridazine is associated with significantly lower LH and testosterone levels in men compared to other antipsychotics.27 Table 28-2 lists other xenobiotics associated with sexual dysfunction.

Xenobiotics Erectile

Used

in

the

Treatment

of

Dysfunction

Intracavernosal

Use

The three most common intracavernosal agents used for erectile dysfunction are papaverine, prostaglandin E1 , and phentolamine. Papaverine is a benzylisoquinoline alkaloid derived from the poppy plant Papaver somniferum . It exerts its effects through nonselective inhibition of phosphodiesterase, leading to increased cAMP and cGMP levels and to subsequent cavernosal vasodilation. Papaverine was used for the treatment of cardiac and cerebral ischemia, but had limited efficacy. Presently, it is used as intracavernosal therapy for erectile dysfunction either alone or in conjunction with phentolamine. Systemic side effects include dizziness, nausea, vomiting, hepatotoxicity, lactic acidosis with oral administration, and cardiac dysrhythmias with intravenous use. P.445 Intracavernosal administration is associated with penile fibrosis which is usually a dose-related phenomenon, although fibrosis can also occur with limited use.43 More concerning is the development of priapism with papaverine use. Anabolic steroids Cyclic antidepressants Anticholinergicsa Ethanol Anticonvulsants

Lead Antiestrogens Lithium α-Adrenergic antagonists Monamine oxidase inhibitorsa β-Adrenergic antagonistsa Opioids (high dose) Benzodiazepines Oral contraceptives Calcium channel blockers Phenothiazines Diuretics Selective serotonin reuptake inhibitors Cimetidine Spironolactone a

Associated with erectile dysfunction. TABLE 28-2. Xenobiotics Associated with Sexual Dysfunction (Particularly Diminished Libido and Impotence)

Prostaglandin

E1 (alprostadil) is a nonspecific agonist of

prostaglandin receptors resulting in increased levels of intracavernosal cAMP, cavernosal smooth muscle relaxation, and penile erection. It is effective via intracavernosal administration as a single agent. Other preparations include an intraurethral preparation, which is less efficacious, and a topical gel formulation.71 Penile fibrosis can occur, but the incidence is lower than with papaverine. Other adverse effects include penile pain, secondary to its effects as a nonspecific prostaglandin receptor agonist, and priapism. Phentolamine is a competitive α-adrenergic antagonist at α1 and Î ±2 receptors. It effects erection by inhibiting the normal resting adrenergic tone in cavernosal smooth muscle, thus allowing

increased arterial blood flow and erection. Intracavernosal use can cause systemic hypotension, reflex tachycardia, nasal congestion, and gastrointestinal upset. Penile fibrosis and priapism are also reported.

Oral

Use

Phosphodiesterase

5

Inhibitors

Since the development of the phosphodiesterase 5 inhibitors, oral therapy has replaced intracavernosal injections as the mainstay for treatment of erectile dysfunction. Sildenafil was the first agent developed, followed by vardenafil and tadalafil. These medications have similar mechanisms of action but differ in their pharmacokinetics. Phosphodiesterase 5 inhibitors increase nitric oxide-induced cGMP concentrations by preventing phosphodiesterase breakdown of cGMP, enhancing nitric oxideinduced vasodilation to promote penile vascular relaxation and erection.21 After oral administration, sildenafil is rapidly absorbed, with a bioavailability of 40% and a median peak plasma concentration of 60 minutes. Its mean volume of distribution is 105 L, and its elimination half-life is 3–5 hours. Metabolism is primarily by the cytochrome P450 (CYP) 3A4 pathway, with some minor metabolic activity via the CYP2C9 pathway. Plasma concentrations of sildenafil are increased in patients older than age 65 years, as well as in patients with hepatic dysfunction or severe renal dysfunction (creatinine clearance Part B - The Fundamental Principles of Medical Toxicology > Section III - Special Populations > Chapter 30 - Reproductive and Perinatal Principles

Chapter

30

Reproductive

and

Perinatal

Principles

Jeffrey S. Fine Reproductive and perinatal principles in toxicology derive from many areas of basic science and are applied to many aspects of clinical practice. This chapter reviews several principles of reproductive medicine that have implications for toxicology: the physiology of pregnancy and placental xenobiotic transfer, the effects of xenobiotics on the developing fetus and the neonate, and the management of overdose in the pregnant woman. One of the most dramatic effects of exposure to a xenobiotic during pregnancy

the birth of a child with congenital malformations. Teratology, the study of birth defects, has principally been concerned with the study of physical malformation A broader view of teratology includes “developmental― teratogens—agents that induce structural malformations, metabolic or physiologic dysfunction, or psychological or behavioral alterations or deficits in the offspring, either at or after birth.216 Only 4–6% of birth defects are related to known pharmaceuticals or occupational and environmental exposures.31 , 216 Reproductive effects of xenobiotics may occur before conception. Female germ cells are formed in utero; adverse effects from xenobiotic exposure can

theoretically occur from the time of a woman's own intrauterine development to the end of her reproductive years. An example of a xenobiotic that had both teratogenic and reproductive effects is diethylstilbestrol (DES), which caused vaginal and/or cervical adenocarcinoma in some women who had been exposed to DES in utero and also had effects on fertility and pregnancy outcome.17 , 23 Men generally receive less attention with respect to reproductive risks. Male gametes are formed after puberty; only from that time on are they susceptible to xenobiotic injury. An example of a toxin affecting male reproduction is dibromochloropropane, which reduces spermatogenesis and, consequently, fertility. In general, much less is known about the paternal contribution to teratogenesis.266

Occupational exposures to xenobiotics are potentially important but often poorly

defined. In 2004, it was estimated that there were 41 million women of reproductive age in the workforce.181 Although approximately 90,000 chemicals are used commercially in the United States, only a few thousand industrial and pharmaceutic agents have been specifically evaluated for reproductive toxicity. Many xenobiotics have teratogenic effects when tested in animal models, but relatively few well-defined human teratogens have been identified (Table 30-1 ) .224 Thus, most tested xenobiotics do not appear to pre-sent a human teratogenic risk, but most xenobiotics have not been tested. Some of the

presumed safe xenobiotics may have other reproductive, nonteratogenic toxicities. Several excellent reviews and online resources are available. 79 , 185 , 216 , 224

Another type of xenobiotic exposure for a pregnant woman is the intentional overdose. Although a xenobiotic taken in overdose may have direct toxicity to the fetus, fetal toxicity frequently results from maternal pulmonary and/or hemodynamic compromise, such as hypoxia or shock, further emphasizing the critical nature of the maternal–fetal dyad.

Xenobiotic exposures before and during pregnancy can have effects throughout gestation and may extend into and beyond the newborn period. In addition, the effects of medication administration in the perinatal period, and the special case of delivering xenobiotics to an infant via the breast milk, deserve special consideration.

Physiologic Changes During affect Drug Distribution

Pregnancy

that

Many physical and physiologic changes that occur during pregnancy affect both absorption and distribution of xenobiotics in the pregnant woman and consequently affect the amount of xenobiotics delivered to the fetus.103 , 166

During pregnancy there is delayed gastric emptying, decreased gastrointestinal (GI) motility, and increased transit time through the GI tract. These changes result in delayed but more complete GI absorption of xenobiotics and, consequently, lower peak plasma concentrations. Because blood flow to the skin

and mucous membranes is increased, absorption from dermal exposure may be increased. Similarly, absorption of inhaled xenobiotics may be increased becaus of increased tidal volume and decreased residual lung volume. Amiodarone Transient neonatal hypothyroidism, with or without goiter; hyperthyroidism Amiodarone contains 39% iodine by weight. Small to moderate risk from 10 weeks to term for thyroid dysfunction. Androgens (eg, methylsteroidtestosterone, danazol) Virilization of the female external genitalia: clitoromegaly, labioscrotal fusion Effects are dose dependent. Stimulates growth of sex-steroid, receptor–containing tissue. Effects are dose dependent. Stimulates growth of sex-steroidtestosterone, receptor–containing tissue. Growth retardation, cleft palate, microphthalmia, hypoplastic ovaries, cloudy corneas, renal agenesis, malformations of digits, cardiac defects, other anomalies A 10–50% malformation rate, depending on the agent. Cyclophosphamideinduced damage requires cytochrome P450 oxidation. Aminopterin, methotrexate (amethopterin) Hydro/microcephaly; meningoencephalocele; anencephaly; abnormal cranial ossification; cerebral hypoplasia; growth retardation; eye, ear, and nose malformations; cleft palate; malformed extremities/fingers; reduction in

derivatives of first branchial arch; developmental delay254 These folate antagonists inhibit dihydrofolate reductase. High rate of malformations. Methotrexate is used to terminate ectopic pregnancies. Angiotensin-converting enzyme inhibitors Fetal/neonatal death, prematurity, oligohydramnios, neonatal anuria, IUGR, secondary skull hypoplasia, limb contractures, pulmonary hypoplasia Does not interfere with organogenesis. Significant risk of effects related to chronic fetal hypotension during second/third trimester. If used during early pregnancy, can be switched during first trimester.31 Carbamazepine Upslanting palpebral fissures, epicanthal folds, short nose with long philtrum, fingernail hypoplasia, anticondevelopmental delay, NTD110 Risk unquantified, but may be significant for minor anomalies. Risk is increased in setting of therapy with multiple anticon-vulsants, particularly valproic acid. Mechanism may involve an epoxide intermediate. A 1% risk for NTD. High-dose

folate, although unproven, is recommended to try to prevent NTD. Increased ris of perinatal/neonatal bleeding related to deficiency of vitamin K-dependent clotting factors, requires vitamin K prophylaxis and therapy. Carbon monoxide

Cerebral atrophy, mental retardation, microcephaly, convulsions, spastic disorders, intrauterine/death With severe maternal poisoning, high risk for neurologic sequelae; no increased risk in mild exposures. Cocaine IUGR, microcephaly, neurobehavioral abnormalities, vascular disruptive phenomenon (limb amputation, cerebral infarction, visceral/urinary tract abnormalities) Vascular disruptive effects because of decreased uterine blood flow and fetal vascular effects from first trimester through the end of pregnancy. Risk for major disruptive effects is low. Corticosteroids Cleft palate, decreased birth weight (up to 9%) and head circumference (up to 4%) Low risk. Most information related to prednisone or methylprednisolone.

Coumadin Fetal warfarin syndrome: nasal hypoplasia, chondrodysplasia punctata, brachydactyly, skull defects, abnormal ears, malformed eyes, CNS malformations, microcephaly, hydrocephalus, skeletal deformities, mental retardation, spasticity A 10%–25% risk of malformation for first-trimester exposure, 3% risk of hemorrhage, 8% risk of stillbirth. Bleeding is an unlikely explanation for effects produced in the first trimester. CNS defects may occur during second/third trimesters and may be related to bleeding. 108 ,253 Diazepam Cleft palate, other anomalies Controversial association, probably low risk.32 ,62 ,79 Risk may extend to other benzodiazepines. Also risk for neonatal sedation or withdrawal following maternal use near delivery. Diethylstilbestrol (DES) Female offspring: vaginal adenosis, clear cell carcinoma, irregular menses, reduced pregnancy rates, increased rate of preterm deliveries, increased perinatal mortality and spontaneous abortion Male offspring: epididymal cysts, cryptorchidism, hypogonadism, diminished

spermatogenesis A synthetic nonsteroidal estrogen that stimulates estrogen-receptor–containin tissue and may cause misplaced genital tissue with propensity to develop cance A 40–70% risk of morphologic changes in vaginal epithelium. Risk of

carcinoma approximately 1/1000 for exposure before the 18th week. Most patients exposed to DES in utero can conceive and deliver normal children. Ethanol Fetal alcohol syndrome (FAS): pre-/postnatal growth retardation, mental retardation, fine motor dysfunction, hyperactivity, microcephaly, maxillary hypoplasia, short palpebral fissures, hypoplastic philtrum, thinned upper lips, joint, digit anomalies FAS in 4% of offspring of alcoholic women consuming ethanol above 2 g/kg/d (6 oz/d) over the first trimester. There may be a threshold for effects, but a safe dose has not been identified. Can see partial expression or other congenital anomalies (see text). Other effects: increased incidence of spontaneous

abortion, premature delivery, and stillbirth; neonatal withdrawal. Fluconazole Brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease Risk related to high dose (400–800 mg/d), chronic, parenteral use. Single 150-mg oral dose probably safe. Indomethacin Premature closure of the ductus arteriosus; in premature infants, oligohydramnios, anuria, intestinal ischemia NSAIDs generally labeled as category B. However, there is concern when used after 34 weeks' gestation and for more than 48 hours and/or immediately prior to delivery. Risk may extend to other NSAIDs. Iodine and iodinecontaining products Thyroid hypoplasia after the 8th week of development High doses of radioiodine isotopes can additionally produce cell death and mitotic delay. Tissue and organ-specific damage is dependent on the specific radioisotope, dose, distribution, metabolism, and localization. Lead Lithium carbonate Lower scores on developmental tests Ebstein anomaly Higher risk when maternal lead is >10 g/dL. Low risk. Methimazole Aplasia cutis, skull hypoplasia, dystrophic nails, nipple abnormalities, hypo- or hyperthyroidism Small risk of anomalies or goiter with first-trimester exposure. Hypothyroidism risk after 10 weeks' gestation. Methylmercury, mercuric sulfide Normal appearance at birth; cerebral palsy–like syndrome after several months; microcephaly, mental retardation, cerebellar symptoms, eye/dental anomalies Inhibits enzymes, particularly those with sulfhydryl groups. Of 220 babies born following the Minamata Bay exposure, 13 had severe disease. Mothers of

affected babies ingested 9–27 ppm mercury; greater risk with ingestion at 6–8 months' gestation. In acute poisoning, the fetus is 4–10 times more sensitive than an adult. Pathologically, there is atrophy and hypoplasia of the brain cortex and abnormalities in cytoarchitecture.93 ,259 Methylene blue (intraamniotic injection) Intestinal atresia, hemolytic anemia, neonatal jaundice This xenobiotic was used to identify a twin. Misoprostol Vascular disruptive phenomena (eg, limb reduction defects); Moebius syndrome (paralysis of 6th and 7th facial nerves) Synthetic prostaglandin E1 analog. Effects mostly observed in women after unsuccessful attempts to induce abortion. Oxazolidine-2,4-diones (trimethadione, paramethadione) Fetal trimethadione syndrome: V-shaped eyebrows, low-set ears with anteriorly folded helix, high-arched palate, irregular teeth, CNS anomalies, severe developmental delay, cardiovascular, genitourinary, and other anomalies An 83% risk of at least one major malformation with any exposure; 32% die. Characteristic facial features are associated with chronic exposure. Penicillamine Cutis laxa, hyperflexibility of joints Copper chelator—copper deficiency case reports; low risk. Phenytoin

inhibits

collagen

synthesis/

maturation.

Fe

Fetal hydantoin syndrome: microcephaly, mental retardation, cleft lip/palate, hypoplastic nails/phalanges, characteristic facies—low nasal bridge, inner epicanthal folds, ptosis, strabismus, hypertelorism, low-set ears, wide mouth Phenytoin has a direct effect on cell membranes and on folate and vitamin K metabolism. May reduce the availability of retinoic acid derivatives or alter the genetic expression of retinoic acid. Epoxide intermediate may play a role in teratogenesis. Effects seen with chronic exposure. A 5–10% risk of typical syndrome, 30% risk of partial syndrome. Risks confounded by those associated with epilepsy itself and use of other anticonvulsants. Increased risk of perinatal and neonatal bleeding related to deficiency of vitamin K-dependent clotting factors requires vitamin K prophylaxi

and therapy. Possible increased risk of developing tumors, in particular, neuroblastoma, although absolute risk is very low. Polychlorinated biphenyls Cola-colored children; pigmentation of gums, nails, and groin; hypoplastic, deformed nails; IUGR; abnormal skull calcifications Cytotoxic agent. Body residue can affect subsequent offspring for up to 4 years after exposure. Most cases followed high consumption of PCB-contaminated rice oil; 4–20% of offspring were affected. Progestins (eg, ethisterone, norethindrone) Masculinization of female external genitalia Progestogens are converted into androgens or may have weak androgenic activity. Stimulates or interferes with sex-steroid receptors. Effects occur only after exposure to high doses of some testosterone-derived progestins and may be at the rate of 1% of those exposed. Oral contraceptives containing these agents are not thought to present teratogenic risk, despite their category X designation. Quinine Radiation, ionizing Hypoplasia of 8th nerve, deafness, abortion Microcephaly, mental retardation, eye anomalies, growth retardation, visceral malformations

Effects related to high doses used as abortifacients. Significant doses of radiation from diagnostic or therapeutic sources produce ce death and mitotic delay. There is no measurable risk with X-ray exposures of 5 rads or less at any stage of pregnancy.22 ,30

Retinoids (isotretinoin, etretinate, high-dose vitamin A) Spontaneous abortions; micro-/hydrocephalus; deformities of cranium, ears, face, heart, limbs, liver Retinoids can cause direct cytotoxicity and alter apoptosis. Neural crest cells ar particularly sensitive. For isotretinoin, 38% risk of malformations; 80% are CNS malformations. Effects are associated with vitamin A doses of 25,000–100,00 U/d. Exposures below 10,000 U/d present no risk to fetus. Topical retinoids are not considered a reproductive risk.239 Smoking Placental lesions, IUGR, increased perinatal mortality, increased risk of SIDS77,129,227,260

Effects related to a combination of vasoconstriction (nicotine effect), hypoxia secondary to hypoperfusion, CO, and CN, and altered development of neurons and neural pathways.212,230 Streptomycin Hearing loss Rare reports. A low-risk phenomenon that could be associated with long-duratio maternal therapy during pregnancy. Tetracycline Yellow, gray-brown, or brown staining of deciduous teeth, hypoplastic tooth enamel Effects seen after 4 months of gestation, because tetracyclines must interact with calcified tissue. Effects occur in 50% of fetuses exposed to tetracycline and in 12.5% of fetuses exposed to oxytetracycline. Thalidomide Limb phocomelia, amelia, hypoplasia, congenital heart defects, renal malformations, cryptorchidism, abducens paralysis, deafness, microtia, anotia Approximately 20% risk for exposure during days 34–50 of gestation. Trimethoprim NTD, oral clefts, hypospadias, and cardiovascular defects Approximately 1% risk of NTD for first-trimester exposure. Mechanism is folic acid inhibition. Valproic acid Lumbosacral spina bifida with meningomyelocele; CNS defects, microcephaly,

cardiac defects; narrow face with high forehead, epicanthal folds, broad, low nasal bridge with short nose, long philtrum with a thin vermilion border; long, thin fingers and toes Risk for spina bifida is approximately 1%, but the risk for dysmorphic facies ma be greater. The mechanism of teratogenicity is unknown. Possible explanations include interference with glutathione, folate, or zinc metabolism, or regulation o intracellular pH. Risk is confounded by those risks associated with epilepsy itsel or use of other agents. Vitamin D Possible association with supravalvular aortic stenosis, elfin facies, and mental retardation

Large doses of vitamin D may disrupt cellular calcium regulation. Genetic susceptibility may play a role. IUGR = intrauterine growth retardation; NSAID = nonsteroidal antiinflammatory drug; NTD = neural tube defect. Adapted from Brent RL: Environmental causes of human congenital malformations: The pediatrician's role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics 2004;113:957–968; Nulman I, Atanackovic G, Koren G: Teratogeni drugs and chemicals in humans. In: Koren G, ed: Maternal–Fetal Toxicology: Clinician's Guide, 3rd ed. New York, Marcel Dekker, 2001, pp. 57–72; and Polifka JE, Friedman JM: Medical genetics: 1. Clinical teratology in the age of genomics. CMAJ 2002;167:265–273. Xenobiotic

Reported

Effects

Comments

TABLE 30-1. Known and Possible Human Teratogens P.466 P.467 P.468

An increased free xenobiotic concentration in the pregnant woman can be cause by several factors, including decreased plasma albumin, increased binding competition, and decreased hepatic biotransformation, during the later stages o pregnancy. Fat stores increase during the early stages of pregnancy; free fatty

acids are released during the later stages and, with them, xenobiotics that may have accumulated in the lipid compartment. The increased concentration of free fatty acids can compete with circulating free xenobiotic for binding sites on albumin. Other factors may lead to decreased free xenobiotic concentrations. Early in pregnancy, increased fat stores, as well as the increased plasma and extracellular fluid volume, lead to a greater volume of distribution. Increased renal blood flow and glomerular filtration may result in increased renal elimination. Cardiac output increases throughout pregnancy, with the placenta receiving a

gradually increasing proportion of total blood volume. Xenobiotic delivery to the placenta may therefore increase over the course of pregnancy.

These processes interact dynamically, and it is difficult to predict their net effect. The concentrations of many xenobiotics, such as lithium, gentamicin, and carbamazepine, decrease during pregnancy, even if the administered dose is no changed. 143

Although this is not specifically related to the physiologic changes occurring during pregnancy, the fetus may be exposed to xenobiotics that accumulated in adipose tissue before pregnancy. For example, typical retinoid malformations were seen in a baby born to a woman whose pregnancy began 1 year after she discontinued use of the xenobiotic etretinate (retinoic acid).130

Xenobiotic

Exposure

in

Pregnant

Women

Exposure to xenobiotics during pregnancy is common. Between 30 and 80% of pregnant women take xenobiotics sometime during pregnancy—primarily analgesics, antipyretics, antimicrobials, and antiemetics, as well as vitamins, caffeine, ethanol, and nicotine.25 , 37 , 49 , 56 , 158 , 207 , 208 Some pregnant women use medications to treat chronic disease; others use medications unknowingly, prior to the recognition that they are pregnant.

Pharmaceutical manufacturers are required by law to label their products with respect to use in pregnancy, according to standards promulgated by the US Foo

and Drug Administration (FDA) (Table 30-2 ). 248 Similar classification systems have been developed in Sweden and Australia.6 , 198 , 214 The original intent of the US regulations was to inform practitioners about the nature of the available evidence regarding risk in pregnancy; however, the general impression is that the categories refer to teratogenic risk.220 In this the FDA grading system has been criticized for conveying an impression of a hierarchy of harmful effects and of equivalence of risk within any category.61 , 78 , 198 , 221 For example, in the US system, a category C medication is generally considered more dangerous than a category B medication in pregnancy, even though category C is the default category for medications about which there is little or no specific information available, and for which the risk is unknown. Approximately 90% of

medications are classified as category C.141

There is significant discordance between the use–pregnancy labeling and the teratogenic risk, as determined by clinical teratologists,141 and the FDA system has been criticized for being too conservative.78 Manufacturers may label certai medications as category X even when there is only limited information associating the medication with any adverse fetal or neonatal effects. For example, oral contraceptives generally carry a category X classification, even though they are not considered teratogenic. Certain agents with a category D classification may cause problems only at certain times during pregnancy. Even medications that are classified as category D or X may only have a very low risk

of teratogenicity or other adverse effect, and exposure to these agents, even during the first trimester, may not be a sufficient indication to terminate a pregnancy. Specific current information on individual xenobiotics can be obtaine from P.469 local and regional teratogen 216 , 225 some of which also Canadian program that uses actual risk to them of using planned

information services124 and published books,32 , 79 have online versions.118 , 242 Motherisk is a specific information to advise women about the a particular medication or xenobiotic in a current or

pregnancy.170 , 172

A No known risk Multiple vitamins Controlled studies show no risk. Adequate, well-controlled studies in pregnant women do not demonstrate a risk to the fetus and if animal studies exist, they do not demonstrate a risk. B Unlikely risk Acetaminophen, penicillin No evidence of risk in humans. Either animal studies show risk but human studies do not, or if no adequate human studies have been done, animal studies show no risk. C

Unknown risk Albuterol Risk cannot be ruled out. Animal studies may or may not show risk, but human studies do not exist. However, benefits may justify the potential or unknown risk. D Known risk, but benefit may outweigh risk Tetracycline Positive evidence of risk. Investigational or postmarketing data or human studies show risk to the fetus. Nevertheless, potential benefits may outweigh th potential risk; for example, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective. X Known risk but risk significantlying outweighs benefit Isotretinoin

Contraindicated in pregnancy. Studies in animals or humans or investigation or postmarketing reports have shown fetal risk that clearly outweighs any possible benefit to the patient. a Based on US Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs. 21 CFR Ch. I (4–1–04 ed.) $ 201.57. Category

Risk to Human Fetus

Example(s)

Basis

TABLE 30-2. FDA Use-in-Pregnancy Ratings a

The FDA is revising the approach to labeling medications, as well as the labels themselves. However, the questions raised during the revision process are extraordinarily complex; for example: How should animal data in general be evaluated? How should animal data be extrapolated to humans? How should the teratogenic risk be defined and quantified for any particular xenobiotic? How should the risk of not treating a particular disease be compared with the risk of using a particular medication to treat that disease? How should any of this information be communicated to practitioners and the public?221

Although most women are concerned about the teratogenic effects of medications, in utero exposure to therapeutic medications can have other pharmacologic effects on the newborn infant, such as hyperbilirubinemia or withdrawal reactions.32 , 58 , 170 Estimates of substance use in pregnancy vary tremendously, depending on the geographic location, practice environment, patient population, and screening method.42 , 132 Among a large national sample screened for xenobiotic use during pregnancy, 20% of pregnant women smoked, 20% drank ethanol, 3% used marijuana, 0.5% used cocaine, 0.1% used methadone, and fewer than 0.1% used heroin. Women tend to decrease their exposure to xenobiotics once they know they are pregnant.26 , 104 , 107

Placental Regulation the Fetus

of

Xenobiotic

Transfer

to

With respect to the transfer of xenobiotics from mother to fetus, the placenta functions like other lipoprotein membranes. Most xenobiotics enter the fetal circulation by passive diffusion down a concentration gradient across the

placental membranes. The characteristics of a substance that favor this passive diffusion are low molecular weight, lipid solubility, neutral polarity, and low protein binding.176 Polar molecules and ions may be transported through interstitial pores.245

Xenobiotics with a molecular weight (MW) greater than 1000 Da do not diffuse passively across the placenta, and this characteristic is used to therapeutic advantage. For example, warfarin (MW 1000 Da) easily crosses the placenta an causes specific fetal malformations.253 However, heparin (MW 20,000 Da), whic is too large to cross the placenta, is not teratogenic and, consequently, is the preferred anticoagulant during pregnancy. Most therapeutic medications have molecular weights between 250 and 400 Da and easily cross the placenta. For example, thiopental is highly lipid soluble and crosses the placenta rapidly. Feta plasma levels reach maternal levels within a few minutes. Muscle relaxants such as vecuronium are more polar and cross the placenta slowly. 64 Although the state of ionization is a limiting factor for diffusion, some highly

charged compounds can still diffuse across the placenta. Valproic acid (pKa 4.7) is nearly completely ionized at physiologic pH, yet there is rapid equilibration across the placental membrane. The small amount of xenobiotic that exists in the nonionized form rapidly crosses the placenta; as equilibrium is reestablished a new, small amount of nonionized xenobiotic becomes available for diffusion.17

Fetal blood pH changes during gestation. Embryonic intracellular pH is high relative to the pregnant woman. During this developmental stage, weak acids will diffuse across the placenta to the embryo and remain there because of “ion trapping.― Many teratogens, such as valproate, trimethadione, phenytoin, thalidomide, warfarin, and isotretinoin, are weak acids. Although ion

trapping does not explain the mechanism of teratogenesis, it may explain how xenobiotics accumulate in an embryo. Late in gestation the fetal blood is 0.10 t 0.15 pH units more acidic than the mother's blood; this may permit weakly basi xenobiotics to concentrate in the fetus during this period.176

The relative concentrations of protein binding sites in the pregnant woman and fetus also have an impact on the extent of xenobiotic transfer to the fetus.176 A

maternal free fatty acid concentrations increase near term, these fatty acids can displace xenobiotics such as valproic acid or diazepam from maternal protein binding sites and make more free xenobiotic available for transfer to the fetus. Fetal albumin concentrations increase during gestation and exceed maternal

albumin concentrations by term. Because the fetus does not have high concentrations of free fatty acids to compete for protein binding sites, these sites are available for binding the xenobiotics. At birth, when neonatal free fatty acid levels increase 2- to 3-fold, they displace stored xenobiotic from the bindin protein. In the cases of valproic acid and diazepam, the elevated concentrations of free xenobiotic have adverse effects on the newborn infant.84 , 105 , 177 , 192

P.470 The placenta may also affect xenobiotic presentation to the fetus by ion trappin and xenobiotic metabolism. The placenta blocks the transfer of some positively charged ions such as cadmium and mercury,93 and may even accumulate them. This barrier does not necessarily protect the fetus, however, because these heavy metal ions interfere with normal placental function and may lead to placental necrosis and subsequent fetal death.169

The placenta contains xenobiotic-metabolizing enzymes capable of performing both phase I and phase II reactions (Chaps. 9 and 2 6 ). However, the concentration of biotransforming enzymes in the placenta is significantly lower than that in the liver, and it is unlikely that the level of enzymatic activity is protective for the fetus. Moreover, the fetus may be exposed to reactive intermediates that form during these processes. On the other hand, glutathione may also be present in the placenta and detoxify some of these reactive intermediates.111

Placental transfer of xenobiotics can have a positive effect when it provides feta therapy. For example, if a fetus is found to have supraventricular tachycardia o

atrial flutter, digoxin can be given to the mother in order to treat the baby.123 , 205

Effects

of

Xenobiotics

on

the

Developing

Organism A basic premise of teratogenicity is that the particular toxic effects of a xenobiotic are determined by the organism's stage of development.29 , 222 Although the fertilized ovum is generally thought to be resistant to toxic insult before implantation,29 xenobiotics in the fallopian or uterine secretions may prevent implantation of the embryo. Xenobiotic exposure leading to cell loss or chromosomal abnormalities may also lead to a spontaneous abortion, possibly even before pregnancy has been detected. If the preimplantation embryo survives a xenobiotic exposure, the functional cells usually proceed to normal development.222 Teratogens that act in such a manner elicit an “all-or-none response―; that is, the exposed embryo will either die or go on to normal development.

Figure

30-1. Critical periods of fetal development. (Modified

with

permission

from Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology, 7th ed. Philadelphia, WB Saunders, 2003, p. 520.)

Teratogens generally behave according to a dose–response curve; there is a threshold dose below which no effects occur and as the dose of the teratogen increases above the threshold, the magnitude of the effect increases. The effec

might be the number of offspring that die or suffer malformations or the extent or severity of malformations. Strictly, teratogenic effects are those that occur a doses that do not cause maternal toxicity because maternal toxicity itself might be responsible for an observed adverse or teratogenic effect on the developing organism.29

Organogenesis occurs during the embryonic stage of development between days 18 and 60 of gestation. Most gross malformations are determined before day 36 although genitourinary and craniofacial anomalies occur later.29 The period of susceptibility to teratogenic effects varies for each organ system (Fig. 30-1 ). For instance, the palate has a very short period of sensitivity, lasting approximately 3 weeks, whereas the central nervous system (CNS) remains susceptible throughout gestation.29

Theoretically, knowing the exact time of teratogen exposure during gestation would allow prediction of a teratogenic effect; this is true in animal models, where dose and time can be strictly controlled. It is also true for thalidomide, where different limb anomalies are specifically related to exposures on particula days of gestation.222 In many clinical situations, relating teratogenicity to a particular xenobiotic exposure is difficult: Because the exact time of conception is unknown, the exact time of exposure is unknown, both for xenobiotics administered intermittently and chronically.

P.471 During the fetal period, formed organs continue their cellular differentiation and grow to functional maturity. Exposure to toxic agents such as cigarettes during this period generally leads to growth retardation. Teratogenic malformations or death may still occur as a result of disruption or destruction of growing organs, as has been the result of exposure to the angiotensin-converting enzyme inhibitors during the second and third trimesters.20 Another concern during the fetal period is the initiation of carcinogenesis.

Significant cellular replication and proliferation lead to a dramatic growth in size of the organism. At the same time, when the fetus is exposed to xenobiotics, development of biotransformation systems may expose the organism to reactive metabolites that might initiate tumor formation. Some tumors, such as

neuroblastoma, appear early in postnatal life, suggesting a prenatal origin. In pregnant rats given ethylnitrosourea during the embryonic period, lethal or teratogenic effects occur.193 If ethylnitrosourea is administered during the fetal period, there is an increased incidence of tumors in the offspring. Clear cell vaginal and cervical adenocarcinomas are seen in the female offspring of wome exposed to DES during pregnancy.23

Mechanisms

of

Teratogenesis

Cytotoxicity is one mechanism of teratogenesis and is the characteristic result o exposure to alkylating or antineoplastic agents. Aminopterin, for example, inhibits dihydrofolate reductase activity and leads to suppression of mitosis and cell death. If exposure to a cytotoxic agent occurs very early in development,

the conceptus may die, whereas sublethal exposure during organogenesis may result in maldevelopment of particular structures. There is evidence that following cell death, the remaining cells in an affected region may try to repair the damage caused by the missing cellular elements. This “restorative growth― may lead to uncoordinated growth and exacerbate the original malformation.

In the case of the cytotoxic agents, the mechanism of action is understood, although it is not always clear why particular agents affect particular structures With other agents, the structural effects have a clearer relationship to the site o action. For instance, when glucocorticoids are administered in large doses to

some experimental animals during the period of organogenesis, malformations the palate occur. Glucocorticoid receptors are found in high concentrations in th palate of the developing mouse embryo.188 Corticosteroid exposure can also cause cleft palate in humans at a low frequency.183 , 225 Caloric deficiency is not considered teratogenic during the period of organogenesis. However, specific nutritional or vitamin deficiencies can be

teratogenic; an increased incidence of neural tube defects is seen with folate deficiency, and the incidence has been reduced following the use of folate supplementation before and during pregnancy.142 Ethanol affects the fetus both directly and indirectly. The craniofacial malformations seen in the fetal alcohol syndrome probably result from the effects of ethanol during the period of organogenesis. Growth retardation may result from direct effects of ethanol on fetal growth, or from indirect effects resulting from ethanol-induced maternal nutritional deficiencies.

Management of Acute Poisoning in the Pregnant Woman

Suicide and suicide attempts during pregnancy are uncommon. Each year a sma number of women die during pregnancy or the postpartum period; 1–5% of these pregnancy-related deaths may be the result of suicide. Between 2 and 12% of women who attempt or commit suicide may be pregnant.119 , 186 , 262 Reported reasons for these suicide attempts include loss of a lover, economic

crisis, prior loss of children, and unwanted pregnancy and desire for an abortion.53 , 139 , 262 In one series, 12% of ingestions were attempts to terminate pregnancy 186 (Chap. 28 ). Medication ingestion is pregnancy. Analgesics, account for 50–79% These medications are

a common method of attempting suicide during vitamins, iron, antibiotics, and psychotropic medications of the reported ingestions by pregnant women.186 , 189 frequently prescribed for, and used by, pregnant women

Managing any acute overdose during pregnancy provokes discussion of several questions. Is the general management different? Do altered metabolism and pharmacokinetics increase (or decrease) the woman's risk of morbidity or mortality from a medication overdose? Is the fetus at risk of poisoning from a maternal overdose? Is there a teratogenic risk to the fetus from an acute overdose or poisoning? Is the use of an antidote contraindicated, or should use be modified? When should a potentially viable fetus be emergently delivered to prevent toxicity? When should termination of a pregnancy be recommended?

As described above, physiologic changes during pregnancy affect pharmacokinetics; xenobiotics taken in overdose also have unpredictable toxicokinetics. In any significant overdose during pregnancy, pregnancy-related alterations in pharmacokinetics are unlikely to protect the woman from significant

morbidity

or

mortality.

Although a single high-dose exposure to a xenobiotic during the period of

organogenesis might seem analogous to an experimental model to induce teratogenesis, most xenobiotics ingested as a single acute overdose do not induce physical deformities. Anticonvulsant agents are teratogenic and may be ingested in toxic doses, but their teratogenicity is probably related more to chronic exposure. Ethanol teratogenicity may be related to binge drinking, but a single binge is unlikely to have significant effects. Acute acetaminophen intoxication in the first trimester may lead to an increased risk of spontaneous abortion,196 suggesting a teratogenic effect similar to the all-or-none response described earlier. In general, however, it is extremely difficult to associate teratogenicity with a particular xenobiotic exposure following a single case report. There is, for example, a report of multiple severe congenital malformations in the stillborn fetus of a woman who overdosed on isoniazid

during the 12th week of pregnancy.136 However, because the background incidence of congenital malformations is 3–6%, it is almost impossible to determine for a single case whether a particular xenobiotic exposure is the etiology of any observed malformations.54 It is very unlikely that the small risk of possible teratogenesis would ever lead to a recommendation for termination of pregnancy after an acute overdose of most xenobiotics.

In general, any condition that leads to a severe metabolic derangement in the pregnant woman is likely to have an adverse impact on the developing fetus. Therefore, the management of overdose in a pregnant woman usually follows th principles outlined in Chap. 4 , with close attention paid to the airway, oxygenation, and hemodynamic stability. The use of naloxone or dextrose has not been specifically assessed in pregnancy, but should be guided by the same considerations raised in managing the nonpregnant patient with alterations in respiratory or neurologic function. Opioid-induced respiratory failure in the

pregnant patient will lead to fetal hypoxia and adverse effects; opioid withdraw in a P.472 pregnant woman, whether induced by abstinence or the use of naloxone, may adversely affect the fetus or the pregnancy. Consideration of the benefits and risks of the use of naloxone for an opioid-poisoned woman in or coma suggests that reduced morbidity, for both mother and achieved by the use of carefully titrated doses of naloxone to likelihood of maternal withdrawal (see Chap. 38 and Antidotes

respiratory distres fetus, may be minimize the in Depth: Opioid

Antagonists ).

Gastrointestinal decontamination is frequently a part of the early management acute poisoning in the nonpregnant patient. Gastric lavage is not specifically contraindicated for the pregnant patient; the usual concerns about protecting th airway apply to the pregnant patient. Even though the syrup of ipecac is no longer recommended as a standard therapy for the management of ingestions, pregnancy was previously considered a relative contraindication to its use because vomiting increases both intrathoracic and intraabdominal pressure. There is no specific contraindication to the use of activated charcoal in a pregnant woman. There may be a specific role for whole-bowel irrigation in the

management of several xenobiotic exposures, particularly in the treatment of iron overdose in pregnancy. The use of polyethylene glycol is safe in pregnant women.178

When considering the use of antidotes, the primary concern should be for the health of the pregnant woman. Almost all antidotal agents are designated as FD pregnancy-risk category C; that is, there is little specific information to guide their use. Ethanol is labeled as category D (positive evidence of risk), although this is presumably related to chronic use throughout pregnancy, not as an antidote. Fomepizole, which has replaced ethanol as the preferred antidote for toxic alcohol poisoning, is labeled as category C. Pyridoxine and thiamine are

category A medications; N -acetylcysteine, magnesium, glucagon, and naloxone are category B medications. Thus far, there are no reports of adverse effects on the fetus from antidotal treatment of a poisoned pregnant woman. Conversely, in at least one case, withholding deferoxamine therapy may have contributed to the death of both a woman and her fetus.154 , 238 In the hypothetical case of a pregnant woman poisoned with a toxic alcohol for whom fomepizole is not available, the use of ethanol is essential until hemodialysis can be performed, especially outside of the first trimester, although there are no data to predict outcome. In most cases, the physician will need to weigh the short-term toxicity of high serum ethanol concentrations against the unknown risk of fomepizole.

Acetaminophen

Acetaminophen is the most common analgesic and antipyretic agent used during pregnancy and is one of the most common xenobiotics ingested in overdose during pregnancy.164 , 196 There are two published series, as well as a number of individual reports, totaling more than 100 cases of acute acetaminophen overdose during all trimesters of pregnancy. In the two large series representin 112 acute and chronic overdoses, 33 patients had serum acetaminophen concentrations in the toxic range.164 , 196 These studies, in addition to the case reports described below, demonstrate that most pregnant women recover from an acetaminophen ingestion without adverse effects to themselves or their babies.

In the two large series of acetaminophen overdose during pregnancy,164 , 196 8 of 28 women who overdosed in the first trimester and continued their pregnanc experienced spontaneous abortions, most within 2 weeks of the ingestion. Of th 8 women, 5 had toxic serum acetaminophen concentrations; 1 woman received -acetylcysteine (NAC) within 8 hours, and 4 received NAC between 12 and 17 hours after ingestion. In one of these cases there was both maternal and fetal death. Five patients with toxic serum acetaminophen concentrations and 14 with nontoxic serum concentrations delivered healthy term newborns. Ten women ha elective terminations of pregnancy.

The 2 large series include 32 second-trimester acute overdoses.164 , 196 Two women who had nontoxic serum acetaminophen concentrations had spontaneou abortions—one had symptoms of a threatened abortion several days prior to the overdose, and the second was assaulted the day before the overdose and aborted the next day. Six women with toxic serum acetaminophen concentration delivered full-term healthy infants; 19 women with nontoxic serum concentrations delivered full-term babies, and 1 woman with a nontoxic serum concentration delivered a premature infant 2 months after the overdose. Four women had elective terminations of pregnancy.

There are 3 case reports of women with acute overdoses in the second trimeste One woman who overdosed at 15.5 weeks of gestation had a toxic serum

acetaminophen concentration, was treated with intravenous NAC beginning 20 hours after the ingestion, and developed hepatotoxicity. She had a spontaneous rupture of membranes at 31 weeks and delivered a male infant at 32 weeks.146 One woman who overdosed at 16 weeks had a toxic serum acetaminophen concentration, was treated with NAC within 8 hours, and did not develop hepatotoxicity.201 She delivered a normal female infant at term. One woman overdosed at 20 weeks, received intravenous NAC starting some time between 8 and 18 hours after ingestion, and developed hepatotoxicity. She had labor induced at 41 weeks because of weight loss and delivered a male infant.235 The infant was irritable and developed hyperbilirubinemia, both of which resolved after phototherapy. The 2 large series described above included 39 third-trimester overdoses.164 , 196 Twelve women had toxic serum acetaminophen concentrations: 8 delivered

healthy term infants, 2 women who had no evidence of hepatotoxicity delivered premature infants 2 days after the overdose, 1 woman with hepatotoxicity delivered a moderately ill premature infant at 32 weeks of gestation, and 1 woman with severe hepatotoxicity delivered a stillborn infant with hepatic necrosis at 33 weeks of gestation (Table 30-3 ). Twenty-seven women had nontoxic serum acetaminophen concentrations; 2 delivered premature infants (1 of whom had respiratory distress), and 25 delivered full-term infants. Of these full-term infants, 1 developed a withdrawal syndrome, 1 developed pyloric stenosis, and 3 had physical anomalies. Altogether, in these 2 series, 6 of 39 women with third-trimester overdoses had premature delivery, usually within 2 to 3 days of the overdose.

In addition to the large series described, there are 11 case reports of thirdtrimester acetaminophen overdoses (Table 30-3 ). Three additional thirdtrimester cases are briefly described; 2 women had an acute overdose and 1 ha

a chronic overdose. All 3 women had toxic serum acetaminophen concentrations were treated with NAC, and delivered healthy infants while receiving NAC.100 There are also several case reports of adverse pregnancy outcome in the setting of chronic use of acetaminophen, or acute overdose in the setting to other chronic substance use.41 , 100 , 127 , 148 , 196 It is difficult to interpret these reports with respect to specific acetaminophen effect because of the confounder of chronic disease, chronic use, or use of additional medications or substances. 27 0 (36 h) 1226 (36 h) ND No C/S for fetal distress. Infant: mild respiratory distress syndrome. 80

27–28 56 (16 h) 6226 (96 h) ND Yes

Ingestion over 24 h. No fetal movements at presentation. PO NAC started at 20 h. Induced labor at 4 d. Infant: stillborn with diffuse hepatic necrosis. Hepatic APAP 250 µg/g. 90

29 160 (10 h) 4300 (50 h) 76 (16 h, cord) No Ingestion of aspirin, caffeine, and quinine, followed 17 h later by APAP. Presented in labor. Treated with oral methionine. Spontaneous delivery at 16 h. Infant: moderate hyaline membrane disease. Peak AST 86 (cord). Four wholeblood exchange transfusions. Discharge home at 54 d of life. Died at 106 d, no apparent cause. 135

31 40 (26) 13320 (60 h) 41 (27)

Yes APAP only, C/S for fetal distress 1 h after initial maternal evaluation. Infant's birth weight was 1620 g. Apgars 0, 0, 1.b lnfant died at 34 h of life. Mother die at 34 h post ingestion. No autopsy of mother or child. 251

32 448 (12 h) 5269 (48 h) 0 (84 h, cord) No IV NAC started at 12 h. Induced delivery at 84 h. Infant: transient hypoglycemia, mild respiratory distress, mild jaundice. Peak AST 56 (day 1 of life). 264

33

135 (28 h) 6237 (66 h) 330 (3 d, cord) Yes Oral NAC at 12 h. Fetal death at 2 d, spontaneous delivery at 3 d. Infant: stillborn with diffuse hepatic necrosis. 196

36 280 (3–4 h) Normal 217 (6–7 h, cord) No Ingestion of APAP, ethanol, barbiturates. Elective C/S at 6–7 h. Infant: double volume exchange transfusion at 18 h. Discharge at 40 d, “cot death― at 157 d. 200

36 200 (5 h) 25 (24 h)

ND No Oral NAC (? time). Infant: spontaneous delivery 6 weeks after ingestion. Norma neonatal course. 38

38 216 (4 h) Normal 13 (17 h, cord) No NAC (? route). Infant: normal neonatal course. 126 210

“Term― 147 (9 h)

28 (9 h) 133 (9 h, 4 h of life) No Infant PT 44 at 4 h of life. IV NAC. No problems. AST 86 at 4 h of life. 15

Term? 89 (11 h) 326 (35 h) 144 (11 h, 4 h of life) No Mother presented in labor at 6 h. Infant received IV NAC at 4 h of life. AST 55 a 4 h of life. 213

APAP = acetaminophen; AST= aspartate aminotransferase; C/S = cesarean section; IV = intravenous; NAC = N -acetylcysteine; ND = not done or not reported; PO = oral; PT = prothrombin time. a Time after maternal ingestion. b Apgars are at 1, 5 and 10 minutes. Maternal

Gestational Age (weeks)

APAP Level (µg/mL) (timea )

AST Peak (IU/L) (timea )

Infant

APAP Level (µg/mL) (timea )

Hepatotoxicity (Yes/No)

Comment

Re

TABLE 30-3. Reported Cases of Third-Trimester Acetaminophen Overdose

P.473 Acetaminophen is a FDA use-in-pregnancy category B medication; at recommended doses, it is considered safe for use during pregnancy. However, i overdose, it may put the developing organism at risk. As the third-trimester cases described above demonstrate, acetaminophen crosses the placenta to

reach the developing fetus. The clinical series164 , 196 suggest that there may b some increased risk of spontaneous abortion after overdose during the first trimester. There is also a question about whether overdose during the first trimester can lead to late sequelae, for instance, premature labor.

Some experimental work may help to explain early pregnancy loss after overdose. Acetaminophen prevented the development of preimplantation (twocell stage) mouse embryos in culture, an effect that was not associated with alterations in glutathione concentrations,133 and also led to abnormal neuropore development in cultured rat embryos.234 These data suggest that acetaminophe may be directly toxic to the immature organism. However, other work reported that similar embryotoxic effects were associated with reductions in glutathione concentrations258 and that N -acetyl-p -benzoquinoneimine (NAPQI) produced nonspecific toxicity when added to the rat embryo culture medium.234 The fetal liver has some ability to metabolize acetaminophen to a reactive intermediate in vitro. Cytochrome P450 (CYP) activity was detected in intact hepatocytes, as well as in microsomal fractions isolated from the livers of

fetuses aborted between 18 and 23 weeks of gestation.203 Fetal CYP activity wa only 10% of the activity of hepatocytes isolated from adults without cerebral activity selected as kidney donors; fetal CYP activity increased with increasing gestational age. In 2 clinical cases, cysteine and mercapturate conjugates were

identified in newborns exposed to acetaminophen in utero, suggesting that the fetus and neonate can metabolize acetaminophen through the CYP system. Thes data suggest that the fetus in utero and the neonate can generate a toxic metabolite; the clinical cases suggest that the fetal liver is susceptible to injury This CYP activity has not been further characterized. However, the cytochromes responsible for acetaminophen metabolism, is fetal tissues as early as 16 weeks of gestation.167 CYP3A4 and involved in acetaminophen metabolism, but are not present in is a functional fetal form of the CYP3 family, but its metabolic respect to acetaminophen has not been studied.91

CYP2E1, one of present in huma CYP1A2 are also fetal liver. CYP3A activity with

P.474 The most difficult questions relate to management of overdose during the third trimester. Can acetaminophen overdose lead to premature labor even if a

pregnant woman does not have a toxic serum concentration or develop hepatotoxicity? Should a woman be emergently delivered following overdose? Does NAC treatment of the mother help the fetus? What is the appropriate treatment of a neonate exposed to acetaminophen in utero?

The clinical cases may help with at least the last two questions (see Table 30-3 ). Six women, all less than 36 weeks of gestation, developed hepatotoxicity. Tw infants died in utero with evidence of severe hepatotoxicity, although what effe in utero postmortem changes may have had on serum acetaminophen concentrations or liver pathology is unclear. One infant died on the second day of life with hepatotoxicity. The other 3 infants experienced problems associated

with prematurity but did not develop obvious hepatotoxicity. One of these 3 had an exchange transfusion, and had an unexplained death at 3 months of age. Fiv women, all at 36 or more weeks of gestation, did not develop hepatotoxicity. One infant had an exchange transfusion and did not develop hepatotoxicity but died a “cot death― at 5 months of age. One infant received IV NAC and had a transient elevation of aspartate aminotransferase (AST) and prothrombin time. Two infants were not treated; both did well, although 1 had a transient elevation of AST. One infant was born 6 weeks after the overdose and was normal.

Severe maternal hepatoxicity that is associated with any sign of fetal distress is

an indication for urgent delivery. Although a fetus with prolonged exposure to acetaminophen in utero is at risk of developing severe hepatotoxicity, not all at risk infants are affected. What role gestational age, maternal disease state, or other maternal factors may play is unknown. Although there are insufficient cas data to suggest that acetaminophen overdose per se is an indication for urgent delivery, there may be an indication for urgent delivery when the maternal serum acetaminophen concentration is in the toxic range but hepatotoxicity has not yet developed.241 Significant acetaminophen overdose with or without hepatotoxicity can precipitate premature spontaneous labor, and even women with nontoxic serum concentrations may be at a slightly increased risk.

In 2 cases, exchange transfusion was employed to treat the exposed neonate. I both cases, the acetaminophen half-life was prolonged, and in neither case was this affected by the transfusion. Disturbingly, these 2 infants had unexplained

deaths at several months of age. There is insufficient information on which to base a recommendation regarding exchange transfusion as therapy for prenatal exposure.

The pregnant woman with acute toxic acetaminophen ingestion should be treate with N -acetylcysteine (see Chap. 34 and Antidotes in Depth: N -Acetylcysteine ). This is therapy to treat the mother. Although maternal hepatoxicity or delaye NAC therapy may be associated with fetal toxicity,196 there is insufficient information to indicate that prevention of maternal toxicity will prevent fetal toxicity in either the first or the third trimester. NAC was found in cord blood after administration to 4 mothers before delivery,100 although NAC did not cros

the sheep placenta in vivo223 or the perfused human placenta in vitro.104 Even NAC does cross the placenta, whether it prevents fetal hepatotoxicity is unknow because not all exposed fetuses develop hepatotoxicity.

In 4 third-trimester cases where the mothers overdosed at or after 36 weeks of gestation and did not develop hepatotoxicity, the infants did well. One infant received NAC. There are anecdotal reports of infants who received NAC postnatally and did well. Current are less likely than teenagers or acetaminophen overdose because sulfation activity. It is intriguing

theory suggests that infants and young childre adults to develop hepatoxicity after of immature CYP activity and increased to consider that this metabolic protection migh

extend to the newborn exposed to acetaminophen in utero. It also makes difficult to know to what extent postnatal NAC therapy for the prenatally newborn might prevent toxicity. Although there are no reported cases, it seem that the premature newborn exposed in utero is the best candidate postnatal NAC therapy.

it expose would for

Iron Iron is another common ingestant during pregnancy; maternal toxicity is generally greater than fetal toxicity. In 2 reported cases, normal babies were delivered although the mothers died.182 , 194 In another case, the mother had severe iron toxicity with acidosis, shock, renal failure, and disseminated intravascular coagulation but was not treated with deferoxamine because of concerns about its teratogenic risks. Instead, the mother received an exchange

transfusion followed 45 minutes later by a spontaneous abortion of the 16-week fetus.154 , 238 Neonatal and cord blood iron concentrations were not elevated. I several cases, pregnant women who had signs and symptoms of iron poisoning and elevated serum iron concentrations were treated with deferoxamine and subsequently delivered normal babies.24 , 116 , 128 , 190 , 217 , 247

Although the placenta transports iron to the fetus efficiently, 171 it also blocks the transfer of large quantities of iron. In a sheep model of iron poisoning, only a small amount of iron was transferred across the placenta despite significantly elevated serum iron levels.52

Deferoxamine is an effective antidote for iron poisoning (see Chap. 40 and Antidotes in Depth: Deferoxamine ), but it is reported to be an animal teratogen that causes skeletal deformities and abnormalities of ossification (FDA class C

pregnancy risk). An animal model observed similar effects, but only with doses of deferoxamine that caused maternal toxicity.27 Experimentally, in sheep, little transfer of deferoxamine across the placenta was demonstrated;52 therefore, th reported fetal effects may be secondary to chelation of essential nutrients (such as trace metals) on the maternal side of the placenta.241

In clinical case reports of iron overdose for which deferoxamine was used, there have been no adverse effects on the fetus, although most have been either

second- or third-trimester poisonings.24 , 116 , 128 , 182 , 190 , 217 , 247 In a case series of 49 patients with iron poisoning during pregnancy, few of the patients exhibited any clinical toxicity other than vomiting and diarrhea; 25 received deferoxamine, most by the oral route.163 One woman with a first-trimester overdose, 8 women with second-trimester overdoses, and 12 women with thirdtrimester overdoses were treated with deferoxamine and subsequently delivered full-term infants. One infant whose mother overdosed at 30 weeks of gestation had webbed fingers on one hand. One woman overdosed at 20 weeks, had minimal clinical toxicity, received deferoxamine, and delivered a 2.5-kg male infant at 34 weeks. One woman with a first-trimester overdose and 2 women with second-trimester overdoses elected to terminate their pregnancies.

Further support for the safe use of deferoxamine in pregnancy is the experience with its use for pregnant women with thalassemia. For many years Deferoxamin has been administered as part of the therapy for posttransfusion iron overload

without

adverse

effects.229

P.475 Deferoxamine is probably safe for use in pregnant women. Considering the potentially fatal nature of severe iron poisoning, deferoxamine should be administered when signs and symptoms indicate significant poisoning. Iron overdose may be one of irrigation because iron is not Depth: Activated Charcoal ). fragments following treatment irrigation.249

Carbon

the few specific indications for whole-bowel adsorbed to activated charcoal (see Antidotes in A case report demonstrated elimination of pill of a pregnant woman with whole-bowel

Monoxide

Carbon monoxide is the leading cause of poisoning fatalities in the United State In contrast to iron and most other xenobiotics, when pregnant women are exposed to carbon monoxide, the fetus may be at greater risk of toxicity than the woman herself. There are reports of both the mother and fetus dying, the

mother surviving but the fetus dying, and both the mother and fetus surviving but with adverse neonatal outcome, primarily brain damage resembling that see following severe cerebral ischemia.39 , 51 , 121 , 144 , 155 , 180 , 249 , 265 Similar clinical effects have also been observed in animal models.63 , 85 , 145

The case literature suggests increased risk of poor fetal outcome with clinically severe maternal poisoning or significantly elevated carboxyhemoglobin levels.12 , 180

Women with minimal symptoms and/or low levels of carboxyhemoglobin have a low risk of fetal toxicity, but a lower limit of exposure without effect has not been specifically defined.125

In animal models, under physiologic conditions, the fetus has a carboxyhemoglobin concentration 10–15% higher than the mother. After exposure to carbon monoxide, the fetus achieves peak carboxyhemoglobin level 58% higher than those achieved by the mother at steady state, and the time to peak level is also delayed compared to the mother. Similarly, the elimination of carbon monoxide occurs more slowly in the fetus than in the mother. 96 , 144 , 1 One case report describes such a phenomenon: after 1 hour of supplemental

oxygen, the maternal carboxyhemoglobin was 7% and the fetal carboxyhemoglobin was 61% at the time of death in utero.69

Carbon monoxide leads to fetal hypoxia by several mechanisms: (a) maternal carboxyhemoglobin leads to a decrease in the oxygen content of maternal blood and therefore, less oxygen is delivered across the placenta to the fetus, which normally has an arterial PO2 of only 20–30 mm Hg; (b) fetal carboxyhemoglobin causes a decrease in fetal PO 2 ; (c) carbon monoxide shifts the oxyhemoglobin dissociation curve to the left and decreases the release of oxygen to the fetal tissues (an exacerbation of the physiologic left shift found with normal fetal hemoglobin); and (d) carbon monoxide may inhibit cytochrom oxidase or other mitochondrial functions (Chap. 120 ). The treatment for severe carbon monoxide poisoning is hyperbaric oxygen

therapy (HBO) (see Chap. 120 and Antidotes in Depth: Hyperbaric Oxygen ). There are questions about the use of HBO in pregnant women because animal models suggest HBO adversely effects the embryo or fetus.73 , 168 , 215 , 240 Th applicability of the animal models to humans is difficult to assess; many of the

animal models employed hyperbaric conditions of greater pressures and duratio than those clinically employed for humans.

HBO has been used therapeutically for carbon monoxide poisoning in pregnancy

with good results reported, although there are limited data on the long-term follow-up of the children.34 , 72 , 81 , 88 , 97 , 125 , 250 One large series reported 44 women who were exposed to carbon monoxide during pregnancy and were treated with HBO, regardless of clinical severity or gestational age: 33 had term births; 1 had a premature delivery 22 weeks after HBO, during an episode of maternal fever; 2 had spontaneous miscarriages (one 12 hours after severe poisoning and one 15 days after mild poisoning); 1 delivered a child with Down syndrome; 1 had an elective abortion; and 6 were lost to follow-up. 69 Unfortunately, details regarding trimester of exposure, maternal carboxyhemoglobin level, and severity of symptoms are not available, making it difficult to interpret the reported outcomes. Although HBO appears safe for pregnant women and seems to present little risk to the fetus, it is not clear whether HBO prevents carbon monoxide-related fetal toxicity for those at risk. Carbon monoxide can have a severe impact on fetal health and development,

and, as noted above, the maternal carboxyhemoglobin level may not accurately reflect the fetal carboxyhemoglobin level.

HBO should be considered for any pregnant woman exposed to carbon monoxide especially for a woman with an elevated serum carboxyhemoglobin concentratio or any evidence of fetal distress. If HBO therapy is not available, 100% oxygen should be administered to the mother for a period of time five times longer than the time needed for the maternal carboxyhemoglobin to return to the normal range.

Substance

Use

During

Pregnancy

One of the most complex areas of toxicology deals with issues of substance use during pregnancy, and its effects on the woman, on the pregnancy itself, and on fetal and postnatal development. This section reviews of some of the important aspects of this topic.

Clinical research in the area of substance use during pregnancy is very difficult to perform. With the increased use of cocaine during the latter half of the 1980 and 1990s, there was great interest in determining the effects of cocaine use during pregnancy. As research in this area progresses, many of the critical methodologic issues related to substance use research are highlighted.74 , 102 , 138 , 179 , 268

Substance-using women often have multiple risk factors for adverse pregnancy

outcomes, such as low socioeconomic status, polysubstance use, ethanol and cigarette use, sexually transmitted diseases, AIDS, malnutrition, and lack of prenatal care. Lack of prenatal care is highly correlated with premature birth, and smoking is associated with spontaneous abortion, growth retardation, and sudden infant death syndrome (SIDS).115 , 260 Other factors not specifically related to substance use such as age, race, gravidity, and prior pregnancies als effect pregnancy outcome. Each of these factors represents a significant potential confounding variable when the effects of a particular agent such as cocaine or marijuana are evaluated during pregnancy and must be controlled fo in research design. Many of these factors are also significant confounders in evaluation of postnatal growth and development.

There may be bias in the selection of study subjects. For example, if all the patients are selected from an inner-city hospital obstetric service, there is potential for overestimating the effects of the xenobiotic being studied. If cohorts are followed over a long time, study subjects are frequently lost to follow-up. Are the ones who continue more motivated, or do they have more problems that need attention?

Categorizing patients into substance-use groups is difficult. Self-reporting of substance use is frequently unreliable or inaccurate, and making determinations about the nature, frequency, quantity (dose),

P.476 or timing (with respect to gestation) of xenobiotic exposure is difficult. Because substance users frequently use multiple xenobiotics, it may be difficult to categorize subjects into particular xenobiotic-use groups, and patients using different xenobiotics may be grouped together. In fact, there may be no actual xenobiotic-free control groups.

When urine drug screens are used to identify substance users, there is a high probability of false negatives because drug screens reflect only recent use. This factor is particularly important because substance use tends to decrease later in pregnancy, and a negative urine drug screen in the third trimester or at deliver may fail to identify a woman who was using xenobiotics early in pregnancy. Testing for xenobiotics in hair or meconium may improve the accuracy of the analysis with regard to the entire pregnancy.121 , 137

Another bias involves selection of infants who are exposed to xenobiotics. Evaluating newborns who are “at risk,― show signs of withdrawal, or have positive urine drug screens will miss some exposed infants. When research concerns the neurobehavioral development of children exposed in utero to substances, it is important that the examiners performing the evaluation be blinded to the infants' xenobiotic exposure category.

Finally, there may be a bias against publishing research that shows a negative o no significant effect. 122

Ethanol

Chronic ethanol use during pregnancy produces a constellation of fetal effects. The most severe effects are seen in the fetal alcohol syndrome (FAS), which is characterized by (a) intrauterine or postnatal growth retardation, (b) mental retardation or behavioral abnormalities, and (c) facial dysmorphogenesis, particularly microcephaly, short palpebral fissures, epicanthal folds, maxillary hypoplasia, cleft palate, hypoplastic philtrum, and micrognathia.108 A child can be diagnosed with FAS even when a history of regular gestational alcohol use cannot be confirmed. In an attempt to formalize diagnostic criteria for FAS and other gestational alcohol-related effects, the Institute of Medicine has proposed some additional descriptors.236 Partial FAS is applied to a child with some of the characteristic facial features and with either growth retardation, neurodevelopmental abnormalities, or other behavioral problems. Alcohol-related birth defects are congenital anomalies other than the characteristic facial features described above, such as cleft palate, which are sometimes seen with regular gestational alcohol use. Alcohol-related neurodevelopmental disorder describes neurodevelopmental abnormalities or other behavioral problems, which are sometimes seen with regular gestational alcohol use. Differential expression of the syndrome may reflect the effects of different ethanol doses at critical periods specific for particular effects. The craniofacial

anomalies probably represent teratogenic effects during organogenesis, wherea some central nervous system abnormalities and growth retardation may result from adverse effects later in gestation.

The fully expressed syndrome may be related to consumption of the equivalent of 2–3 ounces of 100% ethanol (4–6 “standard― drinks of hard liquor per day throughout pregnancy,236 although binge drinking (at least 5 standard drinks per occasion), with a significantly elevated peak blood ethanol concentration, may be more important.3 , 152 Approximately 20% of women consume some ethanol during pregnancy;175 only 1–2% consume 4 or more drinks each day. In this regard, it might be more appropriate to attribute all the fetal alcohol syndromes described above to alcoholism, or chronic regular use o frequent binging, rather than to any level of gestational ethanol exposure, no matter how little or how infrequent.3 , 4 Even so, a no-effect level for ethanol

has not been defined, and a safe level of ethanol use in pregnancy has not been determined.109

The incidence of FAS is 0.5–3 per 1000 live births; 4% of women who drink heavily may give birth to children with FAS.2 , 160 This means that several hundred children with FAS and several thousand with fetal alcohol effects will be born each year; ethanol use is considered the leading preventable cause of mental retardation in this country.236 Although the primary determinant of FAS and its effects is the level of maternal ethanol consumption, there is some evidence that paternal ethanol exposure may play a contributing role.1

Other effects of ethanol use during pregnancy include an increased incidence of spontaneous abortion, premature deliveries, and stillbirths,50 , 140 neonatal ethanol withdrawal,50 and possibly carcinogenesis.117 Infants may be irritable o hypertonic and may have problems with habituation and arousal. Long-term behavioral and intellectual effects include decreased IQ, learning disability, memory deficits, speech and language disorders, hyperactivity, and dysfunctional behavior in school.159 , 237

Brain autopsies of children with FAS demonstrate malformations of gray and white matter, a failure of certain regions (eg, the corpus callosum) to develop, failure of certain cells (eg, cerebellar astrocytes) to migrate, and a tendency fo tissue in certain regions to die. The mechanisms of ethanol-induced teratogenesis are not fully elucidated.19 , 92 Much of the work in animals has focused on the developing nervous system, where ethanol adversely affects nerve cell growth, differentiation, and migration, particularly in areas of the neocortex, hippocampus, sensory nucleus, and cerebellum.67 , 89

Several mechanisms are potential contributors to ethanol's effects. 87 Ethanol interferes with a number of different growth factors which may affect neuronal migration and development.261 In addition, ethanol interferes with the development and function of both serotonin and N -methyl-D-aspartate (NMDA) receptors. Ethanol, or its metabolite acetaldehyde, may also cause necrosis of certain cells directly or through the generation of free radicals and excessive apoptosis.48 , 94 In particular, craniofacial abnormalities may be related to apoptosis of neural crest cells, through the formation of free radicals, a deficiency of retinoic acid, or the altered expression of homeobox genes which

regulate growth and development.

One integrative model of ethanol induced teratogenesis proposes that sociobehavioral risk factors, such as drinking behavior, smoking behavior, low socioeconomic status, and cultural/ethnic influences, create provocative biologic conditions, such as high peak blood ethanol concentrations, circulating tobacco constituents, and undernutrition. These provocative factors exacerbate fetal vulnerability to potential teratogenic mechanisms, such as ethanol-related hypoxia or free radical-induced cell damage.5

Opioids Opioid dependency remains a significant cause of both maternal and neonatal morbidity. Approximately 0.2% of pregnant women may use heroin or methadone, and up to 75,000 babies per year may be exposed to opioids, in utero.175 Pregnant opioid users are at increased risk for many medical complications of pregnancy, such as hepatitis, sepsis, endocarditis, sexually transmitted diseases, and AIDS, and may be at increased risk for obstetric complications, such as miscarriage, premature delivery, or stillbirth.74 , 86 Som of

P.477 the obstetric complications may be related to associated risk factors in addition to the opioid use.

The most common effect of maternal opioid use is on fetal growth.86 , 268 There is an increased incidence of low birth weight in babies born to opioid-using mothers, compared to controls, and the effect is greater for heroin than for methadone. Women who receive low-dose methadone and good prenatal care have birth outcomes similar to nonusers, but they are at increased risk for pregnancy-related complications.74

The most significant acute neonatal complication of opioid use during pregnancy is the neonatal withdrawal syndrome (NWS), characterized by hyperirritability, gastrointestinal dysfunction, respiratory distress, and vague autonomic symptoms, including yawning, sneezing, mottling, and fever (Table 30-4 ).10 Myoclonic jerks or seizures may also signify neurologic irritability. Withdrawing

infants are recognizable by their extreme jitteriness, despite efforts at consolation; ecchymoses and contusions may be found on the tips of their fingers or toes, as a result of trauma from striking the sides of the bassinet. From 60 to 90% of opioid-exposed offspring will show some signs of withdrawal.74

Some of the manifestations of the neonatal withdrawal syndrome may be caused by enhanced α-adrenergic activity in the locus ceruleus. Firing of neurons in this region of the brain leads to such NWS-like behaviors as wakefulness and tremors—effects that are inhibited by opioid agonists. Chronic opioid administration leads to tolerance, as well as an increased number of α 2 -

adrenergic receptors. Presumably, withdrawal of opioids causes increased stimulation of a large number of receptors in this region, leading to clinical sign of withdrawal. Opioid withdrawal symptoms typically occur within 2 weeks of birth. Heroin withdrawal usually occurs within the first 24 hours; however, methadone withdrawal may be delayed because it has a larger volume of distribution and slower metabolism in Methadone withdrawal mg/mL.204 The onset heroin, methadone, or

the neonate, and therefore an increased half-life. occurs when the plasma concentration falls below 0.06 and severity of symptoms may be related to whether both were used; how much was used chronically; how

much was used near the time of delivery; the character of the labor; whether analgesic or anesthetic agents were used; and the maturity, nutrition, and medical condition of the neonate.57 Acute neonatal withdrawal symptoms generally last from days to weeks, but some symptoms may persist for months.10 Exaggerated Moro reflex Dehydration Frequent yawning and sneezing Diarrhea High-pitched crying Poor feeding Hyperactive deep tendon reflexes Poor weight gain

Increased muscle tone Uncoordinated and constant Increased wakefulness sucking Irritability Vomiting Seizures Autonomic signs Tremors Fever Increased sweating Mottling Nasal stuffiness Temperature instability Reproduced with permission from the Committee on Drugs. Neonatal drug withdrawal. Neurologic

Pediatrics

1998;101:1079–1088.

excitability

Gastrointestinal

dysfunction

TABLE 30-4. Signs and Symptoms of Neonatal Opioid Withdrawal

From 5–7% of babies showing signs of withdrawal experience seizures, generally by 10 days after birth.95 Seizures may be more likely after methadone withdrawal than after heroin withdrawal.267 These seizures do not necessarily predispose to idiopathic epilepsy; in one small study, children who had withdrawal seizures were normal at 1-year follow-up.60 Treatment of withdrawal begins with provision of a comforting environment: swaddling or tightly wrapping the infant, minimal handling or stimulation, and demand feeding. More severe symptoms may require pharmacologic therapy. One way of determining the need for therapy is the application of a severityscoring scale. In general, babies who are extremely irritable, have feeding difficulties, diarrhea, or significant tremors, or are crying continuously, are candidates for pharmacologic therapy. 10 , 112

Opioid agonists such as morphine, methadone, tincture of opium and paregoric;

and sedative-hypnotic agents such as diazepam and phenobarbital have been used to treat withdrawal symptoms.10 , 112 Tincture of opium, diluted to a final dose of 0.4 mg/mL of morphine equivalent, may be the preferred agent because it is a pure opioid agonist, and the formulation has no additives. However, there are few well-controlled trials evaluating the relative efficacy of the different agents. 243 Opioid agonists may be more effective at preventing withdrawal seizures from heroin or methadone than from phenobarbital or diazepam.95 , 113 However, sedative-hypnotic agents are commonly used by heroin users or adults maintained on methadone, and sedative-hypnotic withdrawal seizures may

contribute to the overall neonatal abstinence symptomatology. In this setting there may be a role for phenobarbital. Because oral administration of phenobarbital may delay achieving a therapeutic level, parenteral administratio may be required. Infants of opioid-using mothers are at increased risk for SIDS compared to controls.114 , 115 The relative risk is 3.6 for methadone and 2.3 for heroin. The

mechanism may be related to a decreased medullary responsiveness to CO2 , or the effect may be related to some condition of the postnatal environment.115 , 252

Although young children born to opioid users do not seem to have significant differences in behavior compared to controls, older children have increased learning problems and school dysfunction particularly related to behavior difficulties.268

Cocaine Approximately 1% of pregnant women in the United States use cocaine some time during their pregnancy.175 The rate may be as high as 15% in certain populations,55 and it is estimated that more than 100,000 infants born in the United States each year may be exposed to cocaine in utero.42 The consequences of cocaine use during pregnancy have been extensively reviewed.99 , 102 , 187 The most commonly reported obstetric complications of gestational cocaine use

are abruptio placentae, premature delivery, and intrauterine growth retardation Significant perinatal problems include seizures, cerebral infarctions, and other CNS effects.46 , 187 A meta-analysis of studies published before 1989 concluded that adverse effects on head circumference, gestational age, and birth weight that had been attributed to the maternal use of cocaine during pregnancy were related to polysubstance use, but not necessarily to cocaine.147 In this analysis no increased risk of abruptio placentae was demonstrated. However, later work which tried to control for polysubstance use although not always for smoking or ethanol use, suggested that there were significant effects of P.478 prematurity.120 , 187 , 233

gestational cocaine use on intrauterine growth and The incidence of abruptio placentae may also be significant when related to acute use.226 It seems that good prenatal care can mitigate many of the advers effects of cocaine. 149 , 195 , 268 Significant congenital malformations have been reported among some infants

who were exposed to cocaine in utero, specifically genitourinary malformations, cardiovascular malformations, and limb-reduction defects.36 , 79 In one large population-based study, there was no increase in the incidence of malformations.156

Animal models have also identified teratogenic effects of in utero cocaine exposure. Decreased maternal and fetal weight gain and an increased frequency of fetal resorption were demonstrated in rats;71 sporadic physical anomalies have also been observed.47 Teratogenic effects similar to those observed in humans were reported in mice: bony defects of the skull, cryptorchidism, hydronephrosis, ileal atresia, cardiac defects, limb deformities, and eye abnormalities.75 , 150 , 151 , 165 Cocaine caused hemorrhage, edema, and, subsequently, limb-reduction defects in rats when administered during midgestation in the postorganogenic period.255 The perinatal effects of cocaine are probably mediated through a vascular mechanism. Cocaine administration in the pregnant ovine model causes increased uterine vascular resistance, decreased uterine blood flow, increased fetal heart rate and arterial blood pressure, and decreased fetal PO2 and O2 content.14 , 263 Similar effects have been seen in rats.184 Fetal hypoxia may

cause rupture of fetal blood vessels and infarction in developing organ systems such as the genitourinary system45 , 165 , 231 or the CNS.44 , 59 , 256 Hyperthermia or direct effects of cocaine in the fetus may exacerbate these effects.28 Limb-reduction defects similar to those attributed to cocaine have been produced after mechanical clamping of the uterine vessels.28 , 257 A developing concept is that following vasospasm and ischemia, reperfusion occur with the generation of oxygen free radicals and subsequent injury.263 , 264 Despite the reported malformations and a possible mechanism, neither the human epidemiology, nor the effects observed in animal models, suggest a specific teratogenic syndrome. The risk of a significant malformation from prenatal cocaine exposure is low, but the effect, if one occurs, may be severe.2 , 65 , 79

One of the greatest concerns about prenatal cocaine exposure is the potential adverse effect on the developing child, and this is an intensive area of epidemiologic research. The most common findings in early infancy are lability state and autonomic regulation, decreased alertness and orientation, and abnormal effect.70 difficulty evidence

reflexes, tone, and motor maturity; however, many studies show no For some children, these effects may manifest in later infancy as with information processing and learning. However, preliminary suggests that, for school-age children, any observed cognitive deficits

may be more related to the home environment than to prenatal cocaine exposure, even for those children who showed some of the typical neonatal behaviors.43 , 76 , 246 Nonetheless, there is also evidence of impairment in modulating attention and impulsivity, which makes handling unfamiliar, complex and stressful tasks more difficult,162 and these effects are also observed in animal models of prenatal cocaine exposure.65 , 232 Cohorts of children exposed to cocaine in utero are now older and in school, and studies of development and behavior are in progress.

The mechanism of neurotoxicity has not been specifically elucidated. As described above, for many of the maternal and fetal physical defects, cocaine may have direct toxicity, or effects may be mediated through hypoxia or oxygen free radicals. Because cocaine interferes with neurotransmitter reuptake, it is likely that cocaine also disrupts normal neural ontogeny by interfering with the

trophic functions of neurotransmitters on the developing brain.153 , 161

Breast-Feeding

In the United States, breast-feeding is the recommended method of infant nutrition because it offers nutritional, immunologic, and psychological benefits. Many women use prescription and nonprescription medications while breastfeeding, and are concerned about the possible ill effects on the infant of these medications in the breast milk. This concern extends to the possible exposure o the infant to occupational and environmental xenobiotics via breast milk.202 , 21 The response to many of these concerns can be determined by the answer to th following question: Does the risk to an infant from a xenobiotic exposure via breast milk exceed the benefit of being breast-fed?134

Pharmacokinetic factors determine the amount of xenobiotic available for transfer from maternal plasma into breast milk; only free xenobiotic can travers the mammary alveolar membrane. Most xenobiotics are transported by passive diffusion. A few xenobiotics, such as ethanol and lithium, are transported

through aqueous-filled pores. The factors that determine how well a chemical diffuses across the membrane are similar to those for other biologic membranes such as the placenta: molecular weight, lipid solubility, and degree of ionization

Large-molecular-weight compounds, such as heparin or insulin, will not pass int breast milk. Lipid solubility is important not only for diffusion but also for xenobiotic accumulation in breast milk, because breast milk is rich in fat,

especially breast milk that is produced in the postcolostral period (3–4 days postpartum). With a pH near 7.0, breast milk is slightly more acidic than plasm Consequently, weak acids in plasma exist largely as ionized molecules and cannot be easily transported into milk. Conversely, weak bases exist in plasma largely as nonionized molecules and are available for transport into breast milk. Once in the breast milk, ionization of the weak base occurs, and the chemical is concentrated as a result of ion trapping. In other words, weak bases may concentrate in breast milk. Sulfacetamide (pKa 5.4, a weak acid) has a concentration in plasma 10 times its concentration in breast milk, whereas sulfanilamide (pKa 10.4, a weak base) is found in equal concentrations in both plasma and breast milk. 134

The net effect of these physiologic processes is expressed in the milk-to-plasma (M/P) ratio. Xenobiotics with higher M/P ratios have relatively greater concentrations in breast milk. The M/P ratio does not, however, reflect the absolute concentration of a xenobiotic in the breast milk, and a xenobiotic with high M/P ratio is not necessarily found at a high concentration in the breast mil For example, morphine has an M/P ratio of 2.46 (is concentrated in breast milk) but only 0.4% of a maternal dose is excreted into the breast milk.13 In general, for most pharmaceuticals, approximately 1–2% of the maternally administere dose is presented to the infant in breast milk.134

The M/P ratio has several limitations. It does not account for differences in xenobiotic concentration that may result from (a) repeat or chronic dosing, (b) breast-feeding at different times relative to maternal medication dosing, (c) differences in milk production during the day or even during a particular breastfeeding session, (d) the time postpartum (days, weeks, or months) when the measurement is made, and (e) maternal disease. P.479 While being cognizant of the limitations, a spot breast milk xenobiotic concentration or a concentration estimate based on the M/P ratio allows a

simplistic estimation of the quantity of xenobiotic to which an infant is exposed, assuming a constant breast-milk concentration: Infant dose = Breast-milk concentration × amount consumed

The effect of this dose on the infant depends on the bioavailability of the xenobiotic in breast milk, the pharmacokinetic parameters that determine xenobiotic levels in the infant, and the infant's receptor sensitivity to the xenobiotic. These parameters are often different in neonates than in adults and may lead to xenobiotic accumulation; generally, absorption is greater, but metabolism and clearance are reduced.7 These effects are exaggerated in premature infants.191 , 199 The amount of most xenobiotics delivered to infants in breast milk is adequately metabolized and eliminated.134

Many of the considerations above are theoretical, and the number of specifically contraindicated xenobiotics is quite small. 11 Published guidelines on the advisability of breast-feeding during periods of maternal therapy are generally

based on the expected effects of full doses in the infant or on case reports of adverse occurrences. Interestingly, when the reports of adverse effects were reviewed, 37% of cases were in infants younger than 2 weeks old, 63% were in infants younger than 1 month old, and 78% were in infants younger than 2 months old; 18% were in infants 2 to 6 months old; and only 4% were in infant older than 6 months.12 It seems, therefore, that adverse effects are most likely to be observed in the first few weeks of life, when an infant's metabolic capacit is only 20–40% that of an adult.7

Every few years the American Academy of Pediatrics (AAP) publishes recommendations regarding breast-feeding in the setting of xenobiotic exposure

In the latest revision, the AAP continues to discourage the use of xenobiotics such as cocaine or heroin during the breast-feeding period because of direct effects on the baby, as well as detrimental effects on the physical and emotiona health of the mother and on the caregiving environment.11 Although ethanol is not specifically contraindicated for the breast-feeding mother, decreased milk production and adverse effects in the infant are noted with maternal consumption of large amounts of ethanol.134 The AAP recommends the temporary cessation of breast-feeding when the mother is exposed to metronidazole, an in vitro mutagen, or to certain radiopharmaceuticals, specifically isotopes of copper, gallium, indium, iodine,

sodium, and technetium. In these cases, breast milk can be collected and stored before medication use for later feeding to the baby. Breast-feeding is resumed when the milk is no longer radioactive, generally 1 to 3 days for most of the isotopes mentioned except gallium, after which radioactivity may be present for 2 weeks. Metronidazole can be administered as a single 2-g dose, allowing breast-feeding to be discontinued for only 12 to 24 hours.134

Although there are few data demonstrating specific effects, the AAP suggests caution with regard to breast-feeding while using sedative-hypnotic, antidepressant, and antipsychotic medications. These medications modulate neurotransmitters in the CNS, which can adversely effect the developing nervou system. For most xenobiotics, a risk-to-benefit analysis must be made. For example, lithium is transferred in breast milk and may lead to measurable, although

subtherapeutic, serum concentrations in the breast-fed infant. Although the effects of such exposure to lithium are unknown, many practitioners believe tha the benefit of treating a mother's bipolar illness outweighs the potential risk to the infant.134 , 218

Similarly, the breast-fed infant of a woman who smokes is exposed to nicotine and other tobacco constituents, both by inhalation and via breast milk. Although this child may be at increased risk for respiratory illness as a result of exposure to tobacco smoke, some of the risk may be reduced by breast feeding.11 , 197 Many xenobiotics, including pharmaceuticals, foods, and environmental agents, have been found in breast milk, and Table 30-5 lists some of their effects. In addition to the effects listed, there may be a small increased risk of carcinogenicity associated with exposure to some environmental xenobiotics through breast milk.202 In most cases, women do not need to stop breast-feeding while using pharmaceuticals, such as most common antibiotics. However, “compatibility― with breast-feeding is generally based on a lack of reported adverse effects, which may reflect limited clinical experience with a particular xenobiotic in breast-feeding patients. Therefore, in the setting of limited information, exposure to a xenobiotic through breast milk should be

regarded as a small potential risk, and the infant should receive appropriate medical follow-up. Not all “compatible― medications are safe in all situations. For instance, phenobarbital can produce CNS depression in an infant if the mother's serum concentration is in the high therapeutic or supratherapeutic range, which often occurs while dosage adjustments are being made. Such a concentration may or may not produce CNS depression in the mother. Nalidixic acid, nitrofurantoin, sulfapyridine, and sulfisoxazole, although generally safe, can cause hemolysis in a breast-fed infant with glucose-6phosphate dehydrogenase deficiency.

Decisions on breast-feeding should be made with the informed involvement of the woman, her physicians, and, when necessary, a consultant with special expertise in this field. Guidelines are available from several sources. 21 , 32 , 134 170

Toxicologic

Problems

in

the

Neonate

Approximately 8% of all medication doses administered in neonatal intensive care units (NICU) may be up to 10 times greater or lesser than the dose

ordered.174 As many as 30% of newborns in NICUs may sustain adverse drug effects, some of which may be life-threatening or fatal.13 Physiologic difference between adults and newborn infants affect xenobiotic absorption, distribution, and metabolism; 7 , 191 these pharmacokinetic differences account for some cases of xenobiotic toxicity seen in the newborn infant. GI absorption of xenobiotics in the neonate is generally slower than in adults.7 191 This delay may be related to decreased gastric acid secretion, decreased gastric emptying and transit time, and decreased pancreatic enzyme activity. The GI environment of the newborn and young infant may allow the growth of Clostridium botulinum and the subsequent development of infantile botulism (Chap. 46 ). Infantile botulism has been reported in infants several weeks of age.101 , 244

Although it is uncommon, cutaneous absorption of xenobiotics may be a route o toxic exposure in the newborn.68 , 211 Aniline dyes used for marking diapers are absorbed, causing methemoglobin-emia,211 and contaminated diapers were responsible for one epidemic of mercury poisoning.16 The absorption of hexachlorophene antiseptic wash has led to neurotoxicity with marked vacuolization of myelin seen microscopically.131 , 157 , 228 The dermal application of antiseptic ethanol has caused hemorrhagic necrosis of the skin of P.480

P.481 some premature infants. Iodine antiseptics have led to hypothyroidism in matur newborns.40 An increased potential for absorption and toxicity has followed the application of corticosteroids82 , 209 and boric acid 66 to the skin of children with cutaneous disorders.

Use with Caution 5-Aminosalicylic acid Diarrhea

Acebutolol, atenolol, nadolol, sotalol, timolol Hypotension, bradycardia, tachypnea, cyanosis Amiodarone Possible hypothyroidism Aspirin Metabolic acidosis; may affect platelet function; rash Bromocriptine Suppresses lactation Chloramphenicol Potential risk for aplastic anemia or gray-baby syndrome134 Chlorpromazine Galactorrhea in mother; drowsiness and lethargy in infant; decline in developmental scores Cimetidine Possible antiandrogenic effects134 Clemastine Drowsiness, irritability, refusal to feed, high-pitched cry, meningismus Clofazimine Possible increased skin pigmentation Cyclophosphamide, cyclosporine, doxorubicin, methotrexate Neutropenia, thrombocytopenia, possible immune suppression; on growth or association with carcinogenesis Ergotamine

unknown

Vomiting, diarrhea, seizures; may inhibit prolactin secretion and lactation Fluoxetine Colic, irritability, feeding and sleeping disorders, slow weight gain Haloperidol Decline in developmental scores Lamotrigine Potential therapeutic serum concentrations in infant Lithium Subtherapeutic concentrations in infant Metronidazole, tinidazole In vitro mutagen

effect

Phenindione Risk of hemorrhage Phenobarbital Sedation in exposed infants; withdrawal after weaning from phenobarbitalcontaining milk; methemoglobinemia Primidone Sedation, feeding problems Sulfapyridine, sulfisoxazole Caution in infant with jaundice or G6PD deficiency and in ill, stressed, or premature infant Sulfasalazine Bloody diarrhea Tetracycline May cause staining of infant teeth after prolonged maternal use134 Thiouracil, methimazole May cause thyroid suppression and goiter134 Use Is Compatible with Breast-feeding Despite Known Effect Ethanol Large doses: decreased milk ejection reflex; infant: drowsiness, diaphoresis, decreased growth and weight gain Bendroflumethiazide Suppresses lactation Caffeine Irritability, poor sleeping pattern (no effect with usual amount of caffeinated beverages) Carbimazole Goiter Chloral hydrate Sleepiness Chlorthalidone Excreted slowly Contraceptive pills with estrogen/progesterone Rare breast enlargement; decrease in milk production and protein content (not

confirmed in several studies) Danthron Increased bowel activity Dexbrompheniramine maleate with d -isoephedrine Crying, irritability, poor sleeping pattern Estradiol Withdrawal vaginal bleeding Indomethacin Seizure Iodine topical Odor of iodine on infant's skin Iodine, iodides Goiter Methyprylon Drowsiness Nalidixic acid Hemolysis in infant with G6PD deficiency Nitrofurantoin Hemolysis in infant with G6PD deficiency Phenytoin Methemoglobinemia Theophylline Irritability Specific Risk Categories Aspartame Caution if mother has phenylketonuria Chocolate (theobromine) Irritability or increased bowel activity if mother consumes large amounts Fava beans Hemolysis in infant with G6PD deficiency Hexachlorobenzene Skin rash, diarrhea, vomiting, dark urine, neurotoxicity, death Lead

Possible neurotoxicity Methylmercury, mercury Possible neurodevelopmental toxicity Polyhalogenated biphenyls Lack of endurance, hypotonia, sullen expressionless facies Silicone Esophageal dysmotility Tetrachloroethylene Obstructive jaundice, dark urine Vegetarian diet Vitamin B12 deficiency Adapted with permission from American Academy of Pediatrics, Committee on Drugs: The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–789. Xenobiotic

Effect

TABLE 30-5. Xenobiotics Associated with Effects on Some Nursing Infants Other routes of exposure have led to clinical poisoning. Several children

aspirated talcum powder and died.33 , 173 Inhalation of mercury from incubator thermometers may be a potential risk.9 One child died following the ophthalmic instillation of cyclopentolate hydrochloride.18

Because of differences in total body water and fat compared to the adult, the distribution of absorbed xenobiotics may differ in neonates. Water represents 80% of body weight in a full-term baby, compared to 60% in an adult. Approximately 20% of a term baby's body weight is fat, compared to only 3% in a premature baby. The increased volume of water means that the volume of distribution for some water-soluble xenobiotics, such as theophylline or phenobarbital, is increased. Protein binding of xenobiotics is reduced in newborns compared to adults: the serum concentration of proteins is lower, there are fewer receptor sites that become saturated at lower xenobiotic concentrations, and binding sites have

decreased binding affinity.191 Protein binding has potential relevance with respect to bilirubin, an endogenous metabolite that at very high concentrations can cause kernicterus; bilirubin competes with exogenously administered xenobiotics for protein binding sites. In vitro, certain xenobiotics, such as sulfonamides and ceftriaxone, displace bilirubin from protein receptor sites, which might increase the risk of kernicterus, although this has not been clinical demonstrated. Conversely, bilirubin may itself displace other xenobiotics, such as phenobarbital or phenytoin, leading to increased plasma xenobiotic concentrations.

Newborn infants have decreased hepatic metabolic capacity compared to adults which ability active which

may lead to xenobiotic toxicity. For instance, the newborn has limited to oxidize xenobiotics, so theophylline is metabolized primarily to the metabolite caffeine instead of methylxanthine and 1,3-dimethyluric acid, are the primary inactive metabolites in the adult. In addition, immaturity

of the CYP system leads to increased elimination half-lives of xenobiotics such a phenytoin, phenobarbital, and theophylline.

Two syndromes related to immature metabolic function are described. The “gasping baby syndrome,― characterized by gasping respirations, metabolic acidosis, hypotension, central nervous system depression, convulsion renal failure, and, occasionally, death, is attributed to high concentrations of

benzyl alcohol and benzoic acid in the plasma of affected infants.8 , 35 , 83 Benzyl alcohol, a bacteriostatic agent, was added to intravenous flush solutions and accumulated in newborns after repetitive doses. The high concentrations of benzoic acid could not be further metabolized to hippuric acid by the immature liver. Immature glucuronidation in the neonate is responsible for the “graybaby syndrome― following high doses of chloramphenicol (Chaps. 31 and 5 3 ) .98

The umbilical vessels are a common site of vascular access in sick neonates. Because blood drains into the portal vein, it is possible that IV medications experience a “first-pass― effect, although whether this route of xenobiotic administration affects metabolism or clearance has not been well studied. Most renal functions, including glomerular filtration rate and tubular secretion, are relatively immature at birth;106 the glomerular filtration rate of the newborn is

approximately 30% of that of an adult. Xenobiotics such as aminoglycoside antibiotics and digoxin are excreted unchanged by the kidney and, therefore, depend on glomerular filtration for clearance. Dosing of these agents in the newborn must account for these differences.

Very little information is available to guide the clinician in the management of xenobiotic poisoning in the newborn infant. Cutaneous absorption is probably already complete by the time toxicity is noted, although further exposure may b prevented. Gastrointestinal decontamination is not generally performed in neonates, and the neonate may be at increased risk of fluid, electrolyte, and thermoregulatory problems following gastric lavage or the use of cathartic agents. Multiple-dose activated charcoal was used in a 1.4-kg 2-week-old premature infant to treat theophylline poisoning. Hemodialysis, hemoperfusion, and exchange transfusion are used in neonates to treat xenobiotic toxicity (Chaps. 10 and 3 1 ).

Summary

The use of xenobiotics in the pregnant or breast-feeding woman is a complex area of medical practice and presents the clinician with potentially difficult management decisions. This chapter highlights some of the important principles of xenobiotic effects in both the pregnant woman and the fetus. Appropriate management of many of the potential problems will be facilitated by the coordinated efforts of obstetricians, perinatologists, neonatologists, pediatricians, and toxicologists.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section III - Special Populations > Chapter 31 - Pediatric Principles

Chapter

31

Pediatric

Principles

Jeffrey S. Fine Because phone xenobiotics are poisoning is a been active in

calls to poison centers regarding child exposures to potential more frequent than those for any other age group, and because important cause of pediatric injury morbidity, pediatricians have helping to establish and promote the field of medical toxicology,

as well as in supporting the need for and use of regional poison control centers. Although the basic approach to the medical management of toxicologic problem outlined in Chap. 4 is generally applicable to both children and adults, there are issues, such as abuse by poisoning, that are of particular concern regarding children and when special considerations may be appropriate. This chapter provides a pediatric perspective on the application of toxicologic principles.

Epidemiology

To analyze the problem of pediatric poisoning, it is necessary to understand the magnitude of the problem. When assessing the impact of a particular type of injury such as poisoning, epidemiologists examine multiple parameters, such as exposure, morbidity, mortality, and cost, to measure the injury's effects. These parameters are difficult to measure accurately. An important source for

information on the extent and effects of poisoning exposures is the American Association of Poison Control Centers (AAPCC). Each year the AAPCC compiles standardized data collected from poison centers throughout the United States; the 2003 annual review includes information submitted by 64 poison centers. In the following discussion, comments on AAPCC data refer to cumulative information from the last 5 published reports covering the years 1999 to 2003 (Chap. 130 ).

The AAPCC reports approximately 1.5 million potentially toxic exposures per year for children and adolescents ages 0 to 19 years, and these pediatric exposures represent 67% of the reported exposures for all age groups. Children

younger than age 6 years account for 79% of all reported pediatric exposures; children between 6 and 12 years of age account for 10%, and adolescents 13 to 19 years of age account for 11% of reported pediatric exposures. Children younger than age 6 years account for 53% of all reported pediatric and adult poisoning exposures. Girls represent 47% of the reported poisoning exposures among young children and 56% of the reported exposures among adolescents. Almost 99% of the AAPCC-reported poisoning exposures in children younger than 6 years of age are unintentional. In contrast, only 51% of the reported adolescent poisoning exposures are unintentional; 45% of exposures are intentional, mostly the result of substance use or suicide attempts. This high frequency of suicidal intent has also been reported by others.171 The remaining 4% of adolescent exposures have miscellaneous causes, such as adverse drug reactions, or are unknown. These differences in the reason for exposure between young children and adolescents account for differences in the outcomes of these exposures (discussed below). Approximately 11,000 exposures each year are classified as adverse drug reactions. These account for approximately 0.3% of exposures in children less than 6 years of age and approximately 2% of exposures in older children and adolescents.

Table 31-1 shows the leading causes of reported exposures in children and adolescents. According to the AAPCC, approximately 56% of pediatric exposures are to xenobiotics that are commonly found around the house, such as cleaning products, cosmetics, plants, hydrocarbons, and insecticides, whereas

approximately 44% are to pharmaceutical agents. This is in contrast to hospitalizations and death rates the majority of which are accounted for by pharmaceutical xenobiotics.

Table 31-1 lists the most common reported exposures , but not all these products lead to serious morbidity and mortality (Table 31-2 ). For example, children frequently ingest cosmetic products, so the number of reported exposures is large, but cosmetics manufactured in the United States are mostly nontoxic. For children younger than age 6 months, poisoning is unusual but may result from the inadvertent administration of an incorrect drug or drug dose by a parent,56 intentional administration of a drug by a parent or sibling,15 , 41 o r passive exposure, for instance, to the smoke of “crack― cocaine or phencyclidine. 13 , 70 , 115 , 148 , 178 Any poisoning in a child younger than 1 year of age should be carefully evaluated for possible child abuse or neglect (see below).15

Several characteristics associated with ingestions in toddlers differentiate them from ingestions in adolescents or adults: (a) they are without suicidal intent; (b) there is usually only 1 xenobiotic involved; (c) the xenobiotics are usually nontoxic; (d) the amount is usually small; and (e) toddlers usually present for evaluation within 1 hour after the ingestion or soon after the ingestion is discovered. As many as 30% of children who experience one ingestion will experience a repeat ingestion.77 Children who ingest poisons may also be at risk for other types of injuries.11 , 47 Adolescents may also be at risk for repeated ingestions.57

The peak age for childhood poisoning is between 1 and 3 years.29 Unintentional ingestion is unusual after age 5 years, although it can result from mistaken consumption of a xenobiotic from a

P.488 mislabeled container.24 Between the ages of 5 and 9 years, poisoning may be a reflection of intrafamilial stress or suicidal intent. After age 9 years and through adolescence, overdose or poisoning frequently results either from a suicidal gesture or attempt, or from an adverse effect while seeking drug-induced euphoria. Unintentional poisonings are largely preventable (Chap. 130 ).

Cosmetics/personal care 157,834 Analgesics 51,943 Cleaning substances 119,752 Cough/cold preparations 21,069 Analgesics 88,086 Antidepressants 18,007 Topical agents 78,419 Cleaning substances 17,795 Plants 69,655 Cosmetics/personal

care

17,703 Cough/cold preparations 63,107 Stimulant/street drugs 15,151 Insecticides/pesticides/rodenticides 47,618 Sedative-hypnotic drugs 13,297 Vitamins 41,918 Antihistamines 12,637 Gastrointestinal preparations 35,357

Art/craft supplies 12,399 Antimicrobials 33,847 Plants 11,833 a See Chap. 130 for references and discussion. b Does not include AAPCC categories “Bites/envenomations― and “Foreign bodies.― Age 90% bound to albumin,

Liver

Normal

illness

especially in overdose; interpretation of serum concentration altered

↓Size ↓Hepatic blood flow

Liver enzymes not predictive; drugs with high extraction may increase (propranolol, triazolam)

Kidney

Normal

↓Renal blood flow ↓GFR

Accumulation (lithium, aminoglycosides,

↓ Tubular secretion

N-acetyl procainamide, ACE inhibitors, cimetidine, digoxin

Modified with permission from Mayersohn M: Special pharmacokinetic considerations in the elderly. In: Evans WE, Schentag JJ, Justo WJ, eds: Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 3rd ed. Vancouver, WA, Applied Therapeutics, 1992, pp. 1–43; and Fox FJ, Auestad A: Geriatric emergency clinical pharmacology. Emerg Med Clin North Am 1990;8:221–239.

Basic drugs are not bound to albumin but to α-acid glycoprotein (AAG), an acute-phase reactant that tends to increase, rather than decrease, with age.1 However, the increase attributed to age is most likely related to underlying disease. These unpredictable changes would be expected to have the reverse effect on the ratio of bound to unbound drug in any laboratory report.59 The correlation between clinical effect and free drug levels requires further study because there may be complex factors involved, including alterations in Vd and specific tissue concentrations. The contribution of gastrointestinal absorption to drug toxicity is unknown. Absorption declines modestly, if at all, with advancing age. However, age-related changes in the gastric mucosa may account for enzymatic changes, as demonstrated in the case of alcohol dehydrogenase, noted above.

Pharmacodynamics Pharmacodynamic factors may also affect a patient's response to a particular drug. In general, age-related physiologic changes in target or nontarget organs lead to increased sensitivity to a given drug, although sensitivity to some drugs may also be decreased. For P.504 example, there is evidence that β-adrenergic receptor sensitivity declines with aging, leading to a diminished response to both βadrenergic agonists and antagonists.14,76 However, clinical experience demonstrates that the elderly respond normally to drugs of this category in terms of therapeutic response, adverse effects, and toxicity.23

TABLE

32-4.

Pathophysiologic Disorders Drugs in the Elderly

Exacerbated

by

Disorder

Drug

Possible Outcome

ADH secretion (increased)

Antipsychotics, SSRIs

Hyponatremia

Androgenic hormones (males, decreased)

Digoxin, spironolactone

Gynecomastia

Baroreceptor dysfunction,

Antipsychotics, diuretics, tricyclic

Orthostatic hypotension

venous insufficiency

antidepressants

Bladder dysfunction

Diuretics

Incontinence

Cardiac

Thiazolidinediones

Congestive

disease

heart

Dementia

Gastritis

(atrophic)

Immobility, cathartic bowel

failure

Sedatives, anticholinergics, and many others

Confusion

NSAIDs,

Gastric hemorrhage

salicylates

Anticholinergics, opioids

Constipation

Nodal disease (sinus or AV)

β-Adrenergic antagonists, digoxin, diltiazem, verapamil

Bradycardia

Parkinson

Antipsychotics, metoclopramide

Parkinsonism

Prostatic hyperplasia

Anticholinergics, tricyclic antidepressants, disopyramide

Urinary retention

Thermoregulation,

Antipsychotics

Hypo- or

disease

disordered

Venous insufficiency

hyperthermia

Calcium channel blockers, others

Edema

The observation of enhanced sensitivity to drugs is probably related to altered pharmacokinetics in many, if not most, cases.29 Proving that enhanced sensitivity is related to altered pharmacodynamics would require demonstrating that the concentration of drug at the tissue site was not increased as the result of diminished elimination.21 Regardless of the mechanism, it is important to recognize that the response to a given drug might be altered in specific ways among the elderly. These altered responses are probably caused less by chronologic aging and more by an increased prevalence of disease in the elderly.29 Table 32-4 provides examples of pathophysiologic changes that frequently occur in the elderly and are unmasked by medications.

Adverse

Drug

Events

The likelihood of experiencing an ADE increases with the increasing number of drugs prescribed for a patient.32 Geriatric patients take more prescription and nonprescription drugs than any patient group.8,37 A complicated drug regimen reduces adherence, increases medication errors, and increases the risk of clinically important drug interactions. ADEs may occur as a consequence of drug–drug interactions, but the relationship between the two phenomena is sometimes difficult to quantitate.32 Concurrent disease in target or nontarget organs also may alter the patient's sensitivity to a drug,33 resulting in a serious ADE even when the patient is given a standard or previously used dose of the drug. Coexistent disease is often subclinical, and the patient's enhanced sensitivity may not be anticipated. A patient with subclinical Alzheimer disease whose cognitive function is overtly normal may acutely develop delirium or symptoms of dementia when given ordinary doses of drugs such as sedativehypnotics and tricyclic antidepressants. Delirium is a medical emergency and an important cause of emergency department visits by the elderly.33 Another contributing factor is physician lack of knowledge about principles of geriatric therapeutics.22 In a series of hospitalized patients, failure to consider advanced age was the most common factor associated with clinically important prescribing errors, and inattention to abnormal renal function was the second most important.35 New drugs deemed safer than older agents may be problematic, and inattention to risk factors can lead to significant morbidity. For example, the hypnotic agent, zolpidem, was marketed as a safe alternative to benzodiazepines for the elderly. However, like benzodiazepines, zolpidem may cause confusion, memory loss, and falls, leading to hip fracture.77,78 Another example is enoxaparin, which has more predictable pharmacokinetics than unfractionated heparin, and is associated

with a lower rate of bleeding. Therapeutic monitoring via antifactor Xa activity is cumbersome and not recommended except in unusual circumstances,31 and therefore, enoxaparin may be perceived as more convenient as well as safer. However, enoxaparin is eliminated by the kidney and repeated doses lead to progressive increases in antifactor Xa activity when creatinine clearance is ≤30 mL/min,13 a degree of renal insufficiency that is common in frail elderly patients, despite normal serum creatinine concentration. It is notable that most reported cases of serious, unexpected enoxaparin-induced bleeding occur in elderly patients who are receiving “standard,― and not age appropriate, dosing. 50,74,75 In addition to inadequate prescribing methods, physicians often prescribe drugs deemed inappropriate in the elderly at any dose,16 such as tricyclic antidepressants, longacting benzodiazepines, and anticholinergic agents.12 Compounding the problem of lack of knowledge is the fact that new drugs are often inadequately studied in the elderly (see Chap. 133 for further details).65,73 Reactions occurring in a small percentage of patients in a special subgroup can easily be missed during the initial investigations. Even when a substantial number of subjects older than age 60 years are studied, much smaller proportions of patients older than age 70 years may be included in clinical trials.2,45 Thus, the adults at highest risk for many forms of drug toxicity are those least-often studied. Subjects undergoing drug testing are generally young adults and disease free, so pharmacokinetic profiles do not reflect patterns of drug disposition that are characteristic of geriatric patients. Pharmacokinetic testing may be limited to a one-time dose, and frequently the evaluation takes place over a short time. On average, approximately 5 half-lives of a drug are necessary to achieve steady-state drug levels. Thus a drug with a half-life of 24 hours might not reach a steady state for 5 days, and in the presence of prolonged elimination associated with age-related factors, a steady state might not be reached for substantially longer. As a result,

even if the elderly are included in a drug trial, the ultimate effect of that drug might not be noted during testing intervals that are frequently designed for younger patients. P.505 Morbidity and mortality occurring in elderly patients as a result of specific drugs might be avoided if the responsible drugs were studied under the predictably high-risk conditions typically present in the elderly. For example, benoxaprofen, a long-acting nonsteroidal antiinflammatory agent, was responsible for cholestatic jaundice and death in several elderly patients. Following the drug's introduction there was a substantial delay before the jaundice and other serious drug-related toxicities were recognized. Another example is the antibiotic temafloxacin. Temafloxacin was available for only 3 months before it was withdrawn following 3 reported deaths and more than 300 cases of hypoglycemia, many of which occurred in elderly patients with diminished renal function. If pharmacokinetic studies identify vulnerable subgroups, safe maximum doses could be recommended for specific populations at risk, theoretically limiting the risk for these individuals.4 As a result of these problems, the Food and Drug Administration (FDA) now requires sponsors of new drug applications to present effectiveness and safety data for important demographic subgroups, including the elderly, in their FDA submission data.18 Drugs involved in serious drug interactions, such as digoxin, warfarin, and diuretics, are commonly prescribed in the elderly population. This situation is complicated by the fact that elderly patients often have multisystem disease and may visit several physicians, who prescribe medications without specific knowledge of, or attention to, the remainder of the patient's drug regimen, thereby increasing the risk of inappropriate drug combinations.72 Herbal preparations also may interact with prescription medications.25,52 The use of herbal preparations has increased

substantially in recent years, particularly among patients with illnesses that afflict the elderly, such as cancer, dementia, and depression. Very few patients voluntarily report use of these or other nonprescribed therapies to their physicians, and too often the physician fails to inquire specifically about such “alternative― or “complementary― therapies. Drug interactions involving herbals also occur with nonprescription preparations such as dextromethorphan, a common component of cough medicine, and St. John's wort (hypericum), a heavily promoted herbal remedy for depression that can reduce warfarin sensitivity.43 Ginkgo biloba, commonly taken for memory loss, inhibits platelet function40 and has the potential to enhance bleeding tendency when used with warfarin.20,61 Combinations of herbals and SSRIs have been reported to cause serotonin syndrome.9,25 Poisonings and other problems related to herbal preparations are discussed further in Chap. 43. The use of nonprescription pharmaceuticals may cause serious adverse effects. For example, excessive use of magnesiumcontaining preparations can cause severe toxicity, often in older individuals. Impaired renal clearance, decreased gastrointestinal motility, and other medical comorbidities are just 3 risk factors that potentiate magnesium toxicity in the elderly. The source of magnesium in these cases may include the cathartics magnesium hydroxide (“milk of magnesia―) and magnesium citrate, antacid preparations, and magnesium sulfate (Epsom salts).26 Virtually all of the most popular nonprescription medications37 are more likely to produce problems in the elderly than in younger patients, including gastrointestinal bleeding (aspirin and other nonsteroidal antiinflammatory agents), enhanced warfarin sensitivity (cimetidine), confusion and urinary retention (anticholinergic antihistamines), and cardiovascular symptoms (pseudoephedrine). Outdated and discontinued drugs are an additional problem for the elderly who often retain products in their homes for decades.

Patients may be unwilling to change, or successive physicians may continue to renew the prescription without sufficiently reevaluating the patient. Other age-related factors can increase the risk of unintentional poisonings in geriatric patients: impaired vision, hearing, and memory may lead to misunderstanding or the inability to follow directions concerning the use of prescription and nonprescription drugs. Dementia is an important risk factor in unintentional poisonings. In addition to cognitive impairment, patients with dementia sometimes exhibit abnormal feeding behaviors, including ingestion

of

inappropriate

substances.

Management Management decisions must be made with the foregoing principles in mind. Gastrointestinal decontamination should proceed as in younger patients. Because constipation is a more frequent problem in the elderly, when multiple-dose activated charcoal is indicated, particular attention must be paid to gastrointestinal function and motility. The specific precautions and contraindications in the basic management of gastrointestinal decontamination detailed in Chap. 8 are particularly pertinent for the geriatric population. The presence of clinical or subclinical heart failure or renal failure may increase the risk of fluid overload when sodium bicarbonate is used. In the elderly, hemodialysis or hemoperfusion may be indicated earlier in cases of lithium or theophylline poisoning, where elimination may be hampered by a decreased creatinine clearance or reduced endogenous clearance, respectively. A problem that may go unrecognized in geriatric patients is the development of alcohol or drug withdrawal symptoms. Because elderly patients are typically not perceived as drug users, the physician may not be aware of the chronic use of prescribed benzodiazepines or opioid analgesics, and consequently might fail

to consider the possibility of substance withdrawal when unanticipated complications occur during the hospitalization. Strategies to limit unintentional toxic exposures in elderly patients with cognitive or sensory impairment should be similar to those employed in young children, who are at high risk for ingesting toxic substances or pharmaceuticals prescribed for others in the household. The strategies should include the removal of potentially dangerous substances and unnecessary drugs from the el-derly patient's environment. The physician should request that the patient or caregiver bring all medications to the office in the original bottles and then limit the number of pills dispensed. It may be necessary to limit medications such as antidepressants to a 1-week supply or to choose alternative medications with a safer therapeutic toxic index ratio. Administration and control of the medications by directly observed therapy may, of necessity, become the responsibility of the caregiver rather than the patient.

Admission

Criteria

When geriatric patients are evaluated in the emergency department for poisonings or serious ADEs, the need for hospital admission should be guided by concerns about the patient's frailty, weighed carefully against the known hazards of hospitalization for the elderly.15 The physician should be particularly alert to certain situations that might mandate admission: elder abuse or neglect, unresolved mental status changes, inadequate home care manifested P.506 by unexplained falls or overdose of medications with prolonged durations of action. When there is concern that the established caregivers at home are abusing the patient, the patient will require further observation, removal from the environment, and possibly hospitalization. Signs

of actual physical abuse may be more obvious than signs of neglect.41 Vulnerable elderly who are physically disabled or cognitively impaired may be brought to the hospital because of presumed illness, but the source of the problem may actually be the caregiver. The caregiver, frequently a family member, may be depleting the patient's funds for personal use. Patients may become ill because funds were diverted from the purchase of food or because the patient's prescription drugs were sold on the street. More direct abuse may take the form of intentional poisoning of the patient by overdose of the patient's own prescription drugs. Unresolved mental status changes may require close observation and hospitalization. Elderly patients who are confused or unable to walk are sometimes mistakenly assumed to be chronically impaired. However, incomplete explanation of an altered mental status or physical impairment should prompt careful inquiry into the patient's baseline functional status. Functional deterioration should not be assumed to be age related. Many very elderly patients are cognitively normal, physically robust, and independent in all activities of daily living. Overdose with long-acting agents requires careful monitoring. Because duration of action of certain drugs may be markedly prolonged among geriatric patients, a higher degree of vigilance is required. A classic example is associated with the use of the sulfonylurea, chlorpropamide, which has a half-life of 24–72 hours or more and can cause protracted hypoglycemia. This drug is rarely used today, but observational studies suggest that severe hypoglycemia (glucose Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section III - Special Populations > Special Considerations: Organ Procurement from Poisoned Patients

Special Considerations: Organ Procurement from Poisoned Patients Rama B. Rao Xenobiotics can cause brain death because of the vulnerabilities of the central nervous system. With supportive care, however, such patients may be suitable candidates for organ donation.8,26 Early identification of donors is critical, as the viability of transplantable tissue diminishes as duration of brain death progresses.26 Timely identification may be further complicated by the presence of xenobiotics that mimic brain death (Tables SC-1 and SC-2) .3,5,24 Protocols to establish brain death are reviewed elsewhere.3,5,24 Once brain death is established, organ procurement personnel assist in obtaining familial consent, deciding which organs are most suitable for transplant, and maximizing physiologic support and perfusion until organ procurement occurs.26 Successful transplantation of organs is reported from poisoned donors associated with a multitude of xenobiotics (Table SC3) .1,2,5,7,10,18,20,21,22 a n d 23 Although some xenobiotics, such as cyanide and carbon monoxide (CO), are highly toxic, transfer of

clinical poisoning to the organ recipient is not reported. This is likely a result of several factors, including xenobiotic metabolism, tissue redistribution or binding prior to procurement, as well as the means of handling organs during the transplantation process. For example, some xenobiotic clearance may occur in the myocardium during organ rinsing and cardiopulmonary bypass. 20 Furthermore, individual organs may not uniformly manifest toxicity in response to xenobiotic insults. For example, the heart of a COpoisoned donor was examined after a transplantation failure from technical reasons. The myocardium did not demonstrate histologic signs of CO poisoning.23

TABLE SC-1. Conditions That Can Mimic Brain Death3, 5, 2 4

Guillain-Barré Hypoglycemia

Syndrome

Hypothermia Poisonings Amitriptyline Bismuth salts Inhaled anesthetics Sedative hypnotics Barbiturates Benzodiazepines Meprobamate Chloral hydrate Trichloroethylene Pontine hemorrhage Rabies Tetrodotoxin

Probably more critical to transplantation success is adequate

tissue perfusion and well-maintained cellular morphology. For example, patients suffering brain death from acetaminophen poisoning are not suitable liver donors, given the specific destruction of hepatic cells. Alternatively, xenobiotics considered toxic to organ function by impairing enzymes have resulted in successful transplantation if the cellular structure is otherwise maintained. For example, a donor with cardioactive steroid poisoning did not preclude successful heart transplantation, even when the donor had a bradydysrhythmia, elevated serum digoxin concentration, and required cardiopul-monary resuscitation.23 In another case, the liver of a patient poisoned with brodifacoum was transplanted after donor administration P.519 of fresh-frozen plasma and vitamin K1 . The recipient's INR (international normalized ratio) after transplantation was 2 and corrected rapidly with supportive care. Recipient concentrations of brodifacoum were not reported and not clearly causative of the elevated INR.20 In both the examples of brodifacoum and cardioactive steroids, the target of toxicity was enzymatic and the tissue morphology was otherwise minimally affected.

TABLE SC-2. Clinical Criteria for the Diagnosis of Brain Death

No alternative cause for the clinical condition (eg, hypothermia) Poisoning not or no longer a consideration as the cause of the clinical condition Coma: No motor responses to appropriate painful stimuli Absence of brainstem reflexes Pupillary responses to light and pupils at midposition (4–6 mm) Corneal reflexes

Caloric (oculocephalic) responses Gag reflex Coughing in response to tracheal suctioning Sucking and rooting reflexes Apnea test Respiratory drive at a PaCO2 that is 60 mm Hg or 20 mm Hg above normal baseline values Interval between 2 evaluations, according to patient's age

Term to 2 mo, 48 h

>1 yr to < 18 yr, 12h

> 2 mo to 1 yr, 24 h

≥18 yr, interval optional

Confirmatory

tests

Term to 2 mo, 2 confirmatory tests

>1 yr to 2 mo to 1 yr, 1 confirmatory test

≥18 yr, optional

Confirmatory tests include: Cerebral angiography Electroencephalography Cerebral scintigraphy Transcranial Doppler ultrasonography

TABLE SC-3. Organs Transplanted After Donor Poisonings

Organ

Xenobiotics

Identified

Corneaa1,18,20,22

Brodifacoum,

Heart5,10,20,23

Acetaminophen, benzodiazepines, βadrenergic antagonists, brodifacoum, carbamazepine, carbon monoxide,

cyanide

clomethiazole, cyanide, digitalis, digoxin, ethanol, flurazepam, glyburide, insulin, meprobamate, methanol, organic phosphorus compounds, thiocyanate Kidneya2,7,10,20,22

propoxyphene,

Acetaminophen, monoxide, methanol,

brodifacoum,

cyanide, tricyclic

carbon

ethylene glycol, antidepressants

Liver7,10

Brodifacoum, carbon monoxide, cyanide, ethylene glycol, methanol, tricyclic antidepressants

Lung4,10,20,21,22

Brodifacoum, methanol

Pancreas7,20

Acetaminophen, brodifacoum, carbon monoxide, cyanide, ethylene glycol, methanol, tricyclic antidepressants

carbon

monoxide,

Skin22 a Can

Cyanide

be cadaveric procurement.

Most failures of transplant organs from poisoned donors are a result of rejection, sepsis, or technical reasons. The 1-year survival in recipients of transplant organs from poisoned donors approximates that of recipients of transplant organs from nonpoisoned donors, and in one series was reported at 75%. 7 Ideally, a comprehensive international registry of transplant organs from poisoned donors will be established to improve understanding of transplanting organs from such patients. It appears that patients who suffer brain death from poisoning are potentially suitable donors when cellular infrastructure is preserved.16,17,19,26 Consideration for organ procurement should not be limited by the xenobiotic itself.

References 1. Basu PK: Experimental and clinical studies on corneal grafts from donors dying of drug overdose: A review. Cornea 1984–85;3:262–267. 2. Brown PW, Buckels JA, Jain AB, McMaster P: Successful cadaveric transplantation from a donor who died of cyanide poisoning. Br Med J Clin Res 1987;294:1325. 3. de Tourtchaninoff M, Hantson P, Mahieu P, Geurit JM: Braindeath diagnosis in misleading conditions. QJM 1999;92:404–414.

4. Evrard P, Hantson P, Ferrant E, et al: Successful double lung transplantation with a graft obtained from a methanol-poisoned donor. Chest 1999;115:1458–1459. 5. Hantson P, de Tourtchaninoff M, Guerit JM, et al: Multimodality evoked potentials as a valuable technique for brain death diagnosis in poisoned patients. Transplant Proc 1997;29:3345–3346. 6. Hantson P, Kremer Y, Lerut J, et al: Successful liver transplantation with a graft from a methanol-poisoned donor. Transplant Int 1996;9:437. 7. Hantson P, Mahieu P, Hassoun A, Otte JB: Outcome following organ removal from poisoned donors in brain death status: A report of 12 cases and review of the literature. J Toxicol Clin Toxicol 1995;33:709–712. 8. Hantson P, Mahieu P: Organ donation after fatal poisoning. QJM 1999;92:415–418. 9. Hantson P, Squifflet JP, Vanormelingen P, Mahieu P: Organ transplantation after fatal cyanide poisoning. Clin Transplant 1999;13:72–73. 10. Hantson P, Vanormelingen P, Lecomte C, et al: Fatal methanol poisoning and organ donation: Experience with seven cases in a single center. Transplant Proc 2000;32:491–492. 11. Hantson P, Vanormelingen P, Squifflet JP, et al: Methanol poisoning and organ transplantation. Transplantation 1999;68:165–166.

12. Hantson P, Vekemans MC, Laterre PF, et al: Heart donation after fatal acetaminophen poisoning. J Toxicol Clin Toxicol 1997;35:325–326. 13. Hantson P, Vekemans MC, Squifflet JP, Mahieu P: Organ transplantation from victims of carbon monoxide poisoning. Ann Emerg Med 1996;27:673–674. 14. Hantson P, Vekemans MC, Squifflet JP, Mahieu P: Outcome following organ removal from poisoned donors: Experience with 12 cases and a review of the literature. Transplant Int 1995;8:185–189. 15. Hantson P, Vekemans MC, Vanormelingen P, De Meester J, et al: Organ procurement after evidence of brain death in victims of acute poisoning. Transplant Proc 1997;29:3341–3342. 16. Jones AL, Simpson KJ: Drug abusers and poisoned patients: A potential source of organs for transplantation? QJM 1998;91:589–592. 17. Leikin JB, Heyn-Lamb R, Aks S, et al: The toxic patient as a potential organ donor. Am J Emerg Med 1994;12:151–154. 18. Lindquist TD, Oiland D, Weber K: Cyanide poisoning victims as corneal transplant donors. Am J Ophthalmol 1988;106:354–355. 19. Lopez-Navidad A, Caballero F. Extended criteria for organ acceptance: Strategies for achieving organ safety and for increasing organ pool. Clin Transpl 2003;17:308–324.

20. Ornstein DL, Lord KE, Yanofsky NN, et al: Successful donation and transplantation of multiple organs after fatal poisoning with brodifacoum, a long-acting anticoagulant rodenticide: Case report. Transplantation 1999;67:475–478. 21. Shennib H, Adoumie R, Fraser R:. Successful transplantation of a lung allograft from a carbon monoxide poisoning victim. J Heart Lung Transplant 1992;11:68–71. 22. Swanson-Bieraman B, Krenzelok EP, Snyder JW, et al: Successful donation and transplantation of multiple organs from a victim of cyanide poisoning. J Toxicol Clin Toxicol 1993;31:95–99. 23. Tenderich G, Koerner MM, Posival H, et al: Hemodynamic follow-up of cardiac allografts from poisoned donors. Transplantation 1998;66:1163–1167. 24. Wijdicks EF: The diagnosis of brain death. N Engl J Med 2001;344:1215–1221. 25. Wood DM, Dargan PI, Jones AL: Poisoned patients as potential organ donors: Postal survey of transplant centres and intensive care units. Crit Care 2003;7:147–154. 26. Wood KE, Becker BN, McCartney JG, et al: Care of the potential organ donor. N Engl J Med 2004;351:2730–2739.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > A - Analgesics and Antiinflammatory Medications > Chapter 34 - Acetaminophen

Chapter

34

Acetaminophen Robert G. Hendrickson Kenneth E. Bizovi

Figure. No Caption Available.

A 21-year-old woman was brought to the emergency department (ED) by her boyfriend when he learned that she ingested

approximately 30 (325-mg) acetaminophen tablets in an attempted suicide. He was unaware of any previous significant medical or psychiatric illness but reported that she was seen in another ED several days earlier for persistent headaches. He said that she did not abuse alcohol or any other drugs. The patient was able to provide a history and admitted to taking approximately 30 tablets approximately 3 hours before coming to the hospital because she wanted to kill herself. Shortly after taking the tablets she developed a bad “stomach ache,― felt extremely nauseated, and vomited once. She denied taking any other medications or alcohol in the suicide attempt. On physical examination the woman was diaphoretic and pale, and she appeared uncomfortable. Her vitals signs were blood pressure, 95/70 mm Hg; pulse, 100 beats/min; respiratory rate, 20 breaths/min; oral temperature, 98.6°F (37°C). Examination of the head, eyes, ears, nose, and throat was unremarkable. Her neck was supple, her lungs were clear, and the cardiac examination was within normal limits. Examination of the abdomen revealed only moderate midepigastric tenderness without peritoneal signs. Bowel sounds were normoactive. Cranial nerves were grossly intact and reflexes were 2+ bilaterally. She was oriented to time, place, and person. The patient was given 50 g of oral activated charcoal along with 40 mL of 70% sorbitol. A 4-hour serum acetaminophen concentration was 215 µg/mL, and as a result the patient was treated with intravenous N-acetylcysteine (NAC) over 20 hours. The patient's aminotransferase concentrations remained normal, and after treatment was completed she was transferred to a psychiatric facility. P.524

History

and

Epidemiology

Acetaminophen (N-acetyl-p-aminophenol [APAP]), a metabolite of phenacetin, was first used clinically in the United States in 1950. The well-known toxicity of phenacetin led to unfounded concerns about acetaminophen safety that delayed widespread acceptance of acetaminophen until the 1970s. Acetaminophen has since proved to be a remarkably safe drug at appropriate dosage, which has made acetaminophen the analgesic-antipyretic of choice in many circumstances. Acetaminophen is available alone in a myriad of single-agent dose formulations and delivery systems and in a variety of combinations with opioids, other analgesics, sedatives, decongestants, expectorants, and antihistamines. The diversity and wide availability of acetaminophen products dictate that acetaminophen toxicity be considered not only after identified acetaminophen exposures but also after exposure to unknown or multiple drugs in settings of drug overdose, drug abuse, and therapeutic misadventures. The Toxic Exposure Surveillance System of the American Association of Poison Control Centers reports well over 100,000 calls to US poison centers each year resulting from potential acetaminophen exposures, and more hospitalizations are reported after acetaminophen overdose than after overdose of any other common pharmaceutic agent (Chap. 130) . Despite enormous experience with acetaminophen toxicity, many controversies and challenges are unresolved. In order to best understand the continuing evolution in approach to acetaminophen toxicity, it is critical to start with an analysis of certain fundamental principles and then to apply these principles to both typical and atypical presentations in which acetaminophen toxicity must be considered.

Pharmacology Acetaminophen is an analgesic and antipyretic with weak peripheral antiinflammatory properties. Analgesic activity is

reported at a serum acetaminophen concentration ([APAP]) of 10 µg/mL and antipyretic activity at 4–18 µg/mL. Antipyresis is mediated by central nervous system (CNS) inhibition of prostaglandin E2 (PGE2 ) synthesis via either direct inhibition of cyclooxygenase (COX)-2 or inhibition of membrane-associated PGE synthase.10,93,104,148 PGE synthase inhibition may be a result of local reductions of glutathione concentrations initiated by conversion of APAP to reactive metabolites via the COX-2 enzyme.104 Although binding and inhibition of COX-3 by APAP may have an antipyretic effect,34,35,57 its clinical relevance remains unclear.31,104 The analgesic effect of acetaminophen is also mediated by its central inhibition of COX-2 and prostaglandin synthase and by possible indirect modulation of serotonergic pathways.104 In animal models, several serotonin antagonists, as well as serotonin depletion, inhibit the analgesic effect of APAP.2,30,192,193,230 This effect may be a result of decreased stimulation of serotonergic neurons from APAP-induced inhibition of prostaglandin synthesis.104 Additional effects may be linked to indirect stimulation of descending opioid pathways.212,213 Although APAP functions as a central COX-2 inhibitor, it has mild peripheral antiinflammatory properties that are attributed to its mild inhibition of peripheral prostaglandin synthetase96 and limited inhibition of peripheral COX.64 APAP previously was considered a weak inhibitor of peripheral COX in general; however, its poor peripheral antiinflammatory properties more likely are the result of differences in receptor utilization (COX-1 and COX-2) in various cellular conditions.103,104 In circumstances where peroxidase and arachidonic acid concentrations are low, such as in the CNS, prostaglandin is predominantly metabolized by COX-2,178 and prostaglandin synthesis is blocked by APAP.180 However, in peripheral inflammatory lesions, where peroxidase and arachidonic acid concentrations are elevated, COX-1 metabolism predominates,

and APAP is less effective in decreasing inflammation.36,104,109

Pharmacokinetics Following oral ingestion, immediate-release acetaminophen is rapidly absorbed with a time to peak [APAP] of approximately 45 minutes.4,77 Liquid acetaminophen has a time to peak of 30 minutes.4,77 Extended-release acetaminophen has a time to peak of 1–2 hours but is almost entirely absorbed by 4 hours.81 Time to peak is delayed by food77 and coingestion of opioids or anticholinergic agents.107,177 Oral bioavailability is 60–98%. Peak [APAP] after recommended dose ranges from 8–32 µg/mL. After administration of rectal suppositories in children, the time to peak [APAP] ranged from 107–288 minutes, with bioavailability of 30–40%. Peak [APAP] after single 20-mg/kg doses given rectally varied from 4.1–13.6 mg/L.23 Acetaminophen has total protein binding of 10–30% that does not change in overdose.167 APAP crosses both the placenta and the blood–brain barrier.147 First-pass metabolism removes 25% of a therapeutic dose. Once absorbed, approximately 90% of acetaminophen normally undergoes hepatic conjugation with glucuronide (40–67%) and sulfate (20–46%) to form inactive metabolites, which are eliminated in the urine.231 A small fraction of unchanged acetaminophen (10,000 IU/L are common, even in patients without other evidence of liver failure. In fact, the highest reported ALT concentration caused by acetaminophen toxicity is >100,000 IU/L.186 Much more important than the degree of aminotransferase concentration elevation, abnormalities of PT, bilirubin, glucose, lactate, and phosphate concentrations,

and pH indicate the degree of liver failure and are essential determinants of prognosis and treatment. Fatalities from fulminant hepatic failure generally occur between 3 and 5 days after an acute overdose. Death results from either single or combined complications of multiorgan failure, including hemorrhage, acute respiratory distress syndrome, sepsis, and cerebral edema.156 Patients who survive this period reach stage I V, defined as the recovery phase. Hepatic regeneration becomes complete in survivors. No cases of chronic hepatic dysfunction attributable solely to acetaminophen poisoning have been reported. The rate of recovery varies; in most cases, laboratory evaluation is normal by 5–7 days after an acute overdose. However, recovery may take much longer in severely poisoned patients, and histologic abnormalities may persist for months.146,160,195 Renal function abnormalities are rare overall108,201 but occur in as many as 25% of in >50% of those renal insufficiency concentrations.37

patients with significant hepatotoxicity69,208 and with hepatic failure.156,285 Infrequently, mild occurs without elevations in aminotransferase Renal abnormalities may be more common after

sustained repeated excessive dosing.203 When overt renal failure necessitating hemodialysis occurs, it nearly always does so among patients with marked hepatic injury.53 In cases of acetaminopheninduced fulminant hepatic failure, the incidence of acute renal failure is nearly the same as among patients with hepatic failure of other causes.285 Serious clinical manifestations other than hepatic and renal injury are unusual. Electrocardiographic and histologic evidence of myocardial injury, first noted in early case reports,63,190 is most often noted in patients with fulminant hepatic and multisystem failure, but never as an isolated problem.152 Hyperamylasemia and pancreatitis80,102 have been attributed to acetaminophen overdose P.527

alone or in combination with ethanol abuse.90 Clinical findings in these rare cases are typical of acute pancreatitis.

Diagnostic

Testing

Assessing the Risk of Toxicity Principles That Approach

Guide

the

Diagnostic

Fatalities from acetaminophen overdose are common but preventable by timely diagnosis and treatment with NAC. At the same time, the overwhelming majority of acetaminophen exposures result in no toxicity. Therefore, an appropriate approach must avoid the enormous costs of unnecessary overtreatment while eliminating patient risk. To balance these seemingly divergent goals, the clinician must understand the basis for and sensitivity of current toxicity screening methods. When considering risk determination, it is useful to separate different categories of acetaminophen exposure. There is an extensive body of experience and literature on acute overdose in typical circumstances, permitting a more systematic approach with demonstrated efficacy. For issues related to repeated excessive acetaminophen dosing, uncertain circumstances, patients with possible predisposition to toxicity, new acetaminophen formulations, and many other permutations, there is an important conceptual framework for decision making but little in the way of validated strategies. For these challenges, the central concepts and one approach are presented, with the understanding that they are dynamic and that more than one approach may have validity. The clinician must rely solely upon the often unreliable ingestion history and measurement of [APAP] in the patient to assess the risk for subsequent toxicity and thus the need for treatment for

the following reasons: the amount and rate of NAPQI formation, the availability of hepatic GSH, the balance of NAPQI formation (CYP2E1 activity) and hepatic GSH supply, and the capacity for nontoxic metabolism are major determinants of toxicity. 169,225 Thus the ideal model for determining risk after acetaminophen overdose assesses each of these factors. At present, none of these measures is available to clinicians. The profile of urinary acetaminophen metabolites may reflect increased NAPQI formation,72 but there is no indication that measurement is of any predictive value in any given case. Plasma GSH concentration can be measured but has an uncertain relationship to hepatic GSH availability.246 Protein adducts, indicating binding of NAPQI to hepatocyte proteins, can be determined experimentally and are a marker of covalent binding 211,279 but are unlikely to prove useful as a screening measure. Because some degree of hepatocyte necrosis must precede the appearance of measurable serum adducts, the early warning value of the test is limited. Prior to actual hepatotoxicity, there are no reliable indirect measures of acetaminophen excess.

Risk

Determination

After

Acute

Overdose

Acute overdose usually is considered a single ingestion, although in fact many patients overdose incrementally over a brief period of time. For purposes of this discussion, an acute overdose is arbitrarily defined as one in which the entire ingestion occurs within a single 4-hour period. Figures of 7.5 g in an adult or 150 mg/kg in a child are widely disseminated as the lowest acute dose capable of causing toxicity.7,151,201 These standards have stood the test of time as sensitive markers, but they are not based on human data and are quite conservative. Although there is wide interspecies variation in susceptibility to acetaminophen,203 animal data suggest that a single dose of at least 15 g is required to cause consequential GSH depletion in a human adult.173

Higher dose cutoffs for consideration of risk would improve specificity; however, the value of improving specificity has not been weighed against the current, sensitive lower cutoff. In the face of an enormous variety of potential outliers, the near absence of screening failures almost certainly results from the use of these standards and of a very sensitive screening nomogram. The adult standard may be considered less controversial than that for children because massive ingestions, unreliable histories, and factors that might predispose to toxicity occur primarily in adults, justifying continued use of 7.5 g as a screening amount to avoid missing serious toxicity. The dose history should be used in the assessment of risk only if there is reliable corroboration or direct evidence of validity. Therefore, dose estimates may be useful in determining risk in many cases of unintentional or therapeutic acetaminophen exposures, but this information is not sufficiently reliable in patients with attempted self-harm or drug abuse. When the history suggests possible risk, however, the reported dose is insufficient evidence on which to base treatment decisions; risk then should be assessed using determination of [APAP]. Interpretation of [APAP] after acute exposures is based on adaptation of the Rumack-Matthew nomogram (Fig. 34-2) .226 The original nomogram was based on the observation that untreated patients who subsequently developed AST or ALT concentrations >1000 IU/L could be separated from those who did not on the basis of the initial [APAP]. A nomogram was constructed that P.528 plotted the ln [initial APAP] versus time since ingestion, and a discriminatory line was drawn to separate patients who developed hepatotoxicity from those who did not. The initial discriminatory line stretched from [APAP] of 300 µg/mL at 4 hours to 50 µg/mL at 12 hours but was lowered to between 200 µg/mL at 4 hours and 50 µg/mL at 12 hours after evaluation of additional patients.225 The half-life of acetaminophen was not a factor in the

development of the nomogram, and the slope of the treatment line does not reflect any discriminatory APAP half-life or acetaminophen kinetics.225 Although patients who develop hepatotoxicity tend to have half-lives greater than 4 hours,206 use of a half-life to determine risk is not practical. At the time the nomogram was developed, acetaminophen absorption was known to be generally complete within 4 hours, so the nomogram does not begin until 4 hours after ingestion. The nomogram was later extrapolated to 24 hours using the same slope of the original nomogram line.225

Figure 34-2. The Rumack-Matthew nomogram (reconstructed) for determining the risk of acetaminophen-induced

hepatoxicity following a single acute ingestion. Levels above the treatment line on the nomogram indicate the need for Nacetylcysteine therapy.

It is important to realize that the line was based on aminotransferase concentration elevation rather than on hepatic failure or death, and it was chosen to be very sensitive, with little regard to specificity. Without antidotal therapy, only 60% of those with an initial [APAP] above this original line will develop hepatotoxicity as defined by aminotransferase concentrations >1000 IU/L,205 but the risk of hepatotoxicity is not the same for all such patients. Elevated aminotransferase concentration develops in virtually all untreated patients with [APAP] far above the line and serious hepatic dysfunction occurs frequently, whereas the incidence of hepatotoxicity among untreated cases with [APAP] immediately above the line is very low, and the risk of hepatic failure or death is far less.201,205 The original line is still used in the United Kingdom, Canada, Europe, Australia, and other locations. The line used in the United States runs parallel to the original but was arbitrarily lowered by 25% in order to add even greater sensitivity.225,227 The lower line, subsequently referred to as the treatment line, starts at an [APAP] of 150 µg/mL at 4 hours postingestion; declines with a 4hour half-life; and ends at 4.7 µg/mL, 24 hours after the overdose. The treatment line is one of the most sensitive screening tools used in medicine. The incidence of nomogram failures in the United States, using this line, is only 1–3% (depending on time to treatment) and most likely results predominately from inaccurate ingestion histories.225 A vanishingly small number of anecdotal cases of nomogram failure involve special circumstances of increased risk,59,162,179 questionable facts, or both.241 Cases of nomogram failure using the original line in the United

Kingdom are published. In some cases the patients described had no potentially predisposing factors,46 and all had [APAP] above the treatment line and below the original line. Some authors suggest that the incidence of nomogram failures may be higher in the United Kingdom and recommend that the nomogram being used in the United Kingdom is not sensitive enough for patients with comorbid factors that potentially predispose to hepatotoxicity.42,46,71,270 The validity of this observation is not adequately studied. Based on these observations and more than 20 years of use, the treatment line should be considered an adequate screening device in nearly all cases and reliable when rigorously followed. When using the acetaminophen nomogram, it is essential to precisely define the time “window― during which acetaminophen exposure occurred and, if the time is unknown, to use the earliest possible time as the time of ingestion. Using this approach, patients with [APAP] below the treatment line, even if only slightly so, do not require further evaluation or treatment for acute acetaminophen overdose. This also applies to most patients with factors that may predispose them to acetaminophen-induced hepatotoxicity. There appears to be adequate experience with acute acetaminophen overdose in the settings of potentially predisposing factors such as chronic alcohol abuse, chronic medication with CYP-inducing drugs, and inadequate nutrition to recommend that no special approach is required in such cases. Further study is needed to determine whether there are exceptions. Isolated case reports179 suggest that chronic use of isoniazid, for example, may uniquely predispose patients to toxicity after acetaminophen overdose.89,291 The goal should be to determine [APAP] at the earliest point at which it will be meaningful in decision making. Measurement of [APAP] 4 hours after ingestion or as soon as possible thereafter is used to confirm risk of toxicity and thus the need to initiate NAC. There are no established guidelines for use of determinations

made less than 4 hours after ingestion, and because of variability in absorption such values will have less predictive value. Although it is optimal to start NAC therapy as soon as possible after confirmation of risk, most patients will have excellent outcomes if therapy is started earlier than 8 hours after the overdose.243 Although this fact is not a license to delay the initiation of NAC treatment until 8 hours postingestion, it allows clinicians some leeway to wait for the laboratory results of [APAP] prior to starting therapy in patients in whom the history of ingestion suggests that concentration will fall below the treatment line. Factors that complicate diagnostic decision making after acute overdose include situations that prevent the return of an [APAP] measurement prior to 8 hours postingestion, inability to establish the time of ingestion, presentation more than 24 hours postingestion, and newer formulations of acetaminophen. Only if the results of [APAP] determination cannot be obtained within 8 hours of the overdose should history alone be considered adequate to consider the patient at risk and as an indication to start NAC. In such cases, [APAP] still should be determined as soon as possible. The result, when it becomes available, should be interpreted according to the treatment line on the acetaminophen nomogram and NAC either continued or discontinued on the basis of this result. In the unusual circumstance where no determination of [APAP] can ever be obtained, evidence of possible risk by history alone is sufficient to initiate and complete a course of NAC therapy.

Early

Measurement

of

[APAP]

Measurement of [APAP] between 1 and 4 hours after ingestion may be helpful only to exclude ingestion of APAP. If [APAP] is Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > A - Analgesics and Antiinflammatory Medications > Antidotes in Depth - NAcetylcysteine

Antidotes in Depth N-Acetylcysteine Mary Ann Howland

Figure. No Caption Available.

N-acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially lethal acetaminophen overdose. If administered early in the course of exposure, NAC can prevent significant acetaminophen-induced toxicity. Later, it can ameliorate toxicity. NAC also has a role in limiting toxicity caused by glutathione depletion and free radical formation, such as from carbon tetrachloride, chloroform, pennyroyal oil, and possibly valproic acid.17,25,26,93 Finally, NAC is useful in the management of fulminant hepatic failure caused by toxicologic and nontoxicologic etiologies. Its beneficial effects are also under investigation in

critically ill patients with a variety of stress-induced disorders,46,83,90 perhaps in the prevention of further renal impairment in patients with chronic renal insufficiency administered a radiographic contrast agent, and in those with hepatorenal syndrome.32,33,76,86 Furthermore, NAC is potentially beneficial following exposure to certain metals such as cobalt. 45

History Shortly after the first case of acetaminophen hepatotoxicity was reported, Mitchell and coworkers described a protective effect of glutathione.52,73 Prescott et al.59 first suggested the use of Nacetylcysteine (NAC) for acetaminophen poisoning in 1974. Early experiments demonstrated that NAC could prevent acetaminopheninduced toxicity in mice when treatment was initiated within 4.5 hours of ingestion and that the oral and intravenous (IV) routes were equally efficacious when treatment was initiated within 1 hour of ingestion.58 Mitchell et al.,52 Prescott et al.,59,62 and Rumack and Peterson74 performed human research with oral and IV NAC in the 1970s. The United States Food and Drug Administration approved oral NAC in 1985 and IV NAC in 2004. Cysteamine, methionine, and NAC, which are all glutathione precursors or substitutes, have been used successfully to prevent hepatotoxicity, but cysteamine and methionine both produce more adverse effects than does NAC therapy, and methionine is less effective than NAC. Therefore, NAC has emerged as the preferred treatment.63,78,87

Background:

Toxicology

Ninety percent of a therapeutic dose of acetaminophen is metabolized to nontoxic glucuronide (approximately 60%) and sulfate (approximately 30%) conjugates.60 Only 4% is metabolized by the cytochrome P450 mixed-function oxidase system (3A4 at

low doses; 2E1 predominantly at high doses) 51 to the potentially toxic reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI). This intermediate is conjugated with glutathione to form nontoxic cysteine and mercapturic acid conjugates. After acetaminophen overdose, both the fraction and the total amount of drug undergoing P450 metabolism increase, leading to glutathione depletion, binding of the highly reactive intermediate, liberation of reactive oxygen and nitrogen species, and resultant centrilobular hepatic necrosis.18,35,64 It is postulated that the ensuing oxidative stress causes mitochondrial and other damage to cardiac, pulmonary, and hepatic tissues (Chap. 12) .9,27,64,79 NAC is a thiol-containing compound that is deacetylated to cysteine, a thiolcontaining amino acid that is used intracellularly in addition to the amino acids glycine and glutamate to synthesize glutathione.72 The availability of cysteine becomes the rate-limiting step in the synthesis of glutathione, and NAC is effective in replenishing diminished supplies of cysteine.

Mechanism

of

Action

When administered shortly following acetaminophen ingestion, NAC acts to prevent toxicity. Later in the clinical course, NAC modifies the subsequent xenobiotic-induced inflammatory response. NAC effectively prevents acetaminophen-induced hepatotoxicity if it is administered before glutathione stores are depleted to 30% of normal. This level of depletion occurs approximately 8 hours after toxic acetaminophen ingestion.62,70,81 NAC acts as a precursor for the synthesis of glutathione,41 as a substrate for sulfation,80 as an intracellular glutathione substitute by directly binding to NAPQI,15 and by enhancing the reduction of NAPQI to N-acetyl-p-aminophenol (APAP).41 After NAPQI covalently binds to hepatocytes, 70 NAC modulates the subsequent cascade of inflammatory events in a variety of ways.29 The inflammatory damage can occur in many tissues. Antioxidants

function as electron donors and are oxidized preferentially to relatively less reactive and destructive species.9 Examples of endogenous antioxidants include vitamins C and E and reduced P.545 glutathione. Glutathione protects cells against electrophilic compounds by acting as both a reducing agent and an antioxidant.72 Glutathione replenishment may protect against further cell damage but is incapable of completely restoring damaged tissues. In this second stage, NAC may act directly as an antioxidant; act as a reservoir for thiol groups; increase nitric oxide synthase to improve blood flow by combining with nitric oxide to form the potent vasodilator s-nitrosothiol; increase formation of essential endogenous antioxidants such as glutathione; and increase substances depleted by the oxidant stress such as endothelium-derived relaxing factor.23,29 In this manner NAC can modulate the oxidative stress and inflammatory cascade while improving oxygen delivery and extraction in extrahepatic organs such as the brain, heart, and kidney.46,76,83

Clinical

Use

If the patient's history suggests an acute acetaminophen ingestion ≥150 mg/kg and the results of blood tests will not be available within 8 hours of ingestion or if the serum [APAP] falls on or above the treatment line on the Rumack-Matthews nomogram, NAC should be instituted expeditiously. Aspartate aminotransferase and APAP concentrations should be determined in adults with chronic overdoses who ingest more than the recommended maximum daily dose of 4 g or children who ingest more than 90 mg/kg/d and are at high risk (increased NAPQI formation or reduced glutathione stores). NAC should be administered when hepatotoxicity is manifest by symptoms or liver enzyme elevations (Chap. 34) . Interpretation of acetaminophen concentrations in these chronic overdoses is difficult, and the acetaminophen nomogram can never be applied.

Some patients who are at increased risk for acute or chronic acetaminophen poisoning may require administration of NAC at a lower threshold. Unfortunately, this threshold is not yet defined. Glutathione-deficient patients who are malnourished, have chronic alcoholism, or are receiving CYP2E1-inducing agents such as isoniazid or ethanol may theoretically be at increased risk for acetaminophen toxicity.12,30,42,81 However, an analysis of a small number of patients who received anticonvulsants or chronically ingested alcohol did not demonstrate these patients to be at risk independent of acetaminophen dose.49,82 Also currently no data indicate the need to lower the threshold when evaluating a patient with

hepatic

enzyme

abnormalities.82

Pharmacokinetics When administered, NAC is present in plasma in the reduced or oxidized state and is either free or bound with other thiols such as NAC-cysteine. NAC is metabolized to many sulfur-containing compounds such as cysteine, glutathione, methionine, cystine, disulfides, and conjugates.23,56,61 Thus the pharmacokinetic study of NAC is complex. Oral NAC is rapidly absorbed, but the bioavailability is low (10–30%) because of significant first-pass metabolism.23,61 NAC has a relatively small volume of distribution (0.5 L/kg), and protein binding is 83%. Serum concentrations after IV administration of an initial loading dose of 150 mg/kg over 15 minutes reach approximately 500 mg/L.61 A steady-state plasma concentration of 35 mg/L (10–90 mg/L) is reached in approximately 12 hours with the standard IV protocol.61 Its elimination half-life is 5.7 hours. Severe liver damage does not appear to affect NAC elimination.61 Conflicting in vitro16,39,75 and in vivo14,22,54,66 data regarding the concomitant use of activated charcoal suggest that the resultant

bioavailability of NAC is either decreased or unchanged. This interaction is of limited importance now that IV NAC is available. Oral NAC is being studied as a potential chemopreventive agent. Pharmacokinetics and pharmacodynamics of oral NAC were determined in a phase I trial in 26 adult volunteers at risk for development of cancer or recurrent cancer.56 Absorption of NAC is rapid, with a mean time to maximum peak concentration of 1.4 ± 0.7 hours and a mean elimination half-life of 2.5 ± 0.6 hours that is linear with increasing dose up to 3200 mg/m2 /d given as a single daily dose. Intersubject plasma NAC concentrations vary 10fold from a maximum concentration of 1.7–20.8 mg/L at a dose of 800 mg/m 2 /d. Chronic administration leads to a decrease in plasma concentrations from a Cm a x of 8.9 mg/L at the end of 1 month to 5.1 mg/L at the end of 6 months.56

Oral

Versus

Intravenous N-

Acetylcysteine Although these approaches have never been directly compared, they appear to confer equal protection when either is administered within 8 hours.95 The 20-hour IV NAC protocol is 150 mg/kg loading dose over 15 minutes, followed by an additional dose of 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours for a total dose of 300 mg/kg. The 72-hour regimen is 140 mg/kg loading dose followed by 70 mg/kg for 17 additional doses for a total dose of 1330 mg/kg. Both protocols are effective in preventing hepatic damage when given within 8 hours of acetaminophen ingestion.62 A 48-hour IV regimen studied in the United States appears to be superior to the 20-hour regimen when the first dose is delayed until 16–24 hours after ingestion.81 The 72-hour oral NAC regimen also appears superior to the 20-hour IV NAC protocol when started 16–24 hours postingestion. Perhaps most patients who receive

their first dose of NAC within 8 hours require only the short course because the inflammatory cascade is not initiated, whereas patients whose treatment is delayed benefit from a longer course of therapy and the associated benefits of the antiinflammatory/antioxidant effects of NAC. Some authors recommend a 36-hour oral course in low-risk patients with careful evaluation and follow-up, but this recommendation has not been adequately studied. Only the IV route has been studied in hepatic failure.28,38 The IV route achieves higher serum concentrations than the oral route. It is unclear whether oral or IV dosing results in superior drug delivery to the liver and whether the higher hepatic concentrations enhance drug efficacy.57 The oral route often produces vomiting and requires antiemetics to complete therapy, but it is not usually associated with other serious adverse effects. Theoretically higher serum concentrations may be helpful for extrahepatic effects, whereas the oral route might provide higher intrahepatic concentrations. We now recommend IV NAC for all adult patients without asthma4 or other contraindication to IV NAC and in whom an anaphylactoid reaction would not be devastating. In children who do not tolerate oral NAC, IV NAC may be acceptable. However, the appropriate dilution of IV NAC in children is problematic. Currently, the package insert only provides dosing information down to a patient weight of 40 kg.1 Hyponatremia is possible and has P.546 been reported in a 13-kg child receiving the adult IV dosing volume (1700 mL), leading those authors to suggest a final concentration of NAC of approximately 4% in 5% dextrose in water (D5 W) to avoid the administration of excess free water and the potential for hyponatremia.85 However, the pH of Acetadote (acetylcysteine injection, Cumberland Pharmaceuticals, Nashville, TN) is adjusted close to neutral where NAC is stable, resulting in an osmolarity of approximately 2600 mOsm/L for the 20%

solution. Therefore sodium concentrations and fluid requirements must be meticulously monitored. A 2% final NAC concentration in D 5 W of Acetadote is approximately 485 mOsm/L and may be more appropriate.

Use in Pregnancy and Neonates Untreated acetaminophen toxicity is a far greater threat to the fetus than is NAC treatment.68 The risk of not treating pregnant women almost certainly far exceeds any potential risk to the developing fetus if a toxic ingestion has occurred. Although an earlier sheep model suggested otherwise, human data demonstrate that NAC traverses the placenta and produces cord blood concentrations comparable to maternal blood concentrations.34 NAC is Food and Drug Administration (FDA) Pregnancy Category B. Limited data exist with regard to the management of neonatal acetaminophen toxicity,5,43,71,77 although IV and oral NAC have been used safely.1,5 No adverse effects were observed when preterm newborns were The elimination half-life compared to 5.6 hours advantage of assuring

treated with IV NAC1 (Chaps. 30 and 3 4) . of NAC in preterm neonates was 11 hours in adults.1 IV administration has the adequate antidotal delivery. Oral

administration in general is associated with necrotizing enterocolitis in neonates.

Other

Uses

(Non–Acetaminophen)

Diverse investigations of NAC as a treatment for a number of xenobiotics associated with free radical or reactive metabolite toxicity are reported. Some of these xenobiotics include chloroform, carbon tetrachloride, 1,2-dichloropropane, acrylonitrile, doxorubicin, and cyclophosphamide.17,23,89,93 NAC is under study as a chemopreventive agent against amatoxins cancer, lung injury, cardiac injury, radiographic contrast

exposure,86 and malnutrition.2,20,21,46,72,83,84 NAC has extracellular antimutagenic effects, enhances repair of nuclear DNA damaged by carcinogens, and inhibits malignant cell invasion and metastases.21,55,65 Oral NAC added to prednisone and azathioprine preserves vital capacity in patients with idiopathic pulmonary fibrosis.2 1 a Rescue NAC therapy is being studied with high-dose acetaminophen (≤20 g/m2 ) in patients with advanced malignancies.40 Use of NAC in these settings may further enhance our understanding of the beneficial effects of NAC in both the early and late phases of acetaminophen poisoning.

Adverse

Effects

and

Safety

Issues

Oral NAC may cause nausea, vomiting, flatus, diarrhea, gastroesophageal reflux, and dysgeusia; generalized urticaria occurs rarely. Anaphylactoid reactions described after IV NAC dosing3,10,11,19,24,31,48,50,61,67,88,91 are not noted after oral therapy and may be related to rate, concentration, or high serum NAC concentrations.8,61 Administration of oral NAC via the IV route produced cutaneous reactions in 4 of 76 patients and a generalized anaphylactoid reaction in 1 patient. None of these patients developed adverse hemodynamic

effects.94

The IV route assures delivery, but rate-related anaphylactoid reactions are possible. Although the package insert for Acetadote recommends infusing the loading dose over 15 minutes, many authors, including ourselves, believe that infusion over 1 hour reduces the potential for life-threatening anaphylactoid reactions.48 The manufacturer categorizes the number of anaphylactoid reactions occurring in 109 patients receiving the 15minute loading dose as mild 6%, moderate 10%, and severe 1%.1 Although similar findings are listed for the 60-minute loading dose

infusion, problems with study design cast doubt on these findings.1,96 Of the adverse events occurring in more than 2000 patients who received IV NAC, vasodilation, rash, and pruritus account for approximately 10%, hypotension 4%, bronchospasm 6%, and angioedema 8%.1 If angioedema or an anaphylactoid reaction characterized by hypotension, shortness of breath, or wheezing, flushing, or erythema occurs, NAC should be stopped and standard symptomatic therapy instituted. Once the reaction resolves, NAC can be carefully readministered after 1 hour assuming NAC is still indicated. If the reaction persists or worsens, discontinue IV NAC and consider switching to oral NAC. Adverse reactions confined to flushing and erythema usually are transient, and NAC can be continued with meticulous monitoring for systemic symptoms that indicate the need to stop the NAC. Urticaria can be managed with diphenhydramine with the same precautions.7 Iatrogenic overdoses with IV NAC have resulted in comparable adverse events.3,6,50 IV NAC decreases clotting factors and increases the prothrombin time in healthy volunteers and overdose patients without hepatic damage.36,47,53,92 This effect occurs within the first hour, stabilizes after 16 hours of continuous IV NAC, and rapidly returns to normal when the infusion is stopped.36 Because the prothrombin time is used as a marker of the severity of toxicity and is one of the criteria for transplantation, this adverse effect of NAC should always be considered when evaluating the patient's condition. An elevated prothrombin time without other indicators of hepatic damage probably is related to the NAC.

Dos i n g The manufacturer recommends a loading dose of 150 mg/kg in 200 mL of D5 W (for adults) infused over 15 minutes, followed by a first maintenance dose of 50 mg/kg in 500 mL D5 W (for adults) infused

over 4 hours followed by a second maintenance dose of 100 mg/kg in 1000 mL D5 W (for adults) infused over 16 hours. We recommend infusing the loading dose over 60 minutes. The appropriate dilution of IV NAC in children is problematic. Currently, the package insert only provides dosing information down to a patient weight of 40 kg.1 Because of issues with osmolarity, sodium concentrations, and fluid requirements, meticulous monitoring is required. A 2% final NAC concentration in D 5 W is approximately 485 mOsm/L and may be acceptable until further information becomes available. When NAC is administered orally, the patient should receive a 140mg/kg loading dose either orally or by enteral tube. Starting 4 hours after the loading dose, 70 mg/kg should be given every 4 hours for an additional 17 doses. The solution should be diluted to 5% with a soft drink to enhance palatability. If any dose is vomited P.547 within 1 hour of administration, the dose should be repeated44 or IV delivery used. Antiemetics (such as metoclopramide or a serotonin antagonist) should be used to ensure absorption. If the acetaminophen concentration is above the nomogram line, the standard approach is to administer 72 hours of therapy. Shorter courses may be acceptable (Chap. 34) . If hepatic failure intervenes, IV NAC should be administered at a dose of 150 mg/kg in D5 W infused over 24 hours and continued until the patient has a normal mental status (or recovers from hepatic encephalopathy),29 the patient's international normalized ratio (INR) becomes 30 mg/dL, ALI occurred in 35% of patients older than 30 years of age and none of the 55 patients younger than 16 years of age. Risk factors for developing ALI included cigarette smoking, chronic

salicylate ingestion, and presence of neurologic symptoms on admission. The average arterial blood pH was 7.37 ± 0.022 in the 6 adult patients with ALI and 7.46 ± 0.010 in the 30 adults without ALI. There was no significant difference in salicylate concentrations, which were approximately 57 mg/dL in both groups.118 In a 2-year review of all salicylate deaths in Ontario, Canada, 51 patients were studied, with autopsies performed in 39. The autopsies revealed that 59% had pulmonary pathology. The presence of pulmonary pathology, mostly “pulmonary edema,― was significantly associated with therapy for >4 hours.79 Although the exact mechanism for ALI is obscure, hypoxia may be an important factor.56,57 Hypoxia can result in pulmonary arterial hypertension and a local release of vasoactive substances. Severe salicylate poisoning has been identified as a distinct cause of ALI in children and in adults. 41

Gastrointestinal

Effects

Gastrointestinal manifestations of salicylate use include nausea and vomiting, which probably result from local gastric irritation at lower doses and from stimulation of the medullary chemoreceptor trigger zone at higher doses (27 mg/dL).101 Hemorrhagic gastritis, decreased gastric motility, and pylorospasm also result from the direct gastric irritant effects of salicylates.102 The effects appear more pronounced or consequential in the elderly.64

Renal

Effects

The kidneys clearly play a major role in the handling and excretion of salicylates, and many believe in turn that salicylates are significantly nephrotoxic, but the majority of studies and experimental evidence do not strongly support this notion.26,37,88 Most of the adverse renal effects historically associated with salicylates occurred with use of combination products such as aspirin–phenacetin–caffeine (APC)

tablets and appear to have been due mostly to the nonsalicylate ingredient(s), that is, phenacetin,37 or to a synergistic effect contributed to by salicylates. The synergistic nephrotoxicity of aspirin and acetaminophen results from the effects of each on depleting glutathione.33,89,121 Renal papillary necrosis (RPN) and chronic interstitial nephritis initially characterized by reduced tubular function and reduced concentrating ability are rarely seen in adults using aspirin or salicylates unless they have chronic illnesses that already compromise renal function. Although extremely high doses of aspirin have produced RPN experimentally in 1 rat species, RPN has not been demonstrated following excessive doses of aspirin alone in humans or other species, or after lesser doses of aspirin in other rats.26 Similarly, neither chronic nephrotoxicity nor an increased risk of end-stage renal disease (ESRD) from long-term use of aspirin alone has been demonstrated in humans, with the exception of 1 case control series demonstrating a low but statistically significant risk of ESRD. In adults with preexisting glomerulonephritis, cirrhosis, or chronic renal insufficiency and in children with congestive heart failure, short-term therapeutic doses of aspirin may precipitate reversible acute renal failure, possibly because of inhibition of the vasodilatory prostaglandins necessary to maintain renal blood flow in these conditions.26 In healthy adults, however, short-term therapeutic doses of aspirin do not adversely affect creatinine clearance, urine volume, or sodium and potassium clearance. Aspirin doses >300 mg/kg can cause acute renal failure, and chronic aspirin poisoning can cause reversible or irreversible acute renal failure associated with a pseudosepsis syndrome.26

Hematologic

Effects

Hematologic effects of salicylate poisoning include hypoprothrombinemia and platelet dysfunction.44 Anemia in patients who chronically abuse salicylates may be a result of the effects of

both platelet dysfunction and gastric mucosal barrier breakdown (gastrointestinal bleeding),44 particularly in the elderly.6,25 Hemolysis is unusual, and alterations in leukocyte function are of no apparent clinical significance.103

Musculoskeletal

Effects

Rhabdomyolysis after pure salicylate overdoses probably is another result of the dissipation of heat and energy from uncoupling oxidative phosphorylation.71,80,81 Paratonia, characterized by extreme muscle rigidity, was present in 3 of the 51 cases of salicylate deaths reviewed in Ontario between 1983 and 1984.79 Rapid rigor mortis and paratonia (which are not unique to salicylate poisoning) probably are related to the extreme depletion of ATP and the inability of the muscle fibers to relax. P.556

Clinical Chronic Acute

Manifestations Salicylate

of

Acute

and

Poisoning

Toxicity

The earliest signs and symptoms of salicylate toxicity include nausea, vomiting, diaphoresis, and tinnitus, which is a subjective sensation of ringing or hissing, with or without hearing loss.15,44,110 As CNS salicylate concentrations increase, tinnitus is rapidly followed by diminished auditory acuity that sometimes leads to deafness.15 Other early CNS effects may include vertigo and hyperventilation manifested as hyperpnea or tachypnea (Chap. 3), hyperactivity, agitation, delirium, hallucinations, convulsions, lethargy, and stupor. Coma is rare and generally occurs only after massive ingestions (serum salicylate concentrations >100 mg/dL) or mixed overdoses (Table 35-1) .44 A marked elevation in temperature resulting from the uncoupling of oxidative phosphorylation caused by salicylate

poisoning80 is an indication of severe toxicity and typically a preterminal condition. Unfortunately, many of the signs and symptoms of salicylate toxicity may be mistakenly attributed to the illness for which the salicylates were administered, with disastrous consequences.24,110 In the review of all salicylate deaths in Ontario, Canada, in 1983 and 1984, the author noted that in 6 of the 23 (26%) patients who arrived alert, no salicylate determination appears to have been made and that probably neither the diagnosis nor severity of the lethal salicylate poisoning was recognized.79

TABLE 35-1. Clinical Manifestations and Diagnostic Testing Results of Salicylate Toxicity

Acid–base

and

electrolyte

disturbances

Anion gap increased Metabolic acidosis Metabolic alkalosis (vomiting) Respiratory alkalosis (predominates Respiratory acidosis (late, grave Hyponatremia or hypernatremia Hypokalemia CNS Tinnitus Diminished auditory acuity Vertigo Hallucinations Agitation Hyperactivity Delirium Stupor Coma

early)

prognosis)

Lethargy Convulsions Cerebral edema Syndrome of inappropriate antidiuretic Coagulation abnormalities Hypoprothrombinemia Inhibition of factors V, VII, X Platelet dysfunction Gastrointestinal Nausea Vomiting Hemorrhagic gastritis Decreased motility Pylorospasm Hepatic Abnormal liver enzymes Altered glucose metabolism Metabolic Diaphoresis Hyperthermia Hypoglycemia Hyperglycemia Hypoglycorrhachia Ketonemia Ketonuria Pulmonary Hyperpnea Tachypnea Respiratory alkalosis Acute lung injury Renal Tubular damage Proteinuria NaCl and water retention

hormone

Hypouricemia

Chronic

Toxicity

Chronic salicylate poisoning most typically occurs in the elderly as a result of unintentional overdosing on salicylates used to treat chronic conditions such as rheumatoid arthritis and osteoarthritis.5,32,64 Although neither age nor gender appears to affect the absorption rate or plasma clearance of acute therapeutic doses of aspirin (900 mg) administered to healthy adults,82 when used chronically, a small increase in dosage (eg, in response to increasing pain) or a small decrease in metabolism or renal function can result in substantial increases in serum salicylate concentrations and toxicity.64 Presenting signs and symptoms of chronic

salicylate

poisoning

include hearing loss and tinnitus, nausea, vomiting, dyspnea and hyperventilation, tachycardia, hyperthermia, and neurologic manifestations such as confusion, delirium, agitation, hyperactivity, slurred speech, hallucinations, seizures, and coma.4,44,70 In one review, the authors went so far as to suggest that the diagnosis of salicylate poisoning should be borne in mind when an older patient presents with recent deterioration in activities of daily living of no known cause.31 Although there is considerable overlap with some of the presenting signs slow onset and less chronic poisoning in of the true etiology

and symptoms of acute salicylate poisoning, the severe appearance of some of these signs of the elderly frequently cause delayed recognition of the patient's presentation.45

Typically, ill patients who suffer from chronic salicylate poisoning may be misdiagnosed as having delirium, dementia, encephalopathy of undetermined origin, diseases such as sepsis (fever of unknown origin), alcoholic ketoacidosis, respiratory failure, or cardiopulmonary disease, especially congestive heart failure, acute pulmonary edema, or even unstable angina.4,8,24,34,44

In a study of 73 consecutive adults hospitalized with salicylate poisoning, 27% were not correctly diagnosed for as long as 72 hours after admission.4 These patients manifested toxicity with standard or excessive therapeutic regimens and had significant associated diseases without a history of previous overdoses. In this group, 60% previously had a neurologic consultation before the diagnosis of salicylism was established. When diagnosis is delayed in the elderly, the morbidity and mortality associated with salicylate poisoning are high. Mortality was reported to be as high as 25% in the 1970s,4 and no data suggest that survival after delayed diagnosis is substantially better today (Table 35-2) . Underrecognition or misdiagnosis of chronic salicylate poisoning is not confined to the elderly and may be a problem at the other end of the age spectrum. In one study of all children admitted to a district hospital in Kenya over a 3-month period with the primary diagnosis of severe malaria, 90% had detectable blood salicylate concentrations, and 6 of 143 had plasma concentrations ≥20 mg/dL. All 6 of the children with plasma salicylate concentrations of ≥20 mg/dL had neurologic impairment and metabolic acidosis, and 4 had hypoglycemia, suggesting that salicylates cause or contribute to those complications of malaria that are associated with high

mortality.34

TABLE 35-2. Differential Characteristics of Acute and Chronic Salicylate Poisoning

Acute

Chronic

Age

Younger

Older

Etiology

Overdose usually intentional

Therapeutic misadventures; iatrogenic

Diagnosis

Easily

Frequently unrecognized

Other

None

disease

recognized

Underlying

states

disorders

(especially chronic pain conditions)

Suicidal ideation

Typical

No

Clinical

Rapid

differences

of signs

Serum concentrations

Marked

elevation

Intermediate elevation

Mortality

Uncommon when recognized, unless ingestion massive

Approximately

progression

Acute lung injury (ALI) CNS abnormalities

25%

P.557

Diagnostic Rapid

Testing

Confirmation

of

Salicylate

Use

Serum salicylate concentrations are relatively easy to obtain in most hospital laboratories and with proper attention to the units reported (mg/dL vs. mg/L) and concomitant arterial blood pH values, clinicians can quickly confirm or exclude toxic salicylate concentrations. Salicylate use may be rapidly confirmed qualitatively with a simple point-of-care ferric chloride (FeCl 3 ) test that uses several drops of 10% FeCl3 added to 1 mL of urine. A purple color indicates the presence of salicylic acid, acetoacetic acid, or phenylpyruvic acid.119 However, because this test is extremely sensitive to very small quantities of salicylates, a positive result indicates only salicylate usage and not necessarily poisoning or overdosage. A positive FeCl3 test result must be confirmed by determination of actual serum salicylate concentration, whereas false-negative FeCl3 results either do not occur or are exceedingly rare.42 A false-positive FeCl3 test may also result from use of a small quantity of urine that has already been subjected to dipstick analysis with N-Multistix or Bili Labstix reagent strips. Presumably in this instance impregnated chemical from the dipstick that has dissolved in the urine subsequently causes a false-positive FeCl3 reaction. When urine is not available for FeCl3 testing (because of anuria or oliguria, too short a time after ingestion, or chronic use of salicylates), a possible salicylate-containing product itself can be tested with FeCl3 . All 15 of the salicylate-containing products tested in one study demonstrated a positive FeCl3 reaction, whereas none of the 15 nonsalicylate containing controls did.55 FeCl3 reagent is rarely available in hospital emergency departments, and the unsupervised performance of FeCl 3 testing outside of a certified laboratory is not consistent with the federal Clinical Laboratory Improvement Amendments (CLIA) in the United States.

Another rapid colorimetric urine test for determination of salicylate usage is the Trinder spot test,66 which uses a premixed reagent consisting of mercuric chloride, ferric nitrate, deionized water, and concentrated hydrochloric acid. When 1 mL of urine containing salicylates is mixed with 1 mL of Trinder reagent, it instantly turns violet or purple. The sensitivity of the test was 100% when applied to urine collected 2–4 hours after oral ingestion of 975 mg of salicylate by volunteers.66 (Because of the composition of the testing reagents, this test presumably would be available only in a laboratory.) “Point-of-care― determinations that may help rapidly indicate salicylate poisoning are (A) a positive urine ketone determination reflecting ketogenesis from increased fatty acid metabolism 53 and perhaps the ketone forms of salicylates present; (B) a whole-blood glucose and electrolyte determination performed on a handheld analyzer (I-stat and others); this test can quickly demonstrate decreased HCO3 - 2 (indicating a possible wide anion gap metabolic acidosis) and other glucose and electrolyte abnormalities characteristic of salicylate toxicity; and (C) a whole-blood ABG determination performed on a handheld analyzer indicating acid–base disturbance(s) characteristic of salicylate poisoning.

Serum Salicylate Correlation with

Concentrations Toxicity

and

Serum salicylate concentrations should be requested when clinically significant salicylate exposures are suspected and not as part of a general toxicologic screen. For some, the confusion in correctly identifying aspirin and acetaminophen products and the consequent possibility that either or both may be used in a suicide attempt, coupled with the initial absence (acetaminophen) or unreliability (salicylates) of clinical findings associated with these poisonings, make toxicologic analysis for both salicylates and acetaminophen reasonable when either one is implicated in an intentional poisoning.

The authors of two studies concluded that universal salicylate screening is not indicated for patients with acute self-poisonings (Hong Kong) 22 or patients with suicidal ingestions or altered mental status (United States).107 The latter study found that 0.16% of patients with suicidal ingestions had a toxic salicylate exposure not suggested by history, compared to 0.3% of patients with potentially toxic acetaminophen exposures not suggested by history. Although these authors recommended universal acetaminophen screening to evaluate patients with suspected ingestions, they concluded that salicylate screening was unnecessary because severe salicylate exposures are less frequent and usually are accompanied by an elevated anion gap and altered mental status.107 Except in certain narrowly defined situations, the toxicity of salicylates correlates poorly with serum concentrations. The Done nomogram,29 first published in 1960, continues to be republished in texts despite severely limited applicability. It was based on data from a predominantly pediatric population and intended to be applied only 6 hours or more after a single acute ingestion of nonentericcoated, orally ingested aspirin. Moreover, the patient's blood pH must be approximately 7.4 or higher. Such conditions rarely apply to patients with serious acute and chronic salicylate overdoses and poisonings. An example of the shortcomings of the nomogram is a patient who presents with lethargy and/or a coagulation abnormality associated with salicylism. Such a patient can be classified on the Done nomogram as “mild― or “moderate,― although it is obvious clinically that the patient must be considered severely poisoned. The poor predictive value of the Done nomogram when applied retrospectively to a group of 55 predominantly adults with salicylate poisoning is evident from a 1989 study.32 Patients with acute exposures whose initial serum salicylate concentrations are considered acceptable, low, or moderate sometimes P.558

deteriorate rapidly thereafter. For this reason, careful observation of the patient, correlation of the serum salicylate concentrations with blood pH values, and repeat determinations of serum salicylate concentrations every 2–4 hours are essential until the patient is clinically improving and has a low salicylate concentration in the presence of a normal or high blood pH. Methyl salicylate exposures have resulted in deaths in 100 mg/dL (in the absence of the above)

A combination of therapies that are both useful and practical is to ensure patient report, month

effective alkalinization with sodium bicarbonate while a is waiting and then undergoing HD. In one unique case a patient who overdosed twice on salicylates within a 2period was treated in the first instance with 4 hours of HD but

no effective alkalinization and in the second instance with sodium bicarbonate alkalinization but no HD. In both instances, blood concentrations of salicylates were >65 mg/dL. Although similar decreases in salicylate concentrations were achieved with the two techniques, the rate of decline during the first 4 hours was faster with alkalinization.51 Combining the two therapies makes sense even if part of the reason for the increased early effectiveness of sodium bicarbonate treatment is related to the rapidity with which it can be achieved compared to the 2–4 hours required to institute HD after a patient presents under even the most favorable circumstances.51 Peritoneal dialysis (PD) was sometimes suggested in the past as a simpler extracorporeal procedure for eliminating salicylates in the

setting of hemodynamic compromise, coagulopathy, or inability to perform HP or HD. However, PD is only 10–25% as efficient as HP or HD and not even as efficient as renal excretion itself. The 24-hour clearance of salicylates with PD is less than the 4-hour clearance of salicylates by HP or HD; therefore PD is not recommended (Chap. 1 0) .

Pregnancy Considered a rare event, salicylate poisoning during pregnancy poses a particular hazard to the fetus because of the acid–base and hematologic characteristics of the fetus and placental circulation: salicylates cross the placenta and are present in higher concentrations in the fetus than in the mother. The respiratory stimulation that occurs in the mother after toxic exposures does not occur in the fetus, which has a decreased capacity to buffer acid. The ability of the fetus to metabolize and excrete salicylates is also less than in the mother. In addition to its toxic effects on the mother, including coagulation abnormalities, acid–base disturbances, tachypnea, and hypoglycemia, repeated exposure to salicylates late in gestation displaces bilirubin from protein-binding sites in the fetus. A case report describing fetal demise in a woman who claimed to ingest 50 aspirin tablets per day for several weeks during the third trimester of pregnancy supports the conclusion that the fetus is at greater risk from salicylate exposures than is the mother and that emergent delivery of near-term fetuses of salicylate-poisoned mothers should be considered very seriously 86 (Chap. 30) .

Summary Initial assessment of a patient who has ingested excessive amounts of salicylates includes a determination of the vital signs, particularly the depth and frequency of respiration, and temperature. The clinical

presentation of a patient with a salicylate overdose is characterized by early onset of nausea, vomiting, abdominal pain, blood-tinged vomitus or gross hematemesis, tinnitus, and lethargy. The presence of hyperventilation, hyperthermia, confusion, coma, seizures, and any other nonspecific neurologic presentation should heighten suspicion of salicylate poisoning (Tables 35-1 and 35-2). If either salicylism or salicylate poisoning is suspected, a bedside FeCl3 test can confirm salicylate exposure (but may be unnecessary). Using a combination of symptoms, signs, bedside laboratory studies, and characteristic ABG findings, the clinician can rapidly confirm a significant salicylate ingestion, institute immediate alkalinization with sodium bicarbonate, achieve gastric decontamination by orogastric lavage (if indicated), AC, or MDAC (if indicated), and consider the need for HD (or perhaps hemodiafiltration) early in the course of management. For the salicylate-poisoned patient who presents as severely ill, maintenance of the airway requires an extremely careful approach because during initial airway management, death has occurred following sedation.11 In patients with pulmonary and CNS manifestations of salicylate toxicity, the protective nature of the hyperpnea or hyperventilation in maintaining alkalemia may be compromised by assisted ventilation, unless the clinician is extremely skilled at adjusting the ventilator to ensure hyperventilation, decreased PCO2 , and high pH (7.5) at all times. Moreover, any unnecessary study, such as obtaining a computed tomographic scan that delays definitive treatment aimed at immediately reducing the patient's burden of salicylates quickly by HD can only place the patient at greater risk of death. Urinary alkalinization with sodium bicarbonate to eliminate salicylates is important, even though use of sodium bicarbonate may further complicate electrolyte abnormalities. Maintenance of eukalemia is important to ensure success, and fluid and electrolyte replacement is essential.

Acknowledgment Eddy A. Bresnitz, MD, and Lorraine Hartnett, MD, contributed to this chapter in a previous edition.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > A - Analgesics and Antiinflammatory Medications > Antidotes in Depth - Sodium Bicarbonate

Antidotes in Depth Sodium

Bicarbonate

Paul M. Wax Sodium bicarbonate (NaHCO3 ) is one of the most useful agents available for treatment of the poisoned patient. Unlike more specific antidotes in which utility usually is limited to antagonizing a single drug or toxin, sodium bicarbonate is a nonspecific antidote effective in the treatment of a variety of poisonings by means of a number of distinct mechanisms (Table A6-1). The support for its use in these settings is predominantly based on animal evidence, case reports, and opinion.6 It is most commonly used in the treatment of tricyclic antidepressant (TCA) and salicylate poisonings. Sodium bicarbonate may also have a role in the treatment of phenobarbital, chlorpropamide, and chlorophenoxy herbicide poisonings and wide-complex tachydysrhythmias induced by type IA and IC antidysrhythmics and cocaine. Correcting the life-threatening acidosis generated by methanol and ethylene glycol poisoning and enhancing formate elimination are other important indications for sodium bicarbonate. Use of sodium bicarbonate in the treatment of rhabdomyolysis, lactic acidosis,

cardiac resuscitation, and diabetic ketoacidosis is controversial and is not a focus of this Antidote in Depth.1,21,32,37,39,84,86

Altered

Drug

Altered

Drug

Tricyclic

Ionization

Resulting

in

Distribution

Antidepressants

Sodium bicarbonate's most important role in toxicology appears to be its ability to reverse potentially fatal cardiotoxic effects of the TCA drugs and other type IA and IC antidysrhythmics. Use of sodium bicarbonate for TCA overdose developed as an extension of sodium bicarbonate use in the treatment of other cardiotoxic exposures. Noting similarities in electrocardiographic findings between hyperkalemia and quinidine toxicity (ie, QRS widening), investigators in the 1950s began to use sodium lactate (which is metabolized to sodium bicarbonate) for the treatment of quinidine toxicity.2,5,89 In a canine model, quinidine-induced electrocardiographic changes and hypotension were consistently reversed by infusion of sodium lactate.4 Clinical experience confirmed this benefit.5 Similar efficacy in the treatment of procainamide cardiotoxicity was also reported.89 With the introduction of the TCAs during the late 1950s and early 1960s, conduction disturbances, dysrhythmias, and hypotension following overdose were reported. Extending the use of sodium lactate from the type I antidysrhythmics to the TCAs, uncontrolled observations in the early 1970s showed a decrease in mortality from 15% to 7.40.12 Other methods of alkalinization, including hyperventilation and administration of the nonsodium buffer tris (hydroxymethyl) aminomethane (THAM), was also effective in reversing the dysrhythmias.13,36 A better understanding of the mechanism and utility of sodium bicarbonate has come from a series of animal experiments during the 1980s. In amitriptyline-poisoned canines, sodium bicarbonate reversed conduction slowing and ventricular dysrhythmias and suppressed ventricular ectopy.56 When comparing sodium bicarbonate, hyperventilation, hypertonic sodium chloride, and lidocaine, sodium bicarbonate and hyperventilation proved most efficacious in reversing ventricular dysrhythmias and narrowing QRS interval prolongation. Although lidocaine transiently antagonized dysrhythmias, this antagonism was demonstrable only at nearly toxic lidocaine concentrations and was associated with hypotension. In these studies, hypertonic sodium chloride failed to reverse dysrhythmias. Furthermore, prophylactic alkalinization protected against the development of dysrhythmias in a pHdependent

manner.

In desipramine-poisoned rats, the isolated use of either sodium chloride or sodium bicarbonate was effective in decreasing QRS duration.61 Both sodium bicarbonate and sodium chloride also increased mean arterial pressure, but hyperventilation or direct intravascular volume repletion with mannitol did not. In further studies both in vivo and on isolated cardiac tissue, alkalinization and increased sodium concentration improved TCA effects on cardiac conduction.72,73 Although respiratory alkalosis and sodium chloride each independently improved conduction velocity, this effect was greater when sodium bicarbonate was administered. Another study on amitriptyline-poisoned rats demonstrated that

treatment with sodium bicarbonate was associated with shorter QRS interval, longer duration of sinus rhythm, and increased survival rates.38 Sodium bicarbonate seems to work independently of initial blood pH. Animal studies show that cardiac conduction improves after treatment with sodium bicarbonate or sodium chloride in both normal pH and acidemic animals.61 Clinically, TCApoisoned patients who already were alkalemic also responded to repeat doses of sodium bicarbonate.53 Although several authors suggest that sodium bicarbonate's efficacy is modulated via a pH-dependent change in protein binding that decreases the proportion of free drug,13,43 further study failed to support this hypothesis.64 The administration of large doses of a binding protein α1 -acid glycoprotein (AAG) (to which TCAs show great affinity) to desipramine-poisoned rats only minimally decreased cardiotoxicity. Although the addition of AAG increased the concentrations of total desipramine and proteinbound desipramine in the serum, the concentration of active free desipramine did not decline significantly. A redistribution of TCA from peripheral sites may have prevented lowering of free desipramine concentration. The persistence of other TCAassociated toxicity, such as the anticholinergic effects and seizures,

also P.566

argues against changes in protein-binding modulating toxicity. In vitro studies performed in a protein-free bath further support that sodium bicarbonate's efficacy is independent of protein binding.72

TABLE A6-1. Sodium Bicarbonate in Toxicology: Mechanisms, Site of Action, and Uses

Mechanism

Site of Action

Uses

Altered interaction between drug and sodium channel

Heart

Amantadine Carbamazepine Cocaine Diphenhydramine Flecainide Mesoridazine Procainamide Propoxyphene Quinidine Quinine Thioridazine Tricyclic antidepressants

Altered drug ionization leads to altered tissue

Brain

distribution

Altered drug ionization leads to enhanced drug

Formic acid Phenobarbital Salicylates

Kidneys

elimination

Chlorophenoxy herbicides Chlorpropamide Formic acid Methotrexate Phenobarbital Salicylates

Correct lifethreatening acidosis

Metabolic

Cyanide Ethylene glycol Methanol

Increase drug solubility

Kidneys

Methotrexate

Neutralization

Lungs

Chlorine gas, HCI

Reduce free radical formation

Kidneys

Contrast

media

Sodium bicarbonate has a crucial antidotal role in TCA poisoning by increasing the number of open sodium channels, thereby partially reversing fast sodium channel blockade. This decreases QRS prolongation and reduces life-threatening cardiovascular toxicity such as ventricular dysrhythmias and hypotension.56,61,72 The animal evidence supports two distinct and additive mechanisms for this effect: a pH-dependent effect and a sodiumdependent effect. The pH-dependent effect increases the fraction of the more freely diffusible nonionized drug. Both the ionized drug and the nonionized forms are able to bind to the sodium channel, but assuming TCAs act like local anesthetics, it is estimated that 90% of the block results from the ionized form. By increasing the nonionized fraction, less drug is available to bind to the sodium channel binding site. The sodium-dependent effect increases the availability of sodium ions to pass through the open channels. Decreased ionization should not significantly decrease the rate of TCA elimination because of the small contribution of renal pathways to overall TCA elimination (0.12 seconds, and hypotension corrected within 1 hour in 20 of 21 patients who had systolic blood pressure 0.10 seconds, amplitude of terminal R wave in lead aVR (RaVR ) = 3 mm, or right bundle-branch block, wide-complex tachydysrhythmias, and hypotension.44 Because studies show that there is a critical threshold QRS duration at which ventricular dysrhythmias may occur (≥0.16 seconds),9 it seems reasonable that narrowing the QRS interval through use of sodium bicarbonate or hyperventilation may prophylactically prevent against development of dysrhythmias. Practice patterns vary considerably over use of sodium bicarbonate in situations where the QRS interval is 7.55) and hypernatremia should be avoided. Because sodium bicarbonate has a brief duration of effect, a continuous infusion usually is required after the intravenous bolus. Three 50-mL ampules should be placed in 1 L of 5% dextrose in water (D5 W) and run at twice maintenance with frequent checks of QRS and pH depending on the fluid requirements and blood pressure of the patient. Frequent evaluation of fluid status should be performed to avoid precipitating pulmonary edema. Optimal duration of therapy has not been established. The time to resolution of conduction abnormalities during continuous bicarbonate infusion significantly varies, ranging from several hours to several days.45 Sodium bicarbonate P.567 infusion usually is discontinued once there is improvement in hemodynamics and cardiac conduction and resolution in altered mental status, although controlled data supporting such an approach are lacking.

Other

Sodium

Channel

Blocking

Drugs

Sodium bicarbonate is useful in treating cardiotoxicity from other drugs, with sodium channel blocking effects manifested by widened QRS complexes, dysrhythmias, and hypotension. Isolated case reports provide the bulk of the evidence in these situations. The utility of sodium bicarbonate in treating type IA and IC antidysrhythmics, diphenhydramine, propoxyphene, and quinine is demonstrated.4,8,70,77,81,89 Use of sodium bicarbonate in the treatment of amantadine overdose manifested by prolongation of the QRS and QTc intervals was associated with narrowing of the QTc but not the QRS interval.19 Although the usefulness of sodium bicarbonate in reversing QTc prolongation occasionally observed during fluoxetine and citalopram overdose has been reported,18,25 sodium channel disturbances are uncommon in most cases of selective serotonin receptor inhibitor (SSRI) overdose, and routine use of alkalinization therapy in this setting is unwarranted. Sodium bicarbonate may help in the management of other ingestions associated with type IA-like cardiac conduction abnormalities and dysrhythmias, such as the phenothiazines thioridazine and mesoridazine, and carbamazepine, but documentation of such benefit is lacking. The role of sodium bicarbonate as an antidote has been studied in experimental models of calcium channel toxicity and β-blocker toxicity. In the calcium channel blocker study, hypertonic sodium bicarbonate increased mean arterial pressure and cardiac output in verapamil-poisoned swine.82 Possible explanations for this beneficial effect include the increase in serum pH, reversal of a sodium channel effect, lowering of serum potassium concentration, and/or volume expansion. In a canine model of propranolol toxicity, sodium bicarbonate failed to increase heart rate or blood pressure.46

Cocaine (a local anesthetic with membrane-stabilizing properties resembling other type I antidysrhythmics) may cause similar conduction disturbances. In several canine models of cocaine toxicity, sodium bicarbonate 2 mEq/kg successfully reversed cocaine-induced QRS prolongation3,60 and improved myocardial function.91 Of interest, sodium loading by itself (sodium chloride 2 mEq/kg) failed to produce a benefit. Similar findings were demonstrated in cocaine-treated guinea pig hearts.92 Patients with pH-dependent cocaine-induced cardiotoxicity responded to treatment with sodium bicarbonate.35,59,88 In many of these cases, simultaneous treatment with sedation, active cooling, and hyperventilation confounds the contribution of the sodium bicarbonate to overall recovery.

Altered Drug Ionization Enhanced Elimination

Resulting

in

Salicylates Although there is no known specific antidote for salicylate toxicity, judicious use of sodium bicarbonate is an essential treatment modality of salicylism. Sodium bicarbonate, through its ability to change the concentration gradient of the ionized and nonionized fractions of salicylates, is useful in decreasing tissue (eg, brain) concentrations of salicylates and enhancing urinary elimination of salicylates.66 This therapy may limit the need for more invasive treatment modalities, such as hemodialysis. Salicylate is a weak acid with pKa = 3.0. As pH increases, more of the drug is in the ionized form. Ionized molecules penetrate lipidsoluble membranes less rapidly than do nonionized molecules because of the presence of polar groups on the ionized form. Consequently, weak acids, such as salicylates, may accumulate in an alkaline milieu, such as an alkaline urine, when the ionized

forms

predominate.50,79

Although alkalinizing the urine to increase salicylate elimination is an important intervention in the treatment of salicylate poisoning, increasing the serum pH in patients with severe salicylism may prove even more consequential by protecting the brain from a lethal central nervous system (CNS) salicylate burden. Using sodium bicarbonate to “trap― salicylate in the blood (keeping it out of the brain) may prevent clinical deterioration of the salicylate-poisoned patient. Salicylate lethality is directly related to primary CNS dysfunction, which, in turn, corresponds to a “critical brain salicylate level.―29 At physiologic pH, where a very small proportion of the salicylate is in the nonionized form, a small change in pH is associated with a significant change in amount of nonionized molecules (eg, at pH = 7.4, 0.004% of the salicylate molecules is in the nonionized form; at pH = 7.2, 0.008% of the salicylate is in the nonionized form). In experimental models, lowering the blood pH produces a shift of salicylate into the tissues.14 Hence, acidemia that is observed in significant salicylate poisonings can be devastating. In salicylatepoisoned rats, increasing the blood pH with sodium bicarbonate produced a shift in salicylate out of the tissues and into the blood.28 This change in salicylate distribution did not result from enhanced urinary excretion because occlusion of the renal pedicles failed to alter these results. Enhancing the urinary elimination of salicylate by trapping ionized salicylate in the urine also provides great benefit. Salicylate elimination at low therapeutic concentrations consists predominantly of first-order hepatic metabolism. At these low concentrations, without alkalinization, only approximately 10–20% of salicylate is eliminated unchanged in the urine. With increasing concentrations, enzyme saturation occurs (MichaelisMenten kinetics); thus, a larger percentage of elimination occurs as unchanged free salicylate. Under these conditions, in an alkaline urine, urinary excretion of free salicylate becomes even

more significant, accounting for 60–85% of total elimination.26,68 The exact mechanism of pH-dependent salicylate elimination has generated controversy. The pH-dependent increase in urinary elimination initially was ascribed to “ion trapping―: the filtering of both ionized and nonionized salicylate while reabsorbing only the nonionized salicylate.75 However, limiting reabsorption of the ionizable fraction of filtered salicylate cannot be the primary mechanism responsible for enhanced elimination produced by sodium bicarbonate.47 Because the quantitative difference between the percentage of molecules trapped in the ionized form at pH = 5.0 (99% ionized) and pH = 8.0 (99.999% ionized) is small, decreases in tubular reabsorption cannot fully explain the rapid increase in urinary elimination seen at pH >7.0. “Diffusion theory― offers a reasonable alternative explanation. Fick's law of diffusion states that the rate of flow of a diffusing substance is proportional to its concentration gradient. A large concentration gradient between the nonionized salicylate in the peritubular fluid (and blood) and the tubular luminal fluid is found P.568 in alkaline urine. Because at a higher urinary pH, a greater proportion of secreted nonionized molecules quickly becomes ionized upon entering the alkaline environment, more salicylate (ie, nonionized salicylate) must pass from the peritubular fluid into the urine in an attempt to reach equilibrium with the nonionized fraction. In fact, as long as nonionized molecules are rapidly converted to ionized molecules in the urine, equilibrium in the alkaline milieu will never be achieved. The concentration gradient of peritubular nonionized salicylates to urinary nonionized salicylates continues to increase with rising urinary pH. Hence, increased tubular diffusion, not decreased reabsorption, probably accounts for most of the increase in salicylate elimination observed in the alkaline urine.47

Controversies regarding the indications for alkalinization in the treatment of salicylism persist. Although urinary alkalinization undoubtedly works to lower serum salicylate concentrations and enhance urinary elimination, the risks associated with alkalinization in the management of salicylism are of concern. Questions regarding excessive alkalemia, hypernatremia, fluid overload, hypokalemia, and hypocalcemia, as well as the potential delay in achieving alkalinization with sodium bicarbonate (as opposed to more rapid response achieved with hyperventilation), have all been raised.22,42,62,68,75 Patients with pure respiratory alkalosis often have alkaluria, as well as alkalemia, and do not require urinary alkalinization. In the more common scenario in which patients present with a mixed respiratory alkalosis and metabolic acidosis, sodium bicarbonate must be administered cautiously. The young child, who rapidly develops a metabolic acidosis, often requires alkalinization but should be at less risk for complications of this therapy.58 Sodium bicarbonate is indicated in the treatment of salicylate poisoning for most patients with evidence of significant systemic toxicity. Although some authors have suggested alkali therapy for asymptomatic patients with concentrations >30 mg/dL,90 there are limited data supporting this approach. For patients suffering from chronic poisoning, concentrations are not as helpful and may be misleading; clinical criteria remain the best indicators for therapy. Patients with contraindications to sodium bicarbonate use, such as renal failure and acute lung injury, should be considered for intubation and subsequent hyperventilation, but extracorporeal removal will often be required because of the difficulty and danger of intubation. Dosing recommendations depend on the acid–base status of the patient. For the patient with acidemia, rapid correction is indicated with intravenous administration of 1–2 mEq of sodium bicarbonate per kilogram of body weight.83 Once the blood is

alkalinized or if the patient has already presented with an alkalemia, continued titration with sodium bicarbonate over 4–8 hours is recommended until the urinary pH reaches 7.5–8.0.80,83 Alkalinization can be maintained with a continuous sodium bicarbonate infusion of 100–150 mEq in 1 L of D5 W at 150–200 mL/h (or about twice the maintenance requirements in a child). Obtaining a urinary pH of 8.0 is difficult but is considered to be the goal. Fastidious attention to the changing acid–base status is required. Systemic pH should be kept below 7.55 to prevent complications of alkalemia. Hypokalemia can make urinary alkalinization particularly problematic.42,74 In the hypokalemic patient, regardless of total body potassium stores, the kidney preferentially reabsorbs potassium in exchange for hydrogen ions. Urinary alkalinization will be unsuccessful as long as hydrogen ions are excreted into the urine. Thus, appropriate potassium supplementation to achieve normokalemia may be required in order to alkalinize the urine.93 In the past, proper urinary alkalinization was thought to require forced diuresis in order to maximize salicylate elimination.17,42 Suggestions included administering enough fluid (2 L/h) to produce a urine output of 500 mL/h. Because forced alkaline diuresis appears unnecessary and is potentially harmful as a result of its unnecessarily large fluid load, alkalinization at a rate of approximately twice maintenance requirements to achieve a urine output of 3–5 mL/kg/h is the goal.

Phenobarbital Although cardiopulmonary support is the most critical intervention in the treatment of patients with severe phenobarbital overdose, sodium bicarbonate may be a useful adjunct to general supportive care. The utility of sodium bicarbonate is particularly important considering the long plasma half-life (approximately 100 hours) of phenobarbital. Phenobarbital is a weak acid (pKa = 7.24) that

undergoes significant renal elimination. As in the case of salicylates, alkalinization of the blood and urine can reduce the severity and duration of toxicity. In a study of mice, the median anesthetic dose for mice receiving phenobarbital increased by 20% with the addition of 1 g/kg of sodium bicarbonate (raising the blood pH from 7.23 to 7.41), demonstrating decreased tissue concentrations associated with increased pH.87 Extrapolating the animal evidence to humans has suggested that phenobarbitalpoisoned patients in deep coma might develop a respiratory acidosis, secondary to hypoventilation, with the acidemia enhancing the entrance of phenobarbital into the brain, thus worsening CNS and respiratory depression. Alternatively, increasing the pH with bicarbonate and/or ventilatory support would enhance the passage of phenobarbital out of the brain, thus lessening toxicity. Given the relatively high pKa of phenobarbital, significant phenobarbital accumulation in the urine is evident only when urinary pH is raised above 7.5.7 As the pH approaches 8.0, a 3-fold increase in urinary elimination occurs. The urine-to-serum ratio of phenobarbital, although much higher in alkaline urine than in acidic urine, remains less than unity, thereby suggesting less of a role for tubular secretion than in salicylate poisoning. Clinical studies examining the role of alkalinization in phenobarbital poisoning have been inadequately designed. Many are poorly controlled and fail to examine the effects of alkalinization, independent of coadministered diuretic therapy. In one uncontrolled study, a 59–67% decrease in duration of unconsciousness in patients with phenobarbital overdoses occurred in patients administered alkali compared to nonrandomized controls.52 In other older studies, treatment with sodium lactate and urea reduced mortality and frequency of tracheotomy to 50% of controls, enhanced elimination, and shortened coma.41,55 In a later human volunteer study, urinary alkalinization with sodium bicarbonate was associated with a decrease in phenobarbital elimination half-life from 148 to 47 hours.23 However, this

beneficial effect was less than the effect achieved by multiple-dose activated charcoal (MDAC), which reduced the half-life to 19 hours.23 In a nonrandomized study of phenobarbital-poisoned patients comparing urinary alkalinization alone, MDAC alone, and both methods together, both the phenobarbital half-life decreased most rapidly and the clinical course improved most rapidly in the group of patients who received MDAC alone.51 Interesting, the combination approach proved inferior to MDAC alone but was better than alkalinization alone. The authors speculated that when both treatments were used together, the increased ionization of phenobarbital resulting from P.569 sodium bicarbonate infusion may have decreased the efficacy of MDAC. These studies suggest that MDAC is more efficacious than urinary alkalinization in the treatment of phenobarbital poisoning, although both approaches are beneficial and indicated. Sodium bicarbonate therapy does not appear warranted in the treatment of ingestions of other barbiturates, such as pentobarbital and secobarbital, each of which has pKa >8.0 and is predominantly eliminated by the liver.

Chlorpropamide Chlorpropamide is a weak acid (pKa = 4.80) and has a long halflife (30–50 hours). In a human study using therapeutic doses of chlorpropamide, urinary alkalinization with sodium bicarbonate significantly increased renal clearance of the drug.57 This study showed that nonrenal clearance was the more significant route of elimination at a urinary pH of 5.0–6.0 (only slightly above pKa ) , whereas at pH = 8.0, renal clearance was 10 times that of nonrenal clearance. Alkalinization reduced the area under the curve almost 4-fold and shortened elimination half-life from 50 to 13 hours. Acidification increased the area under the curve by 41% and increased the half-life to 69 hours. Although not a study in

overdose patients, this report suggests that sodium bicarbonate may be useful in the management of patients with chlorpropamide overdose. The effect of urinary alkalinization on elimination of other sulfonylureas is unnecessary because the benefit presumably is limited as these agents are largely metabolized in the liver.

Chlorophenoxy

Herbicides

Alkalinization is indicated in the treatment of poisonings from weed killers that contain chlorophenoxy compounds, such as 2,4dichlorophenoxyacetic acid (2,4-D), or 2-(4-chloro-2methylphenoxy) propionic acid (MCPP).65 Poisoning results in muscle weakness, peripheral neuropathy, coma, hyperthermia, and acidemia. These compounds are weak acids (pKa = 2.6 and 3.8 for 2,4-D and MCPP, respectively) that are excreted largely unchanged in the urine. In an uncontrolled case series of 41 patients poisoned with a variety of chlorophenoxy herbicides, 19 of whom received sodium bicarbonate, alkaline diuresis significantly reduced the half-life of each compound by enhancing renal elimination. 20 In one patient, resolution of hyperthermia and metabolic acidosis and improvement in mental status were associated with a transient elevation of serum concentrations of these compounds, perhaps reflecting chlorophenoxy compound redistribution from the tissues into the more alkalemic blood. The limited data suggest that the increased ionized fractions of the weak-acid chlorophenoxy compounds produced by alkalinization is trapped in both the blood and the urine (as demonstrated with salicylates and phenobarbital); thus its use ameliorates toxicity and shortens duration of effect.

Correcting Toxic

Metabolic

Acidosis

Alcohols

Sodium bicarbonate has two important roles in treating toxic

alcohol ingestions. As an immediate temporizing measure, administration of sodium bicarbonate may reverse the lifethreatening acidemia associated with methanol and ethylene glycol ingestions. In rats poisoned with ethylene glycol, the administration of sodium bicarbonate alone resulted in a 4-fold increase in median lethal dose.10 Clinically, titrating the endogenous acid with bicarbonate greatly assists in reversing the consequences of severe acidemia, such as hemodynamic instability and multiorgan dysfunction. The second role of bicarbonate in the treatment of toxic alcohol poisoning involves its ability to favorably alter the distribution and elimination of certain toxic metabolites.69 In cases of methanol poisoning, the proportion of ionized formic acid can be increased by administering bicarbonate, thereby trapping formate in the blood compartment.34,48 Consequently, decreased visual toxicity results from removal of the toxic metabolite from the eye. In cases of formic acid (pKa = 3.7) ingestion, sodium bicarbonate decreases tissue penetration of the formic acid and enhances urinary elimination.54 Further investigation is required to delineate the beneficial effects of sodium bicarbonate in the treatment of toxic alcohol ingestions. Early treatment of acidemia with sodium bicarbonate is strongly recommended in cases of methanol and ethylene glycol poisoning.27 Sodium bicarbonate should be administered to toxic alcohol-poisoned patients with an arterial pH 3% of all reported cases in 2003 and ranking first among all pharmaceutical product exposures reported.75 In 2003, >91,000 NSAID exposures (excluding aspirin) were reported to TESS, of which 77% involved ibuprofen, 15% naproxen, and 7% COX-2 inhibitors. Remarkably, only 48 deaths were reported, with all but one, presumably the result of a consequential coingestant75 (Chap. 130) . Three NSAIDs (ibuprofen, naproxen, and ketoprofen) currently are available as both prescription and nonprescription products, and individually, as well as in combination with analgesics or analgesic cough and cold products. NSAIDs are available as veterinary products, and additional human exposures are occasionally secondary to inclusion of NSAID adulterants in patent herbal preparations.48

Pharmacology The NSAID class includes at least 20 drugs that share the mechanism of COX inhibition (Table 36-1). Competitive inhibition of COX produces both the therapeutic and some of the toxic effects of this group of drugs. Arachidonic acid is the precursor for the COX enzyme system. The process begins when arachidonic acid is cleaved from the phospholipid membrane of the cell by the action of phospholipase A (Figure 36-1). COX inhibition prevents the formation of prostaglandins, prostacyclins, and thromboxane A2 , but not

leukotrienes and other eicosanoids.28,74 The two isoforms of COX are labeled COX-1 and COX-2.64 COX-1 is vascular Inhibition platelets

present in the kidney and GI tract and is responsible for hemostasis, GI wall integrity, and renal homeostasis.19 of COX-1 decreases synthesis of thromboxane A2 in and interferes with their aggregation.

COX-2 is induced by inflammatory mediators and produces prostaglandins at the site of inflammation. The prostaglandins are responsible for mediating vasodilatation, increasing vascular permeability, and sensitizing pain fibers.47 The discovery that inhibition of COX-2 is associated with both the analgesic and antiinflammatory actions of the NSAIDs led to the introduction of COX-2–specific inhibitors. COX-2 inhibitors demonstrate this property only at therapeutic doses; at very high concentrations the COX-2 specificity is lost. An unanticipated finding of use of COX-2 selective NSAIDs was the finding that COX-2 NSAIDs increased the risk of CV disease. It now appears that this result probably is true of the entire class, although some drugs such as rofecoxib and valdecoxib appear to increase the risk more than others. Salicylates differ from the other NSAIDs in that they irreversibly bind to COX and produce an effect that lasts for the life of the platelet unless it can produce more enzyme. NSAIDs, such as diclofenac and indomethacin, also inhibit various lipoxygenase enzymes and decrease the production of leukotrienes in animals.22,28 Acetaminophen inhibits COX in the central nervous system but does not have clinical antiinflammatory effects and therefore is not an NSAID. Acetaminophen and salicylates are described in Chaps. 34 and 3 5, respectively.

Pharmacokinetics

and

Toxicokinetics

NSAIDs are rapidly absorbed from the GI tract, with peak levels occurring within 2 hours of oral administration for most drugs.

Sustained-release indomethacin, enteric-coated diclofenac, mefenamic acid, piroxicam, and the prodrugs sulindac and nabumetone require 2–5 hours to reach peak levels.7,68 All of these drugs are weakly acidic and highly protein bound (>90%), with volumes of distribution of approximately 0.1–0.2 L/kg. The NSAIDs cross the blood–brain barrier and are found in cerebrospinal fluid (CSF) and brain tissue. Peak CSF concentrations lag behind serum concentrations by at least 2 hours, and the relative ability of different NSAIDs to cross the blood–brain barrier is determined by lipophilicity.2,40

TABLE 36-1. Classes of Nonsteroidal Antiinflammatory Drugs

COX-1 and COX-2 inhibitors Salicylates Acetyl salicylic acid (aspirin) Nonacetylated derivatives (metabolized acid) Salsalate (Disalcid)

to

salicylic

Sodium salicylate Choline salicylate Magnesium salicylate Magnesium choline salicylate (Trilisate) Diflunisal (Dolobid; not metabolized to salicylic acid) Pyrazolones Phenylbutazone Fenamates (anthranilic acids) Meclofenamate (Meclomen) Mefenamic acid (Ponstel) Acetic acids Diclofenac (Voltaren) Etodolac (Lodine)

Indomethacin (Indocin) Ketorolac (Toradol) Nabumetone (Relafen) Sulindac (Clinoril) Tolmetin (Tolectin) Propionic acids Fenoprofen (Nalfon) Flurbiprofen (Ansaid) Ibuprofen (Motrin, Advil, Medipren)b Ketoprofen (Orudis)b Naproxen (Naprosyn, Anaprox)b Oxaprozin (Daypro) Oxicams Piroxicam (Feldene) COX-2 selective inhibitors Celecoxib (Celebrex) a Meloxicam (Mobic) Rofecoxib (Vioxx) Valdecoxib (Bextra) a

COX-2 preferential

b Nonprescription

Hepatic metabolism is the primary route for NSAID elimination, with renal elimination of unchanged drug accounting for Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > A - Analgesics and Antiinflammatory Medications > Chapter 37 - Colchicine and Podophyllin

Chapter

37

Colchicine

and

Podophyllin

Joshua G. Schier

Figure. No Caption Available.

A 48-year-old man presented to the emergency department with chief complaints of uncontrollable nausea, vomiting, and diarrhea. The patient stated that approximately 30 hours earlier, while he was intoxicated with ethanol, he had taken 20 colchicine tablets (0.6 mg) for a gout exacerbation. He developed mild nausea and vomiting several hours after ingestion, followed by diarrhea 14 hours later. The patient

decided to seek medical attention 16 hours after the onset of diarrhea when his symptoms did not improve and he was unable to urinate. He had a medical history significant for gout and ethanol abuse and reported taking only colchicine, naproxen, and indomethacin. On presentation, the patient was a well-nourished, anxious-appearing man in no acute distress. Vital signs were as follows: blood pressure, 117/53 mm Hg; pulse, 88 beats/min; respiratory rate, 22 breaths/min; temperature, 101.2°F (38.4°C). His physical examination was significant only for dry mucous membranes. Initial laboratory results revealed the following: sodium, 148 mEq/L; potassium, 4.5 mEq/L; chloride, 105 mEq/L; bicarbonate, 13 mEq/L; blood urea nitrogen, 20 mg/dL; creatinine 4.5 mg/dL. A complete blood count showed the following: white blood cell count, 15,500/mm3 ; hematocrit, 62.3%; platelets, 394,000/mm3 . Other laboratory results included prothrombin time, 18.7 seconds; activated partial thromboplastin time, 43.9 seconds; creatine kinase 883 IU/L; creatine kinase (MB fraction), 4.11 IU/L; aspartate aminotransferase, 336 U/L; alanine aminotransferase, 53 U/L; total bilirubin, 0.7 mg/dL; direct bilirubin, 0.5 mg/kg but 500

msec.151 Methadone and levo-α-acetylmethadol (LAAM) both prolong the QTc interval via interactions with cardiac K+ channels.116 , 119 LAAM was given a black box warning because of its association with torsade de pointes; this action essentially removed LAAM from use in the United States. Additionally, certain opioids, primarily propoxyphene, can alter the function of myocardial Na+ channels in a manner similar to that of the antidysrhythmics (Chap. 61 ).

Miosis The mechanisms by which opioids induce miosis remain controversial. Support for each of several mechanisms can be found in the literature. Stimulation of parasympathetic pupilloconstrictor neurons in the Edinger-Westphal nucleus of the oculomotor nerve by morphine produces miosis. Additionally, morphine increases firing of pupilloconstrictor neurons to light,138 which increases the sensitivity of the light reflex (central reinforcement of light reflex).255 Although sectioning of the optic nerve may blunt morphine-induced miosis, the consensual reflex in the denervated eye is enhanced by morphine. Because opioids classically mediate inhibitory neurotransmission, hyperpolarization of sympathetic nerves or of inhibitory neurons to the parasympathetic neurons (removal of inhibition) ultimately may be found to mediate the classic “pinpoint pupil― associated with opioid use. Not all patients using opioids present with miosis. Meperidine has a lesser miotic effect than other conventional opioids, and propoxyphene use does not result in miosis.75 Use of agents with predominantly κ-agonist effects, such as pentazocine, may not result in miosis. Mydriasis may occur in severely poisoned patients secondary to hypoxic brain insult. Additionally, concomitant drug use or the presence of adulterants may alter pupillary findings. For example, the combination of heroin and cocaine (“speedball―) may produce virtually any size pupil, depending on the relative contribution by each drug. Similarly, patients ingesting diphenoxylate

and atropine (Lomotil) or those using scopolamine-adulterated heroin86 routinely develop mydriasis.

Seizures Seizures are a rare complication of therapeutic use of most opioids. In patients with acute opioid overdose, seizures most likely are caused by hypoxia. However, experimental models demonstrate a proconvulsant effect of morphine101 in that it potentiates the convulsant effect of other xenobiotics.263 These effects are variably inhibited by naloxone, suggesting the involvement of a mechanism other than opioid receptor binding. In humans, morphine-induced seizures are reported in neonates and are reversible by naloxone, although opioid withdrawal seizures in neonates are more common.41 Seizures should be anticipated in patients with meperidine, propoxyphene, or tramadol toxicity. Naloxone antagonizes the convulsant effects of propoxyphene in mice, although it is only moderately effective in preventing seizures resulting from meperidine or its metabolite normeperidine.76 Interestingly, naloxone potentiates the anticonvulsant effects of benzodiazepines and barbiturates, although in a single study, it antagonized the effects of phenytoin.106 The ability of fentanyl and its analogs to induce seizures is controversial. They are used to activate epileptiform activity for localization in patients with temporal lobe epilepsy who are undergoing surgical exploration.162 Electroencephalograms (EEGs) performed on patients undergoing fentanyl anesthesia did not identify seizure activity even though the clinical assessment suggested that approximately one third had seizures.225 It appears likely that the rigidity and myoclonus associated with fentanyl are readily misinterpreted as a seizure.

Movement

Disorders

Patients may experience acute muscular rigidity with rapid intravenous injection of certain high-potency opioids, especially

fentanyl and its derivatives.238 This condition is particularly prominent during induction of anesthesia7 and in neonates.59 This rigidity primarily involves the trunk and may impair chest wall movement sufficiently to exacerbate hypoventilation. Chest wall rigidity may have contributed to the lethality associated with epidemics of fentanyl-adulterated heroin. Although the mechanism of muscle rigidity is unclear, it may be related to blockade of dopamine receptors in the basal ganglia. Other postulated mechanisms include γ-aminobutyric acid (GABA) antagonism and NMDA agonism.64 Opioid antagonists generally are P.597 therapeutic59 , 174 but may produce adverse hemodynamic effects, withdrawal phenomena, or uncontrollable pain, depending on the situation. Although not a problem for patients taking stable doses of methadone,70 rapid escalation of methadone doses may produce choreoathetoid movements.17 The movement disorder may be related to the opposing effects on GABAergic interneurons produced by µ and κ receptors. Methadone, a µ agonist, inhibits the release of GABA, an inhibitory neurotransmitter, within the striatum and mesolimbic system. The ultimate effect is enhancement of striatal dopamine release. This possibility is intriguing, given the developing concept that many forms of addiction result from the final common pathway

of

enhanced

Gastrointestinal

mesolimbic

dopamine

neurotransmission.

Effects

Historically, the morphine analog apomorphine was used as a rapidly acting emetic whose clinical use was limited by its tendency to depress the patient's level of consciousness. Emesis induced by apomorphine is mediated through agonism at D2 receptor subtypes within the chemoreceptor trigger zone of the medulla. Many opioids, particularly morphine, produce significant nausea and vomiting when used therapeutically.27 Whether these effects are inhibited by

naloxone is not clearly established, but they likely are not. Although diphenoxylate and loperamide are widely used therapeutically to manage diarrhea, opioid-induced constipation is most frequently a bothersome side effect of both medical and nonmedical use of opioids. Constipation, mediated by µ2 receptors within the smooth muscle of the intestinal wall,100 is ameliorated by oral naloxone. Provided the hepatic glucuronidative capacity is not exceeded (at doses of approximately 6 mg), enteral naloxone is poorly bioavailable and thus induces few, if any, opioid withdrawal symptoms.164 Methylnaltrexone and alvimopan are bioavailable, peripherally acting opioids that antagonize the peripheral effects of other opioids on the gastrointestinal tract.261 , 266 Opioid withdrawal does not occur because methylnaltrexone and alvimopan cannot cross the blood–brain barrier.

Figure 38-2. Structural similarity between methadone and propoxyphene and between phencyclidine and dextromethorphan.

Diagnostic Laboratory

Testing Considerations

Although it is always tempting to seek laboratory confirmation of an ingested substance in acutely poisoned patients, current laboratory methodology suffers from several important limitations and the potential for many confounding variables. The most apparent impediment to use of laboratory testing in the acute care setting is the lack of timely reporting of results. Patients may suffer grave consequences if therapy is withheld pending test results. Opioidpoisoned patients are particularly amenable to rapid clinical diagnosis because of the uniqueness of the opioid syndrome. Additionally, even in situations where the assay results are available rapidly, the fact that several distinct classes of agents can produce similar opioid effects limits the use of laboratory tests, such as immunoassays, that rely on structural features to identify drugs. Furthermore, because opioids may be chemically detectable long after their clinical effects have dissipated, assay results cannot be considered in isolation but rather viewed in the clinical context. Several well-described problems with laboratory testing of opioids are described below and in Chap. 7 .

Cros s -Reactivity Many opioids share remarkable structural similarities. Interestingly, structurally similar agents, such as methadone and propoxyphene, do not necessarily share the same clinical characteristics (Figure 38-2 ). Because most clinical assays depend on structural features to identify a drug, structurally similar agents may be detected in lieu of the desired drug. Whether a similar drug is noted by the assay depends on the sensitivity and specificity of the assay used and the serum

concentration of the agent. Some cross-reactivities are predictable, such as that of codeine with morphine, on a variety of screening tests. Other cross-reactivities are less predictable, as with the crossreaction of dextromethorphan and the phencyclidine (PCP) component of the fluorescence polarization immunoassay (Abbott TDx),206 a widely used drug-abuse screening test (Chap. 7 ). P.598

Congeners

and

Adulterants

Commercial opioid assays, which are specific for morphine, likely will not detect most of the semisynthetic and synthetic opioids. In some cases, epidemic fatalities involving fentanyl derivatives remained unexplained despite obvious opioid toxicity until the ultrapotent fentanyl derivative, α-methylfentanyl (although initially misidentified as 3-methylfentanyl), was identified by more sophisticated testing.132 , 154 Oxycodone, hydrocodone, and other common morphine derivatives have variable detectability by different opioid screens.224

Drug

Metabolism

A fascinating dilemma may arise in patients who ingest moderate to large amounts of poppy seeds.124 These seeds, which are widely used for culinary purposes, are derived from poppy plants and contain both morphine and codeine. Following ingestion of a single poppy seed bagel, patients may develop elevated serum morphine and codeine concentrations170 and test positive for morphine.201 Because the presence of morphine on a drug-abuse screen may suggest illicit heroin use, the implications are substantial. Federal workplace testing regulations thus require corroboration of a positive morphine assay with assessment of another heroin metabolite, 6monoacetylmorphine, prior to reporting a positive result.172 , 246 Humans cannot acetylate morphine and therefore cannot synthesize 6-monoacetylmorphine, but humans can readily deacetylate heroin, which is diacetylmorphine.

A similar problem may occur in patients taking therapeutic doses of codeine. Because codeine is demethylated to morphine by CYP2D6, a morphine screen may be positive as a result of metabolism and not structural cross-reactivity.69 Thus, determination of the serum codeine or 6-monoacetylmorphine concentration is necessary in these patients. Determination of the serum codeine concentration is not foolproof, however, because codeine is present in the opium preparation used to synthesize heroin.

Forensic

Testing

Decision making regarding the cause of death in the presence of systemic opioids often is complex.42 Variables that often are incompletely defined contribute substantially to the difficulty in attributing or not attributing the cause of death to the opioid. These variables include the specifics regarding the timing of exposure, the preexisting degree of sensitivity and/or tolerance, the role of cointoxicants including parent opioid metabolites, and postmortem redistribution and metabolism.51 , 118 Interesting techniques to help further elucidate the likely cause of death that have been studied include the application of postmortem pharmacogenetic principles107 and the use of alternative specimens (Chap. 33 ).

Management The consequential effects of acute opioid poisoning are central nervous system and respiratory depression. Although early support of ventilation and oxygenation is generally sufficient to prevent death, prolonged use of bag-valve-mask ventilation and endotracheal intubation may be avoided by cautious administration of an opioid antagonist. Opioid antagonists, such as naloxone, competitively inhibit binding of opioid agonists to opioid receptors, allowing the patient to resume spontaneous respiration. Naloxone competes at all receptor subtypes, although not equally, and is effective at reversing almost all adverse effects mediated through opioid receptors.

(Antidotes in Depth: Opioid Antagonists contains a complete discussion of naloxone and other opioid antagonists.) Because many clinical findings associated with opioid poisoning are nonspecific, the diagnosis requires clinical acumen. Differentiating acute opioid poisoning from other etiologies with similar clinical presentations may be challenging. Patients manifesting opioid toxicity, those found in an appropriate environment, or those with characteristic physical clues such as fresh needle marks require little corroborating evidence. However, subtle presentations of opioid poisoning may be encountered, and other entities superficially resembling opioid poisoning may occur. Hypoglycemia, hypoxia, and hypothermia are common clinical presentations that share features with opioid poisoning and may exist concomitantly. Each can be rapidly diagnosed with routinely available, real-time testing, but the proof of their existence does not exclude opioid toxicity. Other drugs responsible for similar clinical presentations include clonidine, PCP, pheno-thiazines, and sedative-hypnotic agents, primarily benzodiazepines. In such patients, clinical evidence usually is available to assist in diagnosis. For example, nystagmus nearly always is noted in PCP-intoxicated patients, hypotension or electrocardiographic abnormalities in phenothiazine-poisoned patients, and coma with virtually normal vital signs in patients poisoned by benzodiazepines. Most difficult to differentiate on clinical grounds may be toxicity produced by the centrally acting antihypertensive agents such as clonidine (see Clonidine below and Chap. 60 ). Additionally, a myriad of traumatic, metabolic, and infectious etiologies may occur simultaneously and must always be considered and evaluated appropriately.

Antidote

Administration

The goal of naloxone therapy is not necessarily complete arousal; rather, the goal is reinstitution of adequate spontaneous ventilation. Because precipitation of withdrawal is potentially detrimental and

often unpredictable, the lowest practical naloxone dose should be administered initially, with rapid escalation as warranted by the clinical situation. Most patients respond to 0.05 mg of naloxone administered intravenously, although the requirement for ventilatory assistance may be slightly prolonged because the onset may be slower than with larger doses. Administration in this fashion effectively avoids endotracheal intubation and allows timely identification of patients with nonopioid causes of their clinical condition yet diminishes the risk of precipitation of acute opioid withdrawal. Subcutaneous administration may allow for smoother arousal than the high-dose intravenous route250 but is unpredictable in onset and likely prolonged in offset. Prolonged effectiveness of naloxone by the subcutaneous route can be a considerable disadvantage if the therapeutic goal is exceeded and the withdrawal syndrome develops. In the absence of a confirmatory history or diagnostic clinical findings, the cautious empiric administration of naloxone may be both diagnostic and therapeutic. Naloxone, even at extremely high doses, has an excellent safety profile in patients with nonopioid-related indications, such as those with spinal cord injury20 or acute ischemic stroke. Thus, administration in an empiric fashion to most nonopioidpoisoned patients likely will not be harmful. However, administration of naloxone to opioid-dependent patients may result in adverse effects; obviously, precipitation of an acute withdrawal syndrome should be anticipated. The resultant agitation, hypertension, and tachycardia may produce significant distress to both the patient and the clinical staff and occasionally may be life threatening. Additionally, emesis, a common feature P.599 of acute opioid withdrawal, may be particularly hazardous in patients who do not rapidly regain consciousness after naloxone administration. For example, patients with concomitant ethanol or sedative-hypnotic exposure, or those with head trauma, are at substantial risk for pulmonary aspiration of vomitus if their airway is

unprotected. Identification of patients likely to respond to naloxone conceivably would reduce the unnecessary and potentially dangerous precipitation of withdrawal in opioid-dependent patients. Routine prehospital administration of naloxone to all patients with subjectively assessed altered mental status or respiratory depression was not beneficial in 92% of patients.264 Alternatively, although not perfectly sensitive, a respiratory rate ≤12 breaths/min in an unconscious patient presenting via EMS best predicted a response to naloxone.98 Interestingly, neither respiratory rate 30 kg/m2 without comorbid conditions, and for patients with BMI >27 kg/m2 with comorbid diseases of diabetes mellitus, dyslipidemia, or hypertension. Its effectiveness in producing weight loss is demonstrated in several randomized, double-blind studies.55 , 60 Patients receiving intermittent sibutramine therapy have significantly fewer adverse effects than patients who take sibutramine continuously.97 Clinical use of sibutramine for more than 1 year is unstudied. P.624 The pharmacologic activity of sibutramine results from hepatic first-pass metabolism by cytochrome P450 (CYP3A4) transforming sibutramine into the 2 active metabolites, mono-desmethylsibutramine and di-

desmethylsibutramine, which have half-lives of 14 and 16 hours, respectively. These metabolites are further metabolized and renally excreted. Medications that inhibit CYP3A4, such as cimetidine, erythromycin, and ketoconazole, may slow sibutramine metabolism. Moderate hepatic or renal impairment does not significantly alter the pharmacokinetics of sibutramine or its active metabolites. Sibutramine use is associated with psychosis,87 hypertension, cardiac ischemia, and death.37 Since Meridia was approved in 1998, 397 serious adverse reactions have been reported to the FDA, including 29 deaths. Nineteen of the deaths were due to cardiovascular causes, including 3 deaths in women younger than 30 years.37 Sibutramine was banned in Italy in March 2002 after 2 cardiovascular deaths, and its use as a weight loss drug is being scrutinized in other European countries and in the United States. Because sibutramine raises heart rate and blood pressure, it should not be used in patients with poorly controlled hypertension, coronary artery disease, glaucoma, or previous stroke. Use of sibutramine is contraindicated in patients with anorexia nervosa, severe hepatic or renal dysfunction, or seizure disorders. Sibutramine taken in combination with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, or any drug that affects serotonin release or reuptake, could induce serotonin syndrome, which is characterized by agitation, hyperthermia, autonomic instability,

and

myoclonus.

Serotonergic drugs used in the past to treat obesity include dexfenfluramine (Redux) and fenfluramine (Pondimin), but these agents have been withdrawn because of postmarketing reports of serious cardiac effects associated with their therapeutic use.11 , 14 , 20 , 24 , 31 , 95 The diet drug combination known as “Fen-Phen― for its two-drug prescription regimen of fenfluramine and phentermine (an amphetamine derivative) was popular in the 1990s because of the presumed improved side effect profile and efficacy achieved with lower doses of each drug. This drug combination was never approved by the FDA for treatment of obesity, and fenfluramine was withdrawn in 1997 when an unusual cardiac valvulopathy was described in 24 women taking Fen-Phen.20 All of the women presented with new heart murmurs and either right- or left-sided

valvular abnormalities. Eight of the 24 women also developed newly documented pulmonary hypertension. Several of these patients required cardiac surgery and were found to have plaquelike encasement of the leaflets and chordae, with preservation of valvular structure. These pathologic findings are identical to those described in patients with ergotamine-induced valvular disease and in those with carcinoid syndrome. Although subsequent studies confirmed this association, the reported magnitude of risk associated with these drugs has varied.44 , 45 , 95 Cases of regression of these valvular lesions with cessation of the drugs are reported,15 and limited evidence indicates that the valvular effects are milder than initially described.31 Primary pulmonary hypertension has been described in association with fenfluramine and dexfenfluramine since 1981.6 , 14 , 24 , 63 , 75 Primary pulmonary hypertension in association with another anorectic drug aminorex fumarate, was reported earlier in Europe.35 In one multicenter case control study of patients with primary pulmonary hypertension, use of anorectic drugs such as dexfenfluramine and fenfluramine for more than 3 months was associated with a 30-fold increased risk of primary pulmonary hypertension in these patients compared with nonusers.1 Several theories are proposed to explain the mechanism of pulmonary toxicity of these agents, 14 namely, serotonin-mediated constriction of pulmonary arteries,9 , 62

serotonin-mediated platelet aggregation, and vasoconstriction in lungs leading to microembolization, elevated pulmonary vascular resistance, and pulmonary hypertension.62

Agents that Metabolism, Fat

the

Alter Food Absorption, and Elimination

Absorption

Blockers

Orlistat (Xenical) was approved by the FDA in 1999 for treatment of obesity. At the time of this writing, orlistat is the only FDA-approved drug that alters the absorption, distribution, and metabolism of food. Orlistat is a

potent inhibitor of gastric and pancreatic lipase, thus reducing lipolysis and increasing fecal fat excretion.17 The drug is not systemically absorbed but exerts its effects locally in the gastrointestinal tract. It inhibits hydrolysis of dietary triglycerides and reduces absorption of the products of lipolysis, monoglycerides, and free fatty acids. Several clinical trials demonstrate that orlistat reduces gastrointestinal fat absorption by as much as 30%.99 When taken in association with a slightly calorie-restricted diet, weight loss of approximately 10% body weight can be achieved in 1 year.82 Orlistat should be taken only in conjunction with meals that have a high-fat content; it should not be consumed in the absence of food intake. Adverse effects correlate with the amount of dietary fat consumption abdominal pain, oily stool, fecal incontinence, fecal urgency, increased defecation. Concomitant use of natural fibers (6 g mucilloid dissolved in water) may reduce the gastrointestinal

and include flatus, and of psyllium side effects of

orlistat.18 Because orlistat reduces absorption of fat-soluble food constituents, daily ingestion of a multivitamin supplement containing vitamins A, D, and K, and β-carotene is advised to prevent resultant deficiency. Chitosan is a weight loss dietary supplement derived from exoskeletons of marine crustaceans. It is thought to act similarly to orlistat by binding to dietary lipids in the gastrointestinal tract and reducing breakdown and absorption of fat. Some evidence indicates that chitosan may decrease total serum cholesterol concentration in overweight people, but the majority of clinical studies indicate chitosan is ineffective for weight loss in the absence of dietary and lifestyle modifications.80 Chitosan is contraindicated in people with shellfish allergy.

Dietary

Fibers

Guar gum is derived from the bean of the Cyamopsis psorabides plant. It was marketed in pill or tablet form as Cal-Ban 3000 until it was banned by the FDA in 1992 because of its potential to cause gastrointestinal obstruction. The guar gum in Cal-Ban 3000 is a hygroscopic polysaccharide that expands 10–20-fold in the stomach, forming a gelatinous mass. The

purpose of ingesting guar was to cause gastric distension and create the sensation of satiety in the dieter, thus decreasing appetite and food intake. Guar gum resulted in numerous cases of esophageal and small-bowel obstruction both in patients with preexisting anatomical lesions such as strictures and in individuals with normal gastrointestinal anatomy.32 , 57 , 77 , 79

Glucomannan is a dietary fiber consisting of glucose and mannose, which is derived from konjac root, a traditional Japanese P.625 food. Edible forms of glucomannan include konjac jelly and konjac flour, which is mixed with liquid prior to ingestion. Purified glucomannan is available in capsule form and is found in various proprietary products marketed for weight loss. On contact with water, glucomannan swells to approximately 200 times its original dry volume, turning into a viscous liquid. It lowers blood cholesterol and glucose concentrations and decreases systolic blood pressure,5 , 93 but significant weight loss benefits have not been demonstrated. Following several reports of esophageal obstruction, oral glucomannan tablets were banned in Australia in 1985.38 Serious adverse effects are not described with encapsulated glucomannan, presumably because slower dissolution allows for gastrointestinal transit prior to expansion. Glucomannan capsules are available as a nutritional supplement in the United States, although adequate safety and efficacy studies are not published.

Dinitrophenol One of the earliest attempts at a pharmaceutical treatment for obesity was 2,4-dinitrophenol (DNP), which was popularized as a weight loss adjuvant in the 1930s.90 This chemical, which is used in dyes, wood preservatives, herbicides, and explosives, was never approved as a drug product but was legally available as a diet remedy prior to enactment of the US Federal Food, Drug, and Cosmetic Act of 1938. By increasing metabolic energy expenditure in doses of 100 mg three times per day, it reportedly produced weight loss of 1–2 pounds per week.21 DNP increases metabolic work by

uncoupling oxidative phosphorylation in the mitochondria via its action as an ionophore. Through this mechanism, the hydrogen ion gradient that allows ATP synthesis is dissipated, preventing the proton motive force from creating high-energy phosphate bonds (Chap. 13 ). Because the energy loss resulting from inefficient substrate utilization is dissipated as heat, elevated temperature and, occasionally, life-threatening hyperthermia can occur.89 DNP reportedly was administered to Russian soldiers during World War II to keep them warm during winter battles.51 Symptoms related to DNP toxicity include malaise, skin rash, headache, diaphoresis, thirst, and dyspnea. Severe toxic effects include hyperpyrexia, hepatotoxicity, agranulocytosis, respiratory failure, coma, and death.8 , 33 , 51 , 89 Delayed-onset cataract was a frequent and serious complication of DNP use.8 Use of DNP as a dieting aid reemerged in the 1980s when a physician in Texas processed industrial DNP into tablets and distributed them at his weight loss center under the trade name Mitcal. An intentional overdose fatality with Mitcal in 1984 led a Texas court to stop the use of this chemical for weight loss.51 DNP continues to reappear sporadically as a weight loss treatment, and cases of serious toxicity still are reported. Two recent cases include a 22-year-old man who developed fever, agitation, and delirium 16 hours after taking DNP, and a 17-year-old girl who developed fever, hypotension, and seizures.61 , 70 Both young victims died despite maximal resuscitative efforts. Intensive care management and emergent cooling are required in patients who present with hyperthermia after use of a weight loss product containing DNP.

Hypocaloric Abuse

Diets

and

Cathartic/Emetic

Medication abuse among individuals with various eating disorders is common.13 Starvation, as well as abuse of laxatives, syrup of ipecac, diuretics, and anorectic agents, has led to many fatalities, often in young patients.29 , 43 Fad diets and laxative abuse should be strongly considered in young people with unexplained dehydration, syncope, hypokalemia, and metabolic alkalosis. A variety of extreme calorie-restricted diets resulting in

profound weight loss were very popular in the late 1970s, but reports of a possible association between these diets and sudden death followed.81 Myocardial atrophy was a consistent finding on autopsy. Torsades de pointes and other ventricular tachycardias as a result of hypokalemia81 , 85 and protein-calorie malnutrition of the heart are proposed causes of death in these cases.26 , 81 , 85 Following the negative reports and FDA warnings, the enthusiasm for liquidprotein diets waned. Several current diets (Atkin's plan, South Beach diet) advocate intake of high protein, high fat, and low carbohydrates while allowing unlimited amounts of meat, fish, eggs, and cheese. Lack of carbohydrates induces ketosis, which results in diuresis and dehydration, giving the user the appearance of rapid weight loss. With rehydration and resumption of a normal diet, weight gain generally occurs. In addition, dehydration may cause orthostatic hypotension and ureterolithiasis. 2 Atherosclerosis and hypercholesterolemia may occur as a result of substitution of high-calorie, high-fat foods for carbohydrates. Dieter's teas that contain combinations of herbal laxatives, including senna and Cascara sagrada , can produce profound diarrhea, volume depletion, and hypokalemia. They are associated with cases of sudden death, presumably as a result of cardiac dysrhythmias. Despite FDA warnings of the dangers of these weight loss regimens, dieter's teas remain available in retail stores that sell nutritional supplements and are easily accessible to adolescents. Chronic laxative use can result in an atonic colon (“cathartic bowel―) and development of tolerance, with the subsequent need to increase dosing to achieve catharsis. Because cathartics do not decrease food absorption, these agents have limited effects on weight control.7 Various test methods can be used to detect laxative abuse.23 Phenolphthalein can be detected as a pink or red coloration to stool or urine following alkalinization. Colonoscopy reveals the benign, pathognomonic “melanosis coli,― the dark staining of the colonic mucosa secondary to anthraquinone laxative abuse. Chronic use of syrup of ipecac to induce emesis by patients with eating

disorders, such as bulimia nervosa, leads to the development of cardiomyopathy, subsequent dysrhythmias, and death.29 , 71 Emetine, a component of syrup of ipecac, is the alkaloid responsible for the severe myopathy experienced by these patients. In addition, chronic administration of syrup of ipecac results in tolerance to the emetic effects and increased systemic absorption of emetine.71 Emetine can be detected in serum by high-pressure liquid chromatography or thin-layer chromatography. It persists for weeks to months after ingestion. In 2003, an FDA advisory committee recommended that the nonprescription drug status of syrup of ipecac be rescinded because of its use by patients with bulimic disorders.

Novel Loss

Therapeutic

Approaches

to

Weight

Leptin and the leptin gene have been explored as a basis for obesity and as a therapeutic strategy. Genetically leptin-deficient mice are obese, and leptin replacement produces weight loss. Subcutaneous leptin supplementation appears to induce weight loss in lean and obese adults.39 Leptin replacement therapy in three humans with genetically based obesity resulted in profound weight loss and normalization of endocrine function.58 Because β 3

-adrenergic

P.626 receptors mediate lipolysis in adipose tissue, β3 -selective agonists also are under investigation as weight loss agents.78 Neuropeptide Y, a peptide found in the arcuate and paraventricular nucleus of the hypothalamus, is a potent central appetite stimulant. Future drug therapy may target these genes, receptors, and proteins to modify metabolism. As obesity research proceeds and the biologic basis for obesity is defined, new approaches and mechanisms for drug therapy may be identified.

Other

Herbal

Remedies

Several herbal remedies for weight loss have resulted in serious toxicity. In France, germander (Teucrium chamaedrys ) supplements taken for weight

loss resulted in 7 cases of hepatotoxicity.54 A “slimming regimen― first prescribed in a weight loss clinic in Belgium produced an epidemic of progressive renal disease, known as Chinese herb nephropathy, when botanical misidentification led to the substitution of Stephania tetrandra 92 with the nephrotoxic plant Aristolochia fangji . The toxic constituent, identified as aristolochic acid, is implicated in numerous cases of renal failure and urothelial carcinoma.59 A case of profound digitalis toxicity occurred with a laxative regimen contaminated with Digitalis lanata .83 Until regulation of herbal products is improved and manufacturing practices worldwide are standardized, sporadic reports of herb-related toxicity likely will continue (Chap. 43 ).

Summary Although obesity is a major health challenge and a major cause of preventable morbidity and mortality, unproven weight loss treatments are fraught with failure and potential toxicity. There probably is no appropriate substitute for a balanced weight loss plan that encompasses decreased caloric intake with increased energy expenditure through exercise. Clinicians should be aware of the lack of regulation of most available diet remedies and should report adverse events involving these products to poison control centers and to the FDA MedWatch system so that appropriate regulatory actions can be taken to prevent further instances of toxicity. A historical review of compounds used as weight loss agents readily uncovers numerous examples of poorly conceived drug regimens, popular misunderstanding of the benefits and risk of the drugs involved, and relatively poor postmarketing surveillance leading to unnecessary morbidity and mortality.

Acknowledgment Jeanmarie Perrone contributed to this chapter in a previous edition.

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99. Zhi J, Melia AT, Eggers H, et al: Review of limited systemic absorption of Orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol 1995;35:1103–1108.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > B - Foods, Dietary and Nutritional Agents > Chapter 40 - Iron

Chapter

40

Iron Jeanmarie

Perrone

Iron MW Serum

normal

=

55.85

daltons

=

80–180

=

14–32

µg/dL µmol/L

A 17-month-old boy was found by his mother playing with a bottle of iron supplements. The mother noted greenish discoloration around the child's lips and pill fragments in his mouth. She brought him to the emergency department (ED). En route to the hospital, spontaneous vomiting of pill fragments and hematemesis occurred. In the ED, the boy was noted to be lethargic with the following vital signs: blood pressure, 95/55 mm Hg; heart rate, 130 beats/min; respiratory rate, 35 breaths/min; temperature, 96.9°F (36°C). High-flow supplemental oxygen was given, IV access obtained, and fluid resuscitation (20 mL/kg) initiated. An abdominal radiograph revealed a large number of radiopaque fragments in the stomach.

Orotracheal intubation, orogastric lavage (with removal of more green pill fragments), and whole-bowel irrigation were performed. An arterial blood gas following intubation revealed significant metabolic acidosis: pH, 7.15; PCO2 , 34 mm Hg; PO2 , 441 mm Hg. Chelation with deferoxamine 135 mg/h (15 mg/kg/h) was started intravenously. Small amounts of dark brownish red urine from a Foley catheter were noted. Transfer of the patient to a tertiary care pediatric intensive care unit (ICU) was arranged. Other significant laboratory values were: white blood cell count (WBC), 22,000/mm3 ; hemoglobin, 11.6 g/dL; serum bicarbonate concentration, 10 mEq/L; glucose, 384 mg/dL; international normalized ratio (INR), 4.5; iron, 18,570 µg/dL; alanine aminotransfersase (ALT), 700 IU/mL. Upon arrival in the tertiary care pediatric ICU 3.5 hours after initial presentation, the patient was tachycardic with a pulse of 188 beats/min (normal 80–150 beats/min). He was hypotensive with a systolic blood pressure of 70 mm Hg (normal for age 80–110 mm Hg). Additional fluid boluses, transfusions of fresh-frozen plasma, and 2 units of packed red blood cells were administered. A repeat abdominal radiograph revealed persistent radiopaque pill fragments in the gut lumen (Figure 40-1). Lavage was performed again with upper gastrointestinal (GI) endoscopy, but pill fragments were adherent to the gastric mucosa. The patient was taken to the operating room, and a gastrotomy was performed to remove the remaining pill fragments (Figure 40-2). Sixteen hours postingestion, his oxygenation and hemodynamic status deteriorated. Acute lung injury was noted on chest radiograph. Oxygenation worsened despite maximal ventilatory support on 100% FIO2 : pH, 7.18; PCO2 , 41 mm Hg; PO2 , 37 mm Hg. Hypotension refractory to vasopressors and further transfusions of red blood cells and fresh-frozen plasma developed. A fatal cardiac arrest ensued approximately 20 hours postingestion. The patient's terminal serum iron concentration was 4000 µg/dL.

History

and

Epidemiology

Iron has been used therapeutically for thousands of years and continues to be available, both with and without prescription, for the prevention and treatment of iron-deficiency anemia in patients of all ages. Despite this long history of use, the first reports of iron toxicity only occurred in the mid-20th century. Since then, numerous cases of iron poisoning and fatalities have been reported, most of them in children.56,57 In 1950, the manufacturer of “fersolate― included a package warning: “Excessive doses of iron can be dangerous. Do not leave these tablets within reach of young children, who may eat them as sweets with harmful results.― 84 The incidence of iron exposures continued to increase in the 1980s, and in the 1990s iron exposure became the leading cause of poisoning deaths in children younger than 6 years. This finding was publicized by a case series of tragic Los Angeles during a 6-month period prenatal vitamins containing iron.91 availability of these potentially lethal

fatalities involving 5 toddlers in in 1992. All cases involved This association highlights the medications in the homes of

families with young children, paradoxically as a result of more attentive prescribing of prenatal iron. A case control P.630 study in Canada identified a 4-fold increase in the risk of iron poisoning to the older sibling of a newborn during the first postpartum month.41 The authors concluded that almost half of all hospital admissions of young children for iron poisoning could be prevented by safer storage of iron supplements in the year before and the year after the birth of a sibling.

Figure 40-1. A 17-month-old boy presented to the hospital with lethargy and hematemesis following a large ingestion of iron supplement pills. Despite orogastric lavage and whole-bowel irrigation, iron pills and fragments can be visualized in the stomach 4 hours postingestion.

In 1997, the Food and Drug Administration (FDA) mandated that all iron salt-containing preparations have warning labels regarding the dangers of pediatric iron poisoning.23 In addition to the warning labels, the FDA launched an educational campaign to alert caregivers

and prescribers of the potential toxicity of iron supplements.22 Other preventive initiatives instituted by the FDA in 1997 included unit dosing (blister packs) of prescriptions containing more than 30 mg of elemental iron and limitations on the number of pills dispensed (ie, maximum 30-day supply).23 These efforts to prevent unintentional exposure dramatically decreased the incidence of poisoning and are pivotal in decreasing morbidity and mortality associated with iron poisoning (Chap. 130 and associated references). Unfortunately, in 2003 the FDA rescinded the blister packaging requirement in response to a lawsuit charging that the FDA did not have jurisdiction over the packaging of dietary supplements.21 Although isolated fatalities continue to occur,55 the trend in American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) data suggests they are becoming less common (Chap. 130 and associated references).

Figure 40-2. Ten hours postingestion. Persistent iron pills were removed from the stomach by gastrotomy. No further radiopaque fragments can be visualized; however, acute lung injury is now visible.

Iron poisoning can occur after ingestion of other iron salts, such as ferric chloride, used in industry.99 Parenteral iron, such as iron dextran, administered intravenously to patients with renal failure and chronic anemia, also can result in toxicity, especially anaphylactoid reactions. Newer parenteral formulations, including iron sucrose and sodium ferrous gluconate, appear to be safer.20 Iron supplements

are available in two nonionic forms, carbonyl iron and iron polysaccharide, both of which appear to be less toxic following overdose than are iron salts.74

Pharmacology

and

Toxicokinetics

Iron is an element critical to organ function. As a transition metal, iron can easily accept and donate electrons, thereby shifting from a ferric (Fe3 +) to a ferrous (Fe2 +) state (Chap. 12). This redox interchange allows iron to fulfill its role in multiple protein and enzyme complexes, including cytochromes and myoglobin, although it is principally found incorporated into hemoglobin in erythrocytes. Insufficient iron availability results in anemia, whereas excess total body iron results in hemochromatosis. P.631 The body cannot directly excrete iron, so body iron stores are regulated by controlling iron absorption from the gastrointestinal tract. Iron absorption, which occurs predominantly in the duodenum, is determined by the body's iron requirements. In iron deficiency, iron uptake into intestinal mucosal cells may increase from a normal of 10–35% to as much as 80–95%. Following uptake into the intestinal mucosal cells, iron is either stored as ferritin and lost when the cell is sloughed, or released to transferrin, a serum iron-binding protein. In therapeutic doses, some of these processes become saturated, and absorption into the intestinal cell may be limited. However, in overdose the oxidative effects of iron on gastrointestinal mucosal cells lead to dysfunction of this regulatory balance, and increased passive absorption of iron occurs down its concentration gradient78 (see Pathophysiology below). Iron supplements are available as the iron salts ferrous gluconate, ferrous sulfate, and ferrous fumarate, and as the nonionic preparations carbonyl iron and polysaccharide iron. Additional sources of significant quantities of iron are vitamin preparations, especially prenatal vitamins (Table 40-1). Toxic effects of iron

poisoning occur at doses of 10–20 mg/kg elemental iron (elemental iron is a measure of the amount of iron present in an iron salt; Table 40-1). Significant gastrointestinal symptoms occurred in human adult volunteers who ingested 10–20 mg of elemental iron/kg.9,49 In one volunteer study, 6 subjects who ingested 20 mg/kg elemental iron developed nausea and voluminous diarrhea within 2 hours, and 5 of the 6 subjects had serum iron concentrations above 300 µg/dL.9 Chewable vitamins continue to entice children with their sweet taste and recognizable character shapes, increasing the risk of significant exposure. Children's chewable multivitamins contain less iron per tablet (10–18 mg elemental iron) than typical prenatal vitamins (65 mg elemental iron). Toxicity still results when large quantities are ingested, but fatalities are not reported.2 One animal study paradoxically demonstrates higher iron concentrations following ingestion of equivalent doses of chewable versus solid iron tablets.59 This finding was attributed, in part, to the limited gastric irritation associated with the chewable iron preparations, resulting in less vomiting and higher iron concentrations. Iron polysaccharide and carbonyl iron appear to be safer formulations than iron salts despite their high elemental iron content.45 Carbonyl iron is a form of elemental iron that is highly bioavailable in therapeutic doses because of its high elemental iron content and its very fine, spherical particle size (5 µm). However, toxicity is limited in overdose because carbonyl iron has poor solubility and a slow rate of conversion to the toxic ionic form that occurs in the acid milieu of the stomach. This delayed oxidation is the rate-limiting step that prevents excess absorption. 33 In a rat model of iron toxicity, carbonyl iron had an LD50 (median lethal dose for 50% of test subjects) of 50 g/kg compared with an LD50 of 1.1 g/kg for ferrous sulfate. 94 No significant toxicity in humans exposed to carbonyl iron has been reported.74

TABLE 40-1. Common Iron Formulations and Their Elemental Iron Contents

Iron

Formulation

Elemental

Iron

Ionic

Ferrous

chloride

28%

Ferrous

fumarate

33%

Ferrous

gluconate

12%

Ferrous

lactate

19%

Ferrous

sulfate

20%

iron

98%a

Nonionic

Carbonyl

Iron

polysaccharide

46%a

a Although

these nonionic iron formulations contain higher elemental iron content than ionic formulations, carbonyl iron and iron polysaccharide have better therapeutic-to-toxic ratios.

Iron polysaccharide contains approximately 46% elemental iron by

weight. It is synthesized by neutralization of a ferric chloride carbohydrate solution. This form of iron also appears to have much lower toxicity than iron salts. The estimated LD50 in rats is more than 5 g/kg body weight. Retrospective poison center data have shown little toxicity from either of these products.45

Pathophysiology As a transition metal, iron can assume one of several different oxidation, or valence, states. It is an active participant in reductionoxidation (redox) reactions. In particular, iron's participation in the Fenton reaction and Haber-Weiss cycle explains its toxicologic effects as a generator of oxidative stress and inhibitor of several key metabolic enzymes (Chaps. 12 and 9 0). Reactive oxygen species oxidize membrane-bound lipids and cause loss of cellular integrity and tissue injury (Chap. 12) .68,70 The initial oxidative damage to the gastrointestinal epithelium produced by iron-induced reactive oxygen species permits iron ions to enter the systemic circulation. Iron ions are rapidly bound to circulating binding proteins, particularly transferrin. Once transferrin is saturated with iron, “free― iron (iron not bound to a transport protein) is widely distributed to the various organ systems, where it promotes damaging oxidative processes. A postmortem series of 11 patients following iron ingestion substantiated these findings with measurements of elevated iron concentrations in most major organs examined: stomach, liver, brain, heart, lung, small bowel, and kidney.63 Consistent with oxidative damage, congestion, edema, necrosis, and iron deposition in the gastric and intestinal mucosa, as well as hemorrhage and congestion in the lungs, are noted on postmortem examination.30,31,51 Iron ions disrupt critical cellular processes such as mitochondrial oxidative phosphorylation. Subsequent buildup of unused hydrogen ions normally incorporated into the synthesis of ATP, leads to liberation of H + and development of metabolic acidosis (Chap. 13) .

In addition, absorption of iron from the gastrointestinal tract leads to conversion of ferrous iron (Fe 2 +) to ferric iron (Fe3 +). Ferric iron ions exceed the binding capacity of plasma, leading to formation of ferric hydroxide and production of three protons (Fe3 + + 3H2 O → Fe(OH)3 + 3H+) .68,78 Decreased cardiac output contributes to hemodynamic shock in animals.88,97 Although this finding has been attributed to decreased venous filling pressures, decreased preload, and relative bradycardia,88 a direct negative inotropic effect of iron on the myocardium also is demonstrated in animal models.3 Reports of early coagulopathy unrelated to hepatotoxicity80 led to the identification of free iron inhibition of thrombin formation and the effect of thrombin on fibrinogen.71

Clinical

Manifestations

Classic teaching posits five clinical stages of iron toxicity based on the pathophysiology of iron poisoning.6,40,66 Although these stages P.632 are conceptually important, they are of limited benefit to the clinician managing a poisoned patient. A clinical stage should never be assigned based on the number of hours postingestion because patients do not necessarily follow the same temporal course through these stages. The first stage of iron toxicity is characterized by nausea, vomiting, abdominal pain, and diarrhea. The “local― toxic effects of iron predominate, and subsequent salt and water depletion contribute to the ill appearance of the iron-poisoned patient. Intestinal ulceration, edema, transmural inflammation, and, in some extreme cases, smallbowel infarction and necrosis may occur.24,69,82 Hematemesis, melena, or hematochezia may cause hemodynamic instability. Gastrointestinal symptoms always follow significant overdose. Conversely, the absence of symptoms, specifically vomiting, in the first 6 hours postingestion, essentially excludes serious iron toxicity.

The second or “latent― stage of iron poisoning commonly refers to the period 6–24 hours following resolution of gastrointestinal symptoms and before development of overt systemic toxicity. Delineation of this stage may have evolved from early case reports of patients whose gastrointestinal symptoms had resolved prior to subsequent deterioration.84 This second stage is not a true quiescent phase, as ongoing cellular organ toxicity occurs during this phase.6 Although clinicians should be wary of patients who no longer have active gastrointestinal complaints following iron overdose, most such patients have recovered and are not in the latent phase. Patients in the latent phase generally have lethargy, tachycardia, or a metabolic acidosis. They should be readily identifiable as clinically ill, despite resolution of their gastrointestinal symptoms. In summary, patients who have remained well since ingestion and who have stable vital signs, a normal mental status, and a normal acid–base balance will have a benign clinical course. Patients who progress to the third or “shock― stage of iron poisoning have profound toxicity. This stage may occur in the first few hours after a massive ingestion or 12–24 hours after a more moderate ingestion. The etiology of shock may be multifactorial, resulting from hypovolemia, vasodilation, and poor cardiac output,88,97 with decreased tissue perfusion and an ongoing metabolic acidosis. An iron-induced coagulopathy may worsen bleeding and hypovolemia.80 Systemic toxicity produces CNS effects with lethargy, hyperventilation, seizures, or coma. The fourth stage of iron poisoning is characterized by hepatic failure, which may occur 2–3 days following ingestion.30 The hepatotoxicity is directly attributed to iron uptake by the reticuloendothelial system in the liver, where it causes oxidative damage.26,98 The fifth stage of iron toxicity rarely occurs. Gastric outlet obstruction, secondary to strictures and scarring from the initial gastrointestinal injury, can develop 2–8 weeks following ingestion.29,35,82

Patients with chronic iron overload are at increased risk for Yersinia enterocolitica infection. Iron is a required growth factor for Y . enterocolitica; however, the bacterium lacks the siderophore to solubilize and transport iron intracellularly. Because deferoxamine is a siderophore, it fosters the growth of Y. enterocolitica. Patients with chronic iron overload or acute poisoning develop Yersinia infection or sepsis as a complication of iron poisoning or deferoxamine therapy.10,53,55,76 Yersinia infection should be suspected in patients who experience abdominal pain, fever, and diarrhea following resolution of iron toxicity. In this setting, cultures should be obtained and appropriate antibiotic therapy initiated.

Diagnostic

Testing

Radiography Iron is available in many forms, and the different preparations vary with respect to radiopacity on abdominal radiography.75 Factors such as time since ingestion and amount of elemental iron also play a role.58,75 Liquid iron formulations and chewable iron tablets typically are not radiopaque.18 A retrospective review of iron ingestions in children revealed that abdominal radiographs were positive in only 1 of 30 patients who ingested chewable vitamins.18 Because adult preparations have a higher elemental iron content and do not readily disperse, they tend to be more consistently radiopaque.58 Finding radiopaque pills on an abdominal radiograph is helpful in guiding and evaluating the success of gastrointestinal decontamination.36 However, the absence of radiographic evidence of pills is not a reliable indicator to exclude potential toxicity58,62 (Chap. 6) .

Laboratory

Studies

Many different laboratory studies are used as surrogate markers to assess the severity of iron poisoning. An anion-gap metabolic acidosis resulting primarily from lactate is a common finding in

patients with serious iron ingestions. Serial electrolyte concentrations can be used to assess progression and response to volume replacement. Anemia can result from gastrointestinal blood loss but may not be evident initially because of hemoconcentration secondary to plasma volume loss. Although one small retrospective study of iron-poisoned children found that WBC >15,000/mm3 or blood glucose concentration >150 mg/dL was 100% predictive of iron concentration >300 µg/dL,48 three subsequent studies that similarly examined this issue were unable to validate this association.11,47,62 In practice, an elevated WBC or glucose concentration should raise concern about an elevated serum iron concentration; however, assessment of the signs and symptoms of the patient probably is more reliable. Although iron poisoning remains a clinical diagnosis, serum iron concentrations can be used effectively to gauge toxicity and the success of treatment.6 In the previously mentioned human volunteer study of 6 adults who ingested 20 mg/kg elemental iron, all 6 adults demonstrated significant gastrointestinal toxicity, and the 4 who required intravenous fluid resuscitation had peak serum iron concentrations in the range of 300 µg/dL between 2 and 4 hours after ingestion.9 In another study of human volunteers who ingested 5–10 mg/kg elemental iron in the form of chewable vitamins, peak serum iron concentrations occurred between 4.2 and 4.5 hours in all subjects.49 In overdose, peak concentrations of iron are thought to occur 2–6 hours after ingestion, depending on the iron preparation.9,49 Serum iron concentrations between 300 and 500 µg/dL usually correlate with significant gastrointestinal toxicity and modest systemic toxicity. Concentrations between 500 and 1000 µg/dL are associated with pronounced systemic toxicity and shock.92 Concentrations >1000 µg/dL are associated with significant morbidity and mortality.92 Although elevated serum iron concentrations may be an additional indicator of potentially serious toxicity, lower concentrations cannot be used to exclude the possibility of serious toxicity. A single serum iron concentration may

not represent a peak concentration or may be falsely lowered by the presence of deferoxamine, unless an atomic absorption technique is used for measurement.28,34 P.633 Total iron-binding capacity (TIBC) is a measurement of the total amount of iron that can be bound by transferrin in a given volume of serum.19 Previously, clinical iron toxicity was thought not to occur if the serum iron concentration was less than the TIBC because insufficient circulating “free― iron was present to cause tissue damage. Although this may be conceptually true, further research has clarified the limitations of TIBC values. Most importantly, the in vitro value of TIBC factitiously increases as a result of iron poisoning and thus has a tendency to apparently falsely rise above a concurrently measured serum iron concentration.9,83 Because of many confounding issues, the TIBC as currently analyzed has no value in the assessment of the iron-poisoned patient.

Management Initial

Approach

As with any serious ingestion, initial stabilization must include supplemental oxygen, airway assessment, and establishment of intravenous access. Evidence of hematemesis or lethargy following an iron exposure may be a manifestation of significant toxicity. Intravenous volume repletion should begin while orogastric lavage and whole-bowel irrigation (WBI) are considered. In any lethargic patient who likely will deteriorate progressively, early orotracheal intubation may facilitate safe gastrointestinal decontamination measures. An abdominal radiograph can be used to estimate the iron burden in the gastrointestinal tract given the caveats discussed earlier. Laboratory values including chemistries, hemoglobin, iron concentration, coagulation, and hepatic profiles are necessary in the sickest patients. An arterial blood gas, venous blood gas, or stat

electrolytes rapidly detects a metabolic acidosis. Patients who appear well or had only 1–2 brief episodes of vomiting can be observed pending discharge. Alternatively, a serum iron concentration can be measured.

Limiting

Absorption

Gastrointestinal decontamination procedures should be initiated following stabilization. Adequate gastric emptying is critical following ingestion of substances, such as iron, that are not well adsorbed to activated charcoal. Because vomiting is a prominent early symptom in patients with significant toxicity, little benefit is expected from induced emesis, and this technique is no longer recommended. Orogastric lavage is more effective but can be limited because of the large size and poor solubility of most iron tablets, their ability to form adherent masses,24,87 and their movement into the bowel several hours after ingestion.42 The presence and location of radiopaque pills on abdominal radiograph can help guide lavage. Lavage likely will not be successful once iron tablets move past the pylorus, so WBI may be more effective (Figures 40-1 and 40-2) . Many strategies used in the past attempted to improve the efficacy of orogastric lavage. At the present time, no data support the use of oral deferoxamine,32,39,95,96,101 bicarbonate,14,15 phosphosoda,4,27 or magnesium.12,73,90 Although some of these techniques demonstrate efficacy, the associated risks mandate use of only 0.9% sodium chloride solution or tap water for orogastric lavage. Use of WBI in patients with iron poisoning is supported primarily by case reports and one uncontrolled case series.17,42,79,80 However, the rationale for WBI use is logical, especially considering the limitations of other gastric decontamination modalities. The usual dose of WBI with polyethylene glycol electrolyte lavage solution is 500 mL/h in children and 2 L/h in adults. This rate is best achieved by starting slowly and increasing as tolerated, often using a nasogastric tube and an infusion pump to administer large volumes.

Antiemetics such as metoclopramide or serotonin antagonists can be used to treat nausea and vomiting. A large volume (44 L) of WBI was administered safely over a 5-day period to a child who had persistent iron tablets on serial abdominal radiographs42 (Antidotes in Depth: Whole-Bowel Irrigation) . For patients who demonstrate persistent iron in the gastrointestinal tract despite orogastric lavage and WBI, upper endoscopy or gastrotomy and surgical removal of iron tablets adherent to the gastric mucosa may be necessary and lifesaving.24,64,87

Deferoxamine Deferoxamine has been available since the 1960s as a specific chelator for patients with acute iron overdose or chronic iron overload (eg, multiple transfusions). Deferoxamine, which is derived from culture of Streptomyces pilosus, has high affinity and specificity for iron. In the presence of ferric iron (Fe3 +), deferoxamine forms the complex ferrioxamine, which is excreted by the kidneys,43 imparting a reddish-brown color to the urine. (See ILD fourine in the Image Library at http://www.goldfrankstoxicology.com) Deferoxamine chelates free iron and the iron transported between transferrin and ferritin,50,65 but not the iron present in transferrin, hemoglobin, hemosiderin, or ferritin.5,43 Deferoxamine may work by other mechanisms in addition to binding excess systemic iron. Because 100 mg deferoxamine mesylate chelates approximately 8.5 mg ferric iron, recommended or typical therapeutic dosing of deferoxamine does not produce significant excretion of chelated iron in the urine, yet it does often result in dramatic clinical benefits (Antidotes in Depth: Deferoxamine). Sufficient evidence suggests that deferoxamine can reach intracytoplasmic and mitochondrial free iron, thereby limiting intracellular iron toxicity.50 Intravenous administration of deferoxamine should be considered in iron-poisoned patients with any of the following findings: metabolic acidosis, repetitive vomiting, toxic appearance, lethargy,

hypotension, or signs of shock. Deferoxamine administration also should be considered for any patient with an iron concentration >500 µg/dL. In patients manifesting serious signs and symptoms of iron poisoning, deferoxamine should be initiated as an intravenous infusion, starting slowly and gradually increasing to a dose of 15 mg/kg/h. Hypotension is the rate-limiting factor as more rapid infusions are used.37,93,95 Intramuscular administration of deferoxamine once was a popular method of therapy and part of the “deferoxamine challenge― test but is no longer recommended. The “challenge― test consisted of administration of an IM dose of deferoxamine 1–2 g (90 mg/kg), followed by collection of urine samples to assess for a color change indicating the availability of free iron.25 Patients who appear toxic and/or have serum iron concentrations >500 µg/dL should be treated with deferoxamine intravenously. Patients who have concentrations 40 mg/kg elemental iron. Children who appear well with unintentional ingestions between 10 and 20 mg/kg elemental iron and Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > B - Foods, Dietary and Nutritional Agents > Chapter 41 - Vitamins

Chapter

41

Vitamins Beth Y. Ginsburg Vitamins are essential for normal human growth and development.36 By definition, a vitamin is a substance that is present in small amounts in natural foods, is necessary for normal metabolism, and whose lack in the diet causes a deficiency disease. 30 According to the American Medical who eat a varied millions of people vitamins in great

Association, healthy men and nonpregnant women diet do not need supplemental vitamins.8 However, in the United States regularly ingest quantities of excess of the recommended dietary allowances

(RDAs) (Table 41-1 ). Many of these individuals share the mistaken beliefs that vitamin preparations provide extra energy or promote muscle growth. Fortunately, for the most part, even large doses of vitamins do not lead to significant toxicity. However, some vitamins are associated with significant adverse effects when ingested in very large doses. Vitamins can be divided into two general classes. Most of the vitamins in the water-soluble class have minimal toxicity because they are stored to only a limited extent in the body. Thiamine, riboflavin,

cyanocobalamin (vitamin B12 ), pantothenic acid, folic acid, and biotin are not reported to cause any toxicity following oral ingestion.36 Ascorbic acid (vitamin C), nicotinic acid, and pyridoxine (vitamin B6 ) are associated with toxicity syndromes. The fat-soluble vitamins can bioaccumulate to massive degrees. As a result, the potential for toxicity greatly exceeds that of the water-soluble group. Vitamins A, D, and E but not K are associated with toxicity in the setting of very large overdoses. Adverse effects secondary to vitamin K are limited to severe, and sometimes fatal, anaphylactoid reactions with administration of the intravenous (IV) preparation.58

Vitamin

A

Figure. No Caption Available.

History

and

Epidemiology

The term vitamin A , classically used to refer to the compound retinol, now is also used to describe other naturally occurring derivatives of retinol. Vitamin A activity is expressed in retinol equivalents (RE). One RE corresponds to 1 µg of retinol or 3.3 international units (IU) of vitamin A activity as retinol. As a group, these compounds are called retinoids. They have specific sites of action and varying degrees of biologic potency. Vitamin A, in the form of 11-cis -retinal, plays a critical role in retinal function.187 Deficiency results in

nyctalopia, which is decreased vision in dim lighting, more commonly known as night blindness. Retinoic acid is primarily responsible for maintaining normal growth and differentiation of epithelial cells in mucus-secreting or keratinizing tissue.122 Vitamin A deficiency results in the disappearance of goblet mucous cells and replacement of the normal epithelium with a stratified, keratinized epithelium. Dermal manifestations are the earliest to develop and include dry skin and hair and broken fingernails. In the cornea, hyperkeratization is called xerophthalmia and can lead to permanent blindness. Alterations in the epithelial lining of other organ systems may lead to increased susceptibility to respiratory infections, diarrhea, and urinary calculi. Two independent groups discovered vitamin A in 1913.126 , 144 They reported that animals fed an artificial diet with lard as the sole source of fat developed a nutritional deficiency characterized by xerophthalmia. They found that this deficiency could be corrected by adding to the diet a factor contained in butter, egg yolks, and cod liver oil. They named this substance “fat soluble vitamin A.― The chemical structure of vitamin A was determined later in 1930.99 Preformed vitamin A is also found in liver, fish, cheese, and whole milk. In the United States, many breakfast cereals, margarine, and most fat-free milk and dried nonfat milk solids are fortified with vitamin A.193 In some developing countries, sugar, oil, margarine, milk, wheat and corn flours, noodles, and rice are fortified with vitamin A.6 In addition, infant formulas and cereals usually are fortified with vitamin A. Vitamin A content varies widely among different food types. A 3-oz serving of cooked beef liver contains 30,325 IU of vitamin A, whereas 1 cup of whole milk contains 305 IU of vitamin A. Fish-liver oils, such as swordfish and Black Sea bass, have extremely large amounts of vitamin A and may contain more than 180,000 IU of vitamin A per gram of oil. Carotenoids, vitamin A precursors, are present in yellow and green fruits and vegetables. A raw carrot has a high β-carotene content of approximately 20,250 IU. One half-cup serving of spinach contains approximately 7395 IU of βcarotene, whereas an apricot or peach

P.644 contains 500–600 IU. The average American diet provides about half of its daily vitamin A intake as carotenoids and about half as preformed vitamin A.34 The RDA of vitamin A is 900 µg RE/d (3000 IU/d) for adult men and 700 µg RE/d (2300 IU/d) for women (Table 41-1 ).62 The tolerable upper intake level for adults is 3000 µg/d (9900 IU/d).62 Infants 0.0–0.5 400/1300* 5/200* 4/4* 40* 0.1* 2* 0.5–1.0 500/1700* 5/200* 5/5* 50* 0.3* 4* Children 1–3 300/990 5/200* 6/6 15 0.5 6 4–8 400/1300 5/200* 7/7

25 0.6 8 Males 9–13 600/2000 5/200* 11/11 45 1.0 12 14–18 900/3000 5/200* 15/15 75 1.3 16 19–49 900/3000 5/200* 15/15 90 1.3 16 50–70– 900/3000 10/400* 15/15 90 1.7 16 >70 900/3000

15/600* 15/15 90 1.7 16 Females 9–13 600/2000 5/200* 11/11 45 1.0 12 14–18 700/2300 5/200* 15/15 65 1.2 14 19–49 700/2300 5/200* 15/15 75 1.3 14 50–70 700/2300 10/400* 15/15 75 1.5 14

>70 700/2300 15/600* 15/15 75 1.5 14 Pregnant ≤18 750/2500 5/200* 15/15 80 1.9 18 19–50 770/2500 5/200* 15/15 85 1.9 18 Lactating ≤18 1200/4000 5/200* 19/19 115 2.0 17 19–50 1300/4300 5/200* 19/19

120 2.0 17 Adapted from Food and Nutrition Information Center homepage. http://www.nal.usda.gov/fnic/etext/000105.html . Accessed April 27, 2005.

Age (yr)

Vitamin A (µg RE/IU)

Vitamin D (µg/IU)

Vitamin E (mg αTE/IU)

Vitamin C (mg)

Vitamin B6 (mg)

Niacin (mg NE)

TABLE 41-1. Recommended Dietary Daily Allowances/Adequate Daily Intakes Hypervitaminosis A can occur in people who ingest large doses of vitamin A in their daily diets. Vitamin A toxicity is believed to occur in the Inuit population whose diet includes polar bear liver. Polar Eskimos in the 16th century recognized that ingestion of large amounts of polar bear liver caused a severe illness characterized by headaches and prostration.59 Arctic explorers in the 1800s knew of the poisonous qualities of polar bear liver and described an acute illness following its ingestion. 66 However, the toxic substance in polar bear liver was not identified as vitamin A until 1942.158 The vitamin A content of polar bear liver is as high as 34,600 IU/g, supporting the view that vitamin A is the toxic factor in liver.159 Hypervitaminosis A also is implicated in the etiology of pibloktoq, or “arctic hysteria,― as some somatic and behavioral effects of vitamin A toxicity closely parallel many of the symptoms reported in Inuit patients diagnosed with pibloktoq.108 Vitamin A toxicity was reported in an adult who chronically ingested large amounts of beef liver.93 Symptomatology consistent with vitamin A toxicity was reported following ingestion of the liver of the grouper fish Cephalopholis boenak , which has an average vitamin A

content high enough to cause acute toxicity.31 Ingestion of sea whale and seal liver, as well as the livers of large fish, such as shark, tuna, and sea bass, also is associated with development of hypervitaminosis A. The majority of cases of vitamin A toxicity result from use of vitamin supplements.14 , 16 In the United States, approximately 5% of adults take vitamin A supplements.76 Vitamin A is prescribed for some people for dermatologic and ophthalmic conditions. Hypervitaminosis A often occurs in adults who continue to use the vitamin without medical supervision.67 Isotretinoin (Accutane), 13-cis -retinoic acid, is prescribed for treatment of severe cystic acne. Of great concern is the teratogenicity associated with its use. According to the National Disease and Therapeutic Index, 38% of isotretinoin users are females aged 13–19 years. The high likelihood of pregnancy in this group underscores the need to inform all users of the contraindication of this drug's use during pregnancy and the need to demonstrate the absence of pregnancy prior to initiating treatment. In addition, patients must consider the consequences of unintentional pregnancy while they are taking isotretinoin.

Pharmacology

and

Toxicokinetics

Absorption of vitamin A in the small intestine is nearly complete. However, some vitamin A may be eliminated in the feces when large doses are taken. The majority of vitamin A is ingested as retinyl esters, the storage form of retinol.122 Retinyl esters undergo enzymatic hydrolysis to retinol by digestive enzymes in the intestinal lumen and brush border of the intestinal epithelial wall. A small portion of retinol is absorbed directly into the circulation, where it is bound to retinol-binding protein (RBP) and transported to the liver. Most of the retinol is taken into intestinal epithelial cells by the carrier protein cellular RBP.141 Subsequently, retinol is reesterified and incorporated into chylomicrons, which are taken up by the liver.

After large oral P.645 doses, significant amounts of retinyl esters circulate in association with low-density lipoproteins (LDLs) and are delivered to the liver. Approximately 90% of the body's total vitamin A content is stored in the liver as retinyl esters. Vitamin A is released into the plasma for delivery to other tissues as needed. Carotenoid absorption requires the presence of bile and absorbable fat in the intestinal tract. Only a portion of these vitamin A precursors is cleaved into retinaldehyde, which subsequently is reduced to retinol. This process occurs in the intestinal wall. Retinol then is absorbed and transported by RBP or converted to retinyl esters and transported by lipoproteins via lymphatics to the liver and other tissues. Massive doses of carotenoids are not converted rapidly enough to produce vitamin A toxicity. However, high blood concentrations of carotenoids are achieved. Hypercarotenemia produces a yellow-orange skin discoloration that can be differentiated from jaundice by the absence of scleral icterus. The normal plasma retinol concentration is approximately 30–70 µg/dL.169 Blood concentrations are maintained at the expense of hepatic reserves when insufficient amounts of vitamin A are ingested. A normal adult liver contains enough vitamin A to fulfill the body's requirements for approximately 2 years.132 Thus symptoms of vitamin A deficiency can be prevented for many months. Excessive intake of vitamin A is not initially reflected as elevated blood concentrations because vitamin A is soluble in fat but not in water. Instead, hepatic accumulation is increased. This storage system allows for cumulative toxic effects. Although no relationship exists between the magnitude of liver stores and blood concentrations of vitamin A, in chronic hypervitaminosis A, serum concentrations are generally > 3.49 µmol/L (95 µg/dL).16 Vitamin A has a half-life of 286 days in the blood.171 , 191 Clinical toxicity correlates well with total body vitamin A content,

which is a function of both dosage and duration of administration. Hypervitaminosis A is rare, with a reported average incidence of 300 mg/kg died, whereas none died at a dose of 100 mg/kg. Hepatoxicity can occur in humans following an acute ingestion of a massive dose of vitamin A (>600,000 IU).105 Hypervitaminosis A may occur more frequently secondary to chronic ingestions of vitamin A. Hepatotoxicity typically requires vitamin A ingestions of at least 50,000–100,000 IU/d for months or years.6 , 105 One study found that in patients with vitamin A-induced hepatotoxicity, the average daily vitamin A intake was higher in patients who developed cirrhosis (135,000 IU/d) compared to patients who developed noncirrhotic liver disease (66,000 IU/d). 67 However, case reports have documented hepatotoxicity resulting from vitamin A doses as low as 25,000 IU/d,67 , 105 a dose widely available in vitamin A preparations found in health food stores.

Pathophysiology The mechanism of action for many of vitamin A's toxic effects may be at the nuclear level. Retinoic acid influences gene expression by combining with nuclear receptors.122 Retinoids also influence expression of receptors for certain hormones and growth factors. Thus

they are able to influence growth, differentiation, and function of target cells.117 In epithelial cells and fibroblasts, retinoids affect changes in nuclear transcription, resulting in enhanced production of proteins such as fibronectin and decreased production of other proteins such as collagenase.121 Excessive concentrations of retinoids lead to the presence of goblet cells, production of a thick mucin layer, and inhibition of keratinization. In addition, lipoprotein membranes have increased permeability and decreased stability, resulting in extreme thinning of the epithelial tissue. In vitro studies in bone demonstrate that high doses of vitamin A are capable of directly stimulating bone resorption and inhibiting bone formation. This effect is secondary to increased osteoclast formation and activity and inhibition of osteoblast growth.138 , 143 , 165 Hepatotoxicity may develop secondary to an acute overdose or ingestion of “low― or “therapeutic― doses if taken over a prolonged time.67 , 105 Ninety percent of hepatic vitamin A stores are located in the Ito, or fat-storing, cells of the liver, which are located in the perisinusoidal space of Disse, and are responsible for maintaining normal hepatic architecture.79 Ito cells undergo hypertrophy and hyperplasia as vitamin A storage increases.105 This results in transdifferentiation of the Ito cell into a myofibroblastlike cell that secretes a variety of extracellular matrix components, leading to narrowing of the perisinusoidal space of Disse, obstruction to sinusoidal blood flow, and noncirrhotic portal hypertension (Figure 41-1 ).40 , 71 , 89 , 100 , 105 , 162 Continued ingestion of vitamin A and hepatic storage may lead to obliteration of the space of Disse, sinusoidal barrier damage, perisinusoidal hepatocyte death, fibrosis, and cirrhosis.89 , 96 , 105 , 160 Vitamin A toxicity is associated with idiopathic intracranial hypertension (IIH). Although vitamin A's role in the development of IIH is not definitively understood, serum concentrations of vitamin A are significantly higher in patients with IIH compared to healthy

controls.94 In addition, cerebrospinal fluid (CSF) concentrations of vitamin A are significantly elevated in patients with IIH compared to patients with normal intracranial pressure (ICP) or patients with other causes of elevated ICP.190 Unbound, circulating retinol and P.646 retinyl esters are proposed to be capable of interacting with cell membranes and producing damage by membranolytic surface-active properties.94 In the central nervous system (CNS), disruption of cell membrane integrity might lead to disruption of CSF outflow, thereby producing signs and symptoms consistent with IIH.69 , 94 , 103 , 120

Figure 41-1. Schematic demonstration of hepatotoxicity resulting from excessive deposition of vitamin A in the Ito cells of the liver.

Clinical

Manifestations

Hypervitaminosis A affects the skin, hair, bones, liver, and brain. The most common skin manifestations include xerosis, which is associated with pruritus and erythema, skin hyperfragility, and desquamation.45 , 46 , 195 Retinoid toxicity may cause hair thinning and even diffuse hair loss in 10–75% of patients.61 , 70 , 102 In addition, the

characteristics of the hair may change after regrowth. Hair sometimes becomes permanently curly or kinky.10 Nail changes include a shiny appearance, brittleness, softening, and loosening.55 Dryness of mucous membranes develops with chapped lips and xerosis of nasal mucosa, which sometimes is associated with nasal bleeding.38 Epidemiologic studies are consistent with bone loss and a resulting increase in fracture risk. In northern Europe, the region with the highest incidence of osteoporotic fractures, dietary intake of vitamin A is high. A study of this population demonstrated that the risk of first hip fracture was increased by 68% for every 1 mg increase in RE intake.128 This study also showed that compared to intake 1.5 mg/d reduced bone mineral density by 10% at the femoral neck, 14% at the lumbar spine, and 6% for the total body, and doubled the risk of hip fracture. These findings are supported by other studies demonstrating an increased risk of hip fracture among women with elevated serum vitamin A concentrations and in women ingesting large daily amounts of vitamin A.56 , 142 One study found that among women not taking supplemental vitamin A, a diet rich in vitamin A was also associated with an increased fracture risk.56 Other

musculoskeletal

findings

include

skeletal

hyperostoses,

most

commonly affecting the vertebral bodies of thoracic vertebrae, extraspinal tendon and ligament calcifications, soft-tissue ossification, cortical thickening of bone shafts, periosteal thickening, and bone demineralization.38 , 132 , 134 Many of these findings are apparent on radiographs. Patients often complain of bone and joint pain and muscle stiffness or tenderness. Hypercalcemia, with low parathyroid hormone (PTH) concentrations, is thought to be secondary to increased osteoclast activity and bone resorption.23 Premature epiphyseal closure in children is reported. 151 Teratogenic effects include interference with skeletal differentiation and growth.23 The degree of hepatotoxicity appears to correlate with the dose of vitamin A and chronicity of use. With large doses, cirrhosis develops and may lead to portal hypertension, esophageal varices, jaundice,

and ascites.41 , 67 , 105 Hepatotoxicity may be manifested by elevations in bilirubin, aminotransferases, and alkaline phosphatase concentrations. Idiopathic intracranial hypertension, previously known as pseudotumor cerebri and benign intracranial hypertension, is characterized by elevated ICP in the absence of a focal lesion, infective process, or hydrocephalus. It occurs in patients with altered endocrine function, systemic diseases, impaired cerebral venous drainage, or ingestion of various xenobiotics, including excessive vitamin A5 (Table 41-2 ). The syndrome is most common in young obese women, but the etiology remains unknown in the majority of cases. The first case of IIH associated with vitamin A toxicity was described in 1954.66 However, the symptoms were first described in 1856 by an Arctic explorer who noted vertigo and headache after eating polar bear liver.168 Patients typically present with headache and visual disturbances, including sixth nerve palsies, visual field deficits, and blurred vision, and have a normal mental status. Despite severe papilledema, visual loss often is minimal. However, blindness may result from optic atrophy.118 Other symptoms of neurotoxicity include ataxia, fatigue, depression, irritability, and psychosis.21 Drugs Antibiotics: nalidixic acid, tetracycline, ampicillin, minocycline, nitrofurantoin, sulfamethoxazole, metronidazole Corticosteroid therapy (oral and intranasal) and cessation Griseofulvin Lithium Oral contraceptives and progestational drugs Phenothiazlnes Phenytoin Vitamin A Toxins Lead Anesthetics

Enflurane Halothane Ketamine d -Tubocurare TABLE 41-2. Drugs and Toxins Associated with Intracranial Hypertension Isotretinoin is effective in the management of acne. However, its use is associated with teratogenecity. It is thought to interfere with cranial-neural-crest cells, which contribute to the development of both the ear and the conotruncal area of the heart and may cause malformed or absent external ears or auditory canals and conotruncal heart defects.107 Although studies have not shown a teratogenic risk with topical preparations, case reports describe fetal malformations associated with their use during pregnancy.11 , 28 , 97 , 116 , 167 I n addition, mucocutaneous abnormalities, IIH, corneal opacities, hypercalcemia, hyperuricemia, musculoskeletal symptoms, liver function abnormalities, elevated triglyceride concentrations, spontaneous abortion are reported.3 , 60 , 65 , 74 , 75

and

Treatment with tretinoin (all-trans -retinoic acid), followed by anthracycline and cytarabine, improves the complete remission rate and reduces the incidence of relapse in cases of acute promyelocytic leukemia.54 Retinoic acid syndrome is the main adverse effect and may occur in up to 25% of patients who receive tretinoin without prophylactic measures. The syndrome is characterized by dyspnea, pulmonary effusions and infiltrates, fever, weight gain, renal failure, pericardial effusions, and hypotension.53 Elevated leukocyte counts at diagnosis or rapidly increasing counts during tretinoin treatment predict the development of retinoic acid syndrome. Its etiology is thought to be related to cytokine release by maturing blast cells. Addition of dexamethasone to the treatment regimen decreases the incidence of this syndrome to approximately 15% and its mortality to 1%.54

Symptoms of an acute overdose often develop within hours to 2 days after ingestion.132 Initial signs and symptoms include headache, papilledema, scotoma, photophobia, seizures, anorexia, drowsiness, irritability, nausea, vomiting, abdominal pain, liver damage, and desquamation.132 Additional signs and symptoms are associated with chronic toxicity.132 Nonspecific symptoms include fatigue, fever, weight loss, edema, polydipsia, dysuria, hyperlipidemia, anemia, and menstrual abnormalities. P.647

Diagnostic

Testing

An elevated serum vitamin A concentration is greater than 80 µg/dL. However, because the liver has a large storage capacity for excess vitamin A, hepatotoxicity may occur prior to an elevation in the serum concentration, which may be normal or even low, in the setting of an acute overdose. As the liver's storage capacity is overwhelmed, the serum concentration diagnosis of vitamin evidence of Ito cell biopsy.67 Laboratory

may rapidly rise in a nonlinear fashion. The A hepatotoxicity is supported by histologic hyperplasia with fluorescent vacuoles on liver testing should also include serum electrolytes,

including calcium; liver function tests; and a complete blood cell count. Further evaluation should be guided by the clinical presentation and may include bone radiographs, computed tomography of the brain, and lumbar puncture.

Treatment Management of an acute, large overdose should begin with gastrointestinal decontamination. This can be accomplished with a dose of activated charcoal. In extremely large overdoses that are expected to produce significant toxicity, gastric lavage may be considered. Although most signs and symptoms of hypervitaminosis A resolve within 1 week of vitamin A discontinuation and with supportive care, papilledema and skeletal abnormalities may persist for several

months. Visual impairment secondary to optic atrophy may be a permanent sequela of vitamin A toxicity. Hypercalcemia should be treated with IV fluids, loop diuretics, and prednisone 20 mg/d. 20 Bisphosphonates may be beneficial in refractory cases. IIH may require more aggressive therapy, similar to that of other causes of increased ICP. Depending on the severity of the syndrome, patients may require dexamethasone (0.25–0.5 mg/kg/d in children Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > B - Foods, Dietary and Nutritional Agents > Chapter 42 - Essential Oils

Chapter

42

Essential

Oils

S. Eliza Halcomb A 2-year-old boy presented to the emergency department with altered mental status. His mother reported that the boy had developed a low-grade fever earlier that evening. He was given a bath and some ibuprofen. After the bath, the boy's grandmother rubbed him down with a “generous― amount of eucalyptus oil. The child liked the smell and licked his arms. Shortly thereafter, he became lethargic and had a seizure. Upon presentation to the emergency department, the child was sleepy but arousable. His vital signs and results of physical examination, laboratory studies, and head CT were all normal. He was hospitalized for observation overnight and had no further seizure activity. He was discharged home the next day with no further sequelae.

History

and

Epidemiology

“What got you in trouble?― says the

baldhead to t'other. “Well I'd been selling an article to take the tartar off the teeth—and it does take it off, too, and generly the enamel along with it…― --Mark

Twain,74; Huckleberry Finn

Essential oils are a class of polyaromatic hydrocarbons extracted through steam distillation or cold pressed from the leaves, flowers, bark, wood, fruit, or peel of a single parent plant. These organic compounds are a complex mixture of chemicals with structures that give the oil its aroma, therapeutic properties, and occasionally cause toxicity. More than 500 oils exist and can be categorized into five chemical groups: terpenes, quinines, substituted benzenes, aromatic/aliphatic esters, and phenols and aromatic/aliphatic alcohols. Use of plant-derived essential oils in the practice of herbal medicine has a long and colorful history, dating back thousands of years. The virtues of these extracts have been mentioned in ancient Egyptian and Greek medical literature and throughout the Bible. Essential oils were used to treat everything from asthma to snakebites until the early 20th century. In America “Indian doctors― frequently sold these products, claiming they learned medicinal secrets from local Native American tribes. These remedies were advertised at medicine shows and demonstrated by troupes such as the famous Kickapoo Indian Medicine Company. The purpose of these traveling caravans was to sell patent medicines, which typically contained substantial quantities of ethanol, in addition to other substances of uncertain therapeutic value. A bottle of Kickapoo Oil sold at the beginning of the 20th century purportedly contained “camphor, ether, capsicum, oil of cloves, oil of sassafras and myrrh.― Needless to say, many patients did rather poorly with the administration of these tonics,

and the “doctors― who sold them quite rightly earned a reputation for quackery.76 With the ascent of scientific research, many essential oil remedies fell from use. More recently, trends in globalization and natural healing have led to a popular resurgence in the use of essential oils in developed countries. Essential oils currently are marketed for use in aromatherapy and certain complementary medicines. The reintroduction of these agents into mainstream society has highlighted the need for research and toxicity studies to ensure that appropriate decision making and care can be provided to exposed

patients.

Absinthe;

Oil

of

Wormwood

History Absinthe is an emerald green liqueur made from the extract of the wormwood plant Artemisia absinthium. The earliest references to wormwood date to 1500 B.C., when its antihelminthic properties were described. It is thought that Napoleon's soldiers popularized the drink upon their return from Algeria, where they had added wormwood extract to their wine to avoid helminthic infections during the war.35

Thujone

Absinthe reached its pinnacle of popularity by the late 19th century in Europe. Famous artists and authors, including Lautrec, Van Gogh, Baudelaire, Wilde, and Hemingway, sat for hours in the cafes of Paris, drinking the green liqueur and romanticizing its aphrodisiac effects. However, recognition of the devastating side effects led the French, Swiss, and American governments to ban its sale by the early 1900s.35 Absinthe is still sold in its dethujonized

form,

Pernod.

Many people have speculated on the cause of Vincent Van Gogh's bizarre behavior. Some have concluded that his fondness for absinthe may have contributed to his seizures and psychotic episodes. P.658

Toxicokinetics The toxic component in oil of wormwood is thujone, a monoterpene ketone, which exists in α- and β-diastereoisomeric forms.34 After oral absorption, both isomers undergo speciesspecific hydroxylation reactions by the cytochrome P450 system,

followed by glucuronidation in the hepatocyte, leading to production of several renally eliminated nontoxic metabolites.34

Pathophysiology The α-stereoisomer is generally accepted to be the more toxic of the two isomers and the parent compound antagonizes the γaminobutyric acid (GABA)A receptor at the picrotoxin site on the chloride channel, leading to neuroexcitation that may manifest as hallucinations or seizure activity, presumably in a dose dependent fashion.34 Interestingly, ethanol enhances GABA activity and may have a protective effect by reducing seizure activity in mice.34 Thujones are implicated in the development of porphyrialike syndromes by inducing the synthesis of 5-aminolevulinic acid synthetase, leading to increased porphyrin production. This finding suggests that individuals with defects in heme synthesis may unmask a porphyrialike syndrome upon ingestion of thujones.10

Clinical

Features

Case reports of toxicity reflect a recent resurgence in the popularity of the absinthe liquor, which has reappeared on the market in several European countries and is available on the Internet. Clinical features of acute toxicity are similar to those of ethanol intoxication, including euphoria and confusion, which may progress to restlessness, visual hallucinations, and delirium. Chronic abusers may suffer from seizures, hallucinations, and erratic behavior.4 Rhabdomyolysis and acute renal failure have occurred following ingestion of oil of wormwood intended for preparation as absinthe.80 The etiology of the rhabdomyolysis has not been elucidated.80

Camphor

History One of the first western references to camphor is found in Marco Polo's description of his travels.26 Camphor was traded widely throughout Asia. Historically it was used as a rubefacient, antiseptic, decongestant, and moth repellent. It gained immense popularity as a liniment during the American Civil War, and the US government signed a contract with China to buy the entire camphor output of Formosa (Taiwan).

Figure. No Caption Available.

The French introduced camphor to Europe in 1879.24 Vincent Van Gogh's epileptiform illness may have been exacerbated by his continuous exposure to camphor. Camphor belongs to the terpene family and is capable of causing central nervous system (CNS) toxicity.35 Camphor oil is extracted from an evergreen tree from the Laurel family Cinnamomum camphora, 17 which is native to eastern China, Japan, and Taiwan. It is primarily used today in nasal decongestant ointments such as Vicks Vapo-Rub, although in the recent past it was widely used in moth repellents (Chap. 99) .

Toxicokinetics Camphor is a monoterpene ketone, which is rapidly absorbed from the gastrointestinal (GI) tract and then undergoes extensive firstpass metabolism. After hydroxylation and glucuronidation in the liver, its inactive metabolites undergo urinary excretion.59,71

Pathophysiology Camphor toxicity is reported after its ingestion, inhalation, and nasal administration. It is rapidly absorbed from the GI tract or through mucous membranes. Camphor is highly lipid soluble and readily crosses the blood–brain barrier and placenta. Seizure activity is common postingestion, although the specific mechanism of action is not elucidated. Cellular respiration is inhibited by camphor and similar compounds, resulting in increased excitability of neuronal tissue. 63 Other studies suggest that camphor binds noncompetitively to nicotinic acetylcholine receptors, inhibiting an intracellular influx of calcium and sodium, although the investigations fail to explain how this process would be epileptogenic.55 Children seem particularly prone to hepatotoxicity because of the relative develop thought Several of fetal

immaturity of their hepatic enzyme systems, and they may hepatotoxicity resembling Reye syndrome.37 The fetus is to be susceptible to toxicity through the same mechanism. cases of camphor use as an abortifacient and a single case demise after ingestion are reported.58,81

Clinical

Features

Camphor ingestion results in rapid onset of nausea and vomiting, followed by headache, agitation, and seizure activity.16 Symptom onset usually occurs within minutes of ingestion. Seizures can occur in isolation without antecedent gastrointestinal effects.5 Inhalational and dermal exposures typically result in local

irritation.

Oil of Clove History Cloves once were considered one of the world's most important commodities second only to nutmeg in Medieval and Renaissance Europe. Clove oil is extracted from the plant Syzygium aromaticum, also known as Eugenia aromatica. This evergreen plant is native to the islands of the Malaccan Straits. Its unopened buds, when dried, are known as cloves. Eugenol, the main constituent of clove oil, has been used for centuries as a remedy for toothache and in multiple dental products.8

Eugenol

Toxicokinetics Eugenol, a phenol, is the principal component of clove oil. Very little available data on the metabolism of eugenol is available. An in vitro study found that incubation of isolated rat hepatocytes

with eugenol resulted in a glucuronic acid conjugate, although other conjugates with sulfate and glutathione were found.69

Pathophysiology Little is known about the pathophysiology of eugenol toxicity. Intravenous infusion and intratracheal instillation P.659 of eugenol in rats has led to the development of hemorrhagic pulmonary edema, which is thought to result from oxidative damage.42,83 In vitro studies of hepatic cell cultures incubated with eugenol demonstrated marked glutathione depletion, covalent bonding of conjugates to cell proteins, and cell death. These findings indicate that a reactive intermediate might be formed, leading to toxicity.69 Nerve conduction studies performed with frog sciatic nerves demonstrated that eugenol blocked impulse conduction irreversibly. Eugenol has been demonstrated to inhibit peripheral sensory nerve conduction at low doses, but has been associated with CNS manifestations at higher doses.40

Clinical

Features

A case report on the neurotoxicity of eugenol described a 24-yearold woman who spilled a small amount of clove oil on her face in an attempt to relieve a toothache. The topical spillage resulted in permanent infraorbital anesthesia and anhidrosis.36 Likewise, inhibition of the pharyngeal reflex by inhalation of clove cigarettes has been reported to cause aspiration pneumonitis.30 Inadvertent oral administration of 1–2 teaspoons of clove oil resulted in marked CNS depression, metabolic acidosis, and elevation of aminotransferases in 2 children.32,41

Oil

of

Eucalyptus

History The eucalyptus tree is native to Australia. Its extracts were historically used as an aboriginal fever remedy. In 1778, the Surgeon-General of the First Fleet arrived in Australia and noted that these unusual trees produced a gumlike resin, which he distilled into a quart of oil and sent back to England for further examination. The introduction of eucalyptus oil to the west led to an increased demand for the product to relieve the symptoms of the common cold and influenza. Eucalyptol is found in many nonprescription cough preparations and is widely used for treatment of upper respiratory infections because of its purported antiinflammatory effects.38 Although oral administration of eucalyptol-containing products rarely causes toxicity, ingestion of eucalyptus oil has resulted in morbidity and mortality.

Eucalyptol

Toxicokinetics

Eucalyptus oil contains up to 70% eucalyptol, a monocyclic terpene compound with an ether bridge between carbons 1 and 8. Eucalyptol, also known as 1,8 cineole, is rapidly absorbed from the gastrointestinal tract. It undergoes oxidation in the liver to form hydroxycineole, and subsequently undergoes further glucuronidation and excretion.79 In rats, the main urinary metabolites have been characterized as 2-hydroxycineole, 3hydroxycineole, and 1,8-dihydroxycineol-9-oic acids.45 Rabbits excrete 2-exo-hydroxycineole and 2-endo-hydroxycineole, as well as 3-exo-hydroxycineole and 3-endo-hydroxycineole, in the urine after oral administration of eucalyptol.51 The lowest lethal doses reported are 4–5 mL46 in adults and 1.9 g eucalyptus oil in a 10-year-old boy.52 However, ingestion of higher doses in another case series caused less severe effects. 78 Ingestion of 90%.15 , 31

Herbal balls, hand-rolled mixtures of herbs and honey produced in China, are o and mercury contamination.56 Examples include An Gong Niu Huang Wan, Da Hu Chiang Ya Wan.

Renal

Toxins

Aristolochia

An epidemic of renal failure in Belgium was linked to the substitution of Aristolo birthwort, heartwort, and fangchi, for another Chinese herbal, Stephania tetran

weight-loss regimen.165 , 166 Of 70 identified cases of renal fibrosis, 30 patient failure. Aristolochic acid in Aristolochia causes renal fibrosis which typically bec 12–24 months after the initial injury. Patients with Aristolochia -induced neph increased risk for developing urothelial cancer.121

Miscellaneous Chamomile

Tea

Chamomile tea is a popular occur in patients allergic to , 21 Such reactions are rare highly atopic to experience

Rattlesnake

herbal drink made from chamomile flower heads. A ragweed, asters, chrysanthemums, or other member but can be life threatening. The patient need not ha a cross-reaction.

Capsules

Rattlesnake capsules are a common Mexican folk remedy used to treat cancer, These capsules contain dried, pulverized rattlesnake powder and are sold under vibora de cascabel, polvo de P.680 vibora, and carne de vibora, without prescriptions. Infection with Salmonella ingestion.10 , 43 , 124 , 143 , 169

Chinese

Patent

ar

Medications

Chinese patent medicines, a component of traditional Chinese medicine, contain formulated into tablets, capsules, syrups, powders, ointments, and plasters, for by poorly regulated Chinese pharmaceutical agencies and are highly susceptible contamination (Table 43-4 ). They are often sold by nonherbalists at convenien incomplete documentation of ingredients, and, typically, they are not labeled in California Department of Health Services investigated 260 Asian patent medicat determined that 32% contained undeclared pharmaceutics or heavy metals. 90 A determined that 24% of 2609 samples collected were contaminated by at least

Jin Bu Huan is a traditional Chinese preparation used as a sedative and analges an isoquinoline alkaloid L-tetrahydropalmatine (L-THP), is responsible for the m

Bu Huan. In 2 case reports, 3 pediatric patients developed life-threatening brad developed hepatitis while using Jin Bu Huan.26 , 27 Hepatotoxicity may be related structurally similar to the hepatotoxic pyrrolizidine alkaloids.173 Although the pa in these cases indicate that Polygala chinensis was the plant source for L-THP, P L-THP. Plants from the genera Stephania and Corydalis are also known as Jin B appreciable amounts of L-THP. The product implicated in the case reports may by the manufacturer.

Nan Lien Chiu Fong Toukuwan (now withdrawn from the market) was found to phenacetin, phenylbutazone, indomethacin, mefenamic acid, diazepam, hydroc mercuric sulfide, lead, and cadmium, depending on the manufacturer. 38 Several

were reported following ingestion of this preparation.142 Dr. Tong Shap Yee's as contain theophylline.38 Leng Pui Kee cough pills were found to contain bromhex Ansenpenaw Tablets Chung Lien Drug Works (Hankow, China) Mercuric chloride Bezoar Sedative Pills Lanzhou Fo Ci Pharmaceutical Factory (Lanzhou, China) Mercuric chloride 2% or 10% Compound Kangweiling Wo Zhou Pharmaceutical Factory (Zhe Jiang, China) Centipede (scolopendra) 10% Dahuo Luodan Beijing Tun Jen Tang (Beijing, China) Centipede (scolopendra) Danshen Tabletco Shanghai Chinese Medicine Works (Shanghai, China) Borneol Fructus Persica Compound Pills Lanzhou Fo Ci Pharmaceutical Factory (Lanzhou, China) Cannabis indica seed Fuchingsung-N Cream Tianjin Pharmaceutical Corp. (Tianjin, China) Fluocinolone acetanide

Kwei Ling Chi Changchun Chinese Medicines and Drugs Manufactory (Chang Chun, China) Mercuric chloride Kyushin Heart Tonic Kyushin Seikyaku Co., Ltd. (Tokyo, Japan) Toad venom, borneol Laryngitis Pills China Dzechuan Provincial Pharmaceutical Factory (Chengtu Branch, China) Borax 30%, toad-cake 10% Leung Pui Kee Cough Pills Leung Pui Kee Medical Factory (Hong Kong) Dover's powder (opium powder) Lu-Shen-Wan Shanghai Chinese Medicine Works (Shanghai, China) Toad secretion Nasalin Kwangchow Pharmaceutical Centipede 5% Nui Huang Chieh Tu Pien

Industry

Co.

(Kwangchow,

Tung Jen Tang (Beijing, China) Borneo camphor Nui Huang Xiao Yan Wan Bezoar Antiphlogistic Pills Soochow Chinese Medicine Works (Kiangsu, China) Realgar 19.23% Pak Yuen Tong Hou Tsao Powder Kwan Tung Pak Yuen Tong Main Factory (Hong Kong) Scorpion 10% Po Ying Tan Baby Protector Po Che Tong Poon Mo Um (Hong Kong) Camphor 20% Superior Tabellae Berberini HCl Min-Kang Drug Manufactory (l-Chang, China) Berberini HCl Watson's Flower Pagodo Cakes

China)

A.S. Watson & Co., Ltd. (Hong Kong) Piperazine phosphate Xiao Huo Luo Dan Lanzhou Fo Ci Pharmaceutical Factory (Lanzhou, China) Aconite 42% From Appendix E. Alternative Medicine: Expanding Medical Horizons. A report to Health on alternative medical systems and practices in the United States. Presen workshop on alternative medicine. Chantilly, Virginia. Sept. 14–16, 1992. Product

Name

Manufacturer

Toxic

Xenobiotics

TABLE 43-4. The 20 Most Popular Asian Patent Medicines That Contain

Tung Shueh (black ball) contains diazepam and mefenamic acid and is associate nephritis.51 Gan Mao Tong Pian, an herbal cold remedy, contains phenylbutazon in one child.119 Chui Feng Su Ho Wan, which contains Glycyrrhiza glabra , was induced torsade de pointes in an elderly woman. 38

Several Chinese patent medicines contain the mercurials cinnabar (mercuric sul chloride). Tse Koo Choy and Qing Fen, which contain calomel, are associated wi poisoning.84

Many Chinese medicated oils contain oil of wintergreen, which is methylsalicylat

intended for external use, it is a common practice to ingest a few drops undiluted general tonic or specific remedy. Examples of medicated oils include White Flowe wintergreen, 30% menthol, 6% camphor), Red Flower Oil (67% oil of wintergree Kwan Loong Medicated Oil (menthol 25%, methylsalicylate 15%, camphor 10%)

Herbal

Preparations

and

AIDS

Therapies

Many patients infected with human immunodeficiency virus (HIV) have turned to hope of finding less toxic therapy than the conventional modalities currently avai positive patients in a university-based AIDS clinic, 22% used 1 or more herbal p period.85 Twenty-four percent of these patients were unable to state which herb effects included dermatitis, nausea, vomiting, diarrhea, thrombocytopenia, coa P.681

mental status, hepatotoxicity, and electrolyte imbalances. Twenty percent of pa were unaware of their use of herbs. A more recent study reported that more tha were taking alternative medicines, and 24% of AIDS patients were taking Chines botanicals.66

Current popular herbal preparations and dietary supplements for treatment of A include Lactobacillus acidophilus , adrenal cortex, aloe vera, Artemisia , Astraga blue-green algae, cat's claw, Chlorella , coenzyme Q10, colloidal silver, curcum (DHEA), echinacea, elderberry, evening primrose oil, flaxseed oil, garlic, germa glucosamine, glutamine, glutathione, glycyrrhizin, grapeseed, green tea, lipoic palmetto, Siberian ginseng, and silymarin and are used for treatment of HIV in

Treatment

A specific treatment strategy should emphasize identification of the specific herb patient, concurrent medication(s), and medical illness(es). Because herbal prep depending on the preparation used, careful examination may be aided by knowle preparation. In most cases, supportive care and discontinuation of the herbal

Some herbal toxicities require specific laboratory analysis and therapy (Table 4

All adverse events associated with herbal preparations should be reported to th

or to FDA MedWatch by phone at 1-800-FDA-1088 or online at http://www.fda

Summary

The popularity of herbal preparations is expected to increase in the foreseeable users will suffer no ill effects, both herbal users and clinicians should be aware pharmacologically active and have the potential for toxicity. They may interact to increase the toxicity of the medication or decrease its therapeutic effect. Pat conditions may have increased risk for toxicity when using herbal preparations.

Herbal users should be aware that these preparations are poorly studied. Scient for most preparations. No standards exist for their manufacture, quality, or con not contain the purported amount of the active ingredient. Some herbal products active ingredient. Herbal products are reported to be adulterated with prescript contaminants such as heavy metals.

Many herbal stores are staffed by untrained personnel who may dispense incorr unfounded claims concerning their products. 134 Herbalists (eg, Chinese herbalis remedies with the potential for serious toxicity as the result of improper identifi improper preparation of the herbal product by the herbalist or herbal user.38 Mo herbalists may be unaware of the potential for toxicity of their product.

Clinicians should be familiar with herbal preparations and their potential for dru effects. This is especially important because standard herbal reference texts ma on the management of poisoning or other adverse effects.70 Every patient histo assessing the concurrent or recent past use of herbal preparations.

Acknowledgment Mary Ann Howland contributed to this chapter in previous editions.

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McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > B - Foods, Dietary and Nutritional Agents > Chapter 44 - Athletic Performance Enhancers

Chapter

44

Athletic

Performance

Enhancers

Susi U. Vassallo

Case

A 17-year-old boy presented to the emergency department complaining of a bri chest pain while he was playing basketball. The patient stated that he had been basketball court at his high school and had experienced chest discomfort that d

rest. Because of the chest discomfort, the patient decided a few minutes later t instead of playing more basketball. He again developed chest pain with weight ceased his activities. He went home and reported the experience to his mother. mother brought her son to the emergency department and was present at the b history obtained in the presence of his mother revealed that this was the first t had experienced chest discomfort. No one in his family had died suddenly, and family history of structural cardiac abnormalities. Upon questioning, the patient drug use but stated that he took vitamin supplements. He denied anabolic stero he had been considering taking growth hormone to grow taller and bigger. The examination was remarkable for a well-developed, well-conditioned muscular boy athletic physique of normal height. Vital signs were as follows: blood pressure 1 pulse 60 beats/min; respiratory rate 14 breaths/min; temperature 98.6°F (37 examination was unremarkable. Electrocardiogram and chest radiograph were n

patient asked to be discharged to complete his mid-term examinations and cont exercise regimen. An echocardiogram was planned for the following day.

The desire to improve athletic performance in a scientific manner is a relatively development. The emphasis on, and study of, human physical and mental poten centered on the importance of manual work and military service. The role of spo inconsequential, except for its potential in improving military preparedness.102 comes from the Dutch word doop , a viscous opium juice used by the ancient G

Public interest in extraordinary athletic achievement fuels the modern-day scien performance enhancement in sports. In spite of the prohibition of doping, many they would use a banned substance to win if they would not be caught.15

History

and

Epidemiology

Controversy surrounding the systematic use of performance-enhancing drugs by participating athletes has marred many sporting events. Since the International

Committee (IOC) began testing for drugs during the 1968 Olympic games, prom have been sanctioned and even stripped of their Olympic medals because they for banned substances. However, from a public health perspective, the use of enhancing drugs among athletes of all ages and abilities is a far more serious c

highly publicized cases involving a few world-class athletes. The majority of stud epidemiology of performance-enhancing substances have investigated androgen steroid use. Androgenic means masculinizing and anabolic means tissue building process stimulates protein synthesis, promotes nitrogen deposition in lean body

decreases protein breakdown.248 Studies of high school students document that seniors have used anabolic steroids, and 35% of these individuals were not invo organized athletics.32 Others find rates of androgenic steroid use in adolescent from 3%–19%.124 , 112 , 182 , 243 , 247 , 248 According to the 2005 survey of Collegiate Athletic Association (NCAA), 1.2% of college athletes use anabolic ste use ephedrine.161 The Drug Enforcement Agency (DEA) reported that 30–50% androgenic anabolic steroids and human growth hormone sold illegally do not co purport.61

Sudden

Death

in

Athletes

Sudden unexpected death in athletes younger than 35 years is underestimated. According to the IOC, 2 of 100,000 athletes between 12 and 35 years of age die cardiac death each year. In the general population of young nonathletes, the inc times lower, or 0.7 individuals per 100,000. During the 5-year period from 1983 fewer than 60 cases of sudden cardiac death among high school athletes were approximately 12 per year in the United States.142 , 149 In December 2004, the a panel of experts to develop a consensus paper to be known as the Lausanne paper provides the scientific basis for preventing sudden death of athletes.

The leading cause of nontraumatic sudden death in young athletes is most often cardiac anomalies.140 In autopsy studies of athletes with sudden death, hypertr

cardiomyopathy is the most common structural abnormality, followed by corona anomalies.142

Traumatic causes of sudden death include head and spinal cord injuries, often i players and pole vaulters, vertebral artery rupture and subarachnoid hemorrhage the neck by

P.686 hockey pucks, and commotio cordis from blunt impact to the chest wall.142 , 143 Medical causes of sudden death other than cardiac causes include heat stroke (C sickle cell trait, and asthma.76 , 116 , 144 , 229 Many unexpected deaths in certai young competitors have occurred in the absence of obvious medical or traumati these cases, the use of performance-enhancing drugs is linked to the deaths. Th

erythropoietin (EPO), introduced in Europe in 1987, may have contributed to the of deaths in young European endurance athletes over the next few years.68 , 89 In young healthy athletes experiencing cerebrovascular events or myocardial in temporal link between the use of cocaine, ephedrine, or performance enhancers anabolic androgenic steroids suggests a role for these xenobiotics as precipitant adverse events142 (Chap. 74 ).

Principles

Performance enhancers can be classified several ways for the purposes of study categorize agents according to the expected effect of the drug. For example, so increase muscle mass, whereas others decrease recovery time, increase energy, presence of other drugs. However, one drug may have several expected effects.

diuretics may be used to mask the presence of other agents by forcing their ex may be used to reduce weight. Clenbuterol is an anabolic agent, but it also is a because of its β2 -adrenergic agonist effects. Bromontan is another stimulant, b a masking agent. Depending on the xenobiotic, it is used either before competit future performance or during competition to improve immediate results.28

According to the World Anti-Doping Agency (WADA) World Anti-Doping Code, a method constitutes doping and can be added to the prohibited list if it meets two following three criteria: it enhances performance; its use presents a danger to health; and it is contrary to the spirit of sport245 (Table 44-1 ).

Some of the substances on the WADA 2005 Prohibited List are used to treat me frequently encountered in athletes.244 Many athletes have sought to explain a test by claiming the substance was prescribed for a medical condition, such as t

modafinil, a stimulant, for the sleep disorder narcolepsy. However, some athlete medical conditions that may require treatment. For example, the prevalence of increasing in athletes. At least 10–15% of Olympic athletes have exercise-ind , 216 Salbutamol (albuterol) is the most commonly used asthma medicine.44 Alth

adrenergic agonists are commonly used for treatment of asthma, these agents during and out of competition. In the Olympics, use of inhaled β2 -adrenergic a an abbreviated Therapeutic Use Exemption (TUE). With the TUE, the inhaled age if the athlete provides medical justification for therapeutic necessity and docum

investigations performed to establish the diagnosis of asthma. Nevertheless, a concentration (free salbutamol concentration plus glucuronide level > 1000 ng/m considered a positive test and an adverse finding unless the athlete proves that value results from therapeutic use of the drug.244 Systemic administration of such as prednisone, is not permitted. Topical preparations of glucocorticoids are

Substances (S) and Methods (M) Prohibited at All Times (In- and Out-of-Compe S1. Anabolic Agents S2. Hormones and Related Substances S3. β-Adrenergic Agonists S4. Agents with Antiestrogenic Activity S5. Diuretics and Other Masking Agents M1. Enhancement of Oxygen Transfer M2. Chemical and Physical Manipulation

M3. Gene Doping Substances and Methods Prohibited In-Competition In addition to S1 to S5 and M1 to M3 above, the following categories are pro competition: S6. Stimulants S7. Narcotics S8. Cannabinoids S9. Glucocorticosteroids Substances Prohibited in Particular (P) Sports P1. Alcohol P2. β-Adrenergic Antagonists Specified Substancesa Ephedrine Cannabinoids All Inhaled β2 -Adrenergic Agonists, Except Clenbuterol Probenecid All Glucocorticosteroids All β-adrenergic antagonists Alcohol a

In certain circumstances, a doping violation involving specified substances may reduced sanction, provided the athlete establishes that the use was not intended performance.

TABLE 44-1. Abbreviated Summary of World Anti-Doping Agency 2005 List2 4 4

Anabolic Androgenic

Xenobiotics Steroids

Androgenic anabolic steroids (AAS) increase muscle mass, lean body weight, an nitrogen retention.155 Testosterone is the prototypical androgen, and most and steroids are synthetic testosterone derivatives. The androgenic effects of steroid responsible for male appearance and secondary sexual characteristics such as

of body hair and subsequent deepening of the voice.

In the 1970s and 1980s, federal regulation of anabolic steroids was under the d Food and Drug Administration (FDA). Because of increasing media reports on the anabolic steroids in sports, particularly by high school students and amateur at enacted the Anabolic Steroid Control Act of 1990, which amended the Controlle Act and classified anabolic steroids as schedule III. Schedule III implies that a d currently accepted medical use in the United States and has less potential for a drugs categorized as schedule I or II. The Anabolic Steroid Control Act of 2004 steroid precursors, such as androstenedione and dihydrotestosterone, to the list substances that are considered illegal without a prescription. Possession of and P.687

or other metabolic precursors called prohormone drugs is considered a federal by jail. Distributing these substances is a felony that may result in up to 5 year the first offense. Nevertheless, anabolic steroids are still available illicitly throug and over the Internet from international marketers, veterinary pharmaceutical

some legitimate US manufacturers (Table 44-2 ). The US FDA estimates that th AAS amounts to $300–500 million annually.46

Physiology

and

Pharmacology

The Leydig cells of the testis produce 95% of endogenous male testosterone; th comes from the adrenal glands. Normally 4–10 mg testosterone and 1–3 mg

androstenedione are produced daily in men. Women secrete approximately 0.04 testosterone and 2–4 mg androstenedione daily from their ovaries and adrena

Testosterone is rapidly degraded in the liver. The plasma half-life is less than 3 Therefore, in order to create a substance that is useful clinically, testosterone is the 17-hydroxy position, forming a hydrophobic compound that can be administe vehicle for gradual release.12 Most of these esters of testosterone must be inje intramuscularly to avoid extensive first-pass hepatic metabolism associated with administration.14 The alternative to esterification at the 17-hydroxy position is position. Alkylated androgens can be administered orally because they are more hepatic metabolism. These agents, more commonly used by athletes, are respon majority of complications associated with AAS use12 (Table 44-2 ).

17α-Alkyl Derivatives (Oral) Ethylestrenol Maxibolin Fluoxymesterone Halotestin Methandrostenolone Dianabol Methyltestosterone Oxandrolone Anavar Oxymetholone Anadrol Stanozolol Winstrol 17β-Ester Derivatives (Parenteral) Boldenone Equipoise, Equibold, Vebenol Nandrolone decanoate Durabolin, Decadurabolin Nandrolone phenpropionate Durabolin, Hybolin Testosterone esters Testosterone cypionate Testex, Sten Testosterone enanthate Testoviron, Delatestryl Testosterone ester combination Depotest, Sustenon Testosterone heptylate Theramex Testosterone propionate Testex, Testopel

Trenbolone Finajet Transdermal Testosterone Preparations Buccal gel Striant Dermal gel, ointment AndroGel, Testim Transdermal reservoir patch AndroDerm Generic

TABLE

Nomenclature

44-2.

Synthetic

Representative

Testosterone

Trade

Names

Derivatives/Anabolic

Androgenic

S

Figure

44-1. Metabolic

Antiestrogens

pathways

and

of

dehydroepiandrosterone

(DHEA).

Antiandrogens

In sports, the general purpose of taking androgens is to increase the anabolic e avoid the unwanted side effects of feminization, such as gynecomastia, or mas secondary sexual characteristics such as facial hair and deepening voice. Creatin that completely dissociates the desired from the undesired effects has not been Therefore, athletes are directed on the use of agents to manipulate the metabo androgen metabolism and decrease unwanted side effects by combining xenobio antiestrogenic or antiandrogenic activity. Such xenobiotics are divided into aro such as anastrozole (Arimidex) and aminoglutethimide (Cytadren), selective es modulators (SERMs) such as tamoxifen and raloxifene, and other antiestrogenic

such as clomiphene (Clomid). These agents are prohibited for all athletes. Clom indirectly increasing gonadotropin release, is most commonly used by athletes t endogenous testosterone upon discontinuation of androgenic anabolic steroids. such as the 5α-reductase inhibitor cyproterone acetate, prevent masculinization

athletes (Figure 44-1 ). Internet web sites have extensive discussions on the us substances as part of the AAS regimen for muscle building.

Administration

Approximately 50% of AASs are taken orally. The remainder is administered by injection, with one fourth of intramuscular AAS users sharing needles.62 , 162 On

needles and syringes exchanged in a needle-exchange program in Wales were u steroids.171 Unlike therapeutically indicated regimens, which consist of fixed dos intervals, athletes typically use AASs in cycles of 6 to 8 weeks.12 For example, use steroids for 2 months and then abstain for 2 months. Cycling is based on th individual preferences

P.688 and not on any validated protocol. Stacking implies combining the use of severa time, often with both oral and intramuscular administration. To prevent plateau developing tolerance, to any one drug, some athletes who take AASs use an ave different AASs simultaneously. The doses used are frequently hundreds of times

scientifically based therapeutic recommendations.2 , 242 Pyramiding implies star a low dose, increasing the dose many times, and then tapering once again. Fatmay require several months to be totally excreted, whereas water-soluble stero only days to weeks to be cleared by the kidney. Water-soluble testosterone este “bridging therapy.― Bridging refers to the practice of halting the administ lasting alkylated testosterone formulations so that urine analyses at a specific ti evidence of use, while injections of shorter-acting testosterone esters are used orally administered alkylated formulations. This strategy, which was used extens German Democratic Republic, is documented in a review of the subject based o research of previously classified records.75 Clearance profiles for testosterone c determined for each athlete. In general, the daily injection of testosterone ester when termination of the more readily detectable synthetic alkylated testosteron was necessary to avoid a positive doping test. These daily injections of testoste were halted 4–5 days before competition. Testosterone-to-epitestosterone (T/ determined upon the athletes' departure to a sporting event. A few days before European Swimming Championships, Olympic Gold medals) had T/E ratio values would decrease to acceptable athletes' clearance of testosterone

the urine samples of 4 female swimmers (w > 6. Corrupt officials involved in doping wer levels in time for the event, based on the esters. Epitestosterone propionate injections

to bring the T/E ratio back to < 6:1, the acceptable ratio at that time.75 Present > 4:1 is considered positive.244

Clinical

Manifestations

of

Androgenic

Anabolic

Musculoskeletal

Without question, supraphysiologic doses of testosterone, when combined with training, increase muscle strength and size.23 The most common musculoskelet of steroid use are tendon and ligament rupture.77 , 99 , 129 , 134

Hepatic

Hepatic subcapsular hematoma with hemorrhage is reported.201 Peliosis hepatis, blood-filled sinuses in the liver that may result in fatal hepatic rupture, occurs with alkylated androgens and may not improve when androgen use is stopped.1

This condition is not associated with the dose or duration of treatment.12 , 109 , Cyproterone acetate is a chlorinated progesterone derivative that inhibits 5α-r reportedly causes hepatotoxicity.12 , 81 , 85

Infectious

Local complications from injection include infected joints, 71 cutaneous abscess,1 Candida albicans endophthalmitis.241 Injection of steroids using contaminated n to transmission of infectious diseases such as HIV and hepatitis B and C.162 , 16 204 , 207 Severe varicella may occur in long-term AAS users.110

Dermatologic

Cutaneous side effects are common and include keloid formation, sebaceous cy seborrheic furunculosis, folliculitis, and striae.203 Acne is associated with steroid sometimes is referred to as “gymnasium acne.―43 , 175 A common triad o and gynecomastia occurs. The production of sebum is an androgen-dependent p dihydrotestosterone is active in sebaceous glands.12

Endocrine

Conversion of AAS to estradiol in peripheral tissues results in feminization of m Gynecomastia may be irreversible. AAS use causes negative feedback inhibition

gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating h the hypothalamus. This process results in testicular atrophy and decreased spe which may be reversible. In females, menstrual irregularities and breast atrophy AAS use causes virilization in females.220

Cardiovascular

Cardiac complications include acute myocardial infarction and sudden cardiac a 107 , 136 , 138 , 151 Autopsy examination of the heart may reveal biventricular h extensive myocardial fibrosis, and contraction-band necrosis. Myofibrillar disorg hypertrophy of the interventricular septum and left ventricle are present.136 Int and use of AAS impair diastolic function by increasing left ventricular wall thick models and in vitro myocardial cell studies show similar pathologic changes.54 ,

227 , 228

Doppler echocardiography shows that several years after strength ath using AAS, concentric left ventricular hypertrophy remains, compared to similar athletes not using AAS.227 Growth hormone may potentiate the effects of AAS a increase concentric remodeling of the left ventricle.115 In addition to direct my vasospasm or thrombosis may occur.152 Alkylated androgens lower the concentr density lipoprotein (HDL) cholesterol and may increase platelet aggregation.2 , Thromboembolic events such as pulmonary embolus,59 , 83 central nervous syst events such as stroke,119 , 120 , 206 carotid arterial occlusion,128 cerebral sinus popliteal artery entrapment,133 and poststeroid balance disorder occur.26

N europsychi atr ic

Distractibility, depression or mania, delirium, irritability, insomnia, hostility, anx lability, and aggressiveness (“roid rage―) may occur.17 , 79 , 178 , 179 , 22

neuropsychiatric effects do not appear to correlate with plasma AAS concentrat Withdrawal symptoms from AAS include decreased libido, fatigue, and myalgias

Cancer

An association between AAS use and development of cancer has been observed animals.191 Testicular and prostatic carcinomas are reported in more frequent u 82 , 190

Hepatocellular carcinoma,111 , 165 peliosis hepatis, and cholangiocarcino 91 Wilms tumor and renal cell carcinoma are reported in young AAS users.31 , 18

Specific

Anabolic

Xenobiotics

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a precursor to testosterone (Figure 44-1 ). by the FDA in 1996, this drug subsequently was marketed as a nutritional suppl available for purchase without a prescription.220 DHEA is converted to androste then to testosterone by the enzyme 17β-hydroxysteroid dehydrogenase.105 , 13 Administration of androstenedione in dosages of 300 mg/d increases testosteron concentrations in some men and women.132 P.689

Women with adrenal insufficiency given DHEA replacement at a dose of 50 mg/d months demonstrated increased serum concentrations of DHEA, androstenedion and dihydrotestosterone. Serum total and HDL cholesterol concentrations simu decreased. Some women experienced androgenic side effects, including greasy s hirsutism.10 Sense of well-being and sexuality increased in men and women afte treatment.10 , 157 , 158 The neuropsychiatric effects of DHEA have been demons animals. Increased hypothalamic serotonin, anxiolytic effects, antagonism at the aminobutyric acid type A (GABAA ) receptor, and agonism of the N -methyl-D-a 10 , 140 , 153 receptor are demonstrated.

Cl enb uterol

Clenbuterol is a β2 -adrenergic agonist that decreases fat deposition and preve breakdown in animal models.6 , 41 Clenbuterol is also a potent nutrient partition term implying it can increase the amount of per pound of feed given to cattle and other is illegal. Nevertheless, the consumption of resulted in sympathomimetic symptoms and

muscle and decrease the amount o animals.78 , 189 Use of clenbuterol i veal liver contaminated with clenbut positive urine tests in affected ind

Clenbuterol increases the glycolytic capacity of muscle and causes hypertrophy, growth of fast-twitch fibers.141 , 251 Î ²2 -Adrenergic receptors are present in sk and may mediate the anabolic effect of this class of drugs. Athletes typically use 60–100 µg/d clenbuterol and in some cases as much as 600 µg/d. Clenbute

characterized by the typical symptoms of sympathomimetic overdose40 , 103 (Ch Several drug users became ill when they used a substance they thought was he was determined to contain only clenbuterol.

Other β2 -adrenergic agonists, such as oral albuterol, have similar anabolic pr however, the half-life of oral albuterol is much shorter, making it less attractive agent.156 The half-life of clenbuterol is approximately 27 hours, whereas the ha albuterol is 3–6 hours. Inhalational use of β2 -adrenergic agonists has not be demonstrated to share the anabolic properties associated with parenteral or ora 235

Peptides

and

Glycoprotein

Hormones

Creatine

Creatine is an amino acid formed by combining the amino acids methionine, arg glycine. It is synthesized naturally by the liver, kidneys, and pancreas. Creatine

protein-containing foods such as meat and fish.154 In its phosphorylated form it the resynthesis of adenosine triphosphate (ATP) from adenosine diphosphate (A Supplemental creatine bound to phosphorous acts as a substrate to donate pho formation of ATP.219 Because ATP is the immediate source of energy for muscle creatine is used by athletes to increase energy during short, high-intensity exe than 2.5 million kg of creatine is consumed annually in the United States.4 Exce have admitted to using creatine as part of their training nutritional regimen, lea by athletes at all levels. Creatine supplementation increases total creatine conte muscle by up to 20%.33 , 93 Numerous studies demonstrate improved performan creatine

supplementation,

particularly

in

sports

requiring

short,

high-intensity

, 126 , 150 , 231

Creatine is found in skeletal muscle and in the heart, brain and kidney. Two thir stored primarily as phosphorylated creatine (PCr) and the remainder as free cre Consuming carbohydrates with creatine supplements increases total creatine and skeletal muscle.93 This process explains why creatine is marketed in combinatio

carbohydrate. Human endogenous creatine production is 1 g/d, and normal diet meat and fish offer another 1 to 2 g/d as dietary intake. From 1–2 g of creat daily by irreversible conversion to creatinine.237

Creatine supplementation is most commonly accomplished with creatine monohy of 20–25 g/d can increase the skeletal muscle total creatine concentration by Creatine uptake in skeletal muscle occurs via the creatine transporter proteins a sarcolemma. Creatine stores do not increase in some individuals despite creatin supplementation. Creatine transporter expression and activity, as well as exerci influence the uptake of creatine and the effect of creatine loading on athletic p 211 , 214

One adverse effect of creatine supplementation is weight gain, which is thought primarily from water retention.95 , 150 However, evidence indicates that net pro partially responsible for the weight gain associated with long-term creatine use. was the most commonly reported side effect of creatine use in one study of 52

athletes. Other complaints were muscle cramping and dehydration, although ma no complaints.113

Creatine supplementation increases urinary creatine and creatinine excretion an serum creatinine concentrations by 20%.95 , 114 Long- and short-term creatine supplementation does not appear to have an adverse effect on renal function.17 patient who had been taking creatine 5 g/d for 4 weeks developed interstitial n improved with cessation of creatine use. Whether ingestion of creatine caused t unknown.125 A young man with focal segmental glomerular sclerosis developed creatinine concentration and decreased glomerular filtration rate (GFR) when c supplementation was started. The values returned to baseline upon cessation of supplementation.181 The possibility of developing decreased renal function is a concern. Ingestion of large amounts of creatine may result in formation of the substance N -nitrososarcosine, which induces esophageal cancer in rats.8 , 9

Human

Growth

Hormone

Human growth hormone (hGH) is an anabolic peptide hormone secreted by the

pituitary gland. It causes its anabolic effect by stimulating protein synthesis an growth and muscle mass in children. Recombinant human growth hormone has since 1984. It is commonly used therapeutically for children with growth hormo daily doses of 5–26 µg/kg body weight.232

Growth hormone secretion is stimulated by growth hormone-releasing hormone by somatostatin. Growth hormone receptors occur in many tissues, including th

of hGH to hepatic receptors causes secretion of insulinlike growth factor-1 (IGFpotent anabolic effects and is the mediator responsible for many of the actions

Human growth hormone is released in a pulsatile manner, mainly during sleep. stimulates hGH release, and more intense exercise causes proportionately more , 51 , 220

P.690 Amino acids such as ornithine, L-arginine, tryptophan, and L-lysine, increase hG through an unknown mechanism and often are ingested for this purpose.51 , 96

Human growth hormone stimulates protein synthesis and tissue growth by nitro and increased movement of amino acids into tissue. The effects on increasing m

size are well proven in growth hormone-deficient individuals, but studies do not resultant increase in strength related to the increase in muscle size.49 , 137 Hum hormone improves muscle and cardiac function, increases red cell mass and ox capacity, stimulates lipolysis, normalizes serum lipid concentrations, and decrea subcutaneous fat. It also improves mood and sense of well-being.49 , 50 , 98 , 19

Growth hormone is used by athletes for its anabolic potential. As an agent of ab particularly attractive because laboratory detection is difficult. In one survey, 12 gyms used hGH for body building.70 In another survey of adolescents, 5% of 10 had used hGH.188 Recombinant human growth hormone (rhGH) was found in the Chinese swimmers at the 1998 World Swimming Championships and of cyclists in

France in 1998, suggesting use of hGH by elite athletes.238 Pituitary-derived hGH illicitly sold as recombinant growth hormone on the black market. Human growth syndrome, and preadolescence, excessive hGH

hormone administration may cause myalgias, arthralgias, carpal edema.106 The effects of hGH on skeletal growth depend on the excessive hGH may cause increased bony growth and gigantism may cause acromegaly.228 , 230 Growth hormone may cause glu

and hyperglycemia. Skin changes, such as increased melanocytic nevi and occur.174 Lipid profiles may be adversely affected. HDL concentrations are associated with increased risk of coronary artery disease.252 Because hGH parenterally, there is risk of transmission of infection.137 The illicit sale of

altere decre must cada

pituitary-derived growth hormone is associated with a risk of Creutzfeldt-Jakob Long-term users of hGH may be at increased risk for prostate cancer because of complications associated with IGF-1.90

Insulinlike

Growth

Factor

IGF-1 is a peptide chain structurally related to insulin. Parenteral administration approved for clinical treatment of dwarfism and insulin resistance. Children who antibodies to recombinant growth hormone may respond to IGF-1.

IGF-1 is produced in the liver and many other cell types. A recombinant form is Human growth hormone is the primary stimulus for release of IGF-1, although i nutrition play a role.193 The effects of growth hormone are primarily mediated b binds principally to the type I IGF receptor, which has 40% homology with the

and a similar tyrosine kinase subunit.223 IGF-1 also binds to insulin receptors, b 1% of insulin's affinity for the insulin receptor. IGF-1 increases glucose utilizatio the movement of glucose into cells, increasing amino acid uptake and stimulatin synthesis. The actions of IGF-1 can be classified as either anabolic or insulinlike.193 Both and DHEA increase IGF-1 levels.157

Side effects are similar to those associated with use of growth hormone and inc acromegaly. Other effects include headache, jaw pain, edema, and alterations in A potentially serious side effect of IGF-1 is hypoglycemia. High endogenous plas are associated with an increased risk for prostate cancer.38

In one group of 189 weightlifters, 14.3% had taken what they believed to be IG

knowledge of the substance, and most said they would consider using it in the studies on the efficacy of IGF-1 in improving the conditioning of athletes are av attractive to female athletes because it does not cause virilization.220

Insulin

Insulin is used by body builders for its anabolic properties. It has been describe

magazines― as “the most powerful anabolic hormone on the planet.―12 identified anabolic androgenic steroid users in 1 gym, 5 (25%) who had no med take insulin reported using it to increase muscle mass.186 These individuals stat had injected insulin from 20–60 times over the 6 months prior to the study.18

was to inject 10 U regular insulin and then eat sugar-containing foods after inje

Insulin inhibits proteolysis and promotes growth by stimulating movement of glu acids into muscle and fat cells. It increases the synthesis of glycogen, fatty acid proteins53 (Chap. 48 ).

Two cases of hypoglycemia have been reported in body builders using insulin. O 80 U regular insulin in both thighs every hour over a 3- to 4-hour period while eating large amounts of carbohydrates on each of the previous 2 days. On the d presentation, he had injected 320 U regular insulin over the previous 4 hours w The patient had a seizure at the gym and arrived comatose in the emergency d serum glucose concentration was 18 mg/dL.183 Another young body builder dev posthypoglycemic encephalopathy after using intravenous insulin.66

Human

Chorionic

Gonadotropin

Human chorionic gonadotropin (hCG) is a glycoprotein that stimulates testicula

in men. In women, hCG is secreted by the placenta during pregnancy. Human c gonadotropin may be used by male athletes to prevent testicular atrophy during androgen administration.121 Analysis of hCG in 740 urinary specimens of male abnormal concentrations in 21 individuals. This finding prompted the IOC ban on 1987.31 , 51 Presently, distinguishing exogenous hCG administration from hCG early pregnancy is not possible, so the urine samples of women are not tested.1

Very small amounts of hCG are normally present in men and nonpregnant wome measurement is made by immunoenzymatic assay. The decision limit, the conce which the test is considered positive, is set at 5 IU/mL urine. Trophoblastic tum nontrophoblastic tumors can increase hCG concentrations, and this possibility m considered in the evaluation of elevated urinary hCG concentration.57

Although administration of hCG causes an increase in the total testosterone pro ratio is unchanged because epitestosterone production also is stimulated. P.691

Oxygen

Transport

Erythropoietin

(EPO)

EPO induces erythropoiesis by a receptor-mediated mechanism that stimulates s develop into mature red blood cells (RBCs). EPO has been available since 1988 human erythropoietin (rhEPO). Its use in international competition has been pr 1990. Because EPO increases exercise capacity and hemoglobin production, it is athletes, often with additional iron supplementation, for these purposes. The cli increased hematocrit occur several days after administration.80 , 167 EPO increa oxygen uptake by 6–7%, an effect that lasts approximately 2 weeks after rhE administration is completed.64

Two EPO analogs exist. Darbopoietin, also known as new erythropoiesis-stimulat (NESP), differs from EPO by 5 amino acids. It has a much longer half-life and ca

weekly.169 Another protein known as synthetic erythropoiesis protein (SEP) has protein structure to EPO. The protein polymers created in this molecule have le immunogenicity, fewer biologic contaminants, and more predictable pharmacok

EPO is secreted primarily by the kidney, although some is produced by other ti the liver. The mean half-life of EPO is 4.5 hours following IV administration and subcutaneous administration.195

In patients with renal failure who are on dialysis, a typical dose is approximately weight given 3 times per week.100 , 195 EPO enhances endothelial activation and reactivity and increases systolic blood pressure during submaximal exercise.21 , effects, in addition to the increase in hemoglobin, increase the risk for thrombo hypertension, and hyperviscosity syndromes.21 , 148 , 167 Evidence indicates tha rhEPO might pose a risk for decreased endogenous EPO production and subseq of reticulocytosis and anemia.36 , 167

Increases in hematocrit subsequent to EPO use are believed to have contributed of a number of competitive cyclists in Europe. Nineteen Belgian and Dutch cyclis

uncertain causes between 1987 and 1990.63 The 1998 Tour de France was marr discovery of widespread EPO use by members of several different cycling teams

An EPO overdose occurred in a patient who self-administered 10,000 U/d for an of time as a result of a dosing error. The patient presented to the hospital in a with a plethoric appearance, blackened toes, decreased pulses, and a hematocrit Emergent erythropheresis was performed and resulted in rapid reduction of hem

improvement in the patient's condition.250 Another report of deliberate daily s of an unknown dose of rhEPO resulted in a hematocrit of 70%. The patient was emergently with phlebotomy and intravenous hydration and improved.30

Artificial

Oxygen

Carriers

Artificial oxygen carriers are blood substitutes that supplement the oxygen-carry RBCs.202 Artificial oxygen carriers fall into two categories: hemoglobin-based o (HBOC) and perfluorocarbon (PFC) emulsions. Athletes may experiment with th to increase endurance.

Hemoglobin can be genetically engineered or obtained from cattle or outdated b hemoglobin may serve as a source for human HBOC products. Hemoglobin is com

subunits, 2 α-chains and 2 β-chains. When removed from erythrocytes, hemog unstable and dissociates into dimers. Therefore, hemoglobin must be stabilized variety of methods before an exogenous therapeutic agent is created. These m modification of hemoglobin by polymerization, conjugation, or cross-linking.202 of human purified hemoglobin with glutaraldehyde, surface conjugation of hemo polyethylene glycol, or linking of recombinant hemoglobin with short peptides ar hemoglobin stabilization. The life of HBOCs is much shorter than that of RBCs. hemoglobin has a half-life of 12 hours, and surface-modified hemoglobin product In comparison, erythrocytes may survive 120 days. In 1 report, healthy exercis suffered no ill effects from infusion of Hemopure, a product of purified bovine h cross-linked to glutaraldehyde.106 HBOCs cause vasoconstriction resulting in hig and pulmonary pressures.202 , 217

The differences in molecular weights of native hemoglobin and stabilized hemog determined by size-exclusion high-performance liquid chromatography, which is primary methods of doping analysis for HBOCs.233

Perfluorocarbons

PFCs are synthetic oxygen-carrying compounds that can be used as RBC substit liquids, which are composed of 8–10 carbon atoms with fluorine substitution serve as excellent solvents for gases.92 In 1966, it was shown that mice could

fully submerged in PFCs infused with oxygen.42 Compared to RBC transfusions, without risk of infection, require no cross-matching, and do not increase the vis PFCs are stable at room temperature and have a shelf life of greater than 1 ye that make them convenient to use.

Several cyclists have been hospitalized for illnesses that were possibly associate Symptoms included transient back pain, malaise, flushing, and fever of several duration.92 Dose-related thrombocytopenia is transient and occurs 3–4 days administration.209

PFCs increase vascular tone, which may cause hypertension. Both systemic and vascular resistance is increased.92 For unclear reasons, intravenous infusion of can cause cardiac arrest.224 Allergic reactions are reported to the egg yolk em , 163 , 202

Because PFCs are perceived by the immune system as foreign substances, they cleared by the reticuloendothelial system. The plasma half-life is approximately accumulate in the liver and spleen and are slowly transported to the lung. Over months to years, the PFCs are eliminated unchanged in the expired air and can expired air by thermal conductance or in blood by using gas chromatography-m spectrometry.224 , 202

Autotransfusion

Infusion of autologous or heterologous blood for the purpose of increasing the known as blood doping. Blood doping was used in the Olympic Games as early a Finnish steeplechaser. During subsequent summer and winter Olympics, distanc cyclists, and skiers acknowledged their use of this practice. The US cycling team using blood transfusions in the 1984 Olympics. Subsequently, the IOC banned t

P.692 Blood doping is beneficial in endurance athletes. Infusion of 400 mL packed RBC runners increased the total RBC concentration and substantially improved perfor km races.29 Blood doping also increases the speed performance of cross-countr

preparatory technique involves the removal of 1000 mL blood, the immediate r plasma volume, and the freezing and storage of RBCs. After 5–6 weeks (the t return to normocythemia), reinfusion of frozen RBCs resulted in increased hem from 45% to 49%, 5% increase in oxygen utilization, and increased endurance

Reinfusion of packed RBCs resulted overnight in an increase in maximal exercise 23% and increased maximal oxygen uptake by 9%. These improvements correla increase in hemoglobin concentration.65

Altitude acclimatization, which is considered an acceptable practice by WADA, y improvements in performance similar to the banned practice of blood doping. E athletes living at sea level are at a disadvantage in their training compared to at high altitudes. One problem with altitude training is that exercise capacity is intensity of the training is decreased until acclimatization occurs. This offsets so beneficial effects of altitude training. Many athletes avoid this by “living high low― or by training in an oxygen rich environment while acclimatizing to the increase in hemoglobin due to altitude acclimatization resulted in a 6% increase oxygen uptake and 25% increase in endurance capacity upon return to sea leve

Stimulants Caffeine

Caffeine is a CNS stimulant that causes a feeling of decreased fatigue and incre performance69 , 170 (Chap. 63 ). These changes may occur through several diff mechanisms, including increased calcium permeability in the sarcoplasmic reticu enhanced contractility of muscle, phosphodiesterase inhibition and subsequent nucleotides, adenosine blockade leading to blood vessel dilation, and inhibited Caffeine is no longer prohibited by the WADA 2005 Prohibited List World Anti-D Caffeine and pseudoephedrine are included in a monitoring program that was im WADA to detect patterns of misuse for substances that are no longer on the pr

Amphetamines

The beneficial effects of amphetamines in sports result from their ability to mas pain.55 Initial studies of soldiers showed they could march longer and ignore pa took amphetamines.225 In one study of college students, resting and maximal h strength, acceleration, and anaerobic capacity increased. However, although the

fatigue decreased, lactic acid continued to accumulate and maximal oxygen con unchanged.39 Other studies have shown no significant effects on exercise perfo (Chap. 73 ).

Sodium

Bicarbonate

Sodium bicarbonate loading, known as soda loading , has a long history of use racing.16 Sodium bicarbonate may buffer the lactic acidosis caused by exercise, delaying fatigue and enhancing performance.86

During high-intensity exercise, metabolism becomes anaerobic and lactic acid is Intracellular acidosis is said to contribute to muscle fatigue by reducing the sen muscle contractile apparatus to calcium.172 Several studies demonstrated impro performance when sodium bicarbonate was ingested 2–3 hours before compe The study dose was 0.2–0.3 g/kg body weight of sodium bicarbonate, approxi NaHCO3 per day. The effects of sodium bicarbonate are greatest when periods o

longer than 4 minutes because anaerobic metabolism contributes more to total production and energy from aerobic metabolism diminishes.86 , 88 Adverse effec bicarbonate loading include diarrhea, abdominal pain, and possible hypernatrem

An animal model demonstrated that intracellular acidosis, occurring as a conseq production, reversed muscle fatigue.3 , 172 Previously, intracellular acidosis was contribute to muscle fatigue by reducing the sensitivity of the muscle contractile calcium, decreasing the force of muscle contraction. However, the mechanism o excitation–contraction is complex. Because it permeates membranes easily, ch important for maintaining and stabilizing the muscle fiber resting membrane po pH. Because of this characteristic, a large sodium current is needed to overcom

stabilization and produce an action potential. In intracellular acidosis, membran to the chloride ion is reduced, the resting membrane potential is no longer stab inward sodium influx is needed to produce an action potential. The excitability o tubule system is therefore increased by acidosis, protecting against muscle fati

Diuretics

The World Anti-Doping Code bans diuretic use.244 Diuretics are used in sports in athlete must achieve a certain weight to compete in discrete weight classes. In weight loss, body builders find that diuretic use gives greater definition to the p skin draws tightly around the muscles.1 Diuretics also result in increased urine

thereby diluting the urine and making more difficult the detection of other bann xenobiotics.34 , 56 Diuretic use in a body builder caused hyperkalemia and hyp 6 0 ).

Miscellaneous Chromium

Xenobiotics

Picolinate

Chromium acts as a cofactor to enhance the action of insulin.94 It is found natu grains, raisins, apples, and mushrooms.219 It is sold as chromium picolinate be acid is thought to enhance chromium absorption.219 In people who are chromiu chromium supplementation results in increased glycogen synthesis and glucose Studies have not shown an increase in strength or a change in body composition

metabolism when chromium is administered in a controlled fashion.5 , 52 Anemia from chromium picolinate doses > 200 µg/d.48 A 24-year-old body builder dev rhabdomyolysis after ingesting 1200 µg chromium picolinate, 6-24 times the d recommended dose of 50–200 µg, over 48 hours.147

P.693 Renal failure developed in one patient who took chromium picolinate 600 µg/d weight reduction, which is 12–45 times the usual intake of dietary chromium a recommended supplementation dose.240 Another individual who took 1200–24 chromium picolinate for the previous 4 months for weight loss presented with r dysfunction, anemia, thrombocytopenia, and hemolysis. Chromium plasma conc 2–3 times normal (Chap. 88 ). Other causes of the abnormalities were exclud laboratory parameters improved with cessation of chromium ingestion.37

Laboratory

Detection

Enormous amounts of energy and money are expended to determine the presenc

performance-enhancing substances. Nevertheless, the average percentage of po tests analyzed by the IOC accredited laboratories between the years 1993 and 2 1.8%.230 WADA implemented a worldwide testing program before the 2000 Olym Sydney, Australia. In the program, 2846 tests were conducted on athletes from

27 different sports. Unannounced out-of-competition testing was performed for t an Olympic event and began 2 weeks before the games started. The first combi urine testing for EPO use was introduced in Sydney and represented the first us

sampling for the detection of previously undetectable performance-enhancing dr targeted the sports at high risk for EPO use, primarily endurance events. For th teams of independent observers were involved in monitoring all aspects of the process.164 In the 2004 Olympics in Athens, Greece, approximately 3500 tests and yielded 30 positive test results. For the first time, drug testing in Athens in unannounced tests during the games and even subsequently when the athletes home. In previous Summer Olympics, only the top four finishers were tested im the competition.

Analysis of samples on the international level is performed by a limited number laboratories. The majority of tests are performed on urine, with careful procedu requirements regarding handling of samples. From the first moment the athlete

a sample is requested for testing, the athlete must at all times remain within sig chaperone who is an official of the anti-doping association. This official directly athlete urinating to produce the sample. The athlete must report to the doping within 60 minutes for a no-advance-notice sample and within 24 hours for an a sample collection. The sample is collected in “tamper-evident― containers Documentation identifying the athlete is completed but not included with the sa sample is delivered to the laboratory such that the integrity, identity, and secur sample are assured.245 Attention must be paid to proper storage of specimens, bacterial metabolism may increase urinary steroid concentrations.24 , 60 Upon the sample's arrival at the testing laboratory, the integrity of the sample

including the code, seal, visual appearance, density, and pH. Registration of the completed, and the sample is divided into two aliquots. All testing is done on th and any positive results are confirmed on the second aliquot. The aliquots are referred to as sample A and sample B. Sample preparation is difficult and time

Capillary gas chromatography is the most important technique currently used in Gas chromatography typically is combined with mass spectrometry for detection

of substances.160 Analysis of the urine by gas chromatography-mass spectropho current standard for detection of anabolic androgenic steroids.34 Such analysis r amount of reference data.35

The complexity of the laboratory testing is illustrated in the discovery of an AA undetectable by standard sport doping tests of urine. In the summer of 2003, a was provided anonymously to the United States anti-doping authority. The syring the University of California Los Angeles (UCLA) Olympic Analytical Laboratory. T furor, now known as the BALCO scandal, resulted in the implication of many w athletes in sports doping. BALCO is the acronym for the Bay Area Laboratory C company that provides vitamins and nutritional supplements to athletes.

Through a painstaking process of analyses, an impurity in the substance in the identified as a derivative of the AAS norbolethone. “A hypothesis for the mo which fit all the data― resulted in the discovery and synthesis of a new AAS tetrahydrogestrinone (THG). 35 THG has characteristics that differentiate it from anabolic steroids. According to the report describing the discovery, synthesis, a THG, this new chemical was not a known pharmaceutical or a known veterinary

Detection of exogenously administered peptide hormones is difficult because of similarity to endogenous substances. Research continues in this area, as evidenc report using monoclonal antibodies to detect administration of rhGH.246 EPO is measured by a monoclonal anti-EPO antibody test, which does not distinguish b endogenously produced and exogenously administered recombinant EPO. There methods of EPO detection are used, such as measurement of hemoglobin or he Previously, some sports-governing bodies, such as the International Skiing Federation, selected a hematocrit of action level above which an athlete may be disqualified normal hematocrit values vary greatly among athletes.

International Cycling Fed 50% in men and 47% i for presumed EPO use. Several studies have sho

hematocrits above the action values of 50% in men and 47% in women are com From 3–6% of athletes who did not use EPO had hematocrits > 50%.234 Of th living and training at altitudes between 2000 and 3000 m above sea level, 20.5% hematocrit values > 50%.234 Other studies confirm the increased hematocrits o training at altitudes from 1000–6000 m.19 , 198 , 199 , 234

Although many endurance athletes may have increased blood volume, the hema

lowered because of the increased plasma volume, which exceeds the RBC volum dilutional pseudoanemia is sometimes called sports anemia .205 Additionally, h measurements are affected by hydration status, upright versus supine posture, and they demonstrate an approximately 3% diurnal variation.197 Because of na

among individuals, postural effects, and the ease of manipulation through saline indirect detection of EPO use by hematocrit measurement is fraught with potent

The ratio between serum soluble transferrin receptors (sTfr) and ferritin has bee indirect method for detection of EPO use. Soluble transferrin receptor is released progenitors. EPO stimulates erythropoiesis and causes an increase in

P.694 sTfr and a decrease in ferritin.84 Individuals with other causes of polycythemia erythropoiesis also can exhibit increased ratios and be falsely accused of EPO u hematocrit with sTfr > 10 µg/mL and sTfr-to-serum protein ratio > 153 has be an indirect measurement of EPO use.11

A combination of multiple indirect markers of altered erythropoiesis for detection was developed at the 2000 Olympics in Sydney, Australia.167 Current EPO use is “ON-model,― and recent, but not current, use of EPO is known as the â€

Five variables predict current rhEPO use: reticulocyte count, serum EPO concen hematocrit, and percentage of macrocytes. The 3-variable combination of hema reticulocyte count, and serum EPO concentration was the best mechanism for d rhEPO use.167 A major drawback to this method is the instability of these variab blood so that confirmatory testing of the split blood sample is impossible.169

The two isoforms of EPO, recombinant and endogenous, have different carbohy compositions causing differing molecular charges.169 An immunoblotting procedu advantage of these different net charges, and the proteins can be separated by when they are placed in an electric field.131 Subsequently, by isoelectric focusin obtains an image of EPO patterns in the urine.130 The technique is difficult and

WADA considers a positive urine test result by this method definitive, even with testing of indirect markers.169 Because of darbopoietin's structural similarity to detection techniques also are effective for darbopoietin.169

Masking

Agents

Some agents are available for the sole purpose of interfering with urine testing.

are added to the urine. Examples include “Klear,― which is 90% methanol Seal tea, which produces colored urine. 28 Other commercially available products “Xxtra Clean,― which contains pyridinium chlorochromate, and “Urine contains glutaraldehyde. Such adulterants are easily detected.

Any chemical or physical manipulation done with the purpose of altering the inte or blood sample is prohibited by WADA.244 For example, use of intravenous fluid

substitution is prohibited. The list of prohibited masking agents includes diureti epitestosterone, probenecid, plasma expanders such as albumin, dextran, and starch, and α-reductase inhibitors such as finasteride and dutasteride.244 Probe urinary excretion of the glucuronide conjugates of AAS. A number of urine samp to contain probenecid at the 1987 Pan American Games, leading to subsequent probenecid by the IOC.47 , 236

Gene

Doping

The discovery of the genetic codes for some diseases has made gene therapy o conditions, such as muscular dystrophy, a reality. It is now conceivable that thi

be used to enhance athletic performance. For example, insertion of a gene sequ produce a desired effect, such as large muscles or increased body production o advantageous substances such as testosterone or growth hormone. In animal m EPO lead to erythropoiesis and genes for IGF-1 produce increased muscle size a Myostatin, which belongs to a family of proteins that control growth and differe tissues in the body, inhibits skeletal muscle growth.200 Mutations of the myosta result in muscle hypertrophy. A report of an extremely muscular baby born with the myostatin gene illustrates the potential effect of gene alterations on athlet The mother of this infant was a professional athlete, and other members of the known for their strength.200

A gene is introduced into the body by direct injection of DNA or by introduction of a virus vector containing the altered DNA.226 As of 2005, gene doping is inclu WADA prohibited list. Gene doping is defined as “the non-therapeutic use of genetic elements, or of the modulation of gene expression, having the capacity athlete

performance.―244

Summary

Although the press spotlights a few world-class athletes, the vast majority of in performance-enhancing substances are not in the public view. Some individuals consequences. The knowledgeable clinician will identify these health effects whe

and educate susceptible individuals on the risks of using performance-enhancin

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > B - Foods, Dietary and Nutritional Agents > Chapter 45 - Food Poisoning

Chapter Food

45 Poisoning

Michael G. Tunik

Cases 1 and 2

A 30-year-old woman and her 32-year-old husband, who were on a scuba diving Puerto Rico, had a local dinner consisting of rice, beans, a large red snapper, h fruit preserves, and wine. That night, approximately 5 hours after dinner, they

by abdominal discomfort and nausea. These symptoms were followed by vomitin Although they were unsure of the order of events, a throbbing headache, rapid numbness of the arms, legs, and mouth ensued. Each patient described feeling pain with “deep aches in the joints.― The woman stated that when she re warm washcloth to rub on her “freezing skin,― the warm washcloth felt co distressing symptom of temperature misinterpretation lasted for 2 days. The vo during the early morning hours, but the nausea and diarrhea continued for seve crampy, abdominal pain persisted for approximately 4 days. The following morn spoke to some of the local inhabitants. Many of them described similar symptom appear after they ate a large fish, such as sea bass, red snapper, grouper, or b

Because so many people had the same symptoms, the couple did not seek med their return to the mainland 10 days later, they had no clinical or physical com

The most common causes of foodborne disease are bacteria—Salmonella spp, Clostridium perfringens, Staphylococcus aureus, Campylobacter spp, Bacillus ce Escherichia coli, group A Streptococcus, Clostridium botulinum, Vibrio cholera ; viruses—hepatitis A, E, F, and G, Norwalk virus; parasites—Entamoeba histo lamblia, Trichinella spiralis ; fishborne toxins—scombrotoxin, ciguatoxin, para chemicals—heavy metals, monosodium glutamate; and plants—mushrooms 36

Foodborne

Poisoning

with

Neurologic

Symptom

The differential diagnosis of patients with foodborne poisoning presenting with symptoms is vast (Tables 45-2 and 45-3 ). Many of these cases are ichthyosar toxins from the muscles, viscera, skin, gonads, and mucous surfaces of the fish toxicity follows consumption of the fish blood or skeleton. Shellfish poisoning als

considered. Most episodes of poisoning are not species specific, although particu toxicity from Tetraodontiformes (puffer fish), Gymnothoraces (moray eel), and n and other species) are recognized.

Deep-sea fish, eels, mussels, clams, and crabs are all implicated in diarrheal sy cases of ciguatera poisoning, the major symptoms usually are neurotoxic, and t gastrointestinal (GI) symptoms are minor. Scombroid poisoning, which is excep

common, is not associated with neurologic manifestations, but facial flushing, h dysphagia are its major signs and symptoms.

Knowing where the fish was caught often is helpful for the diagnosis, but refrig of foods and rapid worldwide travel can complicate the assessment. Travelers to Pacific islands, as well as individuals traveling within the United States, have su ciguatera poisoning.88 In geographically disparate regions of Canada,120 individu from domoic acid intoxication caused by ingestion of cultivated mussels from Pr Island.

In the differential diagnosis of foodborne poisons presenting with neurologic sy activities other than eating must always be considered. In particular, sport dive their activities in high-risk areas (Florida, California, and Hawaii), and often dur risk periods (May through August). In the process, they may sustain a bite, stin stingray tail), or laceration (from a deltoid or pectoral fin spine of a lion fish or can cause consequential marine toxicity (Chap. 116 ).

Ciguatera

Poisoning

Ciguatera poisoning is one of the most commonly reported vertebrate fishborne accounting for almost half of the reported cases in the United States.36 It is en

water, bottom-dwelling shore reef fish living around the globe between 35° no south latitude, including tropical areas such as the Indian Ocean, the South Pac Caribbean. Hawaii and Florida report 90% of all cases occurring in the United S commonly during May through August.91

More than 500 fish species are involved, with the barracuda, sea bass, parrot fi grouper, amber jack, kingfish, and sturgeon the most common sources. The com the comparably large size of the fish involved.

Large fish (4–6 lb or more) become vectors of ciguatera poisoning in accordan complex feeding patterns inherent in aquatic life. Ciguatoxin can be found in b protozoa, and the free algae dinoflagellates. These plankton members of the P.701

phylum Protozoa are single-celled, motile, flagellated, pigmented organisms thr photosynthesis. Photosynthetic dinoflagellates such as Gambierdiscus toxicus a 45 , 71 , 96 within the dinoflagellates are the origins of ciguatoxin. These dinoflage main nutritional source for small herbivorous fish. Because these small fish are

source for larger carnivorous fish, the ciguatoxin becomes increasingly concentra flesh, adipose tissue, and viscera of larger and larger fish.10 Salmonella 32,610 357 13 Escherichia coli a 3,260 84 8 Clostridium perfringens 2,772 57 0

Other parasitic 2,261 13 0 Other viral 2,104 24 0 Shigella 1,555 43 0 Staphylococcus 1,413 42 1 Norwalk 1,233 9

virus

0 Hepatitis A virus 729 23 0 Bacillus cereus 691 14 0 Other bacterial 609 6 1 Campylobacter 539

aureus

25 1 Scombrotoxin 297 69 0 Ciguatoxin 205 60 0 Streptococcus, group A 122 1 0 Listeria monocytogenes 100 3 2 Clostridium 56 13 1 Glardia 45 4 0 Vibrio 40 5 0 Other 31 6 0

botulinum

lamblia

parahaemolyticus

chemical

Yersinia enterocolitica 27 2 1 Mushroom poisoning 21 7 0 Brucella 19 1 0 Trichinella spiralis 19 2 0 Heavy 17 4

metals

0 Streptococcus, other 6 1 0 Shellfish 3 1 0 Vibrio cholerae 2 1 0 Monosodium glutamate 2

1 0 a

The fatality rate of E. coli 0157:H7 increased dramatically in the late 1990s. Etiology

Cases

TABLE

Anticholinergic Bacterial food

Outbreaks

45-1.

Deaths

Epidemiology3 6 of Foodborne Poisoning Reported to (1993–1997)

poisoning poisoning

Bends type I, II, III (caisson disease) Botulism Carbon monoxide Diphtheria Eaton-Lambert Encephalitis Metals Migraine

syndrome

MSG (monosodium glutamate) Myasthenia gravis Organic phosphorous compounds Plant ingestions Poliomyelitis Tick paralysis

(poison

hemlock,

buckthorn)

TABLE 45-2. Differential Diagnosis of Possible Foodborne Poisoning Pr Neurologic Symptoms

Ciguatoxin is heat stable, lipid soluble, acid stable, odorless, and tasteless. Whe toxin is a large (molecular weight 1100 daltons) complex ester that does not ha is stored in its tissues.91 , 95 The molecule binds to the sodium channel in diver increases the sodium permeability of the channel.9 , 149 Multiple ciguatoxins are the same fish, perhaps explaining the variability of symptoms and differing sev

can be afflicted after they eat fresh or properly frozen fish prepared by all com boiling, baking, frying, stewing, or broiling. The appearance, taste, and smell of fish usually are unremarkable. The majority of symptomatic episodes begin 2†ingestion, 75% within 12 hours, and all but 4% within 24 hours.10 Symptoms in onset of diaphoresis; abdominal pain with cramps, nausea, vomiting; profuse w and a constellation of dramatic neurologic symptoms.165 Headaches are common loose, painful teeth may occur. Typically, peripheral dysesthesias and paresthes predominate. Watery eyes, tingling, and numbness of the tongue, lips, throat, a occur. A strange metallic taste is frequently reported. A reversal of temperatur is reported, but the pathophysiology remains to be elucidated.25 Myalgias, most lower extremities, arthralgias, ataxia, and weakness are commonly experienced and symptoms of dyspareunia and vaginal and pelvic discomfort may occur in w sexual intercourse with men who are ciguatoxic.87 Ciguatoxin may be transmitte milk18 and can cross the placenta.118 Vertigo, seizures, and visual disturbances vision, manifestations of scotomata, and transient blindness) are described.

Bradycardia and orthostatic hypotension are described.55 The GI symptoms usu within 24–48 hours; however, cardiovascular and neurologic symptoms may p several days to weeks, depending on the amount of toxin ingested. Delayed sym include protracted itching and hiccoughs. Although deaths are reported, none ha documented in the United States.36 Mortality is a result of respiratory paralysis apparently managed without adequate life support.

Laboratory analysis using an enzyme-linked immunosorbent assay (ELISA) test toxin can be performed; alternatively, high-pressure liquid chromatography (HPL The original mouse bioassay was the standard, but the method was slow, involv destruction of animals, and did not differentiate the variants in ciguatoxin struc immunobead assay test being developed for field use will allow testing of fish w laboratory processing of the toxin-containing tissues.9 , 69 , 117 A useful approa and management using laboratory testing is excluding other diagnostic possibili determining the need for, or extent of, specific therapeutic interventions.

Initial treatment for victims of ciguatoxin poisoning includes standard supportive toxic ingestion.165 In most patients, elimination of the toxin is accelerated if vo and diarrhea (70%) have occurred. Administration of activated charcoal may be benefit. In patients with significant GI fluid loss through vomiting and/or diarrh

fluid and electrolyte repletion is essential. The orthostatic hypotension may resp intravenous fluids, atropine, and α-adrenergic agonists.

IV mannitol may produce a decrease in neurologic and muscular dysfunctional associated with ciguatera. GI symptoms are less responsive to mannitol.116 , 11 randomized

P.702 controlled trial, mannitol failed to produce any greater improvement in symptom 0.9% sodium chloride solution.137 Mannitol should be used with caution because hypotension. Vascular reexpansion and cardiovascular stability should be initial priorities. Ciguatera 2–30 h

*Months to years t, p, n, v, d Large reef fish: amber jack, barracuda, snapper, parrot, sea bass, moray (dino source) *Ciguatoxin **Increased sodium channel permeability Clinical, mouse bioassay, immunoassay *Supportive, mannitol, amitripyline Tetrodotoxin Minutes to hours *Days p, r, ↓bp n, v, d Puffer fish, fugu, blue-ringed octopus, newts, horseshoe crab *Tetrodotoxin **Blocks sodium channel *Clinical **Respiratory support Neurotoxic shellfish poisoning 15 min to 18 h *Days

b, t, n, v, d, p Mussels, clams, scallops, oysters, P. brevis: “red tide― *Brevetoxin **↑ Sodium channel permeability Clinical, mouse bioassay of food, HPLC Paralytic shellfish poisoning 30 min *Days r, p, n, v, d Mussels, clams, scallops, oysters, P. catanella, P. tamarensis *Saxitoxin **Decreases sodium channel permeability Clinical, mouse bioassay of food, HPLC *Respiratory support Amnestic shellfish 15 min to 38 h *Years a

poisoning

n, v, d, p, r Mussels, possibly other *Domoic acid **Glutamate analog

shellfish; N. pungens;

Clinical, mouse bioassay of food, HPLC *Respiratory support Botulism 12–73 h v, d, r, w Home-canned foods, ? honey, corn syrups, C. botulinum *Botulinum toxin **Binds to presynapse, blocks acetylcholine release Clinical immunoassay *Antitoxin, respiratory support n = nausea; v = vomiting; d = diarrhea; p = paresthesias; r = respiratory depr

bronchospasm; t = temperature reversal sensation; a = amnesia; ↓bp = hypo weakness.

Onset/Duration*

Symptoms

Toxin Source/Toxin*/Mechanism**

Diagno

TABLE 45-3. Common Foodborne Neurologic Diseases (Primary Pr Symptoms)

Admission to the hospital for cautious supportive care is essential when the diag uncertain or when volume depletion or any consequential manifestations are pre differential diagnosis includes botulism, organic phosphorus compound poisoning

potentially life-threatening processes (Tables 45-2 and 45-3 ). The etiology of must be rapidly identified to provide specific therapy, if available. Diaphoresis is clinical finding and an important factor in the differential diagnosis. Late in the ciguatera poisoning, amitriptyline 25 mg orally twice daily may alleviate sympto may persist up to 1 year.

Ciguateralike

Poisoning

Moray, conger, and anguillid eels carry a ciguatoxinlike neurotoxin in their visc and gonads that does not affect the eel itself. The toxin has a complex ester st be structurally very similar to ciguatoxin and is heat stable.113 These same eels

ichthyohemotoxin that is resistant to drying but can be destroyed by heating to (65°C). Individuals who eat these eels may manifest neurotoxic symptomatolog that occurring with ciguatoxin, or they may show signs of cholinergic toxicity, su hypersalivation, nausea, vomiting, and diarrhea. Shortness of breath, mucosal cutaneous eruptions may occur. These findings may be present in addition to th symptoms.65 Management is supportive. Mortality is related to the complications neurotoxicity, such as seizures and respiratory paralysis.

Scombroid

Poisoning

Scombroid poisoning originally was described with the Scombroidae fish (includin dark-meat marine tuna, albacore, bonito, mackerel, and skipjack). However, the

commonly ingested vectors identified by the Centers for Disease Control and Pr are nonscombroid fish, such as mahi mahi and amber jack.35 All of the implicate live in temperate or tropical waters. Ingestion of bluefish in New Hampshire was cause of scombroid poisoning in 5 people,46 and mackerel was the likely offende reported from a prison. The incidence of this disease probably is far greater tha perceived. This type of poisoning differs from other fishborne causes of illness in entirely preventable if the fish is properly stored after it is removed from the w

Scombroid poisoning results from eating cooked, smoked, canned, or raw fish. fish all have a high concentration of histidine in their dark meat. Morganella mor and Klebsiella pneumoniae , commonly found on the surface of the fish, contain

decarboxylase enzyme that acts on a warm (not refrigerated), freshly killed fish histidine to histamine, saurine, and other heat-stable substances. Although saur suggested as the causative toxin, chromatographic analysis demonstrates that h found as histamine phosphate and saurine is merely histamine hydrochloride.50 saurine originated from intoxication. The extent concentrations in healthy the concentration rapidly 12 hours.

saury, a Japanese dried fish delicacy often associated w of spoilage usually correlates with histamine concentra fish are < 0.1 mg/100 g fish meat. In fish left at roo increases, reaching toxic concentrations of 100 mg/100

The appearance, taste, and smell of the fish usually are unremarkable.5 Rarely, abnormal

“honeycombing―

P.703 character or a pungent, peppery taste that may be a clue to its toxicity (Chap. within minutes to hours after eating the fish, the individual experiences numbne a burning sensation of the mouth, dysphagia, headache, and, of particular signi scombroid poisoning, a peculiar flush characterized by an intense diffuse erythem neck, and upper torso.78 Rarely, pruritus, urticaria, angioedema, or bronchospa Nausea, vomiting, dizziness, palpitations, abdominal pain, diarrhea, and prostra develop.58 , 78 , 83 , 105

The prognosis is good with appropriate supportive care and parenteral antihistam diphenhydramine. H2 -Receptor antagonists such as cimetidine or ranitidine may alleviating symptoms.16 The toxic substance should be removed or absorbed fro Inhaled B2 -adrenergic agonists and epinephrine may be necessary if bronchosp

prominent. Patients usually show significant improvement within a few hours.

Elevated serum or urine histamine concentrations confirm the diagnosis. If any remains, isolation of causative bacteria from the flesh is suggestive but not dia capillary electrophoretic assay makes rapid histamine detection possible.108 His concentrations > 50 mg/100 g fish meat is considered hazardous by the US Foo Administration (FDA). Isoniazid may increase the severity of the reaction to sco inhibiting enzymes that break down histamine.72 , 159 The patient may be reassured that he or she is not experience a similar reaction to eating the same fish can be preserved and tested for elevated histamine available, an anaphylactic reaction to the fish must differential diagnosis of flushing, bronchospasm, and

allergic to fish if other indiv at the same time, or if any concentrations. If this inform be considered. Table 45-4 l headache. Because many

consume alcohol with fish, alcohol must be considered an independent variable.

The differential diagnosis of the scombrotoxic flush apart from a disulfiramlike ingestion of niacin or nicotinic acid, carcinoid syndrome, Zollinger-Ellison syndro

pheochromocytoma. The history and clinical evolution usually establish the diag Anaphylaxis (anaphylactoid) Minutes to hours Urticaria, angioedema, bronchospasm, hypotension Allergens—nuts, eggs, milk, fish, shellfish, peanuts, soy Oxygen, epinephrine, β 2 -adrenergic agonist, Corticosteroids, volume expansion, H1 H2 histamine blockers MSG (monosodium glutamate) Minutes Flushing, ↓ BP, palpitations, facial pressure, headaches, bronchospasm Shivering (children) Flavor enhancer in Chinese and other foods Oxygen, β2 -adrenergic agonists, volume expansion, avoidance Metabisulfites Minutes Flushing, low BP, bronchospasm Preservative used in wines, salad (bars), fruit, juice, shrimp

See Anaphylaxis, Avoidance Scombroid Minutes to hours Flushing, ↓ BP, urticaria, headache, pruritis, GI symptoms Large fish—poorly refrigerated; tuna, bonito, albacore, mackerel, mahi mahi See Anaphylaxis, Avoidance Tyramine Minutes to hours Headache, hypertension (INH or MAOI) increases risk Wines, aged cheeses Avoidance As for hypertension, migraines Tartrazine Hours Urticaria, angioedema, brochospasm Yellow coloring Food additive See Anaphylaxis, Avoidance INH = isoniazid; ↓BP = hypotension; MAOI = monoamine oxide inhibitor. Onset

Symptoms/Signs

Cause

Therapy

TABLE 45-4. Common Foodborne Disease Symptoms: Flushing, Bron Headache

Shellfish

(Primary

Presenting

Symptoms)

Poisoning

Healthy mollusks living between 30° north and 30° south latitude ingest and quantities of dinoflagellates. These dinoflagellates are the major source of avail during the “non-R― months (May through August) in the northern hemisp this time, these dinoflagellates are responsible for the “red tides― that ma California to Alaska, from New England to St. Lawrence, and across the west co Europe.102 The number of toxic dinoflagellates may be so overwhelming that bir and humans who walk along the beach may suffer respiratory symptoms caused

toxin.104

Ingestion of shellfish, including oysters, clams, mussels, and scallops, contamin dinoflagellates or algae may cause neurotoxic, paralytic, and amnestic syndrome dinoflagellates most frequently implicated are Ptychodiscus brevis (formerly Gym breve ), the diatom causing neurotoxic shellfish poisoning; Protogonyaulax cata Protogonyaulax tamarensis , which cause paralytic shellfish poisoning; and Nitzs the diatom implicated in amnestic shellfish poisoning. Proliferation of these diato a red tide, but shellfish poisoning may occur even in the absence of this extrem

Paralytic shellfish poisoning is caused by saxitoxin. Saxitoxin blocks the voltag sodium channel in a manner identical to tetrodotoxin (see below). The shellfish usually are clams, oysters, mussels, and scallops. A higher number of shellfish associated with more severe symptoms. Symptoms usually occur within 30 minu

ingestion. Neurologic symptoms predominate and include paresthesias and numb mouth and extremities, a sensation of floating, headache, ataxia, vertigo, musc paralysis, and cranial nerve dysfunction manifested by dysphagia, dysarthria, d transient blindness. GI symptoms are less common and include nausea, vomitin

pain, and diarrhea. Fatalities may occur as a result of respiratory failure, usually 12 hours after symptom onset. Muscle weakness may persist for weeks.

Treatment is supportive, but with early intervention for respiratory failure. Oro

and cathartics were used to remove unabsorbed toxin from the GI tract but pro necessary

P.704 or efficacious.22 , 93 , 109 , 142 Activated charcoal may be given. Antibodies aga have reversed cardiorespiratory failure in animals, 12 but this therapy has not ye humans. Assays for saxitoxin include a mouse bioassay, ELISA, and HPLC. HPLC interlaboratory accuracy,161 but the differences in saxitoxin derivatives make s an analytic test difficult.8 , 89

Neurotoxic shellfish poisoning (NSP) is caused by brevetoxin. Brevetoxin, which Krenia brevis (previously Gymnodium brevis ), is a lipid-soluble, heat-stable po similar to ciguatoxin. It acts by stimulating sodium flux through the sodium cha nerve and muscle.6 , 26 NSP is characterized by gastroenteritis with associated symptoms. GI symptoms include abdominal pain, nausea, vomiting, diarrhea, an burning. Neurologic features include paresthesias, reversal of hot and cold tem

sensation, myalgias, vertigo, and ataxia. Other symptoms may include headach tremor, dysphagia, bradycardia, decreased reflexes, and dilated pupils. Paralysis occur. The combination of bradycardia and mydriasis is unusual. The incubation hours (range 15 minutes–18 hours). GI and neurologic symptoms appear sim Other manifestations of brevetoxin toxicity include respiratory irritation, cough, bronchospasm, which occur when P. brevis is aerosolized by wave action during Duration of symptoms averages 17 hours (range 1–72 hours).109 Brevetoxins can be assayed using mouse bioassay, ELISA, and, more recently, radioimmunoassay (RIA) and reconstituted sodium channels.122 , 158 Treatment and severe respiratory depression is very uncommon. Therapy includes removal

from the environment and the administration of bronchodilators. NSP is not fata

Amnestic shellfish poisoning is caused by domoic acid. The etiologic agent is dom

structural analogue of glutamic and kainic acids produced by the diatom N. pun documented outbreak occurred in Canada in 1987, when 107 individuals who ha mussels harvested from cultivated river estuaries on Prince Edward Island were Other outbreaks are possible because a similar diatom—Pseudonitzschia austr

isolated in shellfish from other areas. 53 Pelican deaths caused by domoic acid-l were reported in 1991. Canada instituted monitoring for domoic acid after this death of 400 sea lions in California in 1998 was linked to domoic acid from the pungens f multiseries . 138

Amnestic shellfish poisoning is characterized by GI symptoms of nausea, vomit cramps, and diarrhea, and by neurologic symptoms of memory loss and, less fr seizures, hemiparesis, ophthalmoplegia, purposeless chewing, and grimacing. O include unstable blood pressure and cardiac dysrhythmias. The onset of sympto ingestion of mussels is 5 hours (range 15 minutes–38 hours). The mortality ra death most frequently occurring in older patients, who suffer more severe neur symptoms. Ten percent of victims may suffer long-term antegrade memory defic motor and sensory neuropathy. Postmortem examinations has revealed neuronal hippocampus and amygdala.153

Tetrodon

Poisoning

This type of fish poisoning involves only the order Tetraodonti-formes. Although

fish is not restricted geographically, it is eaten most frequently in Japan, Califo South America, and Australia.65 Cases in Florida and New Jersey have been rep Approximately 100 freshwater and saltwater species of this order exist, including pufferlike fish such as the globe fish, balloon fish, blowfish, and toad fish.111 Te found in these fish is also isolated from the blue-ringed octopus49 and the gast mollusc.168 It has also caused fatalities from ingestion of horseshoe crab eggs. 7 (a local variety of puffer fish) is considered a delicacy, but special licensing is r prepare this exceedingly toxic fish. In 1989, the FDA legalized the importation o However, prior to exportation from Japan, the fish must be laboratory tested an two Japanese organizations to be tetrodotoxin free. In addition, certain tetrod newts (Taricha , notophthalmus, triturus, and cynops), particularly Taricha gran Oregon, California, and southern Alaska, can be fatal when ingested. Most newts salamanders with bright colors and rough skins contain toxins.20

Tetrodotoxin is a heat-stable (except in alkaline milieu), water-soluble, nonpro

aminoperhydroquanizole found mainly in the fish skin, liver, ovary, intestine, an muscle.65 , 133 The ovary has a high concentration of the toxin and is most pois during the spawning season. Tetrodotoxin is detected by mouse bioassay. It is heated to 212°F (100°C) in acid, distinguishing it from saxitoxin. Tetrodotoxin detected using fluorescent spectrometry8 or detected in the urine of intoxicated a combination of immunoaffinity chromatography with fluorometric HPLC.76 Neu produced by inhibition of sodium channels and blockade of neuromuscular tran

Symptoms of tetrodon poisoning typically occur within minutes of ingestion. He diaphoresis, dysesthesias, and paresthesias of the lips, tongue, mouth, face, fin evolve rapidly. Buccal bullae and salivation may develop. Dysphagia, dysarthria vomiting, and abdominal pain may ensue. Generalized malaise, loss of coordina fasciculations, and an ascending paralysis (with risk of respiratory paralysis) occ hours. Other cranial nerves may be involved. In more severe toxicity, hypotens In some studies, mortality has approached 50%.145

Therapy is supportive. Removal of the toxin and prevention of absorption are th measures. Supportive respiratory care emphasizing airway protection, including necessary, is extremely important.

Less

Common

Poisonings:

Echinoderms

The sea urchin usually causes toxicity by contact with its spinous processes, bu delicacy also is toxic upon ingestion. When the sea urchin is prepared as food, containing gonads should be removed because they contain an acetylcholinelike causes profuse salivation, abdominal pain, nausea, vomiting, and diarrhea. The considered edible by some individuals, although an asteriotoxin with saponinlike produces nausea and vomiting is reported.

Prevention

of

Marine

Foodborne

Disease

Careful evaluation of the symptoms and meticulous reporting to local and state departments, as well as to the CDC, will allow for more precise analysis of epid

poisoning from contaminated or poisonous food or fish. Many states and countri developed rigorous health codes with regard to harvesting P.705 certain species of fish in certain areas at certain times. A review of foodborne reported to the CDC over a 5-year period may be representative of the number

food poisoning in the United States (Table 45-1 ). Some examples of actions tak foreign health agencies in controlling epidemics of fishborne food poisoning are In 1972, the 3230-km Massachusetts coastline was noted to be unsafe for

harvesting. A health emergency was declared because of a red tide bloom. T confiscated shellfish and prohibited the marketing, export, and serving of s

The health code of Miami, Florida, prohibits the sale of barracuda and warns fillets from large and potentially toxic fish containing ciguatoxin.

The Japanese closely regulate preparation and selling of the puffer fish (†requiring that preparers receive special training and licensing.

The Canadian government marks the location and time of harvesting of mus mussels are tested for the presence of domoic acid.53 , 120

Case 3

A 4-year-old child presented to the emergency department (ED) with a 1-week diarrhea, vomiting, and intermittent abdominal pain. The family became concern

and mucus appeared in the stool after 4 days. At that time, blood tests and sto obtained at another hospital. Antipyretics were prescribed for fever, and instru hydration were given. No antibiotics or other therapy was offered, and the child other symptoms began to resolve. The parents again became concerned when t child appeared pale, was more irritable than usual, had a decreased urine outpu uninterested in eating at a favorite fast-food restaurant. The child was brought t evaluation after a brief generalized seizure. The child was otherwise healthy, w medical history, other medication use, or ingestions. The child was attending p

Physical examination revealed an afebrile child with blood pressure 125/80 mm beats/min; and normal respiratory rate. The child appeared pale and irritable. T

the physical examination was significant for a systolic flow murmur on cardiac mild abdominal pain without rebound or guarding, and a liver edge palpable to 3 right costal margin. No meningeal signs were evident, and the neurologic exam nonfocal. Laboratory studies were significant for a white blood count 22,000/mm

25%, and platelet count 80,000/mm3 . A peripheral blood film revealed many s helmet cells. Serum sodium concentration was 128 mEq/L; potassium 5.9 mEq/L nitrogen (BUN) 40 mg/dL; creatinine 2.2 mg/dL; and alanine aminotransferase ( Coagulation studies and cerebrospinal fluid analysis were normal.

Foodborne Poisoning Associated Anemia, Thrombocytopenia, and

with Gastroe Azotemia

This constellation of findings is typical for the hemolytic uremic syndrome (HUS) frequently caused by a bacterial gastroenteritis. The most common organism re coli O157:H7.63 Other bacteria producing a Shigalike toxin can cause the same xenobiotics also implicated as causes of HUS include estrogen-containing oral mitomycin C, cyclosporin A, and radiation therapy.121 Other nontoxicologic cause clinical picture include autoimmune disease, Kawasaki syndrome, and bacterial leading to disseminated intravascular coagulopathy and shock.

Laboratory findings typically include microangiopathic hemolytic anemia, throm acute intrinsic renal failure. Other laboratory findings include hyperkalemia, me hyponatremia, and hypocalcemia. Liver aminotransferase concentrations may be pancreatic involvement may produce hyperamylasemia, elevated lipase concent

hyperglycemia.

Most children with HUS are younger than 6 years, and many are younger than 2 begins with a prodrome of diarrhea 90% of the time. The diarrhea lasts for 3– frequently becomes bloody. Abdominal pain because of colitis is common. Other findings include vomiting, altered mental status (irritability or lethargy), pallor, fever. At the time of presentation, many children have oliguria or anuria. Appro children present with a generalized seizure at the onset of HUS.141 Postdiarrheal endemic in Argentina.97 Frequent epidemics occur in North America, and many describe the association of enterohemorrhagic E. coli (EHEC) or E. coli O157:H7 postdiarrheal HUS.21 , 101 , 114 , 115 , 126 , 163 Postdiarrheal HUS occurs most f

the summer months, matching the peak incidence of positive stool cultures in c common source of the organism).66 Food products from cattle (ground beef, mi cheese) and water contaminated with fecal material are common sources.43 , 66 Contaminated water used in gardens and unpasteurized apple cider have caused diarrhea and HUS as a result of EHEC.14 , 40 EHEC,

including E. coli O157:H7, produces a toxin similar to the toxin produced

dysenteriae type I, referred to as Shigalike toxin (SLT) or verotoxin.52 The prop mechanism for SLT damage is intestinal absorption, bloodstream access to rena endothelium, intracellular adsorption via glycolipid receptors, ribosomal inactivat death.151 In animal models, organ damage is more severe if endothelial cells ha

concentrations of globotriaosylceramide receptors, which have a high binding af toxin. Other organs with these receptors include the renal, GI, and central nerv which may explain the pattern of organ damage in children with HUS. Endotheli and other pathologic processes, including platelet and leukocyte activation, trigg coagulation cascade, and the production of cytokines, occur.75 , 160 More than o exists; SLT-1, SLT-2, and variants of SLT-2 structure have been identified. 15

Detection of E. coli O157:H7 through stool culture early in the course of disease recovery decreases after the first week of illness.121 , 151 E. coli O157:H7 almo produces SLT; therefore, if stool cultures are negative, enzyme immunoassay (E polymerase chain reaction (PCR) tests can be used to detect SLT in the stool wh no longer be identified by culture.23

Treatment of HUS should focus on meticulous supportive care, with fluid and e the priority. Peritoneal dialysis or hemodialysis should be instituted early for az

hyperkalemia, acidosis, and fluid overload. Red blood cells are transfused to m hemoglobin concentrations > 6 g/dL and platelets to maintain hemostasis, espe invasive procedures. Hypertension should be treated with short-acting calcium (nifedipine 0.25–0.5 mg/kg/dose orally) and

P.706 seizures with benzodiazepines. Many therapies have been used for HUS, includi fibrinolytics, IV immunoglobulin, fresh-frozen plasma, vitamin E, and antiplatele has been obviously beneficial, and some have been deleterious.156 Plasmapheres used in nondiarrheal HUS and in recurrent HUS after renal transplants. In a con antibiotics did not change the course or outcome of children with postdiarrheal analysis also found no increased risk of antibiotic therapy.130 Anti–SLT-2 antib protected mice from SLT-2 toxicity, but IV immunoglobulin with SLT-2 activity h outcome in children with HUS. A double–blind, placebo controlled study on the synthetic SLT receptors attached to an oral carrier did not change the mortality morbidity of HUS syndrome.157

The mortality from HUS with good supportive care is approximately 5%; another suffer end-stage renal disease or cerebral ischemic events and chronic neurolog Prolonged anuria (> 1 week) or oliguria (> 2 weeks) or severe extrarenal diseas markers for higher mortality and morbidity.121

Strategies to prevent the spread of E. coli O157:H7 and subsequent HUS include education on thorough cooking of beef to a well-done temperature of 170°F (7

pasteurization of milk and apple cider, and thorough cleaning of vegetables. Pu measures include education of clinicians to consider E. coli O157:H7 in patients diarrhea and routine capability of microbiology laboratories to culture E. coli O1 provide for EIA or PCR determination of SLT. Public health departments should surveillance systems to identify early outbreaks of E. coli O157:H7 infection. Staphylococcus spp 2–6 h + + + -

Prepared foods: meats, pastries, salads Heat-stable enterotoxin Supportive Volume expansion Bacillus cereus Type I 1–6 h + + + Fried rice Heat-labile toxins Supportive

Volume expansion Type II 12 h + + Meats, vegetables Heat-labile toxins

Anisakiasis 1–12 h + + Raw fish, sushi, Eustrongyloides, minnows, salmon, cod, herring, squid, tuna Intestinal larvae Endoscopy Laparotomy Removal Clostridium perfringens 8–24 h + = + = Poultry, heat-processed Heat-labile enterotoxin Volume expansion

meats

Salmonella spp 8–24 h = = + = + Poultry, egg Pets (turtles, lizards, chicks) Bacteria, endotoxin (bacteremia) Antibiotics

E. coli 24–72 h

Water, food Enterotoxin, heat stable Volume expansion Enterotoxigenic + = + + Enteric contact Electrolytes Invasive + + + + Raw produce Bacteria (invasive) Antibiotics Hemorrhagic + + +

+ = Under cooked beef Unpasteurized milk Shigalike toxin Renal, hematologic support Vibrio cholera 24–72 h = = + = Water, food Enteric contact Enterotoxin Heat labile Electrolyte replacement, Shigella spp

antibiotics

24–72 h + = + + = Institutional food handler Household, preschool, enteric Bacteria Endotoxin Antibiotics Campylobacter jejuni 1–7 d + +

contact

+ = + Milk, poultry Unchlorinated water Bacteria Heat-labile enterotoxin Antibiotics Yersinia spp 1–7 d + + + = + Pork, milk, pets Bacteria Enterotoxin Antibiotics A = abdominal pain; V = vomiting; Di = diarrhea; Dy = dysentery; F = fever. Symptoms Etiology

TABLE

Onset

45-5.

A

V

Di

Common

Dy

F

Foodborne

Source

Pathogenesis

Therapy

Disease: Gastrointestinal Symptom)

Foodborne Poisoning Associated Elevated Temperature

with

(Primary

Diarrhea

The initial differential diagnosis for acute diarrhea involves several etiologies: (bacterial, viral, parasitic, and fungal), structural (including surgical), metaboli toxin induced, and food induced. The differential diagnosis is described in greate

Chap. 25 .

An elevated temperature may be caused by invasive organisms, including Salmo Shigella spp, Campylobacter spp, invasive E. coli, Vibrio parahaemolyticus , and as well as some viruses. Episodes of acute gastroenteritis not associated with fe caused by organisms producing toxins, including S. aureus, B. cereus, C. perfri enterotoxigenic E . coli , and viruses.30

Fecal leukocytes typically are found in patients with shigellosis, salmonellosis, enteritis, typhoid fever, invasive E. coli colitis, V. parahaemolyticus , Yersinia and ulcerative colitis. In all of these conditions, except typhoid fever, the leuko primarily polymorphonuclear; in typhoid fever, they are mononuclear. No stool noted in cholera, viral diarrhea, noninvasive E. coli diarrhea, or nonspecific dia P.707

The timing of diarrhea onset after exposure or the incubation period can be use differentiating the cause. Extremely short incubation periods of less than 6 hour Staphylococcus , B. cereus (type I), enterotoxigenic E. coli , 30 , 99 , 152 and pre enterotoxins, as well as roundworm larvae ingestions. Intermediate incubation p

8–24 hours are found with C. perfringens , B. cereus (type II enterotoxin), e coli ,44 , 106 and salmonella. Longer incubation periods are seen in other bacter acute gastroenteritis (Table 45-5 ).

The three most likely etiologies of diarrhea are infectious, xenobiotics, and food three etiologies are not mutually exclusive. The differential diagnosis must be m these groups. When the time from exposure to onset of symptoms is brief, all o nonbacterial infectious etiologies (viral, parasitic, fungal, and algal) except for u invasion by roundworm larvae can be eliminated. The possibility of a bacterial e enterotoxin production should be considered (Table 45-5 ). 30 , 51

Epidemiology

Epidemiologic analysis is of immediate importance, particularly when GI disease than one person in a group. The questions raised in Table 45-6 must be answer available, an infectious disease consultant or infection control officer should be assistance. Alternatively, assistance from state and local health departments sh Often only the CDC or state health department has the resources to investigate

presumptive diagnosis in an outbreak. Sophisticated techniques such as toxin d matching the organism in the food by phage type with a food handler, matching phage type with other persons, isolating 10 or more organisms per gram of imp 47 or PCR identification of bacterial or plasmid DNA are potentially useful althou possible using the laboratory and personnel available in most hospitals.23 , 33 , metabolic, and functional causes often can be eliminated. As in these diseases, significant grouping of cases nor a limited clinical history is characteristic. Food such as Trichinella spiralis (trichinosis), Toxoplasma gondii (toxoplasmosis), and (giardiasis) must be considered, although acute GI symptoms usually are not p

Staphylococcus

Species

In cases of suspected food poisoning with a short incubation period, the physici assess the risk for staphylococcal causes. The usual foods associated with stap

production include milk products and other proteinaceous foods, cream-filled ba potato and chicken salads, sausages, ham, tongue, and gravy. Pie crust can act maintaining the temperature of the cream filling and occasionally permitting to even during refrigeration.4 A routine assessment must be made for the presence

the hand or nose of any food handlers involved. Unfortunately, “carriers― enterotoxigenic staphylococci are difficult to recognize because they usually lack appear healthy.70 A fixed association between a particular food and an illness w helpful epidemiologically but rarely occurs clinically. Factors such as environmen

resistance, nature of the agent, and dose make the results surprisingly variable

1 . Is the occurrence of the disease in a large group significant enough to be c foodborne disease (two or more cases)? 2 . Is the symptomatology in affected individuals well defined and similar? 3 . Is the onset, time, and duration of illness similar among affected group me (incubation)? 4 . What are the possible modes of transmission (ie, contact, food, water)? 5 . Is there a relationship between the time of exposure of the group and the m transmission? 6 . Do attack rates differ for age, gender, or occupation? 7 . Can it be determined which foods were served and to whom? 8. 9.

6. 7. 8. 9. 10. 11. 12.

Can the items which were not eaten by those who did not become ill be ide What is the food-specific attack rate? How was the food procured? How was it stored? Was cooking technique adequate? Was personal hygiene acceptable? Was there animal contamination?

TABLE 45-6. Epidemiologic Analysis of Gastrointestinal Disease

Although patients with staphylococcal food poisoning rarely have a significant elevation, 16% of patients in a review of 2992 documented cases had a subject fever.70 Abdominal pain, nausea followed by vomiting, and diarrhea dominate th findings. Diarrhea does not occur in the absence of nausea and vomiting. The m period is 4.4 hours with a mean duration of illness of 20 hours. Two staphyloco

food poisoning incidents involving large numbers of people have been reported. people attended a public event in Brazil. Within hours of food consumption, 400 suffered nausea, emesis, diarrhea, abdominal pain, and dizziness. Of these ill p presented to and overwhelmed local emergency departments, 396 (20%) were a

intensive care units), and 16 (young children and elderly) died.143 In another re individuals became ill with symptoms of diarrhea, vomiting, dizziness, chills, an after they ate cheese or milk.144 Staphylococcus enterotoxin was found in the f by the patients in both reports.

Most enterotoxins are produced by S. aureus coagulase-positive species. These initiate an inflammatory response in GI mucosal cells and lead to cell destructio enterotoxins may have a dramatic effect on the emesis center in the brain and organ systems. Discrimination of unique S. aureus isolates from foodborne outb made using restriction fragment length polymorphism analysis by pulsed-field g electrophoresis and PCR techniques. 164

Salmonella

Species

Salmonella enteritidis infections are of great concern in the United States. Two outbreaks define very special problems. In the 1980s, recurrent outbreaks asso grade A eggs or food containing such eggs occurred. In the past, such outbreak

enteritis were attributed to infection of the egg with salmonella (from the chicke through cracks in the shell. More recently, outbreaks have involved noncracked eggs.107 In these cases, presumably the salmonella has infected the eggs before formed. In either case, people who consume raw or undercooked eggs are at mo salmonella enteritis. Raw eggs can be found as ingredients of chocolate mousse sauce, eggnog, egg creams, caesar salads, and

P.708 homemade ice cream. Whole, partially cooked eggs may be eaten as sunny side eggs.28 The second group of outbreaks was associated with raw milk,123 which popular in certain communities. Inadequate microwave cooking may cause sma These outbreaks are of great concern because they frequently involve multiple salmonella infections.41 Drinking pasteurized milk may not be protective. An ou salmonellosis resulting in more than 16,000 culture-proven cases was traced to

dairy. The probable cause of the outbreak was a transfer line connecting raw a milk containment tanks.129

Additional concern has developed over the widespread use of antibiotics in anim poultry, and manure-fertilized vegetables now frequently contain resistant bacte place virtually the entire population at risk.41 , 129 Household pets known to ha also places families at risk. Chicks, turtles, and iguanas carry salmonella and f

transmit the organism to household contacts, including infants, who are at parti invasive diseases.1

Campylobacter

jejuni

Campylobacter jejuni , a curved Gram-negative rod, is a major cause of bacter organism is most commonly isolated in children younger than 5 years and in ad years. Campylobacter enteritis outbreaks are more common in the summer mon temperate climates. Although most cases of Campylobacter enteritis are sporad are associated with contaminated food and water. The most frequent sources of in food are raw or undercooked poultry products48 and unpasteurized milk.31 , 1 common reservoir, and small outbreaks are associated with contamination of mi pecking on milk-container tops.146 Contaminated water supplies are also a frequ Campylobacter enteritis involving large numbers of individuals.17 C. jejuni is he cooking of food, pasteurization of milk, and chlorination of water prevent huma

The incubation period for Campylobacter enteritis varies from 1–7 days (mean Typical symptoms include diarrhea, abdominal cramps, and fever. Other sympto headache, vomiting, excessive gas, and malaise. The diarrhea may contain gros frequently leukocytes are present on microscopic examination.68 Illness usually days (range 1–8 days). Rarely, symptoms last for several weeks. Severe pre include lower GI hemorrhage, abdominal pain mimicking appendicitis, a typhoid reactive arthritis, and meningitis. The organism may be detected using PCR ide techniques.57 Treatment is supportive, consisting of volume resuscitation and p quinolone antibiotics in more severe cases.30

Group

A Streptococcus

Bacterial infections not usually associated with food or food handling occasionall transmitted by food or food handling. Streptococcal pharyngitis can be transmitt prepared by an individual with streptococcal pharyngitis.42

Clostridium

botulinum

In the last 3 decades, a median of 4 cases of foodborne botulism, 3 cases of w and 71 cases of infant botulism have been reported annually to the CDC.140 Hom and vegetables, as well as commercial fish products, are among the common fo

botulism. The incubation period usually is 12–36 hours; typical symptoms inc GI symptoms, followed by malaise, fatigue, diplopia, dysphagia, and rapid deve muscle incoordination.90 In botulism, the toxin is irreversibly bound to the neu junction, where it impairs the presynaptic release of acetylcholine.84 The diagno

must be made immediately, and aggressive respiratory therapy must be initiated is to survive. Additional therapeutic measures include administering antitoxin (C Antidotes in Depth: Botulinum Antitoxin ). The differential diagnosis of botulism myasthenia gravis, atypical Guillain-Barré syndrome, tick-induced paralysis, a chemical ingestions (see Tables 46-1 and 46-2 ).

Yersinia

enterocolitica

Yersinia enterocolitica is a Gram-negative coccobacillus that causes enteritis mo children and young adults. Typical clinical features include fever, abdominal pai

which usually contains mucus and blood.7 , 150 , 162 Other associated symptoms nausea, vomiting, anorexia, and weight loss. The incubation period may be 1 day more. Less common features include prolonged enteritis, arthritis, pharyngeal a involvement, and rash. Yersinia is a common pathogen in many animals, includin pigs. Sources of human infection include milk products, raw pork products, infe pets, and person-to-person transmission 24 , 64 , 92 Infections may be diagnosed cultures of food, stool, blood, and, less frequently, skin abscesses, pharyngeal cultures from other organ tissues (mesenteric lymph nodes, liver). Yersinia may with PCR.74 Therapy usually is supportive; however, patients with invasive disea bacteremia, bacterial arthritis) should be treated with IV antibiotics. Fluoroquin third-generation cephalosporins are highly bacteriocidal against Yersinia spp.

Listeria

monocytogenes

Listeriosis transmitted by food usually occurs in pregnant women, their fetuses, immunocompromised individuals (corticosteroid use, malignancy, diabetes, renal infection).13 , 29 , 34 , 136 Typical food sources include unpasteurized milk, soft feta, and undercooked chicken. Individuals at risk should avoid the usual source

evaluated for listeriosis if typical symptoms of fever, severe headache, muscle a pharyngitis develop. Treatment with IV ampicillin or trimethoprim–sulfametho indicated for systemic listerial infections.

Xenobiotic-Induced

Diseases

Careful assessment for possible foodborne pesticide poisoning is essential. For

aldicarb contamination has occurred in hydroponically grown vegetables and w contaminated with pesticides.62 Eating malathion-contaminated chapatti and wh resulted in 60 intoxications and 1 death in one outbreak39 (Chap. 109 ).

The possibility of unintentional acute heavy-metal ingestion must be considered. poisoning most typically occurs when very acidic fruit punch is served in metal Antimony, zinc, copper, tin, or cadmium in a container may be

P.709 dissolved by an acid food or juice medium. Insecticides, rodenticides, arsenic, l preparations can be mistaken for a food ingredient. These poisonings usually ha

of signs and symptoms after exposure.

Mushroom-Induced

Disease

Some species produce major GI effects. Amanita phalloides , the most poisonou usually causes GI symptoms as well as hepatotoxic effects with a delay to clinic manifestations. The rapid onset of symptoms suggests some of the gastroenter mushrooms (Chap. 113 ).

Intestinal

Parasitic

Infections

The popularity of eating raw fish, usually from Japanese restaurants, has led to reported intestinal parasitic infections. The etiologic agents typically are roundw (Eustrongyloides anisakis ) and fish tapeworms (Diphyllobothrium spp). Sympto

anisakiasis, or eustrongylidiasis, that are localized to the stomach typically occu after raw fish is eaten, whereas symptoms of lower intestinal involvement may days or weeks. Typical gastric or intestinal symptoms include nausea, vomiting, crampy abdominal pain that may mimic a gastric ulcer. Typical lower include abdominal cramping and, with perforation of the intestinal wall localized abdominal pain, rebound, and guarding, which may mimic an (appendicitis). In some cases, the symptoms include anaphylaxis with

intestinal by the l acute ab or withou

pain. Without an adequate dietary history (of eating raw fish), the diagnosis ma impossible to establish. Therapy would be directed toward the most likely diagn (gastric ulcer or appendicitis). Diagnosis usually is established on visual inspecti (on endoscopy, laparotomy, or pathologic examination), which typically are pink

fish that may contain Eustrongyloides include minnows (Fundulus spp.) and oth Anisakis simplex and Pseudoterranova decipiens are Anisakidae that may be fou types of frequently consumed raw fish, including mackerel, cod, herring, rockfis yellowfin tuna, and squid. Reliable methods of preventing ingestion of live anisa freezing –4°F (–20°C) for 60 hours or cooking at 140°F (60°C) for 5 m 98 , 128 , 134 , 166

Diphyllobothriasis (fish tapeworm disease) is caused by eating uncooked fish tha parasite. Hosts include, but are not limited to, herring, salmon, pike, and white symptoms are less acute than with intestinal roundworm ingestions and usually

weeks after ingestion.37 Signs and symptoms include nausea, vomiting, abdomi flatulence, abdominal distension, diarrhea, and anemia (megaloblastic). Diagnosis history of ingesting raw fish and on identification of the tapeworm proglottids in Treatment with niclosamide, praziquantel, or paromomycin usually is effective.2

Another foodborne toxin with GI symptoms is associated with eating reheated fr Chinese restaurants. Bacillus cereus type I is the causative organism, and bact and toxin production causes consequential early onset nausea and vomiting.2 In toxin causes liver failure. 100 Bacillus cereus type II has a delayed onset of sim symptoms, including diarrhea.54

Monosodium

Glutamate

The so-called “Chinese restaurant syndrome― is induced by ingestion of

glutamate (MSG); L-sodium glutamate. Individuals present with burning, facial headache, flushing, chest pain, GI symptoms usually limited to nausea and vom infrequently, life-threatening bronchospasm3 and angioedema.148 Intensity and symptoms are dose related, with significant variation in individual responses to

ingested.135 , 169 MSG causes “shudder attacks― or a seizurelike syndrom children. Absorption is more rapid following fasting, and the typical burning sym spread over the back, neck, shoulders, abdomen, and occasionally the thighs. G rarely prominent. Symptoms usually can be prevented by prior ingestion of food

symptoms do occur, they usually last approximately 1 hour. The syndrome is no patrons of Chinese restaurants. It is a reaction to MSG, which is used frequently restaurants. MSG is also marketed as an effective flavor enhancer.11 Many saus canned soups contain heavy doses of MSG.

MSG (regarded as “safe― by the FDA) can cause other acute and bizarre symptoms. The pathophysiology has not been clarified, although studies implica receptors.

Spicy

Food

Certain religious or cultural customs, such as eating bitter herbs at a Passover wasabi147 at a sushi bar, are associated with syncope. The precipitant in both i horseradish. Despite severe oropharyngeal or abdominal pain, no hematemesis

or fever is noted with horseradish. Gastric mucosal contact with pepperoni or j (capsaicin) may produce a similar syndrome.61

Anaphylaxis

and

Anaphylactoid

Presentations

Some foods and foodborne toxins may cause allergic or anaphylacticlike manife are also referred to as “restaurant syndromes―139 (Table 45-4 ). The sim syndromes complicates a patient's future approach to safe eating. Isolating the essential so that the risk can be effectively assessed. Manufacturers of processe provide an unambiguous listing of ingredients on package labels. Sensitive indiv parents) must be rigorously attentive. 131 , 170 Those with severe reactions shou by the immediate availability of epinephrine and antihistamine. Attempts to pre reactions to dairy products by avoiding dairy-containing foods may fail. Nondairy contain flavor enhancers of a dairy origin (eg, partially hydrolyzed sodium casei

cause morbidity and death in allergic individuals.56 Individuals with known food frequently fail to carry prescribed spring-injected epinephrine syringes, believing allergen is easily identifiable and avoidable.77 Food additives to consider as cau anaphylaxis include antibiotics, aspartame, butylated hydroxyanisole (BHA), bu

hydroxytoluene (BHT), nitrates or nitrites, sulfites, and parabens esters.94 Regu preservatives is limited, and agents such as sulfites are so ubiquitous that pred guacamole, cider, vinegar, fresh or dried fruits, wines, or beers do or do not co sensitizing agents may be difficult.

Illegal

Food

Additives

Medications are given to animals to increase their health and growth. Clenbutero agonist, has been administered to cattle raised for human consumption. The su cause toxicity in humans who eat contaminated animal meat. Tachycardia, trem

P.710 nausea, epigastric pain, headache, muscle pain, and diarrhea were present in 5 patients. Other findings included hypertension and leukocytosis.125 No deaths h reported, but use of antibiotics, β 2 agonists, and other growth enhancers will safety concerns and laws against their use, because these practices increase yie

Vegetables

and

Plants

Plants, vegetables, and their diverse presentations often are involved in food p , 80 , 85 , 86 Edible plants and plant products may be poorly cooked or prepared, contaminated. Extensive discussion is given in Chap. 114 .

Food

Poisoning

and

Bioterrorism

The threat of terrorist assaults has received increased attention and is discussed and 127 . Food as a vehicle for intentional contamination with the intent of cau suffering or death has occurred in the United States.38 , 82 , 155 In the first rep laboratory workers suffered GI symptoms, primarily severe diarrhea, caused by

served in the staff break room, which had been purposefully contaminated with type II.82 Four workers were hospitalized; none had reported long-term sequela strain is a rare one to cause endemic disease; the identical strain, as identified gel electrophoresis, was found in 8 of the symptomatic workers, in the pastries

break room, and in the laboratory's stock culture of S. dysenteriae . This findin purposeful poisoning of food eaten by laboratory personnel. The person respons motive remain unknown.

The second case series describes a large community outbreak of food poisoning Salmonella typhimurium .155 The outbreak occurred in the Dalles, Oregon area d 1984. A total of 751 people suffered salmonella gastroenteritis. The outbreak wa

intentional contamination of restaurant salad bars and coffee creamer by membe religious commune using a culture of S. typhimurium purchased before the outb poisoning. A criminal investigation found a salmonella culture on the religious c grounds that contained S. typhimurium identical to the salmonella strain found poisoning victims, as identified by using antibiotic sensitivity, biochemical testing restriction endonuclease digestion of plasmid DNA. More than 1 year of investig needed before this purposeful salmonella outbreak was linked to terrorist activit the delay in identifying the outbreak as a purposeful food poisoning include (1) motive; (2) no claim of responsibility; (3) no pattern of unusual behavior in the (4) no disgruntled restaurant employees identified; (5) epidemic exposure curv multiple time points for contamination, suggesting a sustained source of contam a single act; (6) no previous event of similar nature as a reference; (7) other seemed more likely (eg, repeated unintentional contamination by restaurant wo

fear that the publicity necessary to aid the investigation might generate copyca activity.

The delay in publication of the event (almost 10 years) also resulted from fears activity. The activity of the Japanese cult Aum Shinrikyo and its use of biologic appears to have provided the motivation to release this publication in the hopes purposeful food poisoning patterns can be identified more quickly in the future.

The third report describes a disgruntled employee who contaminated 200 lb of m supermarket with a nicotine-containing insecticide. 38 Ninety-two people became sought medical care. Symptoms included vomiting, abdominal pain, rectal bleedi case of atrial tachycardia.

The capacity for infecting large numbers of people with foodborne agents that a

obtain and disperse is clearly exemplified by two specific outbreaks: the purpos outbreak in Oregon, and the apparently unintentional salmonella outbreak that r 16,000 culture-proven cases traced to contamination in 1 Illinois dairy where th cause of the outbreak was a transfer line connecting raw and pasteurized milk

tanks.129 These events emphasize the vulnerability of our food supply and the ensuring its safety and security because the potential for purposeful contaminat widespread morbidity is an ever-present problem.

Summary

The diversity of etiologies for food poisoning involves almost all aspects of toxi

concerns center around the natural toxicity of a product such as a plant or anim contamination of which can occur in the field, during factory processing, or duri preparation or storage. These events may be intentional or unintentional, but th our approaches to general nutrition and society. The current debates about the role in food preparation and protection range from bacteria such as E. coli 0157 Creutzfeldt-Jacob disease (bovine encephalopathy) to genetically altered materia corn. Future discussions of food poisonings and interpretations of the importanc problems may dramatically alter our food sources and their preparation.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > B - Foods, Dietary and Nutritional Agents > Chapter 46 - Botulism

Chapter

46

Botulism Lewis R. Goldfrank Neal E. Flomenbaum A 27-year-old woman was in excellent health until 3 days before admission, when her family gathered for dinner following her mother-in-law's funeral. Shortly thereafter, the patient began experiencing dysphagia and dysarthria and seemed generally anxious. She saw her family physician, who prescribed diazepam. The day prior to her admission, the patient became dyspneic. She began to communicate by writing when talking became impossible. Writing soon became difficult, and the patient complained of having trouble walking and lifting her head. She would not eat and vomited food when she was force-fed. She then began to look straight ahead without moving her eyes. The next day she was taken to the nearest hospital, where the physicians in attendance noted the peculiarity of the symptoms, the fact that she was taking diazepam, and the temporal relationship to the funeral of her mother-in-law. The family physician was called from the emergency department and told of

the new symptoms that had developed during the previous 2 days. The physician reassured the emergency staff that this was “anxiety―; and the woman was discharged. Shortly after the patient returned home, she became increasingly dyspneic and cyanotic, and then had a cardiopulmonary arrest. Her husband initiated cardiopulmonary resuscitation (CPR) until the paramedics arrived. The paramedics continued CPR and brought her to the hospital. Physical examination on admission revealed an apneic, intubated, comatose young woman with blood pressure 90/40 mm Hg; pulse 80 beats/min; ventilated respiratory rate 14 breaths/min; rectal temperature 97.0°F (36.1°C). Her left pupil was 4 mm in diameter, her right pupil was 3 mm, and both pupils were sluggishly responsive to light. The heart and lungs were unremarkable. The abdomen was soft, and bowel sounds were diminished. The stools were negative for occult blood. There was no response to painful stimuli or coldwater caloric testing. Her upper extremities were flaccid, with absent reflexes. The patient had increased extensor tone in her legs, 2+ patellar reflexes, ankle clonus, and generalized myoclonic jerks. Cerebrospinal fluid (CSF) examination was normal as was edrophonium (Tensilon) testing. An electromyogram (EMG) demonstrated increased muscle action potentials with rapid repetitive stimulation and posttetanic potentiation. Botulism was diagnosed, and the patient was given 2 vials of trivalent botulinum antitoxin. However, her condition steadily deteriorated and she died 3 days after admission. Postmortem examination revealed cerebral edema and herniation. Examination of stomach contents revealed undigested mushrooms, from which Clostridium botulinum toxin type B was isolated. Because of the patient's presentation, the mother-in-law's

hospitalization was reviewed: Twelve days before the daughter-inlaw's first symptoms, the mother-in-law experienced nausea, vomiting, abdominal cramps, and distension, and she was treated with an antiemetic. Three days later, she complained of a dry throat, dysphagia, and chest pains. Two days after that, she had dyspnea. When an electrocardiogram (ECG) revealed inverted T waves in the precordial leads and occasional premature ventricular contractions, she was hospitalized to “rule out myocardial infarction.― The day after the mother-in-law's admission, she was even more dyspneic and stuporous. She was also noted to have dilated, sluggishly reactive pupils. She was intubated and became more alert. However, upon extubation the next day, she developed respiratory distress and required reintubation. A tracheostomy was performed, but she became febrile and died 2 days later. Following the daughter-in-law's hospitalization and death, the body of the mother-in-law was exhumed. An autopsy revealed bronchopneumonia, an enlarged heart, and mushroom fragments in the small intestines. The mushroom fragments yielded C . botulinum toxin type B. When the diagnosis of botulism was first considered and before the mushrooms were implicated, all family members who had been at the funeral meal were admitted to the hospital for observation. At that time, a third member of the family reported having difficulty swallowing. This woman was the only other family member who had eaten mushrooms at the funeral meal. She was given 1 vial of trivalent botulinum antitoxin, and her symptoms resolved in 3 days. Her stool specimens later revealed C. botulinum toxin type B. Twenty days after she was given the antitoxin, the woman developed severe arthralgias and fever suggestive of serum sickness. At the time of presentation, many of the other family members were understandably anxious. Some complained of dry throat,

headache, or tingling in their extremities, although none had eaten any of the mushrooms, and none had stools positive for C . botulinum toxin type B. Most were discharged from the hospital within 24–48 hours.48 A carefully obtained history revealed that the mother-in-law canned her own peppers, eggplant, artichokes, and mushrooms without using a pressure cooker. When the remaining canned foods were obtained from the mother-in-law's house and examined, only the mushrooms were found to contain C . botulinum toxin type B. P.716

Epidemiology Botulism has been recognized since the end of the 18th century. This classic foodborne poisoning was directly linked to inadequate preservation of varied forms of sausages that more than 200 years ago led to religious, legal, and culinary edicts to protect health. The term botulism is derived from the Latin word “botulus― for sausage, demonstrating the epidemiologic link. All clostridial species are ubiquitous, and bacteria and spores are present in soil, seawater, and air.97 Botulism outbreaks can occur anywhere in the world112 and have been reported from such diverse areas as Iran, the former Soviet Union, Japan,71 France, Scandinavia, and Canada.68

Belgium,

Portugal,53

Approximately 1.25 cases of foodborne botulism per 10 million people occur annually in the United States.56 The etiologies of botulism are 72% infant, 24% foodborne, 3% wound, and 1% adult type.92 When botulism is diagnosed, multiple cases per occurrence do not necessarily follow. In a series of hundreds of outbreaks involving more than 400 persons in total, approximately 70% involved only 1 person, 20% involved 2 persons, and only 10% involved more than 2 persons (mean 2.7 cases per outbreak).118 When only sporadic patients were affected, they were more severely ill, with 85% requiring intubation, compared

to only 42% requiring intubation in multiperson outbreaks.118 It is suggested that diagnosis in the index case may lead to appropriate rapid therapeutic intervention for associated cases. It also is possible that these index cases may have been exposed to the greatest amount of toxin and, therefore, had the shortest incubation period. Conversely, a lack of symptoms in others does not necessarily reassure that an individual was not exposed or ultimately will not develop serious sequelae. Although only 4% of foodborne botulism is associated with food purchased in restaurants, restaurant-related outbreaks usually affect large numbers of individuals and account for > 40% of all reported cases.56 Over the last 50 years, commercial food processing has accounted for only 7% of reported cases, with vegetables (peppers, beans, mushrooms, tomatoes, and beets, with or without meat) thought to be the causative agents in approximately 70%, meat in 17%, and fish in 13% of cases related to processed food. Home-processed food accounted for 65.1% of outbreaks, whereas 27.9% of outbreaks were of unknown origin.25 Concern has been raised regarding minimally processed foods (eg soft cheeses) that lack sufficient quantities of intrinsic barriers to botulinum toxin production, such as salt and acidifying agents.80 These foods become high-risk sources of botulism when refrigeration standards are violated. The US Food and Drug Administration (FDA) continuously reviews recommendations for appropriate measures to process such foods. 108 , 109 Common home-canning errors responsible for cases include failure to use a pressure cooker and allowing food to putrefy at room temperature. Outbreaks of botulism are associated with specialty foods consumed by different ethnic groups: chopped garlic in soy oil by Chinese in Vancouver, British Columbia; 68 , 100 fried lotus rhizome solid mustard in Japan;71 uneviscerated salted fish—called kapchunka —eaten by Russian immigrants in New York City;22 , 106 and the same food-called faseikh —eaten by Egyptians in

Egypt.114 Other outbreaks have involved fermented salmon eggs, seal and raw whale muktuk (skin and pink blubber layer) consumed by Inuits and Native Americans in Alaska,27 , 113 and heat shrink-wrapped meat roll (Matambre) consumed in Argentina.112 Over the last 50 years, the botulism case fatality rate was 17% toxin type A, 7.4% toxin type B, 15.5% toxin type E, and 18.6% toxin type unknown.25 As expected, case fatality data have continuously improved, with a fatality rate of 5.8% reported for all types in the most recent analysis.25 Approximately 67% of patients with toxin type A require intubation, compared to 52% of patients with toxin type B, and 39% with toxin type E botulism.118 Although the median incubation period for all patients is 1 day, it ranges from 0–7 days for toxin type A, 0–5 days for toxin type B, and 0–2 days for toxin type E.118 Physicians may need to respond more rapidly to a potential epidemic of toxin type E, but they should be prepared for greater complication rates associated with toxin type A.118 The improvement in case fatality rates for all botulism toxin types probably represents increasing awareness of the problem associated with earlier diagnosis, appropriate and early use of antitoxin, and better and more easily accessible life support

techniques.

Awareness of evolving trends and unusual presentations or locations of botulism and instituting preventive education are important. Although 90% of toxin type E outbreaks have occurred in Alaska because of home-processed fish or meat from marine animals,30 , 56 1 incident occurred in New Jersey.23 In the past decade, 3 cases of botulism involved members of the Native American church after they ingested a ceremonial tea that was made from the buttons of dried, alkaline-ground peyote cactus that were prepared in a water-covered refrigerated jar. The resultant alkaline and anaerobic milieu presumably fostered the growth of toxin from naturally occurring spores.44

In recent times, concern about the use of botulinum toxin as a biologic weapon has increased. Interest in the adverse consequences of therapeutic botulinum toxin injections also has developed.8 In ways unimaginable since the first edition of this chapter was published, the medical and public health issues associated with terrorism and botulinum toxin unfortunately only increase the relevance of this chapter in the 21st century (Chap. 127 ).

Characteristics of Clostridium Botulinum, Clostridium Butyricum , and Clostridium

Baratii

Clostridium botulinum is actually a group of spore-forming, anaerobic, Gram-positive bacilli. Although often classified as a single species, the genus Clostridium consists of at least 4 distinct genetic variants that produce 7 homologous neurotoxic proteins that cause botulism: C. botulinum , which produces toxin types A, B, and E; Clostridium baratii , which produces toxin type F; Clostridium butyricum , which also produces toxin type E, and Clostridium argentinense , which produces toxin type G.45 , 92 Rare instances of both adult and infant botulism are attributed to C. baratii and C. butyricum . 43 , 64 , 72 , 77 This rarity of toxin type F may be exaggerated because of the only recent additional capacity of most laboratories to determine the presence of C . baratii and other clostridial species producing toxin type F. 43 Toxin types A through G, with Cα and Cβ, have been identified to date. In the United States, toxin type A is found west of the Mississippi,58 toxin type B is found east of the Mississippi, particularly in the Allegheny range, and toxin type E is found in the Pacific northwest.24 , 97 Toxin types A and B typically are found in poorly processed meats and vegetables. Toxin type E is commonly found in raw or fermented marine fish and mammals. Toxin type G has

P.717 not been associated with naturally occurring disease. Toxin types C and D cause disease in birds and mammals. Although botulinum toxins have slightly different mechanisms of action, the ultimate pathophysiology and clinical syndromes are identical. All botulinum spores are dormant and highly resistant to damage. They can withstand boiling at 212°F (100°C) for hours, although they usually are destroyed by 30 minutes of moist heat at 248°F (120°C). Factors that promote germination of spores in food are pH > 4.5, sodium chloride content < 3.5%, or a low nitrite concentration. Most viable organisms produce toxin in an anaerobic milieu with temperatures > 80.6°F (27°C), although some strains produce toxins even when conditions are not optimal. C. botulinum organisms can produce toxin type E at temperatures as low as 41°F (5°C). To prevent spore germination, acidifying agents such as phosphoric or citric acid are added to canned or bottled foods that have a low acid content, such as green beans, corn, beets, asparagus, chili peppers, mushrooms, spinach, figs, olives, and certain nonacidic tomatoes. As opposed to the spores, the toxin itself is heat labile and can be destroyed by heating to 176°F (80°C) for 30 minutes or to 212°F (100°C) for 10 minutes. At high altitudes, where the boiling point of water may be as low as 202.5°F (94.7°C), a minimum of 30 minutes of boiling may be required to destroy the toxin. Under high-altitude conditions, pressure cooking at 13–14 lb of pressure often is necessary to achieve appropriate temperatures to destroy the toxin. Food contaminated with C. botulinum toxin types A and B often does not look or smell normal and appears putrefied because of the action of proteolytic enzymes.42 In contrast, because toxin type E organisms are saccharolytic and not proteolytic, food contaminated with toxin type E may look and taste normal.9

Pathophysiology Botulinum toxin is the most poisonous substance known. The LD50 for mice is 3 million molecules injected intraperitoneally. The human oral lethal dose is 1 µg/kg. 85 The toxin is a protein consisting of a single polypeptide chain, with a molecular weight (MW) of 900,000 daltons, which includes a 750,000 MW nontoxic protein and a 150,000 MW neurotoxic component. To become fully active, the single-chain polypeptide 150,000 MW neurotoxin must undergo proteolytic cleavage to generate a dichain structure with a heavy chain (MW 100,000) that is linked by a disulfide bond to a light chain (MW 50,000). It appears that the single polypeptide chain toxin and the dichain form both are resistant to gastrointestinal degradation.59 Because the toxin is often demonstrated only in the stool, determining what percentage of the toxin actually is absorbed is difficult.33 , 34 The botulinum toxin binds to serotype specific receptors on the mucosal surfaces of gastric and small intestinal epithelial cells, where endocytosis followed by transcytosis permits release of the toxin on the serosal cell surface. 51 , 60 The dichain form of the molecule is responsible for all clinical manifestations.45 , 96 The dichain form binds rapidly and irreversibly to the neuronal cell membrane and is taken up by endocytosis. The heavy chain is responsible for cell-specific membrane binding to acetylcholine-containing neurons.74 Once inside the cell, the light chain acts as a zinc-dependent endopeptidase to cleave polypeptides that are essential components of the neurotransmitter release apparatus, thereby inhibiting exocytosis.85 Different botulinum toxin types share the same mechanism of cell entry, but three groups of botulinum toxin types appear to have distinct mechanisms of preventing acetylcholine release, which may be responsible for their variable toxicity.94 Different light chains specifically cleave different members of the SNARE family. Toxin types B, D, F, and G act on vesicle-associated membrane protein (VAMP)/synaptobrevin

localized on the synaptic vesicle, toxin types A and E cleave synaptosomal associated protein (SNAP)-25, and toxin type C cleaves both presynaptic plasma membrane proteins syntaxin and SNAP-25 (Figure 46-1 ). 51 Regardless, cholinergic transmission at all acetylcholine-dependent synapses in the peripheral nervous system is impaired. However, the central nervous system and axonal conduction are not affected. The duration of action of the toxin types may vary, depending on the components of the neurotransmitter release apparatus that are disrupted. The persistence of clinical effect may result from the individual cleavage product, the intraneuronal biological half-life of the toxin, or both. Current evidence indicating intraneuronal toxin metabolism or elimination is inadequate.96

Signs

and

Foodborne

Symptoms Botulism,

Adult

Type

(In

Vi tro) Although botulism is the most dreaded of all food poisonings, the initial phase of the disease (which occurs the first day following ingestion) often is so subtle that it goes unnoticed. Further compromising the care of exposed individuals is the fact that botulism often is misdiagnosed on the first visit to a physician.19 , 119 Conversely, when gastrointestinal symptoms are striking and food poisoning is suspected, the differential diagnosis should include other acute poisonings, such as metals, plants, mushrooms, and the common bacterial, viral, and parasitic agents discussed in Chap. 45 . Because physicians so infrequently (especially compared to other much differential diagnosis), initiation of is seriously delayed (Table 46-1 ).

encounter the disease more common diseases in the appropriate management often This is particularly true of toxin

type E botulism, which typically initially causes much more prominent gastrointestinal signs than neurologic signs.9 The differences in the appearance of food and initial clinical symptoms associated with the various serotypes may be related to the presence of proteolytic enzymes in toxin types A and B and saccharolytic enzymes in toxin types E and C botulism. The index case of an epidemic or an isolated case often is misdiagnosed at a stage when the risk of morbidity and mortality still could be substantially diminished. Early gastrointestinal signs and symptoms of botulism include nausea, vomiting, abdominal distension, and pain. A time lag (from 12 hours to several days, but typically not more than 24 hours) may or may not be observed before one or more of the following signs and symptoms appear: constipation, dry or sore mouth and throat, dysphonia (typically manifested by a nasal quality to the voice), dysarthria, dysphagia (at times predominant and severe); blurred vision with impaired accommodation, diplopia, descending, bilaterally symmetric motor paralysis beginning with abducens (VI) or oculomotor (III) nerve palsy (frequently resulting in strabismus); mydriasis (often fixed); respiratory insufficiency; and urinary retention. Although many of these initial signs and symptoms are anticholinergic in nature, mental status and the remainder of the neurologic examination remain normal. The Centers for Disease Control and Prevention (CDC) case definition for foodborne botulism is established in a patient with a P.718 neurologic disorder manifested by diplopia, blurred vision, bulbar weakness, and symmetric paralysis in whom Botulinum toxin is detected in serum, stool, or implicated food samples or C.

botulinum is isolated from stool, or

A clinically compatible case is epidemiologically linked to a laboratory-confirmed case of botulism24

Figure 46-1. Botulinum toxin consists of two peptides linked by disulfide bonds. The heavy chain is responsible for specific binding to acetylcholine (ACh)-containing neurons. Following binding to the cell surface, the entire complex undergoes endocytosis and subsequent translocation of the light chain into the nerve cell cytoplasm. The light chain contains a zinc-requiring endopeptidase that cleaves proteins required by the docking/fusion complex critical to neuroexocytosis. Botulinum toxin type B targets both vesicle-associated membrane protein (VAMP)/synaptobrevin, a docking protein located on the acetylcholine-containing synaptic vesicles (synaptosome). Botulinum toxins types A and E proteolyse synaptosomal associated protein (SNAP), a component of the presynaptic cell-membrane docking complex (associated with

syntaxin). After these important components of the docking complex are destroyed, neurotransmitter release cannot proceed, resulting in clinical findings consistent with acetylcholine deficiency.

When lateral rectus palsy, ptosis, and sluggish pupillary reactivity occur, respiratory insufficiency usually follows. As weakness progresses, deep-tendon reflexes may diminish. The pulse frequently is normal or slow, and temperature in adults typically remains normal. The absence of a tachycardia is surprising in the presence of other typical anticholinergic findings. The normal mental status and temperature in the presence of ophthalmoplegia and generalized muscle weakness (nicotinic findings) that occur with botulism, but not with antimuscarinic poisoning, should lead the clinician to rapidly suspect or diagnose botulism and institute appropriate management for the patients affected by this lifethreatening toxin.107 When suspicion of disease is high and the vital capacity is < 30% of predicted, intubation should be strongly considered.104 The most difficult and frequently encountered problem in correctly diagnosing botulism is differentiating between botulism and the Miller Fisher variant of the Guillain-Barré syndrome (Table 46-2 ).

Infant Botulism (In Vivo Infant Intestinal Colonization) First described in California6 , 46 , 50 in 1976, several thousand cases of infant botulism have now been confirmed across the world. Interestingly, 95% of these cases are reported in the United States.31 , 72 Although infant botulism is reported from approximately half of the states in the United States and all inhabited continents except Africa,31 50% of reported cases originate from California, Utah, Pennsylvania, and New Mexico.117 In California, aggressive surveillance and educational efforts with

regard to P.719 infant botulism have been practiced since 1976, which may explain in part the disproportionate distribution of cases.5 Aminoglycoside poisoning Postanesthetic paralysis, intraoperative exposure Anticholinergic poisoning Mydriasis, vasodilation, fever, tachycardia, ileus, dry mucosa, altered mental status Buckthorn (Karwinskia humboldtiana ) Rapidly progressive ascending paralytic neuropathy with quadriplegia Carbon monoxide poisoning Headache, nausea, altered sensorium, tachypnea, elevated carboxyhemoglobin concentration Diphtheria (polyneuritis) Exudative pharyngitis, cranial polyneuropathy (late), cardiac manifestations, hypotension Eaton-Lambert syndrome Neoplasm, ophthalmoplegia (rare), no respiratory paralysis, increased strength following sustained contractions, posttetanic facilitation on electromyography, calcium channel-blocking antibodies Elapidae (coral snake) envenomation Euphoria, light-headedness, fasciculations, tremor, weakness, salivation, nausea, vomiting followed by bulbar palsy, paralysis including slurred speech, diplopia, ptosis, dysphagia, dyspnea, respiratory compromise Encephalitis Fever, mental status abnormalities, seizures, elevated CSF protein, pleocytosis Food poisoning (other bacterial) Rapid onset of disease, absence of cranial nerve findings Guillain-Barré syndrome (Miller Fisher variant)

Acute inflammatory demyelinating polyneuropathy, areflexia, paresthesias, ataxia, elevated CSF protein without cells, denervation, prolonged nerve conduction velocity on electromyography Hypermagnesemia Respiratory compromise, diffuse flushing, weakness, thirst Inflammatory myelopathies (acute myelitis, transverse myelitis, necrotic myelopathy) Complete (transverse) or incomplete spinal syndrome: posterior column myelopathy with ascending paresthesias or ascending spinothalamic findings or Brown-Sequard syndrome; typically follows viral illness, back pain, progressive paraparesis, asymmetric ascending paresthesias in legs; CSF: 5–50 lymphocytes/mm3 , elevated creatine kinase concentrations Multiple sclerosis Weakness, visual blurring (optic neuritis), sensory disturbances, diplopia, ataxia; lesions separated in space and time; mononuclear cell pleocytosis in CSF; evoked response testing: slow or abnormal conduction in visual, auditory, somatosensory, or motor pathways; abnormal MRI with a paramagnetic dye (gadolinium) Myasthenia gravis Aggravation of fatigue with exercise, recurrent paralysis, positive edrophonium test, acetylcholine receptor antibodies Organic phosphorus compound poisoning Salivation, lacrimation, urination, defecation, fasciculations, bronchorrhea, delayed neuropathy Paralytic shellfish poisoning Incubation < 1 h, dysesthesias, paresthesias, impaired mentation, respiratory paralysis Poliomyelitis Fever, GI symptoms, asymmetric neurologic findings CSF pleocytosis, elevated CSF protein Polymyositis Insidious onset, proximal limb weakness, dysphagia, muscle

tenderness, cramping, ↑ESR, electromyography: fibrillation and sharp waves Stroke syndrome (midbrain) Asymmetric focal paralysis, abnormal brain neuroimaging (CT, MRI) Tetanus Cranial nerve defects (rare), spasticity, rigidity Thallium poisoning Constipation, cranial neuropathy, ascending sensory neuropathy, Mees lines, alopecia Tick (Dermacentor spp): related paralysis Ataxia, progressive large muscle weakness, ascending paralysis, absence of paresthesias, normal CSF analysis, presence of an embedded tick and resolution upon removal Condition

Diagnostic

Findings

TABLE 46-1. Differential Diagnosis of Conditions Commonly Confused with Botulism

Fever Absent May be present May be present Motor Pupils Dilated or unreactive (50%) Normal Normal Ophthalmoplegia Present (early) Present (late) Present (early) Paralysis

Descending Ascending Descending Deep tendon reflexes Diminished Absent Absent Ataxia Absent Present Present Sensory Paresthesias Absent Present Present Laboratory CSF protein Normal Elevated Elevated

(late) (late)

Botulism

TABLE

46-2.

Guillain-Barré Syndrome

Miller Fisher Variant of Guillain-Barré

Differentiating Botulism Syndrome

from

Guillain-Barré

Infant botulism is the most common form of botulism in the United States, and 99% of these cases are from botulinum neurotoxin type A or B.72 Affected children are always younger than 1 year (usually 1–3 months) and characteristically have normal gestations and births. The first signs of infant botulism are constipation; difficulty with feeding, sucking, and swallowing;

feeble crying; and a “floppy― baby with diffuse, decreased muscle tone. The decreased muscle tone is particularly apparent in the limbs and neck. Ophthalmoplegia, loss of facial grimacing, dysphagia, diminished gag reflex, poor anal sphincter tone, and respiratory failure are present, but fever and enteric symptoms do not occur. The differential diagnosis of infant botulism initially includes dehydration, failure to thrive, hypotonia, sepsis, and a viral syndrome. Conversely, many of the signs and symptoms of infant botulism and many of the syndromes cited in Table 46-1 are relevant to the evaluation of sick children, or children with the rarer neurologic, myopathic, and congenital syndromes that occur in the first year of life.50 Because the P.720 toxin in infant botulism is absorbed gradually as it is produced, the onset of clinical manifestations of botulism may be less abrupt than in severe cases of foodborne botulism caused by large amounts of preformed toxin absorbed over a brief period of time. A single case of foodborne botulism associated with home-canned baby food was reported in a 6-month-old infant.4 Only certain children are susceptible to infant botulism. As opposed to the better-understood foodborne botulism variants, infant botulism may result from ingestion of C. botulinum organisms in food or following the inspiration or ingestion of organism-laden aerosolized dust. Some infants may be immunologically unprepared for spore control, a deficiency that allows subsequent germination and toxin development within their gastrointestinal tracts and subsequent gut absorption. Also, an infant's gastrointestinal tract lacks bile acids and gastric acid, which when present may inhibit clostridial growth in older children and adults. Approximately 70% of infant botulism cases occur in breast-fed infants, even though only 45–50% of all infants are breast-fed. Bacterial growth associated with breast-feeding may favor Bifidobacterium development, whereas formula-fed infants are rapidly colonized by Coliforme spp, Enterococcus spp, and

Bacteroides spp. All three of the species colonizing formula-fed infants may inhibit C. botulinum; conversely, the absence of these typical organisms in breast-fed infants may facilitate C. botulinum multiplication.46 Epidemiologic studies indicate that ingestion of honey was associated with 34.7% of hospitalized cases of infant botulism worldwide. Moreover, of all nutritional items tested as possible epidemiologic sources, only honey was found to contain C . botulinum spores.6 When C. botulinum spores were isolated from honey implicated in cases of infant botulism, the same toxin type was isolated from the infant and, as noted previously, no preformed toxin was isolated. The epidemiologic link to honey is debated, because similar clostridial organisms are found in household dust, yard dirt, and the honey ingested. Previous studies suggested a correlation between the presence of both C. botulinum organisms and toxin and sudden infant death syndrome (SIDS).98 However, in a prospective infants with SIDS, C. botulinum was not found any of the children.20 Cases of infant botulism the hospital, preferably in a pediatric intensive

study of 248 on stool culture of must be managed in care unit for at

least the first week, when the risk of respiratory arrest is greatest. In 1 study, approximately 80% of children with botulism required intubation for reduced vital capacity, and 25% of these children had frank respiratory compromise.87 In a group of 57 affected infants 18 days to 7 months of age managed during the decade ending in the mid-1980s, 77% were intubated and 68% required mechanical ventilation. In the subsequent decade ending in the late 1990s, investigators from the same institution found that 61.7% of 60 infants required endotracheal intubation for a mean of 21 days.2 Better understanding of disease progression with close observation permitted a decrease in intubations and complications. In this study, the investigators also demonstrated that airway complications such as stridor, granuloma formation, and subglottic stenosis were common, yet tracheotomy was

infrequently performed. Loss of airway protection was the best indicator of patients who required aggressive management.88 The survival rate in infant botulism is approximately 98%.88 Several children with infant botulism sustained unexpected respiratory arrests,7 often associated with procedures such as lumbar punctures or radiographic examinations. However, it appears that the cardiopulmonary status was often unintentionally compromised during these procedures.54

Wound

Botulism

(In

Vivo)

Wound contamination previously was considered an uncommon cause of botulism. The first case of wound botulism was not reported until 1943, and the total number of identified by the CDC to date is approximately “classic― presentation of wound botulism injured in an automobile crash who sustains a

wound-related cases 100. The is that of a patient deep muscle

laceration, crush injury, or compound fracture treated with open reduction. The wound typically is quite dirty and usually associated with inadequate débridement, subsequent purulent drainage, and local tenderness, although the wound may appear unremarkable in other cases. Four to 18 days later, cranial nerve palsies and the other neurologic findings typical of botulism may appear.65 Other signs of food-related botulism, such as the gastrointestinal manifestations, usually are absent. Most of the recent cases of wound botulism are associated with subcutaneous injection of heroin. In wound botulism, fever may be prominent and associated with the abscess, sinusitis, or other tissue infection presumed to harbor the clostridial organisms. Although in some cases the patients may require management for wound-related problems, in other cases, the wounds appear clean and uninfected. No particular vehicle, vector, or pathophysiologic etiology for wound botulism has been identified. Recognition of wound botulism as a potential

complication of wound infections is essential for appropriate early and aggressive therapy. In a small series of parenteral drug-using patients with botulism in New York City, the most prominent symptoms were dysphagia, dysarthria, and dry mouth. In these patients and 3 other clinically comparable patients with botulism, the CDC investigators were not able to find any organism or toxin in serum, stool, or skin lesions.57 Cocaine76 , 101 and heroin,19 particularly subcutaneously injected “black tar heroin,― are associated with an increasing number of wound botulism cases.73 , 83 , 115 The markedly increased frequency associated with black tar heroin use appears to be related, at least in part, to physical characteristics such as its viscosity, its potential to facilitate anaerobic growth and spore germination, and its ability to devitalize tissue or inhibit wound resolution.11

Adult Adult

Infectious Botulism (In Vivo Intestinal Colonization)

This fourth class of botulism includes any patient older than 1 year in whom a particular food source cannot be implicated. Until the recent recognition of “therapeutic botulism,― adult infectious botulism was the rarest form of botulism, with only 15 cases reported by 1997.41 , 64 Some cases of in vivo adult intestinal colonization may represent a variant form of infant botulism.67 There is a well-documented case of an adult female with botulism resulting from the ingestion of a food source contaminated with C . botulinum type A organisms and no preformed toxin.29 In this case, the combination of a long incubation period with toxin present in the serum and stool for 3 weeks after exposure and the absence of disease in the patient's spouse who shared the food suggested in vivo intraluminal elaboration of toxin. This patient

was a very unusual host in that she had a history of peptic ulcer disease treated with truncal vagotomy, antrectomy, and a Billroth I anastomosis. She had received perioperative antibiotics 5 weeks prior to the development of botulism. All of these factors may have compromised the gastric and bile acid barrier, gut flora, and motility, thus allowing spore germination, altered bacterial growth, and P.721 toxin development. Other cases of adult infectious botulism occurred in patients after ileal bypass surgery and Crohn disease,12 jejunoileal bypass for obesity,38 , 63 gastroduodenostomy,63 vagotomy and pyloroplasty,63 and necrotic volvulus.56 The general risk factors favoring organism persistence and C. botulinum colonization include recent antibiotic therapy, achlorhydria (surgically or pharmacologically induced), and previous intestinal surgery. In a single case report, production of endogenous antibody to botulinum toxin was demonstrated.41 A 67-year-old man with long-standing Crohn disease who had undergone terminal ileum and right colonic resection presented with abdominal pain. Prior to admission, the patient had experienced several episodes of diplopia. After admission, systemic paralysis developed. The patient had a prolonged recovery after receiving two courses of equine trivalent botulinum antitoxin and 81 days of antibiotic treatment. A mouse assay performed to determine the persistence of any previously administered antitoxin prior to administering additional antitoxin identified a particularly high level of antitoxin specific to toxin type A but not toxin type B. An enzyme-linked immunosorbent assay (ELISA) test performed to distinguish equine from human antitoxin antibodies demonstrated an endogenous human antitoxin response to the toxin. This response points out a distinct characteristic of adult infectious botulism, as other investigators have shown that antitoxin immunity does not develop in patients with foodborne botulism.85

Therapeutic (In Vitro)

and

Inadvertent

Botulism

The fifth and most recently recognized form of botulism is purely iatrogenic. Currently doses ranging between 10 and 100 ng botulinum toxin type A (Botox® or Dysport® [available in Europe]) or botulinum toxin type B (Myobloc®) are used therapeutically.21 The initial therapeutic use of botulinum toxin involved injections into extraocular muscles under electromyographic control as a treatment for blepharospasm or as a supplement to corrective strabismus surgery.49 Its use is supported by animal investigation105 and suggested by clinical experience49 indicating that the neurotoxin—at the smallest effective clinical doses—would not diffuse from the injection site, avoiding the risk of excessive local or systemic complications. Currently used without intensive monitoring, these agents are used to cause the temporary weakness necessary to treat facial nerve disorders and to eliminate frown lines, achalasia, dysphagia, dystonia, torticollis, axillary hyperhidrosis, migraine headaches, obesity, spasticity, voice and speech disorders (spasmodic dysphonia), and chronic anal fissures.18 , 61 The relative potencies of commercially available botulinum toxins are quite variable69 , 81 , 90 (Table 46-3 ). The doses of botulinum toxin selected are measured in functional units corresponding to the median lethal doses (LD50 ) used for female Swiss Webster mice weighing 18–20 g. The units of each marketed agent are distinctly different and may confuse the clinician, leading to inadvertent botulinum toxin poisoning.21 The potential for clinician confusion may be substantial when switching from type A to type B botulinum toxin. For example, 1 U Botox® equals 50 U Myobloc®, which represents 100 U botulinum toxin A per vial and 5000 U botulinum toxin B per vial, respectively.17 The approximate estimate of quantities of type A botulinum toxin

causing disease by different routes of administration are given in Table 46-3 . Doses range widely depending on the size of the muscle to be treated, the degree of weakness required, and the commercial preparation of the toxin.42 These injections irreversibly block the local neuromuscular junction. The affected muscles then weaken by atrophy over a 3-week period but recover within 2–4 months as nerve transmission is restored through sprouting of new nerve endings and functional connections at motor endplates.1 , 85 Repetitive doses of botulinum toxin may be indicated to prolong duration of action for several months.42 , 49 , 55 Intravenous 0.09–0.15 µg (90–150 ng) = 0.001 µg/kg Inhalation 0.70–0.90 µg (700–900 ng) = 0.01 µg/kg Intramuscular 7.0 µg (7000 ng) = 0.1 µg/kg Intraperitoneal 7.5 µg (7500 ng) [approximate, equals] 0.1 µg/kg Oral 70 µg (70,000 ng) = 1 µg/kg 1 U Botox® = lethal intraperitoneal dose in mice 1 U Botox® = 2.5 ng botulinum toxin type A 100 U Botox®/vial powder for reconstitution for intramuscular use68 ,79 1 U Botox® [approximate, equals] 3–5 U Dysport≈107 Route of Exposure

Dose

TABLE 46-3. Botulinum Toxin Type A (Crystalline)3 6 , 8 3 , 8 8 Very Approximate Human LD 50 Although one early marketing assumption was that the neurotoxin

did not diffuse from the injection site,79 botulinum toxin does diffuse into local tissues and adverse effects typically occur locally.79 Systemic manifestations are of concern when an inadvertent, excessive, or misdirected dose of toxin is administered. In addition, a number of studies demonstrate that even appropriately injected doses result in neuromuscular junction abnormalities throughout the body, infrequently producing autonomic dysfunction without muscle weakness.39 , 52 , 70 Several cases of iatrogenic botulism characterized by asthenia, diplopia, and severe generalized muscle weakness with widespread EMG abnormalities have resulted from therapeutic doses of botulinum toxin injected intramuscularly.10 , 13 , 110 In a large series of 107 patients treated successfully for spasmodic torticollis, 44% of all treatments resulted in dysphagia. Of this subgroup, several patients developed stridor and/or aspiration and required hospitalization.3 Following repeated injections of therapeutic doses of botulinum toxin, patients typically develop neutralizing antibodies that subsequently may limit the toxin's efficacy and lead to increased use of a different toxin type.16 In Japan and the United Kingdom, a preparation of botulinum toxin type F is also used when antibodies to type A develop. 93 Some studies14 suggest that animals receiving type F botulinum toxin have a more transient and reversible weakness than that associated with types A and B. Interestingly, however, recurrent episodes of foodborne botulism occurring in one individual suggest that repeated exposure to clinically significant quantities of toxin do not result in long-term immunity.85

Diagnosis Routine laboratory studies, including CSF analysis, are normal in patients with botulism. Specific tests that are uncommonly used but are particularly helpful in diagnosing botulism include the

following.

Tensilon Edrophonium to diagnose differentiate metabolism

Test

(Tensilon) is a rapidly acting anticholinesterase used myasthenia gravis and occasionally used to myasthenia gravis from botulism. This drug prevents of P.722

the available acetylcholine, permitting continued reaction with the reduced number of postsynaptic acetylcholine receptors in myasthenia gravis. An IV injection of 10 mg is prepared and then 1–2 mg is administered slowly to avoid the nausea and vomiting commonly associated with larger doses. The remainder of the edrophonium is given over the next 5 minutes. The strength of patients who have myasthenia gravis but not botulism dramatically improves within 30–60 seconds, and the improvement lasts 3–5 minutes. In rare cases, early in the course of botulism, limited improvement in strength occurs that is far less dramatic than that seen in patients with myasthenia gravis.75 Anticholinesterase drugs, such as edrophonium, have no effect on the toxin's action but may affect patients clinically if some cells can still release acetylcholine. Because acetylcholine release is impaired in botulism, prevention of its metabolism is of limited importance.

Figure 46-2. Electromyographic findings. Schematic representations of repetitive nerve stimulation at low (5/sec) and high (50/sec) frequencies. In botulism (a) , repetitive stimulation produces a small-muscle action potential that facilitates (increases in amplitude) at higher frequencies. This effect results from increased acetylcholine release with high-frequency stimulation because of increased intracellular calcium concentration. In contrast, myasthenia gravis (b) is associated with a normal muscle action potential amplitude and a decremental response at low-frequency stimulation with a normal response at highfrequency stimulation. Myasthenia gravis, a disorder of the muscle endplate, produces this decremental response at low frequencies because the natural reduction in acetylcholine response with subsequent stimulation falls below threshold.75 , 111

Electromyography The EMG pattern in all forms of botulism is characterized by brief, small, abundant motor-unit action potentials (BSAPs; or lowamplitude, short-duration potentials) (Figure 46-2 ). Motor nerve conduction velocity remains normal because axon conduction is not affected. Normal sensory nerve amplitudes and latencies are found. Primary muscle diseases also produce normal conduction velocity and a BSAP pattern, but in botulism, serum concentrations

of muscle enzymes and muscle biopsy are normal. Another typical EMG finding of botulism is an increment in small compound muscle action potential (CMAP) amplitude directly related to acetylcholine release following repetitive stimulation at 20–50 Hz. Posttetanic facilitation may be noted in cases of botulism and in other entities such as Eaton-Lambert paraneoplastic syndrome, aminoglycosideassociated paralysis, and hypermagnesemia. Although not pathognomonic, EMG findings interpreted in light of the total clinical presentation can help establish the diagnosis of botulism.75 , 111

Toxin type A, B, E, F, G in humans; C, D in animals A, B, C, F A, B A Route Ingestion Ingestion Wound, abscess (sinusitis) Ingestion of bacteria and spores Specimens Stool: positive for bacteria/spores and toxin Stool: positive for bacteria/spores and toxin for up to 8 weeks after recovery Wound site: Gram stain, aerobic and anaerobic cultures; positive for bacteria/spores Stool: positive for bacteria/spores and toxin Toxin in serum Yes Yes Yes Yes Toxin, bacteria/spores in food Yes (all)

Bacteria/spores: yes Toxin: no No Bacteria/spores: yes Toxin: no Family and friends At risk if same foods were eaten Unaffected Unaffected (unless shared needle or drug) Unaffected All toxin and positive presence of bacteria/spores refer to C . botulinum .

Classification

Foodborne

Infant

Wound

Adult Infectious

TABLE 46-4. Epidemiologic and Laboratory Assessment of Botulism

Laboratory

Testing

Samples of serum, stool, vomitus, gastric contents, and suspected foods should be subjected to anaerobic culture (C. botulinum ) and toxin mouse bioassay (botulinum toxins) (Table 46-4 ). A medication list for the patient should accompany each sample to exclude any other potential xenobiotics that might be toxic to the mice. The serum samples must be collected prior to initiation of antitoxin therapy. If wound botulism is suspected, serum, stool, exudate, débrided tissue, and swab samples should be collected. For infant botulism, feces and serum samples also should be obtained. Infants who are constipated may require an enema with nonbacteriostatic, sterile water to facilitate collection. All enema fluid and stool should be sent for analysis. The specimens should be refrigerated (not frozen) and examined and tested as soon as

possible after collection. The earlier the specimens are collected after the onset of illness, the more likely the toxin assay will be positive.113 Later in the course of illness, stool culture more likely will be positive. Although polymerase chain reaction studies can determine the presence of C. botulinum in food, this test is not yet available to determine the presence of C. botulinum in human specimens.34 , 103 Stool, serum, or suspected food samples can be used for a mouse neutralization bioassay. Although botulinum poisoning normally is lethal within 6–24 hours, in mice, illness or death may not occur for up to 4 days. The mouse bioassay is the most sensitive diagnostic technique, detecting as little as 0.03 ng of botulinum toxin.84 The materials are injected into the mouse peritoneum, and P.723 subsequent paralysis and death of the mouse are considered to be a positive test. Control animals receive portions of the specimen materials that have been boiled to destroy the toxin or previously incubated with antitoxin to achieve neutralization. Stool specimens are incubated anaerobically and then subcultured on an egg yolk agar to search for lipase-producing Gram-positive anaerobic rods.56 Approximately 60–70% of botulism cases reported since 1950 had an identifiable toxin type. Because isolation of C. baratii and C. butyricum from food and stool requires techniques that deviate from the usual laboratory protocols, it is conceivable that some of the 30–40% of unconfirmed and suspect botulism cases result from the more recently appreciated and more rarely sought after species.43

Treatment Supportive

Care

Respiratory compromise is the usual cause of death from botulism. To prevent or treat this complication, hospital admission of the patient and of all individuals with suspected exposure to a possible source is mandatory. Careful continuous monitoring of respiratory status using parameters such as vital capacity, peak expiratory flow rate, negative inspiratory force (NIF), pulse oximetry, and the presence or absence of a gag reflex is essential to determine the need for intubation or tracheostomy, as the patient begins to manifest signs of bulbar paralysis.87 The most reliable, readily obtainable test is the NIF, which can be used in most institutions to determine the need for intubation. A reverse Trendelenburg positioning at 20–25° with cervical support has been suggested to be beneficial by enhancing diaphragmatic function, but the clinical application to seriously ill patients has not been validated.8 This approach may reduce the risk of aspiration while decreasing the pressure of abdominal viscera on the diaphragm, with resultant improvement in ventilatory effort.

Gastric

Decontamination

An attempt should be made to remove the spores and toxin from the gut. Although most patients present after a substantial time delay, the etiologic agent may still be present hours or even days later. Activated charcoal should be a routine part of supportive care, because it adsorbs C. botulinum type A toxin in vitro and probably also the other botulinum toxin types.40 Gastric lavage or emesis should be initiated only for an asymptomatic person who has very recently ingested a known contaminated food. If a cathartic is chosen, sorbitol is the preferable agent because other agents such as magnesium salts may exacerbate neuromuscular blockade. Theoretically, whole-bowel irrigation may have a role in decontamination, particularly if there is concern about initiating emesis, but interventions other than activated charcoal have not been evaluated under these circumstances.

Wound

Care

Thorough wound débridement is the most critical aspect in the management of wound botulism and should be performed promptly.47 , 56 Antibiotic therapy alone is inadequate, as evidenced by several case reports of disease despite antibiotic therapy. Aminoglycoside antibiotics84 and clindamycin89 should not be used because they may exacerbate neuromuscular blockade.

Botulinum

Antitoxin

Botulinum antitoxins types AB (bivalent) and ABE (trivalent) are available. The type-specific antitoxins are ineffective against any other antigen. In humans, the efficacy of the type-specific antitoxin to type B strain toxin is unknown, whereas the typespecific antitoxins to A and E probably are beneficial.104 A 45-year-old woman with presumed botulism was administered bivalent (AB) botulinum antitoxin, but her condition deteriorated. Four days later, the culture demonstrated type F botulinum toxin, and the CDC released heptavalent experimental botulinum antitoxin.77 Minimal improvement in strength may have resulted. Some debate in the literature exists as to whether type E antitoxin has partial neutralizing potential against type F antitoxin. Currently no human experiences validate this hypothesis, which might lead to use of trivalent (ABE) antitoxin if type F botulinum antitoxin were unavailable.43 , 64 Antitoxin can prevent paralysis but does not affect already paralyzed muscles.37 This finding is supported by the sustained duration of weeks to months of toxin type A and B in tissue after therapeutic injection in humans and animals. For greatest effectiveness, trivalent antitoxin must be used immediately upon consideration of the disease in both symptomatic and asymptomatic individuals recently exposed to a presumptive food source.92 Botulinum antitoxin types AB should be used for

presumptive

wound

botulism.

In a review of 132 cases of type A foodborne botulism, a lower fatality rate and a shorter course of illness were demonstrated for patients who received trivalent antitoxin, even after controlling for age and incubation period.104 The earlier a patient received antitoxin, the shorter was the clinical course. In addition, no respiratory arrests occurred more than 5 hours after antitoxin was administered. In view of the high mortality rate associated with foodborne botulism and the limited statistical data, the antitoxin should be given IV to all exposed patients. Two studies on the use of antitoxin in the presence of wound botulism demonstrate that the longer the delay to antitoxin administration, the more prolonged the requirement for ventilatory support and the poorer the outcome.28 Although specific foods tend to correlate relatively well with botulinum type, trivalent antitoxin (7500 U type A, 5500 U type B, and 8500 U type E) should trivalent antitoxin should be 0.9% sodium chloride over investigation identifies the

be used. An entire 10-mL vial of given IV as a 1:10 vol/vol dilution in several minutes. If epidemiologic organism, subsequent type-specific

antitoxin therapy can be instituted if the product is available. Because antitoxin is an equine globulin preparation, hypersensitivity testing for horse serum has sometimes been recommended. However, this testing is of no value because the predictive value is limited and antitoxin therapy is essential. Epinephrine should always be readily available to treat anaphylaxis. The overall rate of adverse reactions, including hypersensitivity and serum sickness,15 is 9–17%, with an incidence of anaphylaxis as high as 1.9%9 , 66 (Antidotes in Depth: Botulinum Antitoxin ).

Guanidine, 4-Aminopyridine, Diaminopyridine

and

3,4-

Guanidine is no longer recommended for treatment of botulism, because its merits were not substantiated35 (see previous editions of P.724 studies82

this text for a more extensive discussion). Several and case reports32 have proposed that 4-aminopyridine and 3,4diaminopyridine are effective in improving neuromuscular transmission by enhancing acetylcholine release from the motor nerve terminal. 82 In a rat botulinum toxin type A model, 3,4diaminopyridine restored neuromuscular function and enhanced animal survival.95 The therapeutic efforts for those with EatonLambert syndrome and the successful animal results all suggest that further investigative efforts are necessary. It is suggested that 4-aminopyridine's potential for inducing seizures at therapeutic doses limits its clinical usefulness. The fact that 3,4diaminopyridine does not substantially cross the blood–brain barrier, resulting in limited CNS manifestations, makes this agent appropriate for further investigation.

Penicillin Penicillin G is one of many drugs with excellent in vitro efficacy against C. botulinum and is useful for wound management.102 However, penicillin has no role in the management of botulism caused by preformed toxin, nor has it been shown to prevent gut spores from germinating. For these reasons, penicillin is not considered useful in infant and adult infectious botulism, and it is not by itself considered adequate for wound botulism.

Treatment

and

Prevention

of

Infant

Botulism Whether botulinum antitoxin or antibiotics have a role in infant botulism is unclear. Cases of children surviving without either

antitoxin or parenteral antibiotics are documented. Currently, antitoxin is not recommended because circulating toxin is believed to be present at very low concentrations, and antitoxin has no effect on toxin-producing organisms in the gut.50 , 53 , 86 Therefore, antitoxin is not expected to halt syndrome progression. Moreover, in fully recovered children, both toxin and spores can be found in the stools for months despite use of oral or parenteral antibiotics and/or antitoxin administration. Human-derived botulism immune globulin (BIG) is an investigational new drug available for IV treatment only as part of an FDA-approved “open label administration― study by the California Department of Health Services5 , 26 , 36 , 66 (Antidotes in Depth: Botulinum Antitoxin ). Measures used to prevent infant botulism include limiting exposure to spores by thoroughly washing foods and objects that might be placed in a child's mouth. In addition, honey should not be given to infants younger than 6 months.

Prognosis The prolonged and variable period of recovery that occurs after exposure to botulinum toxin is directly related to the extent of neuromuscular blockade and neurogenic atrophy and the regeneration rates of nerve endings and presynaptic membrane.62 If the patient has excellent respiratory support during the acute phase and receives adequate parenteral nutrition, residual neurologic disability may not occur. Although the initial course may be protracted, near total functional recovery can follow within several months to 1 year. Common long-term sequelae include dysgeusia (Chap. 21 ), dry mouth, constipation, dyspepsia, arthralgia, exertional dyspnea, tachycardia, and easy fatigability. The long-term status of 13 patients who survived a toxin type B botulinum outbreak was characterized 2 years later by persistent dyspnea and fatigue, although surprisingly, pulmonary function

tests had returned to normal in all patients.115 Inspiratory muscle weakness persisted in 4 of 13 patients. Maximal oxygen consumption and maximal workload during exercise were diminished in all patients, and all had more rapid shallow breathing and a higher dyspnea score than controls. The reasons for premature exercise termination may be multifactorial. Although persistent respiratory muscle weakness may be an explanation, most dyspnea and fatigue appeared to be related to reduced cardiovascular fitness, leg fatigue, and diminished nutrition.116 Nevertheless, because long-term prognosis can be so good, early recognition of the disease and supportive care are essential.

Pregnancy At least 3 cases of botulism occurring during pregnancy have been reported. One case occurred during the second trimester,78 and 2 cases occurred during the third trimester.99 Although botulinum toxin or C. botulinum was isolated in the mother in 2 of the botulinum cases prior to administration of antitoxin therapy, no detectable toxin was isolated from the neonates in either of the third-trimester cases. The large MW of the neurotoxin (150,000 daltons) makes passive diffusion through the placenta unlikely,45 and, although theoretically possible, no active transport system has been identified.99 None of the three neonates had neurologic evidence of botulism. Appropriate care of the mother and preparation for maternal complications of delivery appear to assure the best potential outcome for a normal infant.

Epidemiologic

and

Therapeutic

Assistance Whenever botulism is suspected or proven, the local health department should be contacted. The health department should report to the CDC Emergency Operations Center at 770-488-7100.

The center, which is available 24 hours per day, 7 days per week, pages the Foodborne and Diarrheal Diseases Branch Medical officer. The CDC can provide or facilitate diagnostic, consultative, and laboratory testing services, access to bivalent or trivalent botulinum antitoxin, and assistance in epidemiologic investigations. All foods that possibly are responsible for the illness should be preserved for epidemiologic investigation. The merits of this surveillance and antitoxin release system were demonstrated in Argentina,112 where the CDC assisted in establishing comparable principles that are nation specific, including local stocking of antitoxin and establishing mechanisms for distribution, emergency identification, response, and laboratory confirmation for suspect cases. Expansion of this system to other nations will enhance worldwide botulism surveillance for foodborne botulism and for potential terrorist dissemination of botulinum toxin.91

Summary Botulism remains one of the rarest poisonings while its etiologies have become increasingly diverse. The incidences of wound botulism and the adult infectious form of botulism have increased dramatically. Previously unrecognized complications of therapeutic botulinum toxin now permit a better understanding of the effects of the toxin and an appreciation of its risks. The international experience with botulism epidemics has allowed the CDC to enhance epidemiologic surveillance and to prepare for the possible use of botulinum toxin as a biologic weapon. Further treatment strategies are being developed to include an F(ab′)2 despeciated heptavalent immune globulin, a human BIG, a recombinant vaccine, and other creative advances (Antidotes in Depth: Botulinum Antitoxin ). P.725

Acknowledgment Richard S. Weisman, PharmD, contributed to this chapter in a previous edition.

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76. Rapoport S, Watkins PB: Descending paralysis resulting from occult wound botulism. Ann Neurol 1984;16:359–361. 77. Richardson WH, Frei SS, Williams SR: A case of type F botulism in Southern California. J Toxicol Clin Toxicol 2004;42:383–387. 78. Robin L, Herman D, Redett R: Botulism in a pregnant woman. N Engl J Med 1996;335:823–824. 79. Ross MH, Charness ME, Sudarsky L, Logigian EL: Treatment of occupational cramp with botulinum toxin: Diffusion of toxin to adjacent noninjected muscles. Muscle Nerve 1997;20:593–598. 80. Sacks HS: The botulism hazard. Ann Intern Med

1997;126:918–919. 81. Sampaio C, Ferreira JJ, Simões F, et al: DYSBOT: A single-blind, randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A-Dysport and botox—Assuming a ratio of 4:1. Mov Disord 1997;12:1013–1018. 82. Sanders DB, Massey JM, Sanders LL, Edwards LJ: A randomized trial of 2,3-diaminopyridine in Lambert Eaton myasthenic syndrome. Neurology 2000;54:603–607. 83. Sandrock CE, Murin S: Clinical predictors of respiratory failure and long term outcome in black tar heroin-associated wound botulism. Chest 2001;120:562–566. 84. Santos JI, Swensen P, Glasgow LA: Potentiation of clostridium botulinum toxin by aminoglycoside antibiotics: Clinical and laboratory observations. Pediatrics 1981;68:50–54. 85. Schantz EJ, Johnson EA: Properties and use of botulinum toxin and other microbial neurotoxins in medicine. Microbiol Rev 1992;56:80–99. 86. Schmidt RD, Schmidt TW: Infant botulism: A case series and a review of the literature. J Emerg Med 1992;10:713–718. 87. Schmidt-Nowara WW, Samet JM, Rasario PA: Early and late pulmonary complications of botulism. Arch Intern Med

1983;143:451–456. 88. Schreiner MS, Field E, Ruddy R: Infant botulism: A review of 12 years' experience at the Children's Hospital of Philadelphia. Pediatrics 1991;87:159–165. 89. Schulze J, Toepfer M, Schroff KC, et al: Clindamycin and nicotinic neuromuscular transmission. Lancet 1999;354:1792–1793. 90. Scott AB, Suzuki D: Systemic toxicity of botulinum toxin by intramuscular injection in the monkey. Mov Disord 1988;3:333–335. 91. Shapiro RL, Hatheway C, Becher J, Swerdlow DL: Botulism surveillance and emergency response. JAMA 1997;278:433–435. 92. Shapiro RL, Hatheway C, Swerdlow DL: Botulism in the United States: A clinical and epidemiologic review. Ann Intern Med 1998;129:221–228. 93. Sheean GL, Lees AJ: Botulinum toxin F in the treatment of torticollis clinically resistant to botulinum toxin A. J Neurol Neurosurg Psychiatry 1995;59:601–607. 94. Sheridan RE: Gating and permeability of ion channels produced by Botulinum toxin types A and E in PC12 cell membranes. Toxicon 1998;36:703–717. 95. Siegel LS, Johnson-Winegar AD, Sellin LC Effect of 3,4diaminopyridine on the survival of mice injected with botulinum

neurotoxin type A, B, E or F. Toxicol Appl Pharmacol 1986;84:255–263. 96. Simpson LL: Botulinum toxin: A deadly poison sheds its negative image. Ann Intern Med 1996;125:616–617. 97. Smith LDS: The occurrence of Clostridium botulinum and Clostridium tetani in the soil of the United States. Health Lab Sci 1978;15:74–80. 98. Sonnabend OAR, Sonnabend WFF, Krech V, et al: Continuous microbiological and pathological study of 70 sudden and unexpected infant deaths: Toxigenic intestinal Clostridium botulinum infection in 9 cases of sudden infant death. Lancet 1985;1:237–241. 99. St. Clair EH, DiLiberti JH, O'Brien ML: Observations of an infant born to a mother with botulism. J Pediatr 1975;87:658. P.727 100. St. Louis ME, Peck SHS, Bowering D, et al: Botulism from chopped garlic, delayed recognition of a major outbreak. Ann Intern Med 1988;108:363–368. 101. Swedberg J, Wendel TH, Deiss F: Wound botulism. West J Med 1987;147:335–338. 102. Swenson JM, Thornsberry C, McCroskey LM, et al: Susceptibility of Clostridium botulinum to thirteen antimicrobial agents. Antimicrob Agents Chemother 1980;18:13–19. 103. Szabo EA, Pemberton JM, Gibson Am, et al: Polymerase

chain reaction for detection of Clostridium botulinum type A, B, E in food, soil and infant faeces. J Appl Bacteriol 1994;76:39–45. 104. Tacket CO, Shandera WX, Mann JM, et al: Equine antitoxin use and other factors that predict outcome in type A foodborne botulism. Am J Med 1984;76:794–798. 105. Tang-Liu DDS, Aoki KR, Dolly JO, et al: Intramuscular injection of 125 I-botulinum neurotoxin-complex versus 125 Ibotulinum-free neurotoxin: Time course of tissue distribution. Toxicon 2003;42:461–469. 106. Telzak EE, Bell EP, Kauter DA, et al: An international outbreak of type E botulism due to uneviscerated fish. J Infect Dis 1990;161:340–342. 107. Terranova W, Palumbo JN, Breman JG: Ocular findings in botulism type B. JAMA 1979;241:475–477. 108. Townes JM, Cieslak PR, Hatheway CL, et al: An outbreak of Type A botulism associated with a commercial cheese sauce. Ann

Intern

Med

1996;125:558–563.

109. Townes JM, Solomon HM, Griffin PM: The botulism hazard. Ann Intern Med 1997;126:919. 110. Tugnoli V, Eleopra R, Quatrale R, et al: Botulism-like syndrome after botulinum toxin type A injections for focal hyperhidrosis. Br J Dermatol 2002;147:808. 111. Valli G, Barbieri S, Scarlato G: Neurophysiological tests in

human botulism. Electromyogr 1983;23:3–11.

Clin

Neurophysiol

112. Villar RG, Shapiro RL, Busto S, et al: Outbreak of type A botulism and development of a botulism surveillance and antitoxin release system in Argentina. JAMA 1999;281:1334–1340. 113. Wainwright RB, Heyward WL, Middaugh JP, et al: Foodborne botulism in Alaska, 1947–1985: Epidemiology and clinical findings. J Infect Dis 1988;157:1158–1162. 114. Weber JT, Hibbs RG, Darwish A, et al: A massive outbreak of type E botulism associated with traditional salted fish in Cairo. J Infect Dis 1993;167:451–454. 115. Werner SB, Passaro D, McGee J, et al: Wound botulism in California 1951–1998: Recent epidemic in heroin injectors. Clin Infect Dis 2000;31:1018–1024. 116. Wilcox P, Andofatto G, Fairbain MS, Pardy RL: Long-term follow-up of symptoms, pulmonary function, respiratory muscle strength and exercise performance after botulism. Am Rev Respir Dis 1989;139:157–163. 117. Wilson R, Morris JG, Snyder JD, Feldman RA: Clinical characteristics of infant botulism in the United States: A study of the non-Californian cases. Pediatr Infect Dis 1982;1:148–150. 118. Woodruff BA, Griffin PM, McCroskey LM, Smart JF: Clinical and laboratory comparison of botulism form toxin types A, B, E

in the United States, 1975–1988. J Infect Dis 1992;166:1281–1286. 119. Wolfe L: Death by botulism: A medical mystery story. New York Magazine 1980;13:56–60.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > B - Foods, Dietary and Nutritional Agents > Antidotes in Depth - Botulinum Antitoxin

Antidotes in Depth Botulinum

Antitoxin

Lewis R. Goldfrank

Equine

Immunoglobulins

The production of antitoxin is complex, requiring almost 2 years to immunize healthy horses against botulinum toxin. The resultant immunoglobulin product, which is then defibrinated, digested, dialyzed, and purified as a 20% protein antitoxin,5 can be lyophilized and preserved.24 Bivalent (serotypes A and B) and trivalent (serotypes A, B, and E) botulinum antitoxin are the equine immunoglobulin preparations available in the United States. The bivalent (AB) preparation is used for patients with presumed wound botulism. The trivalent product is reserved for patients with foodborne botulism. Botulinum antitoxin is distributed from the 9 regional centers of the Centers for Disease Control and Prevention (CDC) on a named patient basis, after a probable diagnosis of botulism is established. Each 10-mL vial of the currently available trivalent botulinum antitoxin contains 7500 IU (2381 US units) of type A botulinum antitoxin, 5500 IU (1839 US units) of type B antitoxin, and 8500

IU (8500 US units) of type E antitoxin.9 The proportion and quantity of types A, B, and E antitoxin are assumed to be adequate to neutralize the quantities of circulating toxins in a typical case of botulism.5,9 Evidence substantiating the efficacy of types A and E antitoxin is available,14,28 but the efficacy of type B antitoxin has not been established in clinical trials. Currently only limited data are available on the relationship of dose and route of administration, the amount of circulating antitoxin found in treated patients, the toxin-neutralizing capacity of this material, and the half-life of the antitoxin. Peak serum concentrations of antitoxin are 10–1000 times higher than the concentrations of antitoxin calculated to be necessary to achieve toxin neutralization.10 Ninety percent of the activity of the equine antitoxin administered was detected when all the circulating toxin was neutralized.16 The half-life for antitoxin persistence in a single patient was calculated at 6.5, 7.6, and 5.3 days for antitoxin types A, B, and E, respectively.10 The prolonged half-life of the antitoxin, and the exceedingly small quantities of toxin measured, explain the limited decrease in antitoxin titers following toxin–antitoxin

binding.

In the presence of disease, 1 vial of the antitoxin is administered slowly IV, over several minutes, as a 1:10 vol/vol dilution in 0.9% sodium chloride solution. Subsequent doses can be given IV every 2–4 hours, depending on the progression of clinical findings. 5,9 Like many other heterologous proteins, administration of this horse serum-derived preparation results in substantial adverse effects.15 Each patient treated during the initial decade during which antitoxin was available (1967–1977) was studied to determine both hypersensitivity reaction rates and the efficacy of the antitoxin in treating botulism. The overall rate of adverse reactions, including hypersensitivity and serum sickness, was 9–17%, with an incidence of anaphylaxis as high as 1.9%.2,18

However, the doses of antitoxin used in that era were substantially larger than those currently used. Because of the lethality of botulinum toxin, the risk of adverse drug reaction for the antitoxin is considered acceptable for anyone with presumed illness and for anyone potentially exposed to the toxin. Pregnancy is not a contraindication to antitoxin administration, and antitoxin has been used successfully in these circumstances.23,28 Anaphylaxis should be anticipated, and the clinician should be prepared to treat this complication immediately with epinephrine. The smaller quantities of botulinum antitoxin used for botulism present a far smaller risk for serum sickness2 than do the larger amounts of antivenom used to treat snake envenomation. The risk of serum sickness from the refined serum proteins in botulinum antitoxin is approximately 4–10%.3,9 Patients who received antitoxin within the first 24 hours after exposure had a shorter clinical course of botulism without regression of symptoms, but a comparable mortality rate to those who received antitoxin later.29 Reduced mortality can only be demonstrated in animal models.20 Morbidity and mortality studies are difficult to perform for a disorder that is so rare and often recognized at a delayed stage, when the toxin already is tightly bound to the neuromuscular junction. Also, most of the reported case series involve patients who received varying degrees of supportive care, further making evaluation or comparison unreliable.

Investigations:

Despeciated

Immune

Globulins F(ab′)2 “despeciated― heptavalent (against toxin types A, B, C1 , D, E, F, and G) botulism immune globulin (dBIG) is currently under investigation and available from the CDC. 22 This equine immune globulin7 is extensively purified to eliminate

fibrinogen, plasminogen, and other proteins. Pepsin is used to remove the Fc fragment of the immunoglobulin in order to reduce the potential for allergic manifestations, should reexposure to equine protein occur.12 The single-dose vials available contain > 4000 IU of serotypes A, B, C, E, and F and > 500 IU for serotypes D and G.22 When given prior to exposure, this F(ab′)2 immunoglobulin protected mice from inhaled toxin at doses 10 times that of the LD50 and was still fully protective when given after exposure but prior to the onset of clinical signs.13 Although 10 of 45 patients given dBIG in the Egyptian type E botulism outbreak manifested adverse reactions, 9 were considered mild and 1 episode was classified as serum sickness.12 In this botulism epidemic, the incidence of adverse effects of dBIG was comparable to those of numerous other internationally available botulinal antitoxins. Although followup of individuals was limited, the agent appeared to be as safe as other commercially available antitoxins. Further investigations with regard to safety and efficacy are necessary.

Human

Immunoglobulins

Human-derived preparations of type E antitoxin were developed as 5000 IU per 2-mL vials for intramuscular use. This human-derived P.729 type E botulinum antitoxin was dosed between 1000 and 5000 IU based on the estimated quantity of toxin ingested for 100 Egyptians who presumably had ingested botulinum toxincontaminated, uneviscerated, salted, mullet fish.8,32 The safety of the human-derived preparation allowed for repetitive dosing in any individual, if clinical findings developed.7 This regimen was based on the premise that effective treatment could be achieved by delivering small antitoxin doses prior to tissue binding of circulating toxin. Human-derived botulism immune globulin (BIG) was developed for

use in the treatment of infant botulism. This pentavalent (types A, B, C, D, and E) immune globulin is harvested by plasmapheresis from human donors who received multiple immunizations with pentavalent botulinum toxoid.21,30 A longer biologic half-life, with a prolonged effective level, should be possible with BIG.14 Both of these effects are substantial clinical advantages, particularly for the infant form of botulism, where toxin is slowly and continuously produced in the intestine and absorbed. Use of a human immune globulin obviously avoids the risk of hypersensitivity that is associated with foreign equine proteins. Results of the orphandrug infant botulism prevention clinical trial of the human BIG suggest many advantages over the current equine antitoxin therapy.1,6 BIG became available for clinical trials in California in 1991.6 Human BIG was used successfully in a 3-year-old child who developed altered gut microbial flora and botulism following bone marrow transplantation.25 This case is a relatively rare example of infant type (in vivo intestinal colonization) botulism, in a 3-yearold child.

Other

Investigatory

Modalities

A pentavalent toxoid vaccine (types A, B, C, D, and E) was developed at the US Army Medical Research Institute of Infectious Diseases (USAMRID) at Fort Detrick, Maryland, and has been studied for more than 40 years.4,16 Its use remains investigational and is suggested only for laboratory personnel who work with Clostridium botulinum or for those who might be first responders in the case of terrorism.26 An additional monovalent toxoid type F vaccine was manufactured for the US Army and has been tested by USAMRID.11,17 Recombinant vaccines,4,27 recombinant monoclonal antibodies, recombinant oligoclonal antibodies,19 and drugs that act as metalloproteinase inhibitors (thereby preventing toxin uptake) are

all currently under investigation by the Department of Defense.7

Summary Consultation with a regional poison center and local health department and ultimately between the health department and the CDC at 770-488-7100, 24 hours per day, 7 days per week (or other comparable agencies in other parts of the world) provide improved access to rapid diagnostic tests for botulism and effective therapeutic modalities. Earlier disease recognition and the currently organized public health approach appear to be responsible for decreasing morbidity and increasing survival after typical foodborne botulism.24,31 Results of current research on infant botulism will demonstrate whether sufficient circulating toxin is present in that variant to be amenable to antitoxin treatment. Antitoxin may be useful if, as suggested, a low level of absorbed toxin is present in these disorders.16 After these issues are clarified, providing adequate treatment for the infant form of botulism, which has become the most prevalent form of botulism, may be possible.

References 1. Arnon SS: Infant botulism. In: Feigen RD, Cherry JD, eds: Textbook of Infectious Diseases, 4th ed. Philadelphia, WB Saunders, 1998, pp. 1570–577. 2. Badhey H, Cleri DJ, D'Amato RF, et al: Two fatal cases of type E adult foodborne botulism with early symptoms and terminal neurologic signs. J Clin Microbiol 1986;23:616–618. 3. Black RE, Gunn RA: Hypersensitivity reactions associated with botulinal antitoxin. Am J Med 1980;69:567–570.

4. Byrne MP, Smith LA: Development of vaccines for prevention of botulism. Biochimie 2000;82:955–966. 5. Food and Drug Administration: Biological products, bacterial vaccines and toxoids: Implementation of efficacy review: Proposed rule. Fed Reg 1985;50:51002–51117. 6. Frankovich TL, Arnon SS: Clinical trial of botulism immune globulin for infant botulism. West J Med 1991;154:103. 7. Franz DR, Jahrling PB, Friedlander AM, et al: Clinical recognition and management of patients exposed to biological warfare agents. JAMA 1997;278:399–411. 8. Goldsmith MF: Defensive biological warfare researchers prepare to counteract “natural enemies― in battle, at home.

JAMA

1991;266:2522–2523.

9. Grabenstein JD: Immunoantidotes: II. One hundred years of antitoxins. Hosp Pharm 1992;27:637–646. 10. Hatheway CH, Snyder JD, Seals JE, et al: Antitoxin levels in botulism patients treated with trivalent equine botulism antitoxin to toxin types A, B, and E. J Infect Dis 1984;150:407–412. 11. Hatheway CL: Toxoid of Clostridium botulinum type F: Purification and immunogenicity studies. Appl Environ Microbiol 1976;31:234–242. 12. Hibbs RG, Weber JT, Corwin A, et al: Experience with the use of an investigational F(ab′)2 heptavalent botulism

immune globulin of equine origin during an outbreak of type E botulism in Egypt. Clin Infect Dis 1996;23:337–340. 13. Investigator's Brochure. Botulinum F(ab′)2 Antitoxin, Heptavalent (Equine Derived). Document no. BB IND #3703. Ft. Detrick, Maryland, Office of the Surgeon General, Department of the Army, USAMRMC (MCMR-RCQ-HR). 14. Koenig MG, Spickard A, Cardella MA, Rogers DE: Clinical and laboratory observations on type E botulism in man. Medicine 1964;43:517–545. 15. Merson MH, Hughes JM, Dowell VR: Current trends in botulism in the United States. JAMA 1974;229:1305–1308. 16. Metzger JR, Lewis LE: Human-derived immune globulins for the treatment of botulism. Rev Infect Dis 1979;1:689–692. 17. Montgomery VA, Makuch RS, Brown JE, Hack DC: The immunogenicity in humans of a botulinum type F vaccine. Vaccine 2000;18:728–735. 18. Morris JG Jr, Hatheway CL: Botulism in the United States, 1979. J Infect Dis 1980;142:302–305. 19. Nowakowski A, Wang C, Powers DB, et al: Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody. Proc Natl Acad Sci U S A 2002;99:11346–11350. 20. Oberst FW, Crook JW, Cresthull P, House MJ: Evaluation of botulinum antitoxin, supportive therapy, and artificial

respiration in monkeys with experimental botulism. Clin Pharmacol Ther 1968;9:209–214. 21. Pickett J, Berg B, Chaplin E, Brunstetter-Shafer MA: Syndrome of botulism in infancy: Clinical and electrophysiologic study. N Engl J Med 1976;295:770–772. 22. Richardson WH, Frei SS, Williams SR: A case of type F botulism in Southern California. J Toxicol Clin Toxicol 2004;42:383–387. P.730 23. Robin L, Herman D, Redett R: Botulism in a pregnant woman. N Engl J Med 1996;335:823–824. 24. Shapiro RL, Hatheway C, Becher J, Swerdlow DL: Botulism surveillance and emergency response. JAMA 1997;278:433–435. 25. Shen WP, Felsing N, botulism in a 3-year-old autologous bone narrow human botulism immune

Lang D, et al: Development of infant female with neuroblastoma following transplantation: Potential use of globulin. Bone Marrow Transplant

1994;13:345–347. 26. Siegel LS: Human immune response to botulinum pentavalent (ABCDE) toxoid determined by a neutralization test and by an enzyme linked immunosorbent assay. J Clin Microbiol 1988;26:2351–2356. 27. Smith LA: Development of recombinant vaccines for botulinum neurotoxin. Toxicon 1998;36:1539–1548.

28. St. Clair EH, DiLiberti JH, O'Brien ML: Observations of an infant born to a mother with botulism. J Pediatr 1975;87:658. 29. Tacket CO, Shandera WX, Mann JM, et al: Equine antitoxin use and other factors that predict outcome in type A foodborne botulism. Am J Med 1984;76:794–798. 30. Thilo EH, Townsend SF, Deacon J: Infant botulism at 1 week of age: Report of two cases. Pediatrics 1993;92:151–153. 31. Villar RG, Shapiro RL, Busto S, et al: Outbreak of type A botulism and development of a botulism surveillance and antitoxin release system in Argentina. JAMA 1999;281:1334–1338,1340. 32. Weber JT, Hibbs RG, Darwish A, et al: A massive outbreak of type E botulism associated with traditional salted fish in Cairo. J Infect Dis 1993;167:451–454.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Chapter 47 - Anticonvulsants

Chapter

47

Anticonvulsants Suzanne

Doyon

Carbamazepine 4–12 17–51 Ethosuximide 40–100 283–708 Gabapentin 2–15* 12–88 Lamotrigine 1–< 5 ≤19.5 Phenobarbital 15–40 65–172 Phenytoin 10–20 40–79

Valproic acid 50–120 347–833 *Proposed. Therapeutic Drug

serum m g /L

concentrations µmol/L

A 45-year-old man with a history of alcoholism, posttraumatic stress disorder, a was brought to the emergency department (ED) after ingesting unknown amount gabapentin. He was suffering from depression, and he had ingested all of his m hours prior to presentation.

Upon arrival to the ED, the patient was unresponsive. His vital signs were: bloo pulse 110 beats/min; respiratory rate 12 breaths/min; temperature 98.6°F (37

all extremities to deep pain. His head was atraumatic with 3-mm pupils that re Gag reflex was absent. Examination of his lungs, heart, and abdomen were norm track marks, cyanosis, or edema. Deep-tendon reflexes were symmetrically bris extension was present.

The patient was endotracheally intubated and connected to a ventilator. A rapid concentration was 70 mg/dL, and 50 mL of 50% dextrose was administered intr

mental status. The electrocardiogram (ECG) revealed sinus tachycardia with norm nasogastric tube was inserted, and 75 g activated charcoal was instilled. Serum ethanol and acetaminophen concentrations were negative. Initial serum

was 236 mg/L, serum ammonia concentration 45 µmol/L (normal 9–33 µm concentration 19 mg/L.

The patient was admitted to the intensive care unit (ICU). Four hours later, rep concentration was 810 mg/L and serum ammonia 82 µmol/L. Multiple doses of administered. Hemoperfusion was considered but was not instituted. The third was 933 mg/L and serum ammonia 141 µmol/L. An intravenous (IV) loading do started, followed by a maintenance dose of 1 g every 4 hours IV for 24 hours. unchanged. Approximately 18 hours postingestion, the valproic acid concentratio The 28-hour valproic acid concentration was 481 mg/L, serum ammonia 37 µm concentration

P.732 2.7 mg/L. The patient's mental status improved, but he developed a fever and He remained intubated and mechanically ventilated. Two days later, his platelet 30,000/mm3 from the admission value of 156,000/mm3 . There were no overt s expanding hematoma developed at an arterial puncture site. He responded well His liver enzymes remained normal throughout his hospital stay. The patient re his complete blood cell count normalized 3 days later. He was discharged witho with psychiatric support.

History

and

Epidemiology

The prevalence of seizures in the United States is 3%. Historically, seizures were methods, including barbiturates, bromides, ketogenic diets, fluid restriction, and or irritable cortical foci. The first truly effective therapy was introduced in 1857

bromides was noted to sedate patients and significantly reduce their seizures. P to treat seizures in 1912. Consequently, sedation was erroneously believed to b seizure therapy.

The search for nonsedating anticonvulsive agents led to the introduction of phen the anticonvulsants introduced subsequently, such as primidone, had chemical s phenobarbital. After 1965, benzodiazepines, carbamazepine, and valproic acid (V gained wide use as anticonvulsants. These anticonvulsants were the only agents

when the US Food and Drug Administration approved numerous new anticonvuls gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, fe zonisamide.

Anticonvulsants are also currently used for treatment of mood disorders, refract trigeminal neuralgia, bruxism, migraine headaches, drug withdrawal syndromes,

In a review of more than 5000 patient suicides, anticonvulsants were implicated suggesting a fairly high rate of suicidal ideation among people with access to t last decade, as reported in the American Association of Poison Control Centers Surveillance System (TESS) data, a shift occurred from predominantly carbama exposures to VPA and newer anticonvulsants. VPA is involved in 44% of reporte anticonvulsants (Chap. 130 ).160

This chapter reviews the toxicity and management of overdoses with anticonvul

benzodiazepines and barbiturates are discussed in Chap. 72 .

Pharmacology

A seizure is defined as the clinical manifestation of excessive neuronal activity system (CNS). It is accompanied by various degrees of motor, sensory, and co result from 1 of 4 cellular mechanisms: sustained repeated firing of the sodium conductance, increased excitatory neurotransmission (eg, glutamic acid), or loss inhibitory neurotransmitters (eg, γ-aminobutyric acid [GABA]).

Correspondingly, the mechanisms of action of anticonvulsants fall into 1 of 4 m channel inhibition, calcium channel inhibition, inhibition of excitatory amines, an Frequently, more than 1 mechanism accounts for a drug's anticonvulsive action.

During seizures, a high-frequency pattern of neuronal firing is detected. This pa normal physiologic neuronal activity. Voltage-gated sodium channels are primari neuronal firing that occurs in epilepsy. Under the influence of anticonvulsants,

channels remain partially open, but their functionality is hindered by persistent gate. The sodium channels cannot recover from inactivation and are prevented f frequencies. Phenytoin, carbamazepine, VPA, lamotrigine, topiramate, oxcarbaze felbamate all attach themselves to the batrachotoxin binding site (or adjacent a

and prolong the channel's recovery from inactivation91 , 99 , 159 , 162 At therap channel blockade is selective. At toxic concentrations, selectivity is lost and bot spontaneous sodium channels are inhibited. For several of these medications, G occurs.

Voltage-gated calcium channels are multisubunit complexes that are broadly cla high-voltage groups. The low-voltage group encompasses the T-type calcium ch and ethosuximide inhibit flow of calcium through these channels, thus reducing t the pacemaker current .50 , 115 , 125 The high-voltage group consists of the L, R Calcium entry into presynaptic nerve terminals is regulated by these channels. inhibits the N-type calcium channels.90 , 125

The N -methyl-D-aspartate (NMDA) receptor is the glutamate receptor of greate respect to development of seizures. When stimulated by glutamate, the NMDA r gated ion channel that permits entry of Na+ and Ca 2 + into the neuronal cells. S glutamate–NMDA interaction is protective against seizures.99 Felbamate and

glutamate antagonists at the NMDA receptors.59 More specifically, felbamate act insensitive glycine recognition site on the NMDA receptor98 (Chap. 14 ). Lamot phenytoin inhibit glutamate release by binding to presynaptic Na+ channels.53 T as opposed to the NMDA glutamate receptor subtype, and blocks Na+ entry into

GABA acts through fast chloride-permeable ionotropic GABAA receptors and thro coupled GABAB receptors.3 Pharmacologic enhancement of GABA receptor-mediat effective approach to epilepsy. Anticonvulsants may interact with the GABAA rec kinetics of GABA itself. Vigabatrin irreversibly inhibits GABA transaminase, the responsible for GABA metabolism.52 VPA may have similar effects.99 Tiagabine i transporter GAT-1 and thereby prevents reuptake of GABA into presynaptic neu 120

Despite its design as a GABA agonist, gabapentin does not mimic GABA, and poorly understood. Gabapentin may increase GABA release from vesicles within 56 or inhibit the L-type high-voltage calcium channel.62 Figure 47-1 summarizes

Figure 47-1. Mechanism of action of anticonvulsants. SSA = succinic acid semi transaminase.

P.733

Phenytoin/Fosphenytoin

Figure. No Caption Available.

Phenytoin, introduced in 1938, is still a first-line anticonvulsant for treatment o except absence seizures.95 It has no role in the treatment of toxin-related seiz withdrawal syndrome.22 It is nonsedating in therapeutic doses and therefore is GABAergic anticonvulsants for long-term management of epilepsy.

Fosphenytoin, a water-soluble phenytoin derivative introduced in 1997, was dev apparent shortcomings of parenteral phenytoin, such as its poor water solubility

intramuscular injection. Its clinical utility derives from the rapid achievement o concentrations, its potential for intramuscular administration, and its lower risk cardiotoxicity.13 , 99

Pharmacokinetics

and

Toxicokinetics

Phenytoin is a weak acid (pKa 8.3) that is highly protein bound and is rapidly d Single-dose oral therapeutic loading using 18 mg/kg phenytoin capsules is well incomplete in 36% of patients at 8 hours.112 In very large oral overdoses, gas be delayed even more, up to several days.21 , 30 Some authors suggest phenyto absorption in the colon because of its lipophilic properties.148 Phenytoin occasion the gastrointestinal tract.21

Phenytoin is extensively bound to serum proteins, mainly albumin. Only the unb biologic membranes and exert pharmacologic action. A significant fraction of ph

neonates, uremic patients, and other patients with hypoalbuminemia.55 Less tha phenytoin is excreted unchanged in the urine. The remainder is metabolized in t phenytoin metabolite, a parahydroxylphenyl derivative, is inactive but is believed hypersensitivity reaction associated with phenytoin administration. 78 The Micha saturable enzyme kinetics explains the relationship between phenytoin doses an steady state. At phenytoin concentrations below 10 mg/L, elimination usually is half-life ranges between 6 and 24 hours. At higher concentrations, zero-order e dependent elimination) occurs as a result of saturation of the hydroxylation rea elimination half-life increases to 20–60 hours. 99 , 24 Therefore, the apparent phenytoin is progressively prolonged as plasma concentration increases99 (Chap

Fosphenytoin (1.5 mg fosphenytoin = 1 mg phenytoin) is a water-soluble phosp phenytoin. It is available in a water-based parenteral formulation that contains a pH of 8–9. Fosphenytoin is converted entirely to phenytoin by circulating p minutes of IV injection. Peak phenytoin concentrations are reached 30 minutes

injection. The loading dose, expressed in phenytoin equivalents (PE), is the sam 47-1 ).

Clinical

Manifestations

Acute phenytoin toxicity produces predominantly neurologic dysfunction that typ and vestibular systems. Phenytoin concentrations greater than 15 mg/L usually

nystagmus, concentrations greater than 30 mg/L are associated with ataxia, an 50 mg/L are associated with lethargy, slurred speech, and pyramidal and extr 101 CNS concentrations correlate best with free serum phenytoin concentrations seizures on extremely rare occasions, usually in the setting of acute overdose in seizures.149 Young children and the elderly may present with atypical manifesta example, phenytoin-induced chorea and opisthotonic posturing are reported follo children. 101

Cardiotoxicity resulting from oral overdoses of phenytoin has not been reported phenytoin impairs myocardial contractility, decreases peripheral vascular resista

P.734 myocardial conduction. In a large case series, IV phenytoin was associated with hemodynamic complications.40 Deaths following IV administration of phenytoin 164 These complications correlate with rate of administration and total dose infu

ascribed to the diluents used in the IV preparation of phenytoin, that is, propyle ethanol (10%).103 Propylene glycol in particular depresses myocardial tissue an vascular resistance (Chap. 53 ). However, fosphenytoin, which does not contain diluent, also impairs cardiac conduction and contractility. Two reports of large d 5–10 times in excess of the required dose, administered to young infants wit in bradycardia, hypotension, and asystole.83 , 127 Still, the water solubility impr therapeutic IV administration, and fosphenytoin can be infused at a maximal rate is 3 times that of phenytoin.13 Carbamazepine 3–24 in overdose 4–12 0.8–1.8 75 1 CBZ 10,11-epoxide 6–20 overdose 4.9–11.5 Felbamate 4 30–50 0.75 25 40 None 20–23 Gabapentin 3 2.7–4 0.8 0 100 None 5–7 Lamotrigine

chronic

2.5 4–18 1.2 55 10 None 14–50 Levetiracetam 1–2 10–70 0.7 10 66 None 5–8 Phenytoin 5–24 in overdose 10–20 0.6 > 90 < 5 None 6–60 Tiagabine 1–2 5–70 ng/mL 1 96 < 5 None 5–9 Topiramate 1–4 4.5–30

0.5–0.8 15 60 None 20–30 Valproic acid 1–24 in overdose 50–120 0.1–0.2 > 90 < 5 2-en-VPA 3-OHVPA 3-keto VPA 6–18 Vigabatrin 4 20–80 0.8 0 100 None 4–8 Zonisamide 4–6 6.7–40 1.2 40–60 < 5 None 60 a After therapeutic oral administration, unless otherwise stated. From references 1 ,5 ,8 ,51 ,53 ,77 ,89 ,99 ,102 ,118 ,119 .

Time to Peak Plasma Concentrationa(h)

TABLE

47-1.

Therapeutic Serum Concentrations (mg/L)

Pharmacokinetics

of

Vd (L/kg)

Plasma protein binding (%)

Urinary elimination unchanged (%)

Anticonvulsants a

Intravenous phenytoin is commonly associated with local irritation. Extravasation necrosis, possibly necessitating surgical intervention.26 , 40 , 75 These complicati from the propylene glycol diluent and pH. The risk of fosphenytoin-induced skin its water solubility.

Chronically elevated phenytoin concentrations may result in gingival hyperplasia behavioral changes, and encephalopathy. Hyperactivity, confusion, lethargy, an the behavioral changes. Chronic use of phenytoin is associated rarely with agra

produce hepatotoxicity, which may or may not be part of the anticonvulsant h (AHS, discussed below under Anticonvulsant Hypersensitivity Syndrome).

Diagnostic

Testing

Serum phenytoin concentrations should be performed in all cases of phenytoin unpredictable absorption, phenytoin concentrations should be repeated and mo

concentrations are 10–20 mg/L. Because of the switch to zero-order eliminati concentrations may take days or weeks before they return to the therapeutic ra

Patients with impaired or decreased protein-binding capacity can develop sympt concentrations within the therapeutic range. Patients at greatest risk include ne hypoalbuminemic, hyperbilirubinemic, and uremic patients, and patients underg with VPA, salicylates, and sulfonamides because these agents displace phenytoin sites. In such patients, determination of the free phenytoin fraction is helpful b reliably with the CSF concentrations than does the total phenytoin concentration fraction can be measured directly by a number of analytical methods, including followed by gas chromatography or enzyme-multiplied immunoassay technique free phenytoin concentrations are 1.0– 2.1 mg/L.

Equation 47-1 approximates the total phenytoin concentration that would be obs measured serum phenytoin concentration and measured albumin concentration.

Management

The treatment of patients with acute or chronic phenytoin overdoses remains l related deaths are rare, even after massive overdoses. Because the use of mu (MDAC) reduces the elimination half-life of intravenously administered phenytoin it is recommended in patients in whom serial serum concentrations are increasi elevated.96 Aggressive lowering of the serum phenytoin concentration may be h

patient, and MDAC should be used cautiously in these patients. Given the exten hemodialysis and hemoperfusion are of little benefit in the management of ph toxicity.71 , 81

Severe ataxia mandates careful evaluation of patients because of concerns for determinations are necessary because of the unpredictable absorption and dela Patients admitted to the hospital after oral phenytoin

P.735 overdoses do not require routine cardiac monitoring because they do not exper cardiovascular

complications.42 , 163

Phenytoin-induced agranulocytosis can be treated successfully with administratio stimulating factor.152

Hypotension, cardiac dysrhythmias, and dyskinesias during IV administration of transient and usually resolve spontaneously in 30–60 minutes unless complica phenytoin infusion for a few minutes and administering a bolus of 250–500 m solution generally is sufficient for treatment of hypotension in an adult. Restartin initial rate is recommended.140 Prolonged periods of cardiopulmonary resuscitatio cases of fosphenytoin- or parenteral phenytoin-induced dysrhythmias, in order t other tissues thereby permitting time for the cardiotoxicity to resolve. 83 , 128 The management of extravasation is discussed in Chap. 6 .

Carbamazepine/Oxcarbazepine

Figure. No Caption Available.

Carbamazepine, which was introduced in 1947, is structurally related to the cy Carbamazepine is a first-line therapy for seizures and may be especially useful epilepsy.95 Oxcarbazepine is a keto-analog of carbamazepine, which functions a

Pharmacokinetics

and

Toxicokinetics

Carbamazepine is lipophilic agent with slow and unpredictable absorption follow

rapid distribution to all tissues. Peak concentrations may not be reached until 2 large overdose or an overdose of sustained-release preparations.33 , 37 , 49 Carb weak anticholinergic properties and can decrease gastrointestinal motility, delay

Hence, no simple relationship exists between the dose of carbamazepine and th

Carbamazepine is metabolized primarily by CYP3A4 to carbamazepine 10,11-epo pharmacologically active. This quantifiable metabolite is further degraded by ep carbamazepine-diol, a largely inactive compound.73 The enzymes responsible fo carbamazepine are not considered saturable.41 Elimination of carbamazepine inc weeks of therapy because of autoinduction, and the half-life on chronic therapy Therefore, the dose must be increased gradually over a 2- to 4-week period to a mg/kg for adults and 20–70 mg/kg for children. Children require a higher dos the drug more rapidly. During chronic therapy, the elimination half-life is on the The elimination half-life after single acute overdoses is unpredictable and poten and 47-2 ).

Carbamazepine 1A2 2C9 None 73, 144 2C8 3A subtype 2C9 3A4 Levetiracetam None None None 119 Phenobarbital 2C9 2C None 4 2C19 3A Phenytoin 2C9 2C subtype None 79 2C19 3A subtype Tiagabine 3A4 None None 1 Topiramate

None 2C19 118 Valproic 2A6

acid

2C9 8 2C9 2C19

Metabolized

by

Induction

Inhibition

References

TABLE 47-2. Anticonvulsants and Cytochrome (CYP) System Oxcarbazepine

is

rapidly

converted

to

the

pharmacologically

active

10-monoh

metabolite before conjugation and renal elimination. It is a less potent inducer

Clinical

Manifestations

Acute carbamazepine toxicity is manifest by neurologic signs and symptoms in cardiovascular effects. The initial neurologic disturbances include nystagmus, ata patients with a large overdose, fluctuations in level of consciousness is common 63 , 135 , 137 , 161 Carbamazepine toxicity may cause seizures both in nonepilept with underlying epilepsy. The mechanism underlying carbamazepine-induced sei understood.63 , 115 In some cases, an increase in seizure frequency, unaccompa symptoms, is the only presenting symptom of carbamazepine toxicity. Status e acute carbamazepine toxicity.139 , 143 , 154 In 1 case series, 55% of adult patie concentrations > 40 mg/L developed seizures.63 Children may experience seizur concentrations.142

Cardiovascular effects include sinus tachycardia, which occurs in 35% of overdose anticholinergic mechanism, hypotension with myocardial depression, and cardia abnormalities.49 , 63 , 84 High concentrations of carbamazepine may cause depres of the action potential in cardiac tissue.147 In a large case series of carbamazep incidence of QRS complex prolongation (> 100 msec), 50% incidence of QTc int msec), and no cases of terminal 40-msec axis deviation of the QRS complex in These abnormalities can be delayed for as long as 20 hours and may occur with 70 , 151

The toxicity of carbamazepine in children differs slightly from that in adults. Ch incidence of dystonic reactions, choreoathetosis, and seizures and have a lower electrocardiographic

abnormalities.12 , 142 , 150

Chronic carbamazepine overdose can result in headaches, diplopia, or ataxia. I

are common.130 Vasopressin secretion can be stimulated at high carbamazepine hyponatremia (syndrome of inappropriate antidiuretic hormone)47 (Chap. 17 ). P.736

Diagnostic

Testing

A serum carbamazepine concentration should be obtained in all cases of suspe exposure. Because of erratic absorption, the concentrations should be repeated closely monitored until a downward trend is observed. Therapeutic concentration

Patients receiving multiple anticonvulsants may not tolerate high concentrations should be maintained at 4–8 mg/L. Concentrations > 40 mg/L tend to be ass respiratory depression, and cardiotoxicity.63 Carbamazepine may cross-react wit tricyclic antidepressants (Chap. 7 ). 46

Carbamazepine None Doxycycline, felbamate, haloperidol, lamotrigine, ?methadone, oral contraceptiv tiagabine, valproic acid, warfarin Allopurinol, cimetidine, danazol, diltiazem, fluoxetine, fluvoxamine, gemfibrozil, lamotrigine, macrolides, nefazodone, nicotine, propoxyphene, protease inhibitor Benzodiazepines, felbamate, isotretinoin, phenobarbital, phenytoin, primidone, Felbamate

Carbamazepine, epoxide, phenytoin, valproic acid Carbamazepine Valproic acid, gabapentin Carbamazepine, phenytoin Gabapentin Felbamate None None Antacids Lamotrigine Carbamazepine None Valproic acid Antituberculous agents, carbamazepine, phenobarbital, Levetiracetam

phenytoin

None None None None Oxcarbazepine Oral

contraceptives

Phenobarbital Valproic acid metabolites Carbamazepine, corticosteroids, doxycycline, estradiol, griseofulvin, lamotrigine, quinidine, theophylline, valproic acid, warfarin Acetazolamide, chloramphenicol, CNS depressants, dextropropoxyphene, furose MAOIs, valproic acid Ammonium chloride, antacids, folic acid, pyridoxine, warfarin Phenytoin N-acetyl-P-benzo quinoneimine (NAPQI), oral anticoagulants, phenobarbital, pr Amiodarone, carbamazepine, cardioactive steroids, corticosteroids, cyclosporine,

doxycycline, furosemide, haloperidol, influenza vaccine, levodopa, methadone, contraceptives, phenothiazines, quinidine, theophylline, tiagabine, tolbutamide, Allopurinol, amiodarone, chloramphenicol, chlorpheniramine, clarithromycin, clo disulfiram, ethosuxamide, felbamate, fluconazole, fluoxetine, fluvoxamine, imipr methylphenidate, metronidazole, miconazole, omeprazole, phenylbutazone, sul tolbutamide, tolazamide, topiramate, valproic acid, warfarin Antacids, antineoplastics carbamazepine, calcium, diazepam, diazoxide, ethanol influenza vaccine, loxapine, nitrofurantoin, phenobarbital, phenylbutazone, pyri sulfisoxazole, sulcrafate, theophylline, tolbutamide, valproic acid, vigabatrin Tiagabine Valproic acid

Carbamazepine, Topiramate

phenytoin

Phenytoin, digoxin Oral contraceptives None Carbamazepine, phenytoin,

valproic

acid

Valproic acid Felbamate, lamotrigine, phenobarbital, Carbamazepine, tiagabine Cimetidine, felbamate, ranitidine

primidone

Antacids, carbamazepine, chlorpromazine, primidone, salicylates Vigabatrin None known Phenytoin None None Zonisamide ?Phenytoin, ?carbamazepine None None

felbamate,

INH,

methotrexate,

phen

Phenytoin, carbamazepine, barbiturates From references 1 ,5 ,8 ,53 ,79 ,102 ,118 ,144 . Increases Concentrations

TABLE

47-3.

of

Anticonvulsant

Decreases Concentrations

Drug

of

Toxicity Enhanced by

interactions

The contribution of active metabolites to the toxicity of carbamazepine must no receiving multiple anticonvulsants, especially combination therapy with VPA and clinical toxicity with carbamazepine concentrations within the therapeutic referen concentrations of the circulating carbamazepine-10,11-epoxide metabolite (Tabl

attributed to the additive inhibitory effects of VPA and lamotrigine on the enzym Carbamazepine-10,11-epoxide concentrations in the 1–10 mg/L range are de carbamazepine/carbamazepine-epoxide ratio usually is > 1.7 and is approximate monotherapy.117

P.737 Oxcarbazepine is detected on the carbamazepine assay and concentrations are o

Management

MDAC has a therapeutic role in the management of patients with carbamazepine particularly helpful by reducing enterohepatic circulation. 109 , 154 Concretions of

suspected when serum concentrations rise or symptom occurrence is delayed. C occurrence of QRS or QTc abnormalities is recommended. Although not formally bicarbonate should be administered if the QRS duration exceeds 100 msec. Ca seizures usually respond to benzodiazepines.

Because carbamazepine is poorly water soluble, hemodialysis is relatively ineffe be associated with a 20% reduction in serum carbamazepine concentrations and improvement.49 Success with use of high-efficiency hemodialysis and venovenou reported.7 , 136 It must be emphasized that MDAC remains as effective as charc less invasive, and is associated with comparable outcomes.154

Valproic

Divalproex

Acid

Sodium

Valproic acid (di-n -propylacetic acid [VPA]), a simple branched-chain carboxylic of a broad spectrum of seizure disorders, ranging from simple and complex abs partial and myoclonic seizures. It is widely used as a mood stabilizer in the ma

psychiatric illnesses, especially bipolar affective disorders for which it is a first-l prophylaxis. VPA inhibits voltage-gated sodium channels and inhibits GABA tran

Pharmacokinetics,

Toxicokinetics,

and

Pathop

VPA is available in soft gelatin capsules, in syrup form, as enteric-coated and e in sprinkle capsules that can be added to food. An IV form is available. Intramu tolerated.

VPA is almost 100% absorbed from the gastrointestinal tract. Peak concentration hours, except for enteric-coated and probably extended release preparations, for for up to 24 hours.14 , 58 VPA is 90% protein bound at therapeutic concentration decreases as the VPA concentration increases (Table 47-1 ).

VPA metabolism is complex. It is extensively metabolized (95%) by hepatocytes using uridine diphosphate glucuronosyltransferase enzymes and β-oxidation. Firs glucuronic acid and then oxidized in 1 of 2 ways: mitochondrial β-oxidation or

Nine different metabolites are isolated. The 3 β-oxidation metabolites are the m metabolites are quantitatively less important.38 Mitochondrial β-oxidation of sho VPA involves activation and linkage to coenzyme A (CoA) followed by transfer t in the mitochondrial matrix87 (Figure 47-2 and Table 47-4 ).

VPA decreases carnitine stores through a number of different mechanisms. VPA excretion via formation of valproylcarnitine, which is renally excreted. Second, ATP-dependent carnitine transporter located on the plasma membrane. Third, V mitochondrial CoA. Mitochondrial CoA trapping (or depletion) decreases ATP pro negatively affects the carnitine transporter.121 Because of the reductions of he fatty acids arriving to the liver for metabolism P.738

via β-oxidation cannot be transported effectively into the mitochondria and inst cytoplasm. This process accounts for the development of fatty liver associated w

Figure 47-2. Valproic acid metabolism by the hepatocyte. Valproic acid, a shor to coenzyme A (CoA) by acyltransferase I and subsequently transferred to carn = carnitine) is shuttled into the mitochondrion where, after transfer back to CoA undergoes β-oxidation yielding several metabolites. These metabolites sequester the β-oxidation of other fatty acids. This process may lead to a Reyelike syndr Alternatively, valproylcarnitine may diffuse from the cell and be renally eliminate uptake of carnitine. In either case, the cellular depletion of carnitine shifts valp microsomal ω-oxidation. This pathway forms 4-en-valproate, a putative hepat severe hepatotoxicity associated with valproic acid. ω-Oxidation products also carbamoylphosphate synthase I (CPS I), the initial step in the urea cycle result

Carbamazepine

Diploplia, dizziness, sedation, headache, nausea, hyponatremia, hypocalcemia, dysrhythmias Agranulocytosis, aplastic anemia, hepatotoxicity, photosensitivity, Stevens- John syndrome, morbilliform rash, thrombocytopenia, pseudolymphoma, myocarditis, hypersensitivity syndrome Felbamate Irritability, insomnia, anorexia, nausea, headache Fulminant hepatic failure, pancreatitis, aplastic anemia,

psychosis

Gabapentin Sedation, dizziness, diplopia, ataxia sedation Dystonic movements, asterixis Lamotrigine Dizziness, tremor, diplopia, ataxia, Sedation Agranulocytosis, rashes, erythema multiforme, Stevens-Johnson syndrome, toxi anticonvulsant hypersensitivity syndrome Levetiracetam Dizziness, asthenia, sedation Psychosis Phenytoin Anorexia, nausea, aggression, ataxia, cognitive impairment, depression, sedatio neonatal hemorrhage, gingival hypertrophy, coarse facies, acne, hirsutism, hy osteomalacia, hypothyroidism, vitamin deficiencies, teratogenicity

Blood dyscrasias, lupus syndrome, reduced IgA, pseudolymphoma, peripheral n intracranial hypertension, rashes, Stevens-Johnson syndrome, Dupuytren contr teratogenicity, gingival hyperplasia, aplastic anemia, anticonvulsant hypersensit Tiagabine Dizziness, asthenia, tremor, diarrhea Spontaneous ecchymoses Topiramate Sedation, dizziness, diplopia, metabolic acidosis, weight loss, paresthesias, ne

Valproic acid Anorexia, nausea, tremor, alopecia, peripheral edema, rashes, sedation, weight Pancreatitis, hepatotoxicity, thrombocytopenia, hyperammonemia, encephalopa Vigabatrin Sedation, weight gain, behavioral changes Psychosis Zonisamide Sedation, ataxia From

references 1 ,5 ,8 ,53 ,57 ,60 ,61 ,66 ,79 ,102 ,118 ,126 ,130 ,144 .

Predictable

Idiosyncratic

TABLE 47-4. Adverse Events Associated with Anticonvulsants

Mitochondrial CoA is essential to the formation of N -acetylglutamate, an activa synthetase I (CPS I). CPS I is the primary enzyme responsible for incorporation cycle. In the absence of adequate mitochondrial CoA stores, CPS I activity cease accumulates. Evidence indicates that CPS I is directly inhibited by VPA. In conc effect of carnitine depletion and/or CPS I inhibition is suppression of hepatic am accumulation of ammonia.

Clinical

Manifestations

Overdoses of VPA result in symptoms varying from lethargy to coma associated Nystagmus, ataxia, and tremor typically do not occur. The neurotoxicity often is

of acute overdose in patients chronically taking VPA.67

Metabolic complications following acute VPA overdoses include hypernatremia, acidosis, hypocarnitinemia, and hyperammonemia.3 , 4 , 74 Metabolic acidosis m overdoses and is a poor prognostic sign.43 , 105 It results from accumulation of carboxylic, and proprionic acids.3 , 27 , 58 , 104 , 105 , 127

Bone marrow suppression occurs 3–5 days following acute massive overdoses by pancytopenia.3 , 27 , 127 These hematopoietic disturbances usually resolve sp days.

Pancreatitis, hepatotoxicity, and renal insufficiency are rare manifestations of a Chronic VPA therapy may lead to hepatotoxicity secondary to the aforementione fatty acid metabolism rather than, as with other anticonvulsants, a hypersensit

findings may vary from asymptomatic elevation of aminotransferase concentratio Microvesicular steatosis, in which the hepatocyte cytoplasm contains large amoun appearance on liver biopsy.15 , 36

Valproate-induced hyperammonemic encephalopathy (VHE) is characterized by confusion or lethargy, focal or bilateral neurologic signs, and increased seizure f accompanied by elevated VPA concentrations. The etiology is uncertain, but ele

concentrations coupled with elevated concentrations of some of the more neuro be responsible.156

Diagnostic

Testing

Serum VPA concentrations should be obtained in all cases of VPA exposure. The obtained every 4–6 hours and closely monitored until a downward trend is o concentrations are 50–100 mg/L, although some clinicians use higher concen

All 9 VPA metabolites can be measured in the urine. The 4-en-VPA concentration indicating excessive ω-oxidation. The β-oxidation metabolite 2-en-VPA may be inhibition of β-oxidation and/or carnitine depletion. Concentrations of the 2-en 1–3 days following acute ingestion, signaling the return to normal β-oxidatio

Electrolytes, blood gases, and serum lactate and serum ammonia concentrations patients. Hyperammonemia (> 80 µg/dL or > 35 µmol/L) occurs in 16–52% chronic VPA therapy.29 , 111 , 156

An inverse correlation exists between serum carnitine concentrations and serum patients receiving chronic VPA therapy.111 Free serum carnitine concentrations â acylcarnitine/free carnitine ratio > 0.4 are indicative of carnitine deficiency.32 T measurement of drug-induced hypocarnitinemia. P.739

Management

Supportive management is sufficient to ensure complete recovery in most patie Discontinuation of all medications that likely affect VPA metabolism is also reco

MDAC reduces the half-life of VPA from a mean of 12 hours to 4.8 hours and is whom serum concentrations are continuously rising.43 Although VPA is extensive theoretically not amenable to MDAC, the percentage of bound VPA decreases sig 29%) as the concentration increases.43

In vitro studies suggest that naloxone has GABA antagonistic properties, perhap endogenous opioid system, and may inhibit the effects of VPA on GABA metabo describe rapid resolution of CNS symptoms in VPA-overdosed patients following

naloxone. 2 , 142 These patients had minimally elevated VPA concentrations (< 2 however, showed no effect in patients with much higher VPA concentrations (> experience does not support the routine use of naloxone for reversing VPA-induc not recommended.

Carnitine should be administered if evidence indicates the presence of hyperam hepatotoxicity.32 The loading dose is 100 mg/kg IV over 30 minutes (maximum

IV over 10–30 minutes every 4 hours until clinical improvement occurs (Antido

Hemodialysis and hemoperfusion increase VPA clearance but should be reserved rapid deterioration, evidence of hepatic dysfunction, apparent continued absorpti VPA concentrations > 1000 mg/L.58 , 104

Gabapentin

Figure. No Caption Available.

Gabapentin is a cyclohexane derivative of GABA approved as adjunctive therapy partial seizures with and without secondarily generalized seizures in adults, part postherpetic neuralgia. It is currently used as a treatment for posttraumatic st disorders, mood disorders, bruxism, migraine prophylaxis, neuropathic pain, and neurologic disturbances.

Pharmacokinetics

and

Toxicokinetics

The bioavailability of gabapentin is approximately 60% in the therapeutic dose

and easily crosses the blood–brain barrier. Dosage adjustments are necessary renal function (creatinine clearance < 60 mL/min). It is not metabolized by, and function oxidase system99 (Table 47-1 ).

Clinical Sedation,

ataxia,

Manifestations movement

disorders,17 , 122 slurred speech, and gastrointestin

following acute gabapentin overdose.45 , 76 In a case series of 20 patients with lethargy, ataxia, and gastrointestinal symptoms developed in less than 5 hours hours.76

In 1 case report of chronic overdose in a patient with renal failure, tremulousne were noted. The serum concentration was 85 mg/dL. Symptoms were self-limite dose adjustment.155 Catatonia following abrupt withdrawal of gabapentin is described.129

Diagnostic

Testing

The preferred method for gabapentin analysis is high-pressure liquid chromatog concentration for seizure control is generally 2–15 mg/L, although the therap evolving. Because gabapentin is not appreciably protein bound, this range esse

gabapentin.

Management

The treatment of patients with gabapentin overdose is largely supportive. Activa to limit absorption. No specific antidote exists, but in 1 case report, an elderly dose of flumazenil, a benzodiazepine receptor antagonist devoid of GABA agonis case report, flumazenil is not recommended for the management of gabapentin persistent neurologic symptoms must be admitted to the hospital. Hemodialysis generally required, except in severely symptomatic patients with significant ren supportive care is sufficient in most instances.

Lamotrigine

Figure. No Caption Available.

Lamotrigine is approved as an adjunctive medication for treatment of partial sei patients. It also is approved for maintenance treatment of bipolar mood disorde

Pharmacokinetics

and

Toxicokinetics

The bioavailability of lamotrigine is 98%. It is metabolized predominantly by g 2 -N -glucuronide. The elimination half-life is approximately 25 hours but can be phenytoin and carbamazepine, which can induce glucuronidation, and can be dou because of competition with lamotrigine for the same step in the glucuronidatio reduced clearance of lamotrigine occurs in patients with Gilbert syndrome (a sy glucuronidation). Lamotrigine does not affect the cytochrome P450 system or th except when it is administered concomitantly with carbamazepine, when it is a of the carbamazepine epoxide metabolite.53

P.740

Clinical

Manifestations

Neurologic manifestations such as lethargy, ataxia, nystagmus, and gastrointest described following lamotrigine overdose. Coma, seizures, and cardiac conductio occur.11 , 16 , 88 , 110 The 2-N -methyl metabolite of lamotrigine causes QRS pr

Chronic overdoses of lamotrigine result in multiorgan involvement, including ra elevated hepatic aminotransferase and serum creatinine phosphokinase concent findings represent AHS etiologically is unclear. All abnormalities resolved upon w

Diagnostic

Testing

Lamotrigine concentrations can be measured greater than 18 mg/L are potentially toxic.

by

high-performance

liquid

chrom

Management

Activated charcoal should be administered. Supportive care and ECG monitoring Lamotrigine-induced seizures should be treated hemodialysis and hemoperfusion are available.

with

benzodiazepines.18 No data

Topiramate

Figure. No Caption Available.

Topiramate is a sulfamate-substituted monosaccharide approved as adjunctive th partial-onset seizures. It also is approved for migraine prophylaxis, infantile spa seizure disorders in infants and children. Although the precise mechanism of ac blocks sodium channels, enhances the action of GABA, and diminishes the actio

receptor stimulation.118 Topiramate's sulfamate moiety weakly inhibits carbonic the CA-II and CA-IV isoforms present in the kidney and CNS.35 , 138

Pharmacokinetics

and

Toxicokinetics

Topiramate is readily bioavailable. Only 20% of the dose is hepatically metabol hydrolysis, and glucuronidation; the remaining 80% of the drug is eliminated un plasma elimination half-life is long68 (Table 47-1 ).

Clinical

Manifestations

Lethargy, ataxia, nystagmus, myoclonus, coma, seizures, and status epilepticus topiramate overdose. 25 , 44 , 141 Echolalia and repetitive mouthing are reported metabolic acidosis resulting from inhibition of renal cortical CA may be present

serum chloride, as well as hypokalemia (2.0–3.2 mEq/L). Metabolic acidosis a ingestion and can persist for days.25 , 44 , 94 , 116 , 153

Diagnostic

Testing

Topiramate concentrations are performed by liquid or gas chromatography. The between 4 and 30 mg/L. A death with a postmortem concentration of 170 mg/L

chemistry and/or arterial blood gas analysis should evaluate for hyperchloremia metabolic acidosis.

Management

Activated charcoal and supportive care are recommended. Severe hyperchlorem be treated with sodium bicarbonate 1–2 mEq/kg intravenously. However, sys sodium bicarbonate may impair the anticonvulsive effect of topiramate.25 , 44 Pl topiramate can be significantly affected by hemodialysis, resulting in 4- to 6-fol rates.48 Hemodialysis is generally recommended in patients who overdose on to associated neurologic impairment, electrolyte abnormalities that have not respo therapy, or renal insufficiency.

Tiagabine

Figure. No Caption Available.

Tiagabine inhibits the presynaptic reuptake of GABA and is approved as an adju and secondarily generalized seizures. It is also being prescribed for a variety o

Pharmacokinetics

and

Toxicokinetics

Tiagabine is quickly and completely absorbed within 2–3 hours of ingestion. It easily crosses the blood–brain barrier.69 It is metabolized by the CYP3A4 sys The elimination half-life is reduced by 50% in patients taking enzyme-inducing has no effect on the CYP450 system.82 , 89

Clinical

Manifestations

Lethargy, facial myoclonus (grimacing), nystagmus, and posturing are described on tiagabine. Seizures and status epilepticus are reported at very high serum previously healthy toddler developed 3 seizures after an unintentional overdose

tiagabine concentrations were 530 ng/mL.72 A patient presented in status epilep be noncompliant with therapy until a tiagabine concentration of 1870 ng/mL was overdose determined.113 Stimulation of the presynatpic GABAB receptors in the the underlying mechanism for tiagabine-induced seizures.124

P.741 Symptoms generally persist for 12–24 hours, and permanent neurologic seque , 72 , 113

Diagnostic

Testing

Tiagabine concentrations are performed by high-performance Therapeutic tiagabine concentrations are 5–70 ng/mL.

liquid

chromatog

Management

Activated charcoal and supportive care are recommended. Seizures respond to benzodiazepines. Refractory status epilepticus should be treated with barbiturates hemodialysis and hemoperfusion are available.20 , 72 , 113

Levetiracetam

Figure. No Caption Available.

Levetiracetam is approved as an “add-on― medication for the managemen mechanism of action remains incompletely understood, although it inhibits N-ty Research has illustrated both a neuroprotective and an antiinflammatory effect.

Pharmacokinetics

and

Toxicokinetics

The bioavailability of levetiracetam approaches 100%. The major metabolic pat hydrolysis. There are no active metabolites. Dosage adjustments are necessary renal function (creatinine clearance < 60 mL/min).119

Clinical

Manifestations

In 1 reported case of levetiracetam overdose, lethargy, coma, and respiratory Nystagmus was absent. Symptoms persisted for 24 hours.9

Diagnostic

Testing

Levetiracetam concentrations can be assessed using gas chromatography. Ther 3–70 µg/mL.119

Management Activated charcoal should be administered. Supportive care is recommended. No hemodialysis and hemoperfusion are available.

Other

Anticonvulsants

Vigabatrin

Figure. No Caption Available.

Vigabatrin, or vinyl GABA, is a stereospecific irreversible inhibitor of GABA-tran

vigabatrin has a short elimination half-life, its duration of action is 24 hours. D necessary in patients with impaired renal function.52 Agitation, coma, and longafter acute ingestion.31 , 85

Chronic toxicity may result in psychosis, dizziness and tremor, which usually is as depression and psychosis.85 Treatment of vigabatrin toxicity is largely suppo best treated with IV benzodiazepines. Some cases of mild vigabatrin-induced ps withdrawal of the medication.85

Felbamate

Figure. No Caption Available.

Felbamate is a phenyl dicarbamate derivative structurally similar to meprobama adverse effects, including hepatic failure and aplastic anemia, it is a therapy of of seizures. It is absorbed quickly, and 50% of an ingested dose is excreted unc

Mild lethargy and gastrointestinal symptoms are reported following acute overd reversible renal failure following an acute overdose are reported.123 Treatment largely supportive.

Zonisamide

Figure. No Caption Available.

Zonisamide is structurally similar to other current anticonvulsants. It inhibits s T-type calcium channels, and possibly CA. Somnolence is a commonly reported experience with zonisamide is limited. In one case report, status epilepticus, com attributed to zonisamide overdose despite a minimally elevated concentration of 10–40

mg/L).145

Anticonvulsant

Hypersensitivity

Syndrome

Ill defined since it was first described in 1950, AHS is a disorder that occurs in 1000–10,000 exposures to anticonvulsants. AHS is traditionally associated wit anticonvulsants such as phenytoin, carbamazepine, phenobarbital, and primidon the inclusion of the nonaromatic lamotrigine as a causative agent. The incidence regardless of gender and ethnic origin. Data suggest P.742 a genetic defect in drug metabolism. First-degree relatives of patients with AHS developing this syndrome.78 , 157

AHS occurs most frequently within the first 2 months of therapy and is not relat concentration. The pathophysiology of AHS is related to accumulation resulting

detoxification by the enzyme epoxide hydrolase of arene oxide metabolites of These reactive arene oxides bind to macromolecules and cause cellular apoptosis form neoantigens that may trigger an immunologic response. Interestingly, the to cause other serious dermatologic reactions, such as Stevens-Johnson syndrom necrolysis. The pathophysiology of lamotrigine-induced hypersensitivity syndrom unknown; only a small proportion undergoes CYP450 metabolism.132 , 134

AHS is defined by a triad of fever, rash, and internal organ involvement. The in malaise, and pharyngitis (including tonsillitis). A skin eruption characterized by into a pruritic and confluent papular rash primarily involving the face, trunk and tender lymphadenopathy usually follows. Severely affected cases develop toxic

rash usually spares the mucous membranes. Multiorgan involvement usually occu syndrome. The liver is the most frequently affected organ, although involvemen cardiac muscle (myocarditis), lungs (pneumonitis), renal system (nephritis), an thyroiditis followed by hypothyroidism) are rare but possible. Liver disturbances aminotransferase

concentrations

to

fulminant

hepatic

failure.78 , 157

Leukocytosis is present and consists of a large number of atypical lymphocytes

biopsies reveal perivascular lymphocytic infiltration, spongiotic or lichenoid derm of edema.157 Lymph node histology reveals benign hyperplasia, atypical lymphoi laboratory abnormalities include a positive rheumatoid factor, antinuclear anti DNA smooth muscle antibodies, cold agglutinin, and hypogammaglobinemia or novel, easy, fast, objective lymphocyte toxicity assay is being studied.108

Prompt discontinuation of the offending agent is essential to prevent symptom be admitted to the hospital and receive methylprednisolone 0.5–1 mg/kg/d div Other promising therapies include use of IV immunoglobulin. 97 , 133 , 157

In 1 case study, 90% of patients with AHS showed in vitro cross-reactivity to a anticonvulsant.40 Based on this evidence, avoidance of phenytoin, carbamazep primidone, lamotrigine, and potentially oxcarbazepine is recommended. Benzod topiramate, tiagabine, and levetiracetam are safer alternatives.140

Summary

All anticonvulsant drugs produce CNS symptoms when taken in overdose. Differ findings is difficult. Lethargy, sedation, ataxia, and nystagmus occur following o

anticonvulsants. Coma occurs following substantial overdose of all anticonvulsan Seizures, including status epilepticus, may occur with carbamazepine, phenytoin overdoses.

Hemodynamic instability and abnormal electrocardiograms are rare findings. C and possibly topiramate can cause QRS prolongation. Electrolyte abnormalities with VPA and topiramate. Topiramate is uniquely associated with hyperchloremi

Except for VPA overdoses, no specific antidotes exist for overdoses of anticonv alone usually yields beneficial outcomes. Administration of activated charcoal is because of its safety and efficacy. Anticonvulsant-induced seizures are treated barbiturates. Patients with VPA overdoses in most cases should receive carnitin removal is rarely necessary and should be reserved for patients with severe ca topiramate overdoses and associated electrolyte abnormalities, hemodynamic in

deterioration. Overdoses and toxicity associated with the newer anticonvulsants so few data are available. However, most reported patients do not appear to su consequences.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Antidotes in Depth - L-Carnitine

Antidotes in Depth L-Carnitine Mary Ann Howland

L-Carnitine

L-Carnitine (levocarnitine) [R-3-carboxy-2-hydroxy-N,N,Ntrimethyl-1-propanaminium, inner salt or 3-hydroxy-4-(N,N,Ntrimethylaminobutyrate] is an amino acid that is vital to

mitochondrial utilization of fatty acids. It is an orphan drug approved by the FDA for treatment of L-carnitine deficiency secondary to valproic acid toxicity, resulting from inborn errors of metabolism, associated with hemodialysis, and for zidovudine (AZT)-induced mitochondrial myopathy and pediatric cardiomyopathy. L-Carnitine decreases valproic acid-induced hyperammonemia and limits valproic acid-induced hepatic toxicity. L-Carnitine should be administered IV to symptomatic patients to circumvent the low bioavailability from oral administration.

History L-Carnitine is found in mammals, in many bacteria, and in very small amounts in most plants.27 Carnitine was first discovered in 1905 in extracts of muscle, and its name is derived from carnis, the Latin word for flesh.15 Over the next 25 years, its chemical formula and structure were identified, and in 1997 its enantiomeric properties were confirmed.27 Carnitine was formerly known as vitamin BT.

Chemistry Carnitine can exist as either the D or L form. Only the L isomer is found endogenously, is active, and should be used therapeutically. L-Carnitine (C7 H 15N O3 ) has a molecular weight of 161 daltons. It is a water-soluble amino acid derivative that belongs to the same chemical family as choline. At physiologic pH, L-carnitine contains both a positively charged quaternary nitrogen ion and a negatively charged carboxylic acid group.11 Fatty acids provide 9 kcal/g and are an important source of energy for the body, especially for the liver, heart, and skeletal muscle. The utilization of fatty acids as an energy source requires Lcarnitine–mediated passage through both the outer and inner

mitochondrial membranes to reach the mitochondrial matrix where β-oxidation occurs (Figure 47-2). Enzymes in the outer and inner mitochondrial membranes (carnitine palmitoyltransferase and carnitine acylcarnitine translocase) catalyze the synthesis, translocation, and regeneration of L-carnitine. 23 Binding of Lcarnitine to fatty acid occurs through esterification at the hydroxyl group on the chiral carbon. 11 The L-carnitine regenerated in the mitochondrial matrix is able to translocate in the opposite direction, from the matrix and through the inner membrane back to the space between the outer and inner membrane. The fatty acyl-coenzyme A (CoA) undergoes β-oxidation in the mitochondrial matrix, generating acetyl-CoA that then enters the citric acid cycle.

L-Carnitine

Homeostasis

Approximately 54–87% of endogenous L-carnitine is derived from the diet; the remainder is synthesized.27 Meat and dairy products are the primary dietary sources. Although most plants supply very little L-carnitine, avocado and fermented soy products are exceptionally rich in this amino acid. The remainder of the carnitine needed by the body is synthesized from trimethyllysine. This amino acid, found largely in skeletal muscle, is converted to trimethylammoniobutanoate (γ-butyrobetaine) and then carried to the liver and kidney for hydroxylation to L-carnitine.15 Synthesis of L-carnitine in the liver and kidney occurs at a rate of approximately 2 µmol/kg/d and is regulated by the amount of diet-derived trimethyllysine.15,27 L-Carnitine is filtered by the kidneys, and tubular reabsorption keeps L-carnitine serum concentrations in the normal range.

Pharmacokinetics Carnitine

of

Exogenous

L-

Our current understanding of L-carnitine pharmacokinetics is largely derived from three major studies.7,14,31 L-Carnitine is not bound to plasma proteins. Vc (volume of distribution of the central compartment) is 0.15 L/kg, approximating extracellular fluid volume. Vd (volume of distribution) is 0.7 L/kg. Both vary depending on the compartment model analyzed. The t1 / 2 α is 0.6–0.7 hours. The terminal elimination half-life averages 10–23 hours but may be 25–50% shorter. Baseline plasma values for L-carnitine are 40 µmol/L but increase to 1600 µmol/L following administration of 40 mg/kg of the amino acid intravenously (IV) over 10 minutes. Whereas 2 g of the amino acid administered IV produced a peak plasma concentration of 1000 µmol/L, oral administration of 2 g produced peaks of only 15–70 µmol/L. The time to peak concentrations following oral administration occurs at 2.5–7 hours, indicating slow uptake by intestinal mucosal cells. Oral absorption is already saturated following a 2-g dose, and no further absorption occurs after administration of 6 g. Following a radiolabeled dose, most Lcarnitine is metabolized to trimethylamine N-oxide and butyrobetaine, with only approximately 4–8% remaining unchanged. The metabolites trimethylamine and trimethylamine Noxide may accumulate after chronic high-dose oral therapy in patients with severely compromised renal function.7 Fecal excretion of L-carnitine is < 1% of the total dose. Carnitor (levocarnitine) tablets are bioequivalent to the Carnitor oral solution, with an absolute bioavailability of approximately P.747 15%. After 4 days of dosing at 1980 mg (6 × 330-mg tablets) twice per day or 2 g twice per day of the oral solution, the maximum plasma concentration was 80 µmol/L.

Valproic

Acid

and

Hyperammonemia

Valproic acid can cause hyperammonemia (defined as plasma

ammonia concentration > 80 µg/dL or > 35 µmol/L) with or without symptoms and with or without hepatic dysfunction. Hyperammonemia and hepatic toxicity may occur either with therapeutic dosing or following an acute overdose. Approximately 35% of patients receiving valproic acid demonstrate hyperammonemia, often with corresponding reduced plasma Lcarnitine concentrations.6 In the absence of hepatic dysfunction, the postulated mechanisms for hyperammonemia are unclear but may result from interference with hepatic synthesis of urea or a small increase in ammonia production by the kidney.18,33 Valproic acid induces both carnitine and acetyl-CoA deficiencies by combining with L-carnitine as valproylcarnitine and with acetyl CoA as valproyl-CoA. Ultimately, β-oxidation of all fatty acids is reduced, resulting in decreased energy production. Valproic acid stimulates glutaminase favoring glutamate uptake and ammonia release from the kidney. Reduced glutamate concentrations lead to impaired production of N-acetylglutamate (NAGA), a cofactor for carbamoyl phosphate synthetase I (CPS I), that is used in the liver to synthesize urea from ammonia. In humans taking valproic acid, L-carnitine supplementation reduces ammonia concentrations.1, , 2, , 4, , 6, , 13, , 22, , 24, , 25 The exact time frame for normalization of ammonia concentrations is unknown, but a preliminary report suggests hastening of ammonia elimination with L-carnitine (3–15 h) compared to published controls (11–90 h).30

Valproic

Acid

and

Hepatotoxicity

Valproic acid therapy is commonly associated with a transient dose-related asymptomatic rise in liver enzyme concentrations and a rare symptomatic, life-threatening, idiosyncratic Reyelike hepatotoxic syndrome.3 Liver histology of the latter demonstrates microvesicular steatosis, similar to that described in hypoglycininduced Jamaican vomiting sickness and Reye syndrome. This

occurrence presumably results from L-carnitine and acetyl-CoA deficiency, which inhibits mitochondrial β-oxidation of valproic acid and other fatty acids, causing them to accumulate in the hepatocyte. Evidence for the benefit of L-carnitine treatment in improving survival from valproic acid-induced hepatotoxicity comes from the retrospective analysis of patients identified by the International Registry for Adverse Reactions to valproic acid.5 When 50 patients with acute, symptomatic hepatic dysfunction who were not treated with L-carnitine were compared with 42 similar patients treated with L-carnitine, only 10% of the untreated patients but 48% of the L-carnitine–treated patients survived.5 Early diagnosis of patients, prompt discontinuance of valproic acid, and administration of IV rather than oral L-carnitine resulted in the greatest survival. 5 Most patients received 50–100 mg/kg/d Lcarnitine, regardless of the route of administration.5 Additionally, case reports and animal studies29 offer both support28,32 and lack of support for the beneficial effects of L-carnitine in the presence of valproic acid-induced hepatotoxicity.17,21

L-Carnitine

Concentrations

In the plasma, 80% of L-carnitine is free, and the rest is acylated.10 Normal plasma concentrations of free L-carnitine in omnivorous adults and children older than 1 year are 22–66 µmol/L and of total L-carnitine concentrations are 28–84 µmol/L. Vegetarians have L-carnitine concentrations 12% to 30% lower than omnivores.26 Numerous studies in patients taking valproic acid demonstrate decreases in both free and total plasma L-carnitine concentrations.25 Case studies demonstrate reduced plasma free L-carnitine concentrations and abnormal valproic acid metabolite profiles that

normalize with L-carnitine supplementation.16,19,20 All of these data support the use of L-carnitine and provide a potential mechanism for its beneficial effects in valproic acid-induced hepatotoxicity.

Adverse to

Effects

and

Contraindications

L-Carnitine

L-Carnitine administration is well tolerated. Transient nausea and vomiting are the most common side effects reported, with diarrhea and a fishy body odor noted at higher doses.7 Following chronic high doses of L-carnitine in patients with severely compromised renal function, the potentially toxic L-carnitine metabolites trimethylamine and methylamine N-oxide accumulate. The importance of this accumulation is unknown. Trimethylamine and its metabolite dimethylamine may contribute to cognitive abnormalities and the fishy odor.9 In a pharmacokinetic study following intravenous administration of 6 g over 10 minutes, 2 of 6 subjects complained of transient visual blurring; 1 subject also complained of headache and light-headedness. The manufacturer of L-carnitine has received case reports of convulsive episodes following L-carnitine use by patients with or without a preexisting seizure disorder. This concern is currently included in the package insert. No reports of seizures related to L-carnitine can be found in the human literature. The only data suggesting carnitine-related seizures are found in a rat model.12 There are no known contraindications to the use of L-carnitine. However, only the L isomer and not the racemic mixture should be used because the DL mixture may interfere with mitochondrial utilization of L-carnitine. L-carnitine is considered pregnancy category B.

Overdose

of

L-carnitine

No cases of toxicity from overdose are reported, although large oral doses may cause diarrhea.7 The LD50 in rats is 5.4 g/kg IV and 19.2 g/kg oral.7

Dosage

and

Administration

The optimal dosing of L-carnitine for valproic acid-induced hyperammonemia or hepatotoxicity is not established. Recommendations for intravenous L-carnitine administration to patients with acute metabolic disorders resulting from L-carnitine deficiency range from 50–500 mg/kg/d.7,8 A loading dose equal to the daily dose may be given initially, followed by the daily dose divided into every 4 hourly doses. The 500 mg/kg/d dose was intended we

for

children8 and did not list a maximum dose, although P.748

suggest a maximal daily dose of 6 g in addition to the loading dose. The oral dosing of L-carnitine usually is 50–100 mg/kg/d up to 3 g/d and should be reserved for patients who are not acutely ill. For patients with end-stage renal disease undergoing hemodialysis, the package insert recommends an intravenous starting dose of 10–20 mg/kg dry body weight as a slow intravenous bolus over 2–3 minutes after completion of dialysis, followed by a dose adjustment according to L-carnitine trough (predialysis) plasma concentrations (normal 40–50 µmol/L). For patients with an acute overdose of valproic acid and without hepatic enzyme abnormalities or symptomatic hyperammonemia, L-carnitine administration can be considered prophylactic, and enteral doses of 100 mg/kg/d divided every 6 hours up to 3 g/d is appropriate. For patients with valproic acid-induced symptomatic hepatotoxicity or symptomatic hyperammonemia, intravenous Lcarnitine should be administered. We suggest a dose of 100 mg/kg

IV up to 6 g administered over 30 minutes as a loading dose, followed by 15 mg/kg every 4 hours administered over 10–30 minutes.

Availability L-Carnitine is available as a sterile injection for intravenous use (Carnitor) in 1 g/5 mL single-dose vials. L-Carnitine is supplied without a preservative. Once the vial is opened, the unused portion should be discarded. Carnitor injection is compatible and stable when mixed with normal saline or lactated Ringer solution in concentrations as high as 8 mg/mL for as long as 24 hours.7 LCarnitine as Carnitor is also available as a 330-mg tablet and as an oral solution (with artificial cherry flavoring and methylparaben and propylparaben as preservatives) at a concentration of 100 mg/mL. The oral solution can be consumed without dilution, or it can be dissolved in other drinks to mask the taste. Slow consumption reduces gastrointestinal side effects.7

References 1. Altunbasak S, Baytok V, Tasouji M, et al: Asymptomatic hyperammonemia in children treated with valproic acid. J Child Neurol

1997;12:461–463.

2. Barrueto F Jr, Hack JB: Hyperammonemia and coma without hepatic dysfunction induced by valproate therapy. Acad Emerg Med 2001;8:999–1001. 3. Berthelot-Moritz F, Chadda K, Chanavaz I, et al: Fatal sodium valproate poisoning. Intensive Care Med 1997;23:599. 4. Beversdorf D, Allen C, Nordgren R: Valproate induced

encephalopathy treated with carnitine in an adult. J Neurol Neurosurg Psychiatry 1996;61:211. 5. Bohan TP, Helton E, McDonald I, et al: Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 2001;56:1405–1409. 6. Bõhles H, Sewell AC, Wenzel D: The effect of carnitine supplementation in valproate-induced hyperammonaemia. Acta Paediatr 1996;85:446–449. 7. Carnitor® (levocarnitine). Product information. Gaithersburg, MD, Sigma-Tau, March 2004. 8. De Vivo DC, Bohan TP, Coulter DL, et al: L-carnitine supplementation in childhood epilepsy: Current perspectives. Epilepsia

1998;39:1216–1225.

9. Eknoyan G, Latos DL, Lindberg J: Practice recommendations for the use of L-carnitine in dialysis-related carnitine disorder. National Kidney Foundation Carnitine Consensus Conference. Am J Kidney Dis 2003;41:868–876. 10. Evangeliou A, Vlassopoulos D: Carnitine metabolism and deficit—When supplementation is necessary? Curr Pharm Biotechnol 2003;4:211–219. 11. Evans A: Dialysis-related carnitine disorder and levocarnitine pharmacology. Am J Kidney Dis 2003;41:S13–S26. 12. Fariello RG, Zeeman E, Golden GT, et al: Transient seizure

activity induced by acetylcarnitine. 1984;23:585–587.

Neuropharmacology

13. Gidal BE, Inglese CM, Meyer JF, et al: Diet- and valproateinduced transient hyperammonemia: Effect of L-carnitine. Pediatr Neurol 1997;16:301–305. 14. Harper P, Elwin CE, Cederblad G: Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects. Eur J Clin Pharmacol 1988;35:555–562. 15. Hoppel C: The role of carnitine in normal and altered fatty acid metabolism. Am J Kidney Dis 2003;41:S4-S12. 16. Ishikura H, Matsue N, Matsubara M, et al: Valproic acid overdose and L-carnitine therapy. J Anal Toxicol 1996;20:55–58. 17. Laub MC, Paetzke-Brunner I, Jaeger G: Serum carnitine during valproic acid therapy. Epilepsia 1986;27:559–562. 18. Marini AM, Zaret BS, Beckner RR: Hepatic and renal contributions to valproic acid-induced hyperammonemia. Neurology 1988;38:365–371. 19. Murakami K, Sugimoto T, Nishida, et al: Alterations of urinary acetylcarnitine in valproate-treated rats: The effect of L-carnitine supplementation. J Child Neurol 1992;7:404–407. 20. Murakami K, Sugimoto T, Woo M, et al: Effect of L-carnitine supplementation on acute valproate intoxication. Epilepsia 1996;37:687–689.

21. Murphy JV, Groover RV, Hodge C: Hepatotoxic effects in a child receiving valproate and carnitine. J Pediatr 1993;123:318–320. 22. Ohtani Y, Endo F, Matsuda I: Carnitine deficiency and hyperammonemia associated with valproic acid. J Pediatr 1982;101:782–785. 23. Pande SV: Carnitine-acylcarnitine Am J Med Sci 1999;318:22–27.

translocase

deficiency.

24. Raby WN: Carnitine for valproic acid-induced hyperammonemia.

Am

J

Psychiatry

1997;154:8.

25. Raskind JY, El-Chaar M: The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 2000;34:630–638. 26. Rebouche CJ: Carnitine function and requirements during the life cycle. FASEB J 1992;6:3379–3386. 27. Rebouche CJ, Seim H: Carnitine metabolism and its regulation in microorganisms and mammals. Annu Rev Nutr 1998;18:39–61. 28. Romero-Falc-n A, de la Santa Belda E, Garc'a-Contreras R, Varela JM: A case of valproate-associated hepatotoxicity treated with L-carnitine. Eur J Intern Med 2003;14:338–340. 29. Sugimoto T, Araki A, Nishida N, et al: Hepatotoxicity in rat following administration of valproic acid: Effect of L-carnitine

supplementation.

Epilepsia

1987;28:373–377.

30. Sztajnkrycer MD, Scaglione JM, Bond GR: Valproateinduced hyperammonemia: Preliminary evaluation of ammonia elimination with carnitine administration. J Toxicol Clin Toxicol 2001;39:497. 31. Uematsu T, Itaya T, Nishimoto M, et al: Pharmacokinetics and safety of L-carnitine infused I.V. in healthy subjects. Eur J Clin Pharmacol 1988;34:213–216. 32. Vance CK, Vance WH, Winter SC, et al: Control of valproate-induced hepatotoxicity with carnitine. Ann Neurol 1989;26:456. 33. Verrotti A, Trotta D, Morgese G, Chiarelli F: Valproateinduced hyperammonemic 2002;17:367–373.

encephalopathy.

Metab

Brain

Dis

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Chapter 48 - Antidiabetics and Hypoglycemics

Chapter

48

Antidiabetics

and

Hypoglycemics

George M. Bosse MW = 180 daltons Normal fasting range (blood) = 60–100 = 3.3–5.6

mg/dL mmol/L

Glucose An 80-year-old woman with a history of diabetes mellitus was found by family members to be unresponsive at home. Emergency medical services was called and recorded a rapid reagent glucose concentration of 39 mg/dL. She was given 50 mL of 50% dextrose intravenously, which resulted in rapid improvement of mental status. She had a history of hypertension. Current medications included metformin and atenolol. She denied using any other medications or ethanol, but she smoked cigarettes. Upon further questioning in the emergency department (ED), she stated that she had not eaten much

over the past several days and had “cold― symptoms of nonproductive cough. She denied having fever, shortness of breath, chest pain, nausea, vomiting, or diarrhea. Review of organ systems was negative. Physical examination revealed: blood pressure, 120/67 mm Hg; pulse, 74 beats/min; respiratory rate, 26 breaths/min; temperature, 98.2°F (36.8°C). Initial pulse oximetry was 87% on room air. The patient was alert and oriented, with no focal neurologic deficits. The pupils were equal and reactive to light. Cardiopulmonary examination revealed bilateral rhonchi, expiratory wheezes, and a regular rate and rhythm without murmurs, rubs, or gallops. The abdomen was nontender to palpation. The patient was admitted to the medicine service for monitoring and observation for recurrent hypoglycemia and for treatment of chronic obstructive pulmonary disease exacerbation. Further questioning of family members revealed that the patient was also taking glyburide. Intravenous access was maintained, her antidiabetic medications were withheld, and she was placed on a sliding-scale insulin regimen. During her hospitalization, she had several episodes of altered mental status. Two episodes coincided with rapid reagent glucose readings in the low 40 mg/dL range. Both episodes were treated with 50% dextrose intravenously. The patient was discharged to the care of her private physician 3 days later with an intact neurologic examination. Her respiratory status was improved, but she was instructed to use home oxygen continuously at night and as needed during the day. At discharge, glyburide was restarted, but metformin was withheld. Although various pharmacologic agents and medical conditions may cause hypoglycemia, this chapter focuses on the medications used for treatment of diabetes mellitus. These medications include insulin and oral agents: the sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, and meglitinides. Some of the medications in these chemically heterogeneous groups of xenobiotics can cause unique toxic effects in addition to hypoglycemia. Most patients with diabetes mellitus are classified as having either insulindependent diabetes mellitus (IDDM), also known as type I diabetes, or non–insulin-dependent diabetes mellitus (NIDDM), also known as type II

diabetes. This classification scheme for diabetes mellitus is not perfect. For example, some patients with type II diabetes may require insulin in addition to oral agents. Early in the course of type I diabetes, patients may enter a remission period during which insulin is not required. In diabetes mellitus, the body fails to maintain normal blood glucose concentrations. In general, neurohormonal control of glucose production in healthy individuals maintains a fasting serum glucose concentration in the range from 60–100 mg/dL. The two glycemic complications of diabetes mellitus and its therapy are hyperglycemia and hypoglycemia.

History

and

Epidemiology

Insulin first became available for use in 1922 after Banting and colleagues successfully treated diabetic patients with pancreatic extracts.10 In an attempt to more closely simulate physiologic conditions, newer “designer― insulins with unique kinetic properties P.750 have been developed, including an ultrashort-acting preparation known as lispro . 62 , 125 Several oral delivery systems for insulin have been studied.85 Development of a system for use in humans has not been successful because of degradation of the oral form of insulin by digestive enzymes. Using zonula occludens toxin, modulation of intestinal tight junctions in animal models has resulted in significant increases in enteral absorption of insulin.38 A n inhaled form of insulin has also been studied and appears promising.24 The hypoglycemic activity of a sulfonamide derivative used for typhoid fever was noted during World War II.68 This discovery was verified later in animals. The sulfonylureas in use today are chemical modifications of that original sulfonamide compound. In the mid-1960s, the first-generation sulfonylureas were widely used. Newer second-generation agents differ primarily in their potency. Although insulin is widely used for treating diabetes mellitus, sulfonylurea exposures are much more commonly reported to poison centers than are insulin exposures, based on 15 years of data from 1989–2003 (Chap. 130

). These data likely reflect a significant percentage of intentional overdose cases. In a review of 1418 medication-related cases of hypoglycemia, sulfonylureas (especially the long-acting agents chlorpropamide and glyburide) alone or with a second agent accounted for the largest percentage of cases (63%).115 Only 18 of the sulfonylurea cases in this series involved overdose with suicidal intent. Ethanol, propranolol, and salicylate, either alone or with another hypoglycemic drug, accounted for another 19% of cases of hypoglycemia. Quinine, quinidine, pentamidine, ritodrine, and disopyramide were the most common of the less frequently associated agents. Hypoglycemia is reported in as many as 20% of patients using sulfonylureas.55 Besides sulfonylurea use, advanced age and fasting are identified major risk factors for hypoglycemia. Despite the lack of evidence reported in the literature, we speculate that insulin-induced hypoglycemia occurs frequently in settings other than volitional overdose. The biguanides metformin and phenformin were developed as derivatives of Galega officinalis , the French lilac, recognized in medieval Europe as a treatment for diabetes mellitus.7 Phenformin was used in the United States until 1977, when it was removed from the market because of its association with life-threatening lactic acidosis (64 cases/100,000 patient-years). However, phenformin still is available outside the United States.76 Travelers and immigrants to the United States who continue to receive medication from their native countries may present with phenformin-induced lactic acidosis. Metformin became available in the United States in 1995. Its use is also associated with lactic acidosis but to a much lesser degree than with phenformin (only 3 cases/100,000 patient-years).28 Metformin-associated lactic acidosis is discussed in detail in Metformin-associated Lactic Acidosis below. Several newer agents for treatment of diabetes mellitus have been introduced. They include the α-glucosidase inhibitors acarbose and miglitol; the thiazolidinedione derivatives troglitazone, rosiglitazone, and pioglitazone; and the meglitinides repaglinide and nateglinide. Development of the α-glucosidase inhibitors began in the 1960s when an α-amylase inhibitor was isolated from wheat flour.110 Acarbose was discovered more than 10 years later and approved for use in the United States in 1995.

Troglitazone and repaglinide were approved for use in the United States in 1997. The FDA subsequently directed the manufacturer of troglitazone to withdraw the product from the US market in 2000 because of associated liver toxicity. Endocrine Disorders Addison disease Glucagon deficiency Panhypopituitarism (Sheehan syndrome) Neoplasms Carcinomas (diverse extrapancreatic) Hematologic Insulinoma Mesenchymal Multiple endocrine adenopathy type 1 (Werner syndrome) Reactive Hypoglycemia Hepatic Disease Acute hepatic atrophy Alcoholism Cirrhosis Galactose or fructose intolerance Glycogen storage disease Neoplasia Renal Disease Chronic hemodialysis Chronic renal insufficiency Miscellaneous Acquired immunodeficiency syndrome Anorexia nervosa Autoimmune disorders SLE Rheumatoid arthritis Graves disease Burns Diarrhea (childhood)

(AIDS)

Leucine sensitivity Muscular activity (excessive) Postgastric surgery Pregnancy Protein calorie malnutrition Septicemia Shock Exogenous Ackee (hypoglycin) Alloxan β-Adrenergic antagonists Disopyramide Ethanol Antidiabetics (insulin, sulfonylureas) Pentamidine Propoxyphene Quinine Quinidine Ritodrine Salicylates Streptozocin Sulfonamides Vacor Valproic acid Artifactual Chronic myelogenous Polycythemia vera

leukemia

TABLE 48-1. Causes of Hypoglycemia Various xenobiotics other than the antidiabetic medications can cause hypoglycemia. Ethanol is a common cause of hypoglycemia and is discussed in depth in Chap. 75 . Other xenobiotics, including β-adrenergic antagonists and salicylates, and a variety of medical conditions, such as sepsis and

insulin-secreting tumors, may cause hypoglycemia (Table 48-1 ). Certain plant xenobiotics may be implicated as well. Although not a particular problem in the United States, ingestion of the unripe fruit of the Ackee tree, Blighia sapida , in countries where food is in short supply may result in significant hypoglycemia resulting from the compound hypoglycin contained in the unripe fruit.

Pharmacology Insulin is synthesized as a prohormone in the β-islet cells of the pancreas. Upon release, the prohormone is cleaved, resulting in release of both a Cpeptide and insulin itself, a double-chain molecule containing 51 amino acid residues. Glucose concentration plays a major role in the regulation of insulin release.102 Glucose is phosphorylated after transport into the β-islet cell of the pancreas. Further metabolism of glucose-6-phosphate results in the formation of ATP. ATP inhibition of the K+ channel results in cell depolarization, inward calcium flux, and insulin release. After release, insulin binds to specific receptors on cell surfaces in insulin-sensitive P.751 tissues, particularly the hepatocyte, myocyte, and fat cells. The action of insulin on these cells involves various phosphorylation and dephosphorylation reactions. Figure 48-1 depicts the chemical structures of oral agents representing the major classes of antidiabetic and hypoglycemic agents. The sulfonylureas stimulate the β cells of the pancreas to release insulin; therefore, they are ineffective in type I diabetes mellitus resulting from islet cell destruction (Figure 48-2 ). This stimulatory effect diminishes with chronic therapy. All the sulfonylureas bind to high-affinity receptors on the pancreatic β-cell membrane, resulting in closure of KA T P channels.37 , 43 , 44 Inhibition of potassium ion efflux mimics the effect of naturally elevated intracellular ATP and results in insulin release. High-affinity sulfonylurea receptors also present within pancreatic β cells are postulated to be either located on granular membranes or part of a regulatory exocytosis kinase. Binding to these receptors promotes exocytosis by direct interaction with secretory

machinery not involving closure of the plasma membrane KA T P channels.37 , 43 , 44 Repaglinide is a new oral agent that is structurally different from the sulfonylureas. However, it also binds to ATP-sensitive potassium channels on pancreatic β cells, resulting in increased insulin secretion.83

Figure 48-1. Chemical structures of representative oral antidiabetics and hypoglycemics.

The linkage of two guanidine molecules forms the biguanides. Metformin is an oral compound approved for treatment of type II diabetes mellitus. Its glucose-stabilizing effect is caused by several mechanisms, the most important of which appears to involve inhibition of gluconeogenesis and subsequent decreased hepatic glucose output. Enhanced peripheral glucose uptake also plays a significant role in maintaining euglycemia. Metformin's

ability to lower blood glucose concentrations also occurs as a result of decreased fatty acid oxidation and increased intestinal use of glucose.8 , 127 In skeletal muscle and adipose cells, metformin causes enhanced activity and translocation of glucose transporters. Although the details are unclear, the mechanism by which this process occurs involves an interaction between metformin and tyrosine kinase on the intracellular portion of the insulin receptor. Figure 48-3 depicts the mechanism of action of metformin. Insulin resistance in patients with type II diabetes mellitus may occur because of secretion of biologically defective insulin molecules, circulating insulin antagonists, or target tissue defects in insulin action.92 The thiazolidinedione derivatives decrease insulin resistance by potentiating insulin sensitivity in the liver, adipose tissue, and skeletal muscle. Uptake of glucose into adipose tissue and skeletal muscle is enhanced, while hepatic glucose production is reduced.18 , 54

Figure 48-2. Under normal conditions, cells release insulin in response to elevation of intracellular ATP concentrations. Sulfonylureas potentiate the

effects of ATP at its “sensor― on the ligand-gated K+ channels and prevent efflux of K + . The subsequent rise in intracellular potential opens voltage-gated Ca2 + channels, which initiates a series of phosphorylation reactions culminating in fusion of the insulin-containing granule with the cell membrane and release of insulin. Release of insulin is also caused by binding of sulfonylureas to postulated receptor sites on regulatory exocytosis kinase and insulin granular membranes.

P.752 Acarbose and miglitol are oligosaccharides that inhibit α-glucosidase enzymes such as glucoamylase, sucrase, and maltase in the brush border of the small intestine. As a result, postprandial elevations in blood glucose concentrations after carbohydrate ingestion are blunted.134 Delayed gastric emptying may be another mechanism for the antihyperglycemic effect of these oligosaccharides. 105

Pharmacokinetics

and

Toxicokinetics

Pharmacokinetic parameters of the hypoglycemics are given in Tables 48-2 and 48-3 . Insulin is a peptide that is degraded in the gut and therefore is not active by the oral route. The onset and duration of action in therapeutic doses varies considerably among preparations. Insulin overdose usually occurs after administration by the subcutaneous or intramuscular route. As might be predicted based on slow onset and prolonged duration of action of some of the preparations, insulin overdose may result in delayed and prolonged hypoglycemia. However, hypoglycemia may also occur with shortacting forms because of some unusual toxicokinetic features. Some of these unpredicted responses may be caused by a depot effect following intramuscular or subcutaneous administration, and poor absorption may be further potentiated by the poor perfusion that can occur in hypoglycemia.86 , 124 Further complicating the prediction of the clinical course is the delayed release of insulin from adipose tissue at the injection site(s). In diabetics, the presence of insulin antibodies may explain a patient's recovery in spite of massive overdoses.111 Because there is a finite number of insulin

receptors, insulin overdoses of varying extents probably are equivalent in terms of the degree of hypoglycemia once receptor saturation occurs but not in terms of its duration. A comparison can be made with the current treatment of diabetic ketoacidosis, in which lower doses of insulin are as effective as the higher doses used in the past.61

Figure 48-3. Under normal conditions, insulin binding to its receptor on myocytes and adipocytes activates tyrosine kinase, resulting in phosphorylation and activation of the membrane-bound glucose transporter GLUT. Non–insulin-dependent diabetes mellitus is causally associated with an increased activity of PC-1, a glycoprotein that inhibits tyrosine kinase activity and thus reduces myocyte and adipocyte glucose uptake. Metformin reduces PC-1 activity in these cells, enhancing peripheral glucose utilization. In addition, gluconeogenesis in hepatic cells is reduced through interference

with pyruvate carboxylase, the enzyme responsible for conversion of pyruvate to oxaloacetate.

Many of the sulfonylureas have a long duration of action, which may explain the unusually long period of hypoglycemia that can occur in both therapeutic use and overdose. The first-generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, tolbutamide) reduce hepatic clearance of insulin and produce active hepatic metabolites. These drugs are dependent on their effective urinary excretion to maintain euglycemia and prevent hypoglycemia. Second-generation sulfonylureas (glimepiride, glipizide, glyburide) have half-lives that approach 24 hours and are characterized by substantial fecal excretion of the parent drug. These agents frequently cause hypoglycemia (Table 48-2 ). Like insulin, the sulfonylureas may cause delayed onset of hypoglycemia following overdose.94 , 103 The reason for the potential delayed onset of effects with sulfonylureas cannot be simply explained by known

kinetic

principles.

P.753 Metformin metabolism is negligible, and the majority of an absorbed dose is excreted in the urine unchanged. Plasma protein binding also is negligible.8 The kinetics of acarbose are notable for minimal systemic absorption and metabolism that occurs in the gut. As a result, serious systemic toxicity is not expected.112 Adverse clinical effects usually are gastrointestinal. Repaglinide is a prandial glucose regulator with a short onset and short duration of action. These characteristics allow for flexible dosing in patients with irregular eating habits.87 Despite its short half-life in therapeutic doses, overdose experience and toxicokinetic data for repaglinide are lacking. Whether after overdose hypoglycemia would be prolonged or delayed in onset is not clear. I. Sulfonylureas First generation Acetohexamide (Dymelor)

12–18 Hydroxyhexamide (+++) Hydroxyhexamide (65%) Acetohexamide (2%) Negligible ~1% Chlorpropamide (Diabinese) 24–72 2-Hydroxychlorpropamide (+) 3-Hydroxychlorpropamide (+) Chlorpropamide (20%) 2-Hydroxychlorpropamide (55%) 3-Hydroxychlorpropamide (2%) Negligible 4–6% Tolazamide (Tolinase) 16–24 Hydroxytolazamide (++) Hydroxytolazamide (35%) Tolazamide (7%) Negligible ~1% Tolbutamide (Orinase) 6–12 Hydroxytolbutamide (+) Hydroxytolbutamide (30%) Tolbutamide (2%) Negligible 65 mg/dL in 6 of the 8 octreotide subjects for the 4hour observation period. Without additional octreotide, hypoglycemia continued to recur for as long as 30 hours after the initial glipizide administration.

Adverse

Drug

Effects

Octreotide is generally well tolerated, but experience in the toxicologic setting is limited. Adverse reactions occurring with short-term administration usually are local or gastrointestinal. Stinging at the injection site occurs in approximately 7% of patients but rarely lasts more than 15 minutes.39 Healthy volunteers receiving octreotide noted no side effects when given IV doses of 25 or 50 µg or SC doses of 50 or 100 µg. At higher doses, early transient nausea and later-appearing but longerlasting diarrhea and abdominal pain frequently occur.24,25 Healthy volunteers were given IV bolus doses of octreotide as high as 1000 µg and infusion doses of 30,000 µg over 20 minutes and 120,000 µg over 8 hours without serious adverse effects. Single doses in healthy volunteers resulted in decreased biliary contractility and bile secretion.32 Long-term therapy lasting weeks to months results in biliary tract abnormalities.32,40 Product information warns of the potential for acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, and pancreatitis.32 Octreotide alters the balance among insulin, glucagon, and growth hormone. Glucose concentrations must be serially monitored. Hyperglycemia often occurs, but cases of hypoglycemia are reported. The most likely explanation is glucagon suppression

outlasting

insulin

suppression.32

Other adverse effects reported with long-term administration of octreotide include hypothyroidism, cardiac conduction abnormalities, worsening congestive heart failure (in at-risk patients with acromegaly), bradycardia, pancreatitis, altered fat absorption, and decreased vitamin B 12 levels.32 Anaphylactoid reactions are rarely reported.32 P.772 Drug interactions are expected with xenobiotics that affect glucose regulation. Octreotide may significantly decrease oral absorption of

cyclosporine.32

Administration Both SC and IV administration are acceptable, although the usual route is SC administration.32 The SC administration sites should be rotated. For IV infusion, octreotide can be diluted in sterile 0.9% sodium chloride solution or D5 W and infused over 15–30 minutes or by IV bolus over 3 minutes.32 Rapid IV bolus may be indicated for carcinoid crisis.32 Refrigeration of octreotide is recommended for prolonged storage, although octreotide is stable at room temperature for 14 days when protected from light. Active warming of refrigerated octreotide is not recommended, although passive warming to room temperature prior to administration is suggested and may reduce the pain of SC administration. 29 Using the smallest volume possible reduces the pain with SC administration. A depot formula designed to last for 4 weeks is available (Sandostatin LAR Depot). Although the depot formula is useful for patients with insulinomas, its duration of action far exceeds that of any oral hypoglycemic agent, making it an inappropriate and unnecessary choice for management of xenobiotic-induced hypoglycemia.

Dos i n g No controlled trials have evaluated the dose of octreotide for the management of sulfonylurea overdose. In adults, a 50-µg SC dose of octreotide given every 6 hours is suggested. In children, a dose of 4–5 µg/kg/d SC divided every 6 hours, up to the adult dose, can be used for initial therapy. This pediatric dose is derived from the literature on treatment of persistent hyperinsulinemic hypoglycemia of infancy.16 In situations where compromised peripheral blood flow is expected, octreotide should be administered intravenously in the same dose but every 4 hours instead of every 6 hours. Further experience in the toxicologic setting should permit a better delineation of dosing recommendations. depending on the must be carefully octreotide therapy

Several days of therapy may be required, duration of the offending agent. All patients monitored for recurrent hypoglycemia during and perhaps for 24 hours following termination

of octreotide therapy before discharge. Octreotide is considered a category B drug (Table 30-2), and pregnant women must be carefully monitored for recurrent hypoglycemia. Use of octreotide should not diminish this vigilance.

Availability Octreotide acetate (Sandostatin) injection is available in ampules and multidose vials ranging in concentration from 50–1000 µg/mL. The multidose vials contain phenol.

Summary Octreotide is useful for treating refractory hypoglycemia induced by xenobiotics such as sulfonylureas and quinine that cause endogenous release of insulin. Octreotide is more effective than diazoxide in suppressing insulin and is much better tolerated.

References 1. Alberti KGMM, Christensen NJ, Christensen S, et al: Inhibition of insulin secretion by somatostatin. Lancet 1973;2:1299–1301. 2. Alberts AS, Falkson G: Rapid reversal of life-threatening hypoglycemia with a somatostatin analogue (octreotide). S Afr Med J 1988;74:75–76. 3. Bauer W, Briner U, Doepfner W, et al: SMS 201–995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982;31:1133–1140. 4. Boden G, Ryan IG, Shuman CR: Ineffectiveness of SMS 201–995 in severe hyperinsulinemia. Diabetes Care 1988;11:664–668. 5. Boyle PJ, Justice K, Krentz AJ, et al: Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced sulfonylurea overdoses. J Clin Endocrinol Metab 1993;76:752–756.

by

6. Bradeau P, Vale W, Burgus R, et al: Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973;179:77–79. 7. Braatvedt GD: Octreotide for the treatment of sulphonylurea-induced hypoglycemia in type 2 diabetes. N Z Med J 1997;110:189–190. 8. Brunner JE, Kruger DF, Basha MA, et al: Hypoglycemia after

administration of somatostatin analog in metastatic carcinoid. Henry Ford Hosp Med J 1989;37:60–62. 9. Bruns C, Weckbecker G, Raulf F, et al: Molecular pharmacology of somatostatin-receptor subtypes. Ann N Y Acad Sci 1994;733:138–146. 10. Carr R, Zed PJ: Octreotide for sulfonylurea-induced hypoglycemia following overdose. Ann Pharmacother 2002;36:1727–1732. 11. Crawford BA, Perera C: Octreotide treatment for sulfonylurea-induced hypoglycaemia. Med J Aust 2004;180:540–541. 12. del Pozo E: Endocrine profile of a long-acting somatostatin derivative.

Acta

Endocrinol

1986;111:433–439.

13. Doyle ME, Egan JM: Pharmacological agents that directly modulate insulin secretion. Pharmacol Rev 2003;55:105–131. 14. Gama R, Marks V, Wright J, Teale JD: Octreotide exacerbated fasting hypoglycemia in a patient with a proinsulinoma: The glucostatic importance of pancreatic glucagons. Clin Endocrinol 1995;43:117–120. 15. Gerich J, Lorenzi M, Schneider V, Forsham P: Effect of somatostatin on plasma glucose and insulin to responses to glucagon and tolbutamide in man. J Clin Endocrinol Metab 1974;39:1057–1060. 16. Glaser B, Hirsch H, Landau H: Persistent hyperinsulinemic

hypoglycemia of infancy: Long-term octreotide treatment without pancreatectomy. J Pediatr 1993;123:644–650. 17. Graudins A, Linden C, Ferm R: Diagnosis and treatment of sulfonylurea-induced hyperinsulinemic hypoglycemia. Am J Emerg Med 1997;15:95–96. 18. Green RS, Palatnick W: Effectiveness of octreotide in a case of refractory sulfonylurea-induced hypoglycemia. J Emerg Med 2003;25:283–287. 19. Hansen JB, Arkhammar PO, Bodvarsdottir TB, et al: Inhibition of insulin secretion as a new drug target in the treatment of metabolic disorders. Curr Med Chem 2004;11:1595–1615. 20. Hsu W, Xiang H, Rajan A, et al: Somatostatin inhibits insulin secretion by a G-protein-mediated decrease in Ca2 + entry through voltage dependent Ca2 + channels in the beta cell. J Biol Chem 1991;206:837–843. 21. Hung O, Eng J, Ho J, et al: Octreotide as an antidote for refractory sulfonylurea hypoglycemia [abstract]. J Toxicol Clin Toxicol 1997;35:540. 22. Kane C, Lindley K, Johnson P, et al: Therapy for persistent hyperinsulinemic hypoglycemia of infancy. J Clin Invest 1997;100:1888–1893. 23. Krentz AJ, Boyle PJ, Justice KM, et al: Successful treatment of severe refractory sulfonylurea-induced hypoglycemia with octreotide. Diabetes Care 1993;16:184–186, 189–190.

24. Krentz AJ, Boyle PJ, Mavdonald LM, Schade DS: Octreotide: A long-acting inhibitor of endogenous hormone secretion for human metabolic investigations. Metabolism 1994;43:24–31. 25. Kutz K, Nuesch E, Rosenthaler J: Pharmacokinetics of SMS 201–995 in healthy subjects. Scand J Gastroenterol 1986;21(Suppl 119):65–72. P.773 26. Lamberts SWJ, Vaanderlely AJ, DeHerder WW, Hofland LJ: Octreotide. N Engl J Med 1996;334:246–254. 27. Lightman SL, Fox P, Dunne MJ: The effects of SMS 201–995, a long-acting somatostatin analogue, on anterior pituitary function in healthy male volunteers. Scand J Gastroenterol

1986;21(Suppl

119):84–95.

28. McLaughlin SA, Crandall CS, McKinney PE: Octreotide: An antidote for sulfonylurea-induced hypoglycemia. Ann Emerg Med 2000;36:133–138. 29. Mercadante S: The role of octreotide in palliative care. J Pain Symptom Manage 1994;9:406–411. 30. Moldovan S, Atiya A, Adrian T, et al: Somatostatin inhibits b-cell secretion via a subtype-2 somatostatin receptor in the isolated perfused human pancreas. J Surg Res 1995;59:85–90. 31. Mordel A, Sivilotti MLA, Old AC, Ferm RP: Octreotide for pediatric sulfonylurea poisoning [abstract]. J Toxicol Clin Toxicol 1998;36:437.

32. Octreotide: Product information: Sandostatin octreotide acetate injection. East Hanover, NJ, Novartis Pharmaceuticals Corporation, October 2002. 33. Olias G, Viollet C, Kusserow H, et al: Regulation and function of somatostatin receptors. J Neurochem 2004;89:1057–1091. 34. Pace CS, Tarvin JT: Somatostatin: Mechanism of action in pancreatic islet cells beta cells. Diabetes 1981;30:836–842. 35. Patel YC: Somatostatin and its receptor family. Front Neuroendocrinol 1999;20:157–198. 36. Philips RE, Looareesuwan S, Bloom SR, et al: Effectiveness of SMS 201–995, a synthetic, long-acting somatostatin analogue, in treatment of quinine-induced hyperinsulinemia. Lancet

1986;1:713–715.

37. Stehouwer CDA, Lems WF, Fischer HRA, et al: Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (Sandostatin). Acta Endocrinol 1989;121:34–40. 38. Thorton P, Alter C, Levitt-Katz L, et al: Short- and longterm use of octreotide in the treatment of congenital hyperinsulinism. J Pediatr 1993;123:637–643. 39. Verschoor L, Uitterlinden P, Lamberts J, del Pozo E: On the use of a new somatostatin analogue in the treatment of hypoglycemia in patients with insulinoma. Clin Endocrinol (Oxf)

1986;25:555–560. 40. Waas JAH, Popovic V, Chayvialle JA: Proceedings of the discussion, tolerability and safety of Sandostatin. Metabolism 1992;41(Suppl 2):80–82.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Chapter 49 - Thyroid and Antithyroid Medications

Chapter Thyroid

49 and

Antithyroid

Medications

Nicole C. Bouchard

A 3-year-old boy was found with an empty bottle of his mother's levothyroxine 300-µg tablets). The mother estimated he had ingested as many as 20 tablets were found in the nearby area or in the child's mouth. The child cried when aske “eaten― the pills. He was brought promptly to the hospital. On initial eval

asymptomatic and had stable vital signs: blood pressure, 100/60 mm Hg; pulse respiratory rate, 16 breaths/min; temperature 98.6°F (37.0°C). He was given (1 g/kg) mixed with juice, which he drank readily. A complete blood count, am electrolytes, blood urea nitrogen, serum creatinine, urinalysis, and thyroid funct

and the child was admitted to the pediatric intensive care unit (ICU). His total T 5–12 µg/dL), and total triiodothyronine (T3 ) was 120 ng/dL (normal 40–1 other laboratory test results were within normal limits for his age. He remained days before he was transferred to a regular pediatric ward. His behavior, vital s examination were normal at that time. After 72 hours of observation, he was d from the hospital. The parents were advised to monitor for signs of hyperactivi gastrointestinal upset, and they were taught how to measure his pulse rate. The immediately if the child became symptomatic.

According to his parents, the child became somewhat irritable on day 5 posting

reported that he was more disruptive than usual in day school. That evening he asleep. He was awakened at night with abdominal cramps and had 2 episodes o morning, his parents measured his pulse rate to be 130 beats/min. The parents emergency department, where the triage nurse noted the child was “jumpy.â follows: blood pressure, 120/80 mm Hg; pulse, 153 beats/min; respiratory rate temperature 99.5°F (37.5°C). His physical examination was remarkable for reactive pupils (bilaterally), vigorous bowel sounds, warm skin, and brisk reflexe not diaphoretic or confused. His ECG showed a sinus tachycardia.

He was readmitted to the ICU and treated with 60 mg liquid propranolol orally in days. His pulse rate decreased to 105 beats/min, and his blood pressure returne

after the first dose of propranolol. He remained afebrile. He had 2 more episode complained of mild abdominal cramping for another 24 hours. Otherwise, he re well hydrated, and playful throughout. He was able to tolerate a normal diet. L revealed normal serum electrolyte concentrations and a normal complete blood

tests revealed total T4 of 24 µg/dL (normal 5–12 µg/dL), total T3 206 ng/d ng/dL), and undetectable thyroid-stimulating hormone (TSH). The patient remained in the ICU pediatric ward. On the ward, he asymptomatic, except for a pulse hospital day 4 (postingestion day

for 2 days (postingestion day 8) before he was required no further treatment with propranolol rate of 110 beats/min. He was discharged hom 9). On follow-up with his pediatrician 1 week

asymptomatic. His parents reported no further disruptive behavior, gastrointest tachycardia. His TSH concentration remained suppressed until 3 weeks after in

History

and

Epidemiology

Long before the thyroid was recognized as a functional endocrine gland, the thy serve a cosmetic function, especially in women. Egyptian paintings often empha necks of women with enlarged thyroid glands. Other early theories on the physi thyroid gland include lubrication of the trachea, to protect women from “irri “vexation― from men and from the diversion of blood flow from the brain. defined in historical accounts, symptoms resembling hypothyroidism and myxede sheep thyroid were described 500 years ago. In the 16th century, Paracelus de between goiter (thyroid gland enlargement) and cretinism.67 A syndrome of ca and exophthalmos was first described in 1786.79 Graves and von Basedow furth

and its relationship to the thyroid gland 50 years later.32 , 35 , 63 , 79 , 104

In 1891, injection of ground sheep thyroid extract was formally described as a myxedema.35 Shortly afterward, oral administration of this therapy was determi Seaweed, which contains large amounts of iodine, was used to treat goiter (hy medicine as early as the 3rd century A.D. In 1863, Trousseau100 fortuitously dis Graves disease when he inadvertently prescribed daily tincture of iodine instead a tachycardic, thyrotoxic young woman.

P.775 Sir Charles R. Harington described the chemical structure and performed the fir (tetraiodothyronine [T4 ]) in 1926.81 Triiodothyronine (T3 ) was not isolated an

1950s.35 Prior to this time, desiccated thyroid gland from animal sources was c hypothyroidism. Despite becoming essentially obsolete in the modern medical thyroid can be easily purchased via the Internet and in health food stores as a Unfortunately, the misguided use of thyroid supplements, both organic and synt

stimulants, and weight-loss aids has become increasingly common. Two epidemi thyrotoxicosis that occurred in the United States in the mid 1980s secondary to beef contaminated with bovine thyroid gland demonstrated the potential of wid sequelae following unknown thyroid hormone ingestion by a community.41 , 52

Today, hypothyroidism and hyperthyroidism are relatively common endocrine di incidence of neonatal hypothyroidism is 1 per 3000–4500 births. It is estimat

affects 1–7% of adults.89 According to 2003 US retail pharmaceutical statistic prescriptions, Synthroid (T 4 ) was ranked second overall for total prescription c 47,000–49,000 prescriptions written in 2003.46 , 73 Many cases of intentional overdoses with thyroid hormone are reported in both adults and children. Despit thyroid hormones on physiologic homeostasis and the widespread use and acces hormone, morbidity and mortality from overdose are very low overall.

Figure

49-1. Thyroid hormone synthesis: its control, metabolism, and molecul

and reprinted with permission from Southwestern Medical Illustration Departme

Physiology

To properly understand the impact of thyroid supplements and antithyroid agents human body, an understanding of thyroid physiology is required. Thyroid functio following: (1) the hypothalamus, (2) the pituitary gland, (3) the thyroid gland, a for the thyroid hormones (Figure 49-1 ).

The hypothalamus is an intermediate between cerebral centers and the pituitary hypothalamus receives specific neurotransmitter stimulation, thyroid-releasing h produced. TRH is transported through the venous sinusoids to the pituitary glan thyroid-stimulating hormone (TSH). TSH enters the circulation and stimulates th

of the thyroid hormones T3 and T4 by the thyroid gland. Thyroid physiology exh autoregulation or “feedback control― of hormonal function. When adequat released, they exert an inhibitory effect on the pituitary gland, leading to dimin (Figure 49-1 ). Suppression or upregulation of TSH production is a frequently u the evaluation of the hyperthyroid and the hypothyroid state, respectively.

P.776 Thyroid hormones are tyrosine molecules with iodine substitutions. Two forms of physiologically active: T3 and T4 (Table 49-1 ). Synthesis of these thyroid horm process. The amino acid tyrosine is concentrated in the follicles of the thyroid g epithelial layer surrounding a proteinaceous colloidal substance called thyroglo contains a large amount of tyrosine. After iodide (I- ) is absorbed from the circ in thyroid cells by an active transport process called iodide trapping , when by thyroid (iodide) peroxidase. Iodine rapidly iodinates tyrosine residues to and diiodotyrosine (DIT). These substituted tyrosine molecules then combine ratio of T3 to T4 in thyroglobulin is 1:5. T3 and T4 (thyroxine) ultimately are

it is for to rel

from the thyroglobulin matrix inside the follicles of thyroid gland.

Iodide trapping can be inhibited pharmacologically by monovalent anions such a pertechnetate (TcO4 - ), and perchlorate (ClO4 - ). Thyroid peroxidase is inhibit of intrathyroidal iodide and by thioamide drugs. High intrathyroidal iodide conce the release of thyroid hormone into circulation (Table 49-2 ).

Approximately 95% of circulating or peripheral thyroid hormone is T4 ; the rem the peripheral T3 is secreted directly by the thyroid; the balance results from t of T4 to T3 . When circulating T4 enters the cell, it is deiodinated to T3 . Deiodin occurs by monodeiodination of either the outer ring or the inner ring by 5′-d deiodinase, yielding 3,5,3′-T3 and 3,3′,5′- triiodothyronine (reverse T3 approximately 3 times greater hormonal activity than T4 . rT3 is metabolically in effects by binding to thyroid hormone receptors inside the nucleus. This interac receptors regulates gene transcription and protein synthesis, which ultimately i consumption and underlies the thermogenic effects of thyroid hormones.

β-Adrenergic antagonism, corticosteroids, ipodate, starvation, and severe illnes deiodinase, which results in decreased production of metabolically active T3 and monodeiodination to metabolically inactive rT3 (Table 49-2 ). This energy-conse attenuation of the thermogenic effects of thyroid hormones in times of physiolo

Pharmacology T 4 and T3

Thyroid supplementation for treatment of hypothyroidism is widespread in both medicine. Thyroid hormones historically were derived from animal origin but now synthetically produced. Desiccated thyroid (Armour) still is derived from animal both T3 and T4 . Because it is less pharmacologically stable and carries a risk o thyrotoxicity from T3 , its use has largely been supplanted by safer synthetic is the preparation of choice because of its low immunogenicity, 7- day half-life, regimen. Synthroid is the commercial name of the most commonly prescribed fo

(Cytomel or Triostat, available PO and IV) and liotrix (Thyrolar, available PO) ar are seldom used secondary to their short half-lives, high cost, rare therapeutic risk of thyrotoxicosis. The typical levothyroxine dose in adults is 1.7 µg/kg/d patients are started on lower doses (range 12.5–µg/d [0.0125–0.025 mg/d

sensitivity to thyroxine excess. Infants with congenital or acquired hypothyroidis doses of 8–10 µg/kg/d (~25–50 µg/d). Older infants and children are sta kilogram: age > 12 years: 2–3 µg/kg once daily until the adult daily dose (u reached; 6–12 years: 4–5 µg/kg/d or 100–150 µg once daily; 1–5 ye 75–100 µg once daily; 6–12 months: 6–8 µg/kg/d or 50–75 µg regard to suppression of TSH and elevation of T4 is reached approximately therapy. Doses usually are titrated in increments of 12.5 or 25 µg/d after measurements. Different sources suggest that bioequivalence of Synthroid

once 6– 2– vers

may and may not be equivalent.17 Thyroid hormone concentrations and the pat should be followed when transitioning between levothyroxine formulations becau present an opportunity for an adverse drug reaction.

Pharmacokinetics

and

Toxicodynamics

In circulation, T3 and T4 both are highly and reversibly bound to plasma protei and 99.97%, respectively, in the nonpregnant adult. Thyroxine-binding globulin approximately two thirds of the circulating thyroid hormones; albumin and other remainder. It is estimated that only 0.4% of T3 and 0.04% of T4 exist in the fr derived thyroid hormones exhibit similar binding characteristics when dosing is

The amount of thyroid hormone bound to proteins varies greatly with different pharmacologic conditions, for example, increasing in pregnancy and levothyroxin decreasing in chronic disease. Such changes in protein binding must be conside thyroid hormone concentrations in the blood (see Diagnostic Testing ). The volu thyroid hormones is very large: 40 L/kg for T3 and 10 L/kg for T4 . Table 49-1 pharmacokinetic properties of thyroid hormones.

The oral bioavailabilities of exogenous thyroid hormones are high: 80% for T4 a Gastrointestinal absorption is thought to occur primarily in the duodenum and absorption can be decreased by variations in intestinal flora and binding by age containing antacids, calcium preparations, carbonate salts, sucralfate, iron, bile cholestyramine resins, colestipol hydrochloride), and infant soy formula (Table Oral bioavailability (exogenous 95% 80% Volume of distribution (L/kg) 40 10 Half-life 1

drug)

(days)

7 Protein binding (normal adult) 99.96% 99.6% Relative potency 4 1 Pharmacokinetic

Property

T3

T4

TABLE 49-1. Pharmacokinetic Properties of Thyroid Hormones

Thyroid

hormones

undergo

their

ultimate

metabolism

P.777 peripherally. Intracellular

accounts for approximately two thirds of inactivation. Most of the remaining thi metabolism by glucuronidation or sulfation. Xenobiotics that induce hepatic mic as rifampin, phenobarbital, phenytoin, and carbamazepine, increase the metabol (Table 49-2 ). Inhibit TRH and TSH synthesis Dopamine, levodopa, corticosteroids, somatostatin No hypothyroidism Inhibit thyroid hormone synthesis or release Iodides (including amiodarone), lithium, aminoglutethimide Hypothyroidism Inhibit iodide uptake to thyroid gland Monovalent anions (SCN- , TcO4 - , ClO4 - ) Treatment for iodide-induced hyperthyroidism Increase TBG Estrogens, tamoxifen, heroin, methadone, mitotane Altered thyroid hormone transport in serum ↑ Total measured thyroid hormone (vs. free hormone) Decreased TBG Androgens, glucocorticoids Altered thyroid hormone transport in serum ↓ Total measured thyroid hormone (vs. free hormone) Displace T3 or T4 from TBG Salicylates, mefenamic acid, furosemide Transient hyperthyroxinemia Inhibit thyroid peroxidase Thioamides (methimazole, propylthiouracil) Decrease thyroid hormone synthesis Induction of hepatic enzymes Phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin ↓ Total thyroid hormone measurements Inhibition of 5′-deiodinase Iopanoic acid, ipodate, amiodarone, β-adrenergic antagonists, Decrease peripheral conversion of T 4 (↓T3 , ↑rT3 ) Interfere with GI absorption of T4

corticosteroids,

Cholestyramine, colestipol, aluminum hydroxide, sucralfate, ferrous sulfate, som infant soy formula Decreased oral bioavailability of T4 Induction of autoimmune thyroid disease Interleukin-α, interleukin-2 Hyperthyroidism or hypothyroidism TRH = thyroid-releasing hormone; TSH = thyroid-stimulating hormone; TBG = GI = gastrointestinal. Interaction

Xenobiotic

Effect

TABLE 49-2. Xenobiotic Interactions: Effects on Thyroid Hormones and

Pathophysiology

Thyroid hormones are critical for optimal physiologic growth and function. Thyro

important determinant of basal metabolic rate (BMR). In addition, the thyroid e effect on many hormones, notably catecholamines and insulin.

Hyperthyroidism is a condition characterized by excess active thyroid hormone. carbohydrate and protein metabolism are increased in the presence of thyroid h metabolism and cholesterol synthesis are increased. The clinical picture consists increased metabolism, along with tachycardia, tremor, anxiety, other behavioral

tachydysrhythmias such as atrial fibrillation.24 , 54 , 87 This constellation of sym thyrotoxicosis , may result from overproduction of the hormone, increased conv excess exogenous hormone. Graves disease, an autoimmune disorder, is the mo excess thyroid hormone secretion. It accounts for approximately two thirds of ca accompanied by exophthalmos. Severe thyrotoxicosis accompanied by decompens thyroid storm or thyrotoxic crisis. Mortality in thyroid storm, even with treatme , 24

An increased in sensitivity to catecholamines is suggested to underscore the sy inotropy and chronotropy produced by thyroid hormones. Plasma catecholamine established to be normal or decreased in hyperthyroid states.14 , 84 Although th thyroid hormones can cause decreased systemic vascular resistance leading to a

cardiac output, two general mechanisms are proposed for the direct cardiac effe although their relative contributions are uncertain.3 , 16 , 54 , 99 (1) T3 increases adrenergic receptors in various tissues, including cardiac cells.16 This process o β-adrenergic receptor synthesis at the level of the β-adrenergic gene.4 (2) T3 intracellular signaling mechanisms that lead to increased catecholamine effects. intracellular signaling activity involving protein kinase A, cyclic adenosine mono and increased phosphorylation of thyroid hormone receptor proteins all are imp degrees.23 , 54 , 82 , 83 , 86 , 93 , 101 Enhancement of myocardial transmembrane reticulum ion channel function, L-type voltage-gated Ca2 + channels, and accele sarcoplasmic reticulum also are suggested.50 , 51 , 72 , 92 Whether these effects signaling represents a direct T 3 effect on intracellular signaling mediators or T3 the individual β-adrenergic receptor response to catecholamines with a seconda postreceptor signaling is unclear.3

In addition to these two mechanisms, T3 upregulates synthesis of cardiac thyroi

TRα and TRβ genes). Comprehensive reviews on this topic explore the more c thyroid hormones and their effects on the cardiovascular system.15 , 54 , 77

Hypothyroidism, a condition characterized by decreased BMR and decreased cat common disorder, especially in women and the elderly. It often is autoimmune function diminishes significantly with age in many patients. In infants, untreate deficiency and severe dietary iodine deficiency (goitrous hypothyroidism) result

mental retardation and dwarfism (also referred to as cretinism). In developed n salt has essentially eliminated dietary iodine deficiency as a cause of hypothyroi the world, particularly mountainous regions such as the Andes, Alps, and Himal hypothyroidism still is endemic. Myxedema and myxedema coma

P.778 are potentially life-threatening emergencies that represent extremes of hypoth is not discussed in this chapter, except to note that treatment of hypothyroid with T3 , can result in thyrotoxic symptoms. Comprehensive reviews of hypothy

Clinical

Manifestation

The widespread availability and use of thyroid supplements make thyroid hormo in acute intentional and unintentional overdoses. In addition, chronic excess th is a relatively frequent occurrence. Symptoms of toxicity from exogenous thyro

those of catecholamine excess. Pronounced catecholamine effects occur in the especially tachycardia, tachydysrhythmias (usually atrial fibrillation or flutter), cardiac failure.24 , 54 , 87 Interestingly, although hyperthyroid patients typically agitated, patients with thyroid storm may present with a decreased level of con coma.8 , 45 , 57 , 85 , 91 Hyperthermia can occur secondary to the thermogenic e hormones and psychomotor agitation. Hyperthermia can be extreme (ie, > 106Â tachycardia associated with thyrotoxicosis often is disproportionate to the temp

Acute

Toxicity

Acute overdoses with thyroid hormone preparations most commonly occur with Significant ingestions of levothyroxine usually do not manifest clinically until 7â but are rarely reported to manifest as early as 2–3 days postingestion.18 , 34 peripheral conversion of T4 to the metabolically active T3 and the time to nucle

protein synthesis account for this clinical latency of hours to days following exo administration. Acute overdoses involving preparations containing T3 can manif hours days after exposure.62

In children, acute thyroxine overdoses almost universally are benign because of unintentional nature and lower doses ingested. Most pediatric patients remain a only mild symptoms. No deaths have been reported. 21 , 28 , 48 , 58 , 60 , 63 , 95 I with unintentional overdose, only 3 children developed mild symptoms 12–48

Similarly, large case series that involved 41 children (ages 1–5 years) with u thyroxine (estimated doses ranged from 40–800 µg) found mild symptoms tachycardia, fever, vomiting, diarrhea, diaphoresis, and flushing) in only 27%. A clinical outcomes. The degree of symptoms did not correlate with the amount in serum thyroxine concentrations (measured 1–5 hours postingestion) for most Diagnostic Testing ). 28 Two other series involving 78 and 92 cases of unintentio found that mild symptoms developed in only 4 and 8 patients, respectively.63 , severe toxicity in children are reported: 1 child without a history of a seizure di days after a levothyroxine ingestion (18,000 µg),56 and another child became 12-hour period (blood pressure, 120/68 mm Hg; pulse, 200 beats/min; tempera hours after ingesting a large amount (3.2 g, or “50 grains―) of a desicca containing both T3 and T4 .61

Ingestions in adults have a wide range of toxicity. Many patients are asymptom

symptomatic.30 , 64 , 76 Severe sequelae occur more frequently in adults than i resemble thyrotoxicosis and, in extreme cases, thyroid storm. Hyperthermia,34 58 , 91 and severe agitation34 are well described. Hemiparesis,8 muscle weakne respiratory failure,26 sudden death,7 myocardial infarction,7 cardiac failure,8 foc rhabdomyolysis with muscle necrosis,8 delayed palmar desquamation (> 2 wee and hematuria34 are also described. Because patients are expected to be asym ingestion and laboratory tests correlate poorly with the degree of symptoms, cl findings early in the course of the ingestion are not reliable indicators of which (see Diagnostic Testing ).

Chronic

Toxicity

Following chronic excessive thyroid hormone ingestions, patients may present w have a more subtle and insidious presentation. Classically, chronic ingestion of

occurs in patients with hypothyroidism, psychiatric disorders, and eating disorde thyroid hormones chronically may develop significant weight loss, anxiety, and osteoporosis.75 More severe manifestations, such as cardiac dysrhythmias, tach and psychosis, also occur. As in patients with hyperthyroidism, intercurrent illne stressors can trigger thyroid storm in these patients.

Numerous miniepidemics of hyperthyroidism and thyrotoxicosis have resulted fro ground meat containing neck muscle contaminated with thyroid gland.19 , 41 , 52

these epidemics had 3 volunteers consume a single large portion of “well-co implicated ground beef that previously had been frozen. Although all volunteer the mean serum peak T4 (8–12 hours postingestion) was elevated ~15 µg/dL undetectable for 4–17 days.41 The practice of gullet trimming (using larynx m to these outbreaks has since been prohibited in US slaughter houses. The risk f exists, especially when laryngeal muscles are used or when farmers and hunters meat.78 Until an exogenous source of thyroid hormone is suspected or identified misdiagnosed with painless thyroiditis or thyrotoxicosis factitia.

Thyrotoxicosis factitia is a symptomatic disorder that mimics physiologic disease intentional chronic ingestion of exogenous thyroid hormone. The pattern of inge surreptitious and maladaptive. Patients frequently have comorbid psychiatric dis Munchausen syndrome or eating disorders, or are taking thyroid hormone for s with thyrotoxicosis factitia disorder often have access to thyroid medications bei

friends, or they can obtain the medications at their place of employment.29 , 36

In recent years, thyroid hormones have gained popularity among dieters and ath hormones as weight-loss aids and as stimulants. Severe consequences can occur reported in 3 patients suspected of chronic ingestion of thyroid hormone for we enhancement.7 In 2002, the heavily promoted Singaporean diet pill Slim 10 wa and hyperthyroidism in numerous

P.779 patients.39 Investigators found the proprietary herbal preparation was adulterat amounts of the undeclared ingredients T4 , T3 (from thyroid gland extract), and banned drug). The medication was promptly withdrawn and the manufacturers c Singapore Poisons Act.39 , 40 Unfortunately, supplements containing thyroid hor remain highly promoted and are readily available to the general public without Internet and in stores selling nutritional supplements (Chap. 44 ).90

Diagnostic

Testing

Traditionally, thyroid testing was undertaken using combinations of measurement measurement of hormone binding (T3 uptake). Free T4 and T3 also can be mea

dialysis (free T 4 ), analogue assays (ie, competitive analogs of either free T3 o competitively bind for spaces on the serum-binding proteins), and antibody capt sequential assays that capture a representative portion of the free fraction of t Assessment of pituitary production of TSH has improved greatly in recent years

assays can readily detect suppression of TSH production. TSH is now relied upon thyroid function screening. Suppressed or elevated concentrations of TSH can b with a free T4 assay and, if necessary, a free T3 assay (Table 49-3 ).

The clinical manifestations of thyrotoxicosis and thyroid storm are well known to moderate, and high concentrations of T3 and T4 .10 This lack of correlation betw serum concentrations is also true for exogenous thyroid hormone ingestion.8 , 2 76 , 105 In a large case series of children with unintentional estimated ingestion 40 and 800 µg), serum T4 concentrations were drawn in 11 patients (1–5 h Serum T4 concentrations were normal in 5 of these children and were slightly el (mean 16 µg/dL). In this series, one infant who was estimated to have ingested significantly higher concentration (55 µg/dL at 4.5 hours) and developed only diaphoresis and a “staring spell― 7 days postingestion. Another child who

4200 µg had a concentration of 12 µg/dL and developed significant tachycard In a pediatric case associated with severe toxicity and seizures (see Acute Toxi (estimated ingestion 18,000 µg levothyroxine) had a serum T4 concentration o postingestion and 38 µg/dL on day 7, when he was symptomatic.56 In an adult of levothyroxine (720,000 µg), serum T4 concentrations were > 30 µg/dL and (normal 0.7–1.86 ng/dL). In this case, TSH remained undetectable until day Overall, the observed symptoms following thyroid hormone ingestion correlate p ingested or with measured serum T4 concentrations. Prolonged suppression of T ingestion of excess thyroid hormone. TSH 0.5–5.0 µIU/mL Available assays with respective detection limits: First generation = 1.0 µIU/L Second generation = 0.1 µIU/L Third generation = 0.01 µIU/L Total T4 by RIA 5–12 µg/dL (64–153 nmol/L) ↑ In pregnancy, estrogens, oral contraceptives Total T3 by RIA 40–132 ng/dL (1.1–2.0 nmol/L) ↑ In pregnancy, estrogens, oral contraceptives Free T4 0.7–1.86 ng/dL (9– 24 pmol/L) ↑ In hyperthyroidism, exogenous thyroxine ingestion Free T3 0.2–0.52 ng/dL (3–8 pmol/L) ↑ In hyperthyroidism, exogenous thyroid hormone (T3 or T4 ) a Interlaboratory and interassay variations may occur. RIA = radioimmunoassay; TSH = thyroid-stimulating hormone. Diagnostic

Test

Normal

Valuesa

Comments

TABLE 49-3. Diagnostic Tests for Thyroid Hormone and Thyroid Functio

Routine analysis of laboratory thyroid function tests in the setting of acute thyr likely will not affect management. Analysis of thyroid hormone concentrations is confirmation of a suspected ingestion is desired and in massive ingestions when symptoms may occur. Suppression of TSH and elevated thyroid hormone concen serum thyroglobulin concentration may help to differentiate between thyrotoxico disease.68

Management General

Based on the existing literature, conservative management is adequate in most unintentional thyroxine ingestions in both adults and children. Most children with managed with home observation and follow-up appointments. In cases where th

estimated to be > 4000 µg, patient follow-up by regular telephone contact for Historically, most children with unintentional ingestions have been treated by G activated charcoal and/or syrup of ipecac or by gastric lavage,28 , 48 , 56 , 58 , 6 procedures probably are unnecessary. Based on 2 large series of unintentional

which no toxicity was observed in the vast majority of cases, clinically significan with estimated ingestions < 5000 µg.78 , 102 Because children almost uniformly minor symptoms, activated charcoal administration should be considered only if µg thyroxine. Aspiration risks are minimal in awake, alert children who are abl

and take activated charcoal orally, without nasogastric tube placement. 58 , 102 B acute ingestions > 5000 µg thyroxine also should be treated with activated ch presentations with massive thyroxine ingestions (> 10,000–50,000 µg) in su ingestions of preparations containing large amounts of T3 , gastric emptying pr emesis and orogastric lavage are unwarranted.8 , 34 Similarly, patients with ma 10,000–50,000 µg) or ingestion of T3 -containing products should be admitte anticipation of development of significant symptoms.8 , 34 , 56 , 61 Treatment protection, Adrenergic cases.28 ,

should be based on the development of symptoms and should includ and control of sympathomimetic symptoms, mental status alterations antagonism with propranolol has been used for sympathomimetic sym 48 , 56 , 60 , 76 , 95

P.780

Empirical treatment with β-adrenergic antagonists is not recommended. These a for significant tachycardia, dysrhythmias, and other symptoms of catecholamine

Agitation

When sedation is required, parenteral benzodiazepines and barbiturates are re benzodiazepines such as midazolam or diazepam should be used to control seve symptomatic patients. Phenobarbital should be considered as a sole agent in int adjunct in patients requiring sedation because it offers the added theoretical be enhanced hepatic elimination of thyroxine (Table 49-2 ). Because of the genera the lack of evidence regarding the clinical use of enhanced hepatic elimination sedation with phenobarbital for the sole purpose of enhanced elimination is not antipsychotic agents such as haloperidol and droperidol should be avoided beca anticholinergic properties can exacerbate thyrotoxic symptoms. In addition, the

drugs to prolong the QTc interval and predispose to malignant dysrhythmias is o catecholaminergic patient. Antipsychotic agents should be reserved for medically strong psychiatric behavioral manifestations.

Catecholamine

Excess

and

Cardiovascular

Sym

The principal mechanism of action of β-adrenergic antagonists in hyperthyroidism

receptor–mediated effects.75 In addition to their sympatholytic effects, β-ad inhibit 5′-deiodinase, thereby decreasing peripheral conversion of T4 to T3 (T electrocardiographic and blood pressure monitoring are indicated when β-adren used. The clinical significance of decreased peripheral conversion in the setting

Propranolol is the most frequently used β-adrenergic antagonist in thyrotoxic 63 , 76 , 95 Parenteral β-adrenergic antagonists should be used when symptoms rapid control of heart rate is required. Starting doses of 1–2 mg IV propranol are recommended. High doses have been reported in massive thyroxine overdos received 23 mg propranolol IV over 1 hour on initial presentation, then required mg/day IV for 5 more days.34 Oral propranolol can be used for persistent sympt both hemodynamically and medically stable and are not acutely agitated. High d 20–120 mg every 6 hours may be required. Other β-adrenergic antagonists l provided they do not have intrinsic sympathomimetic activity (ie, partial agonis receptors), such as acebutolol, oxprenolol, penbutolol, and pindolol (Chap. 59 )

When β-adrenergic antagonists are contraindicated, as in patients with asthma heart failure, calcium channel blockers can be used. Among calcium channel blo most studied for the management of thyrotoxicosis.71 , 88 A double-blind, crosso propranolol to diltiazem for thyrotoxic symptoms found that diltiazem was well as effective as propranolol.71 Another study successfully used diltiazem as the s of cardiovascular symptoms in 11 thyrotoxic patients.88 Doses of 60–120 mg daily or 5–10 mg/hour parenterally have been used.71 , 88 A possible explanat calcium channel blockers in thyrotoxicosis is that thyroid hormone enhances Ca2 voltage-gated Ca2 + channels, accelerates Ca2 + entry into the sarcoplasmic reti cellular Ca2 + storage capacity.50 , 51 , 72 , 92 The net effect of these changes is chronotropy. Calcium channel blockers, particularly diltiazem and verapamil, att of parenteral β-adrenergic antagonists in combination with parenteral calcium c contraindicated because of the risk for profound hypotension and cardiovascular

Hyperthermia Antipyretics are recommended for hyperpyrexia, with acetaminophen particularly high doses (1.5–3 g/d), should be avoided because it thyrotoxicity from displacement of T3 and T4 from TBG (Table 49-2 especially extreme hyperthermia (> 106°F [> 41°C]), most likely

being the carries a th ). Note, ho is secondar

agitation and excess heat production from the hypermetabolic, catecholaminerg Extreme hyperthermia should be considered a medical emergency and should be treated with active external cooling with ice baths and with β-adrenergic antag benzodiazepines and/or barbiturates, and intubation with paralysis if necessary

Other

Therapies

Bile acid sequestrants, such as cholestyramine and colestipol, and aluminum hy sucralfate bind to exogenous T4 and decrease GI absorption (Table 49-2 ). Bec supporting their effectiveness is poor, they are not routinely recommended for overdose.58

Oral iodine contrast media is known to decrease peripheral conversion of T4 to T PO daily are routinely used for thyroid storm. Thioamides, such as propylthioura methimazole, and the corticosteroids are thyroid gland inhibitors that are used

non–drug-related hyperthyroidism. In addition, thioamides inhibit peripheral c Evidence from limited case reports suggests poor efficacy of both thioamides an overdose8 , 26 , 58 (see Thioamides ).

Although use of antithyroid drugs such as PTU, corticosteroids, and iodine contr overdose has theoretical benefits, these drugs are unvalidated, potentially harm additional benefit, or be superior, to conventional therapy with activated charc antagonism, and sedation. These treatments are not recommended as adjunctiv of exogenous thyroxine overdose.

Extracorporeal

Drug

Removal

Extracorporeal drug removal procedures, such as plasma exchange or plasmap transfusion (in children), and charcoal hemoperfusion, have been used in extrem

hormone overdose and thyroid storm.1 , 8 , 9 , 26 , 42 , 58 , 62 , 69 , 74 , 97 , 103 O regarding improvement of clinical condition and plasma clearances of thyroid ho methods are

P.781 conflicting. The largest series of acute ingestions involved 6 patients who becam

massive thyroxine ingestions of prescribed capsules containing a 1000-fold conc thyroxine (dose range 50,000–125,000 µg/d for 2–12 days). Charcoal hem plasmapheresis were used in all patients. Plasmapheresis was found to be more hemoperfusion in the extraction of thyroxine. The authors suggest this intervent

duration of thyrotoxicosis. Rebound elevations in plasma concentrations occurred patients, suggesting redistribution between extravascular and intravascular co redistribution is expected given the large volume of distribution for thyroid horm There may be a role for early plasmapheresis in the exceptional situation of a of thyroid hormone. Because the outcomes from most ingestions of thyroid horm with good supportive care, sedation, and β-adrenergic antagonism, the risks o be evaluated on case-by-case basis after consultation with a medical toxicologis

Xenobiotics Thioamides

with

Antithyroid

Effects

Antithyroid drugs are used to decrease the amount of thyroid hormone in hype commonly in Graves disease. Thioamides are a group of chemicals with the bas Methimazole and PTU are the two principal thioamides used for treatment of h Carbimazole, which is bioactivated methimazole, is available in Europe and Chin both inhibit the activity of thyroid peroxidase in the thyroid gland.98 PTU has th inactivating 5′-deiodinase, which decreases the peripheral conversion of T4 t active T3 .20 , 59 Because thioamides act primarily by decreasing thyroid hormo release), a lag time of 3–4 weeks may occur before T4 is depleted. The oral b 50–80%. It is rapidly absorbed from the GI tract and may undergo first-pass Although its plasma half-life is only 1.5 hours, its effects are long-lasting becau thyroid gland. PTU is inactivated by glucuronidation and is renally eliminated. M absorbed, is concentrated in the thyroid, and is more slowly eliminated than PTU Doses of PTU are in the range of 100 mg orally every 6–8 hours. Methimazole daily. Although PTU is 10 times less potent than methimazole, it is more comm for its use are mild-to-moderate hyperthyroidism.

The two thioamides traverse the placenta (methimazole more than PTU) and sh during pregnancy. However, they are minimally secreted in breast milk. Adverse 3–12% of patients taking thioamides. The most common adverse effect is a rash. Methimazole, PTU, and, to a lesser extent, carbimazole can cause immun and age-related agranulocytosis and neutrophil dyscrasias.61 , 70 , 80 This pote adverse effect can be treated by administration of granulocyte colony-stimulatin

withdrawal of thioamides can lead to rebound symptoms and thyrotoxic states.5

Little data exist regarding overdose with thioamides. A 12-year-old girl with a who was estimated to have ingested 5000–13,000 mg PTU, developed only a concentration and elevated alkaline phosphatase concentration (7350 mU/mL).4 functioning thyroid gland may have contributed to the benign course in this pat sequelae have been associated with acute overdose of thioamides.

Iodides

Prior to the development of thioamides, iodide salts were the principal treatme Iodides decrease thyroid hormone concentrations by inhibiting formation and re high-dose iodides (> 2g/d) decrease thyroid hormone release and produce subs 2–7 days. Common sources of iodides include calcium iodide, sodium iodide,

pharmaceutical preparations, oral drops commonly referred to as SSKI [saturate methyl iodide (industrial preparations).

The adverse reaction to chronic ingestion of small or excessive amounts of iodid is characterized by cutaneous rash, laryngitis, bronchitis, esophagitis, conjunctiv taste, salivation, headache, and bleeding diathesis. Immune-mediated hypersen consisting of urticaria, angioedema, eosinophilia, vasculitis, arthralgia, lymphade anaphylactoid reactions may occur. Chronic iodide therapy has produced goiters rarely hyperthyroidism. As much as 10 g sodium iodide has been administered signs or symptoms of toxicity.

Iodide (I- ), unlike iodine (I2 ) (Chap. 98 ), is not a caustic. KI is added to tabl for prevention of goiter. It also is used as a prophylactic agent after exposure t nuclear fallout to prevent uptake of radioactive iodine into the thyroid gland (Ch

most commonly used iodide for thyroid suppression in hyperthyroidism. Iodide m described but rare disorder characterized by severe sialadenitis (or parotitis), conjunctivitis following administration of ionic and nonionic iodine-containing con iodide salts (Table 49-4 ).12 , 13 , 49 Although the mechanism remains unclear, it

idiosyncratic or secondary to iodide accumulation and subsequent inflammation i the salivary gland. Symptoms tend to occur within 12 hours and resolve sponta hours.12

Iodides should be avoided in pregnancy because they readily cross the placenta complications, such as cretinism and death from respiratory failure secondary to reported.22 , 43 , 66 Iodide salts adsorb to activated charcoal.

Methyl iodide is a methylating agent used in the chemical and pharmaceutical in microscopy, as a catalyst in production of organic lead compounds, as an etchin in fire extinguishers, and formerly as a soil fumigant. Methyl iodide toxicity from with early pulmonary congestion, lethargy, and renal failure. It also is associate degeneration, multifocal neuropathies (cranial nerve and spinal), Parkinsonian sy persistent psychiatric symptoms (months to years). 2 , 44 Chronic repeated overe misdiagnoses such as multiple sclerosis. The toxicity is similar to that of the m 112 ). Lithium Goiter (in 37% of patients)

Hypothyroidism (in 5–15% of patients) Mechanism unclear Amiodarone (37% iodine by weight) 1. Hypothyroidism (in 25% of patients) ↑ Peripheral conversion of T4 to T3 1. Inhibition of 5′-deiodinase 2. Hyperthyroidism, type 1: in patients with preexisting goiters from low iodine 2. Type 1: iodine excess stimulates thyroid hormone production 3. Hyperthyroidism, type 2: in patients with previously normal thyroid function 3. Type 2: causes thyroid inflammation β-Adrenergic antagonists ↓ Peripheral conversion of T4 to T3 Inhibition of 5′-deiodinase PTU Decreased thyroid hormone synthesis ↓ Peripheral conversion of T4 to T3 Inhibition of thyroid peroxidase Inhibition of 5′-deiodinase Corticosteroids ↓ Peripheral conversion of T4 to T3 Inhibition of 5′-deiodinase Iodine 1 . Low dose: transient or no effect 2 . High doses (>10 g/d): ↓ thyroid hormone secretion 3 . Transient thyrotoxicosis (ie, Jod-Basedow effect) A . With rapid correction of hypothyroidism from iodine deficiency B . From topical iodine 4 . Delirium 5 . Caustic injury 1. 2. 3. 4. 5.

Transiently stimulates thyroid hormone secretion Inhibition of thyroid hormone synthesis Increases thyroid hormone synthesis Mechanism unclear

3. 4. 5 . Direct cytotoxic injury to cells Iodinated contrast material 1. Rapid ↓ peripheral conversion of T4 to T3 (adjunctive treatment in thyroid 1. Inhibition of 5′-deiodinase 2. Prolonged suppression of T4 to T3 2. Mechanism unclear 3. Causes thyrotoxicosis and thyroid storm 3. Mechanism unclear 4. Iodide mumps 4. Idiopathic, toxic accumulation of iodide Radioactive iodine Treatment of hyperthyroidism, causes hypothyroidism Uptake into thyroid follicles causes local destruction Anion inhibitorsa ↓ Iodine uptake into thyroid follicle, used in iodide-induced hyperthyroidism Blocks uptake of iodide into the thyroid gland by competitive inhibition a Also referred to as monovalent anions, ie, thiocyanate (SCN- ), pertechnetate perchlorate (ClO4 - ). Xenobiotic

Effect

Mechanism

TABLE 49-4. Common Xenobiotics That Alter Thyroid Function and Cau Effects6 , 1 1 , 2 7 , 3 3 , 3 7 , 3 8 , 5 3 , 5 4 , 1 0 6 , 1 0 7 P.782

Summary

Despite the high prevalence of thyroid disorders in the general population and t levothyroxine, remarkably little morbidity and mortality associated with overdos is reported. Most unintentional ingestions in children are benign, and they can b outpatients for 5–10 days. Intentional ingestions in adults may result in seve ICU management. Supportive care with sedation, cooling measures, and β-adre adequate in most cases. Chronic ingestions may produce more severe symptoms more insidiously or are complicated by thyroid storm. Unregulated dietary supp

thyroid hormone used for weight loss and athletic enhancement are becoming i consumers via the Internet and in health food or supplement stores. Clinicians thyroid hormone exposure in patients with thyrotoxicosis and suppressed TSH

Acknowledgment Christopher Keyes contributed to this chapter in previous editions.

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71. Milner MR, Gelman KM, Phillips RA, et al: Double-blind crossover trial of d propranolol in the management of thyrotoxic symptoms. Pharmacotherapy 1

72. Muller A, Zuidwijk MJ, Simonides WS, van Hardeveld C: Modulation of SER thyroid hormone and norepinephrine in cardiocytes: Role of contractility. Am J 1997;272:H1876–H1885.

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74. Nenov VD, Marinov P, Sabeva J, Nenov DS: Current applications of plasm toxicology. Nephrol Dial Transplant 2003;18(Suppl 5):56–58.

75. Nuovo J, Ellsworth A, Christensen DB, et al: Excessive thyroid hormone re Am Board Fam Pract 1995;8:435–439. 76. Nystrom E, Lindstedt G, Lundberg P: Minor signs and symptoms of toxicity spite of massive thyroid ingestion. Acta Med Scand 1980;207:135–136.

77. Pantos C, Malliopoulou V, Varonos DD, Cokkinos DV: Thyroid hormone and cardioprotection. Basic Res Cardiol 2004;99:101–120.

78. Parmar MS, Sturge C: Recurrent hamburger thyrotoxicosis. CMAJ 2003;1

79. Parry CH: Collections from the Unpublished Medical Writings. Underwoods, 2:1–120. Reprinted in Major RH: Classic Descriptions of Disease. Springfield, 1978.

80. Pearce SH: Spontaneous reporting of adverse reactions to carbimazole and UK. Clin Endocrinol (Oxf) 2004;61:5895–5894. 81. Pitt-Rivers R: Sir Charles Harington and the structure of thyroxine. Mayo 1964;39:553–559.

82. Pracyk JB, Slotkin TA: Thyroid hormone differentially regulates developme receptors, adenylate cyclase and ornithine decarboxylase in rat heart and kidn 1991;16:251–261.

83. Pracyk JB, Slotkin TA: Thyroid hormone regulates ontogeny of beta adren adenylate cyclase in rat heart and kidney: Effects of propylthiouracil-induced hypothyroidism. J Pharmacol Exp Ther 1992;261:951–958.

84. Premel-Cabic A, Getin F, Turcant A, et al: Plasma noradrenaline in hypert hypothyroidism [in French]. Presse Med 1986;15:1625–1627.

85. Pugh S, Lalwani K, Awal A: Thyroid storm as a cause of loss of consciousn anaesthesia for emergency Caesarean section. Anaesthesia 1994;49:35–37.

86. Ririe DG, Butterworth JF 4th, Royster RL: Triiodothyronine increases cont beta-adrenergic receptors or stimulation of cyclic-3′,5′-adenosine mono Anesthesiology

1995;82:1004–1012.

87. Roffi M, Cattaneo F, Topol EJ: Thyrotoxicosis and the cardiovascular system effects. Cleve Clin J Med 2003;70:57–63. 88. Roti E, Montermini M, Roti S, Gardini E, et al: The effect of diltiazem, a drug, on cardiac rate and rhythm in hyperthyroid patients. Arch Intern Med 89. Sawin CT: Hypothyroidism. Med Clin North Am 1985;69:989–1004.

90. Sawin CT, London MH: “Natural― desiccated thyroid. A “health-f preparation. Arch Intern Med 1989;149:2117–2118. 91. Schottsaedt ES, Smoller M: “Thyroid storm― produced by a thyroid Intern Med 1966;64:847–849.

92. Seppet EK, Kolar F, Dixon IM, et al: Regulation of cardiac sarcolemmal Ca transporters by thyroid hormone. Mol Cell Biochem 1993;129:145–159.

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94. Silva JE: The thermogenic effect of thyroid hormone and its clinical implica 2003;139:205–213. 95. Singh GK, Winterborn MH: Massive overdose with thyroxine, toxicity and 1991;150:217.

96. Surks MI, Sievert R: Drugs and thyroid function. N Engl J Med 1995;333: 97. Tajiri J, Katsuya H, Kiyokawa T, et al: Successful treatment of thyrotoxic exchange.

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98. Taurog A, Dorris ML: Peroxidase-catalyzed bromination of tyrosine, thyrog serum albumin: Comparison of thyroid peroxidase and lactoperoxidase. Arch 1991;287:288–296.

99. Tielens ET, Forder JR, Chatham JC, et al: Acute L-triiodothyronine admin inotropic responses to beta-adrenergic stimulation in the isolated perfused rat 1996; 32:306–310.

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103. Van Huekelom S, Kinderen LH, der Vingerhoeds PJ: Plasmapheresis in L Vet Hum Toxicol 1979;S21:7.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Chapter 50 - Antihistamines and Decongestants

Chapter

50

Antihistamines

and

Decongestants

Anthony J. Tomassoni Richard S. Weisman A 17-year-old man was brought to the emergency department by friends who noted progressive onset of drowsiness and confusion. The friends indicated the patient became progressively more disoriented and made statements that were out of context. The patient repeatedly told his friends that he was thirsty. Shortly thereafter, his friends reported he seemed to be responding to internal stimuli. Upon questioning by his friends while en route to the emergency department, the patient admitted taking “a bottleful― of diphenhydramine capsules in a suicide attempt between 1 and 2 hours earlier. The bottle was not located. Past medical history obtained from friends and family was negative. Family history was negative for epilepsy. Social history was positive for smoking and occasional ethanol and marijuana use. Upon initial evaluation, the patient was lethargic, he had no verbal response to questions, and when aroused with vigorous stimulation he became agitated and muttered unintelligible sounds. His initial vital signs were: blood pressure, 175/90 mm Hg; pulse, 135 beats/min;

respiratory rate, 18 breaths/min; temperature 100.0°F (37.8°C). His skin was warm, dry, and pink. Examination of the head, eyes, ears, nose, and throat was notable for 7-mm pupils that were sluggishly reactive to light and for dry mucous membranes. His neck showed no evidence of meningismus. Chest and heart examinations were normal except for tachycardia. Abdominal examination was remarkable only for absent bowel sounds. The patient's neurologic status was notable for periods of lethargy alternating with agitation upon stimulation and lack of spontaneous verbal output. During his agitation, the patient sometimes appeared to be picking at the bed sheets or the clothing of caregivers. Occasional myoclonic jerks were present. Deep tendon reflexes were symmetric and plantar reflexes were downgoing. Oxygen was administered via nasal cannula at 2 L/min. Cardiac monitoring was instituted. Intravenous 0.9% sodium chloride solution was administered at a rate of 150 mL/h. Blood was sent to the laboratory for a complete blood count, electrolytes, glucose, toxicology screen, and acetaminophen concentration. A nasogastric tube was inserted, gastric fluid was aspirated to minimize potential for aspiration, and 50 g activated charcoal was administered. A Foley catheter was inserted, and nearly 1 L of clear urine was immediately drained. The patient's agitation improved immediately after this procedure. ECG revealed sinus tachycardia with a normal QRS duration of 0.08 seconds and normal QTc interval. Ethanol concentration was 55 mg/dL. No acetaminophen was detected, and immunoassay-based toxicology screen was negative for cyclic antidepressants and common drugs of abuse. Approximately 3–4 hours after his ingestion, the patient had a grand mal, tonic–clonic seizure that lasted approximately 2 minutes. As the seizure appeared to be subsiding, diazepam 5 mg was administered. Following the seizure, the patient had a brief postictal period. He then remained somnolent but arousable for 4 hours, after which he progressively became alert and oriented over the next 8 hours. His vital signs gradually returned to normal over

the same time period, and bowel sounds returned. The Foley catheter was removed, and the patient was able to void spontaneously. No significant rhabdomyolysis occurred. The patient was transferred for psychiatric assessment.

Antihistamines History

and

Epidemiology

H 1 receptor antagonists were introduced into clinical use in the early 1940s. The class continues to find widespread application in the treatment of anaphylaxis, allergic rhinitis, urticaria, and other histamine-mediated disorders. The numerous functions of histamine and its receptors in the nervous system, immune system, and other organ systems have been further elucidated in recent years. Antihistamines are available worldwide, and many do not require a prescription. They often are used for symptomatic relief of allergy symptoms and are included in many combination cold preparations. They also are found in nonprescription sleeping aids. Antihistamines are frequently ingested in suicide attempts, probably because of their ready availability. Poison center and clinical experience suggests that recreational use of antihistamines is increasing, but whether the increased use results simply from inclusion of antihistamines in cold preparations containing the widely abused cough suppressant dextromethorphan is unclear (Chap. 38 ). Terfenadine and astemizole were associated with cardiac dysrhythmias and are no longer approved for use in the United States47 (Chap. 133 ). Unintentional exposures to antihistamine-containing preparations are common, with > 14,000 cases involving children younger than 6 years reported annually.32 Liquid formulations attractive to children are available, and children occasionally are administered diphenhydramine or another antihistamine as a sedative by parents and daycare workers.3 Although ingestion is the usual route of

exposure, toxicity can also result from exposure to topical preparations containing antihistamines.43 P.786

Physiology Sys tem

of

the

Histamine

Receptor

Four types of histamine receptors are recognized and designated H1 , H 2 , H3 , and H4 . All are helical transmembrane molecules that transduce extracellular signals via G proteins to intracellular secondmessenger systems. H1 receptors are located in the CNS, heart and vasculature, airways, sensory nerves, gastrointestinal smooth muscle cells, immune cells, and adrenal medulla. The many functions of histamine and the H1 receptor include control of the sleep–wake cycle, cognition, memory, and endocrine homeostasis. The H1 receptor also causes vasodilation, increases vascular permeability and bronchoconstriction, and decreases atrioventricular nodal conduction when histamine is present. H2 receptors are located in cells of the gastric mucosa, heart, lung, CNS, uterus, and immune cells. The action of histamine on H2 receptor results in increased gastric acid secretion, increased vascular permeability, and other effects. Endogenous histamine is one of the triggers for gastric acid secretion through interaction with the H2 receptor located on gastric parietal cells. This process results in increased adenyl cyclase and cyclic adenosine monophosphate (cAMP), with activation of the H+ K + -ATPase pump and ultimately release of H+ into the gastric lumen. H 3 receptors are found in neurons of the central and peripheral nervous systems, airways, and GI tract. The action of histamine on H 3 receptors of the CNS decreases further release of histamine, acetylcholine, dopamine, norepinephrine and serotonin.64 H3 receptors partly act to prevent excessive bronchoconstriction. H3 receptors also are implicated in control of neurogenic inflammation and proinflammatory activity.37 The recently identified H4 receptor is located in leukocytes, bone marrow, spleen, lung, liver, colon, and

hippocampus. It apparently has roles in the differentiation of myeloblasts and promyelocytes and eosinophil chemotaxis. This chapter focuses on H1 and H2 antihistamines, as no H3 or H4 receptor active pharmaceuticals are currently in clinical use.

Pharmacology Histamine

Antagonists

All known H1 histamine antagonists function as inverse agonists and not simply competitive antagonists.54 For consistency with the medical literature and the current clinical use of these drugs, we use the terms H 1 antihistamine and histamine antagonist rather than inverse agonist to describe agents of this class. Agonists and antagonists that act at each of the four histaminemodulated receptor sites have been identified. Through these receptors, histamine interacts with G proteins in the plasma membranes. Stimulation of H1 receptors results in increased synthesis of inositol-1,4,5-triphosphate and several diacylglycerols (DAGs) from phospholipids located in cell membranes. Inositol-1,4,5triphosphate causes release of calcium–calmodulin-dependent in enhanced cross-bridging and reaction at the H1 receptors is

calcium, myosin smooth mediated

which then activates light-chain kinase, resulting muscle contraction. The by phospholipase C. H2

receptor stimulation is mediated by adenyl cyclase activation of cyclic AMP-dependent protein kinase in smooth muscle and in parietal cells of the stomach and results in increased gastric acidity through stimulation of the H+ -K+ -ATPase pump. Six major classes of “first-generation― antihistamines are traditionally recognized. They are first-generation derivatives of ethylenediamine, ethanolamine, alkylamines, phenothiazines, piperazines, and piperidines. Many of the classic antihistamines are substituted ethylamine structures with a tertiary amino group linked by a 2- or 3-carbon chain with two aromatic groups. 20 This structure

differs from histamine by the absence of a primary amino group and the presence of a single aromatic moiety. Figure 50-1 shows the structures of the pharmacologic classes of the antihistamines.

Figure

50-1. Structures of diverse H1

receptor

antagonists.

Currently, the more clinically useful classification may distinguish between the older “first-generation― agents, which readily penetrate the blood–brain barrier and produce CNS effects, and the peripherally selective or “second-generation― H1 antihistamines, which have a higher therapeutic index. Central effects of the first-generation H1 antihistamines likely result from their interference with histamine function as a neurotransmitter. The first-generation H1 antihistamines also bind to muscarinic and

perhaps adrenergic receptors. In addition, some first-generation antihistamines are not recognized by the P-glycoprotein efflux pump on the luminal surfaces of vascular endothelial cells in the CNS. Second-generation H1 receptor antagonists are highly specific for peripheral rather than central H1 receptors receptors.45 They do not penetrate the CNS well because of their hydrophilicity, their relatively high molecular weight, and recognition by the P-glycoprotein efflux pump on the luminal surfaces of vascular endothelial cells in the CNS. Cetirizine, fexofenadine, loratadine, azelastine (nasal spray), and ebastine have lower binding affinities for the cholinergic, αadrenergic, and β-adrenergic receptor sites than do the firstgeneration antihistamines. Some second-generation H1 receptor antagonists, such as azelastine, a phthalazinone derivative, do not easily fit the standard classification scheme. Of note, using recommended doses of antihistamines, PET scanning shows that firstgeneration agents occupy > 70% of the H1 receptors in the frontal cortex, temporal cortex, hippocampus, and pons. In contrast, the second-generation agents occupy < 20–30% of the available CNS H 1 receptors.60 , 61 P.787 Given the absence of anticholinergic effects of the second-generation antihistamines, antihistamine therapy for patients with seasonal asthma has been reintroduced and has proved efficacious.19 The relative incidence of anticholinergic and CNS adverse effects caused by second-generation H1 antihistamines is similar to that produced by placebo.2 , 8 However, some patients report sedation, especially if higher-than-recommended dosages are taken.8 Table 50-1 lists the peripheral selectivity of the antihistamine that is principally defined by the relative absence of anticholinergic and sedative properties of the H1 antagonists. Acrivastine Alkylamine +

6–8 8 mg tid Azatadine Piperidine + 12 1–2 mg bid Brompheniramine Alkylamine ++ 4–6 4 mg qid Buclizine Piperazine ++ 4–6 50 mg bid Carbinoxamine Ethanolamine ++++ 3–6 4–8 mg qid Cetirizine Piperazine + 12 5–10 mg qid Chlorpheniramine Alkylamine ++ 4–6 4 mg qid Clemastine Ethanolamine

++++ 12–24 2 mg bid Desloratadine Piperidine 0 24 5 mg qd Dexbrompheniramine Alkylamine ++ 12 3–12 mg bid Dexchlorpheniramine Alkylamine ++ 3–6 4–6 mg tid Dimenhydrinate Ethanolamine ++++ 4–6 50–100 mg qid Dimethindene Alkylamine ++ 8 1–2 mg tid Diphenhydramine Ethanolamine ++++ 4–6 25–50 mg qid Doxylamine

Ethanolamine ++++ 6 7.5–12.5 mg qid Fexofenadine Piperidine + 12 60 mg bid Hydroxyzine Piperazine ++ 6–8 25 mg qid Levocetirizine Piperazine 0 24 5 mg qd Loratadine Piperidine + 8–12 10 mg qd Meclizine Piperazine ++ 6–8 25 mg tid Pheniramine Alkylamine ++ 4–6 5–15 mg q4h

Phenyltoloxamine Ethanolamine ++++ 4–8 7.5–25 mg tid Promethazine Phenothiazine ++++ 4–6 12.5–25 mg qid Trimeprazine Phenothiazine ++++ 4–6 2.5 mg qid Tripelennamine Ethylenediamine +++ 4–6 25–50 mg qid Triprolidine Alkylamine ++ 4–6 2.5 mg qid

Antihistamine

Anticholinergic Class

Sedation

Duration of Action (h)

Typical Adult Dose

TABLE 50-1. The Pharmacologic Characteristics of Antihistamine

H2

Receptor

Antagonists

These histamine congeners are highly selective and competitively inhibit the H2 receptor site. The original compound in this class, which retains the imidazole ring of histamine, is cimetidine (Figure 50-2 ). Although newer compounds, such as ranitidine and famotidine, have replaced this ring with a furan or thiazole group, respectively, they retain significant similarity to the histamine structure.56

Figure

50-2. Structures of H2

receptor

antagonists.

The effectiveness of H2 receptor antagonists in the treatment of gastroesophageal reflux disease is improved further by their concomitant alteration in the response of parietal cells to acetylcholine and gastrin, two other stimulants for gastric acid secretion (Figure 50-3 ). Of note, H2 receptor antagonists have little effect elsewhere in the body, and they have weak CNS penetration secondary to their hydrophilic properties. Reports on the effect of H2 antihistamines on ethanol metabolism yield conflicting results. Definitive studies have not been performed, but at this time any effect at clinically relevant doses of alcohol appears insignificant. Questions regarding the effect of accelerated

gastric emptying time caused by H2 antagonists on ethanol absorption, metabolic enzyme polymorphisms, interindividual variability of the effects of H2 blockers on ethanol metabolism, and magnitude of the effect (if any) caused by different H2 blockers remain to be answered.22 , 59

Pharmacokinetics H1

Receptor

and

Toxicokinetics

Antagonists

The antihistamines are generally well absorbed following oral administration, and most achieve peak plasma concentrations within 2–3 hours. Although less well studied, dermal absorption appears to be consequential, especially with extensive or prolonged application to abnormal skin.43 The maximum antihistaminic effect occurs several hours after peak serum concentrations. The durations of action range from 3 hours to > 24 hours, which is much longer than predicted from the extremely variable serum elimination half-life values of the antihistamines. P.788 Hepatic metabolism is the primary route of metabolism for antihistamines.48 Many Asian patients can acetylate therapeutic concentrations of diphenhydramine to a nontoxic metabolite twice as rapidly as white patients, making Asians much less sensitive to both the psychomotor and sedative effects.58 Alterations in usual dosages may be required for patients taking other medications, those with hepatic or renal dysfunction, the young, and the elderly. Such modifications often must be made empirically because formal studies and recommendations for many agents are lacking. Drug–drug interactions may be caused by modulation of CYP450 metabolism or interference with active transport mechanism (eg, P-glycoprotein).54

Figure 50-3. Schematic representation of a gastric parietal cell demonstrating the mechanism of hydrogen ion secretion into the lumen. Gastric acid is modulated by both calcium-dependent and cyclic adenosine monophosphate (cAMP)-dependent pathways. Histamine binding to the H2 receptor increases gastric acidity by increasing cAMP through the stimulatory G protein Gs . Prostaglandins (P) decrease gastric acidity by decreasing cAMP through the inhibitory G protein Gi . Both acetylcholine and gastrin increase gastric acidity by increasing the influx of calcium through Gs interactions. Acetylcholine binds at the muscarinic3 (M3 ) receptor, whereas gastrin binds at the cholecystokinin B (CCKB ) receptor.

H2

Receptor

Antagonists

Cimetidine is the prototypical H2 receptor antagonist. Cimetidine is rapidly and completely absorbed following oral administration. Cimetidine has a volume of distribution of approximately 2 L/kg, with 13–25% protein binding.1 Up to 75% of cimetidine is eliminated unchanged in the urine, 15% is metabolized by the liver, and 10% is eliminated unchanged in the stool. The elimination half-life in patients with normal renal function is approximately 2 hours, but the half-life is substantially prolonged with impaired renal function.1 Cimetidine is responsible for numerous drug–drug interactions because it can inhibit cytochrome P450 activity, thereby impairing hepatic drug metabolism. It can reduce hepatic blood flow, resulting

in decreased clearance of drugs highly extracted by the liver. None of the other currently available H2 receptor antagonists inhibit the cytochrome P450 oxidase system.42 Additionally, by altering gastric pH, cimetidine and all the other H2 antagonists may alter the absorption of acid-labile xenobiotics. Finally, cimetidine is associated with enhanced myelosuppression if it is administered with xenobiotics capable of causing bone marrow suppression.51 Table 50-2 lists the pharmacologic properties of H2 receptor antagonists. Cimetidine 800 1.0 19 2.0 62 Ranitidine 300 1.3 15 2.1 69 Nizatidine 300 1.2 28 1.3 61 Famotidine 40 1.3 17 2.6 67

Drug

Typical Adult Dose (mg)

Volume of Distribution (L/kg)

Protein Binding (%)

HalfLife (hours)

Urinary Elimination (%)

TABLE 50-2. Pharmacology of Histamine H2 Receptor Antagonists

Clinical H1

Manifestations

Receptor

Antagonists

Although dry mouth and mydriasis are common adverse therapeutic effects, sedation is of the greatest concern. Therapeutic antihistamine use may be as incapacitating as ethanol intoxication with regard to operating motor vehicles.23 Compared with adults, children may more commonly present with excitation and irritability and may be more prone to hallucinations and seizures. The clinical manifestations of H1 receptor antagonist overdose are largely extensions of the adverse effects noted with therapeutic use of these agents. Following overdose with a first-generation H1 antihistamine, patients typically present with CNS depression and an anticholinergic syndrome. Findings typically include mydriasis, tachycardia, fever, dry mucous membranes, urinary retention, diminished bowel sounds, and disorientation (Table 50-3 ). The patient's skin may appear flushed, warm, and dry. Hyperthermia correlates with the extent of agitation, ambient temperature and humidity, and length of time during which the patient cannot dissipate heat because of anticholinergic-mediated reduction in sweating. Ingestion of second-generation antihistamines usually does not result in significant CNS depression or anticholinergic effects. Some patients with therapeutic dosing or following overdose develop the central anticholinergic syndrome, in which CNS anticholinergic

effects, such as delirium or hallucinations, outlast peripheral anticholinergic effects. The lack of tachycardia, skin changes, or other peripheral anticholinergic manifestations complicates obtaining the correct diagnosis for antihistamine-poisoned patients who arrive late to healthcare and have a clear exposure history.18 , 65 In a review of 136 patients with diphenhydramine overdose, somnolence, lethargy, or coma occurred in approximately 55% of patients, whereas 15% experienced a catatonic stupor.34 Several reports suggest that young children experience more respiratory complications, CNS stimulation, anticholinergic effects, and seizures than do adult patients. In a placebo-controlled study comparing the CNS effects of first- and second-generation H1 receptor antihistamines, the second-generation agents caused less cognitive P.789 dysfunction

and

somnolence.8 , 26

This finding was corroborated in

the simulated driving model, in which loratadine produced significantly less impairment than diphenhydramine.23 Use of diphenhydramine compared with loratadine in a work setting results in significantly higher injury rates.14 Agitation Hypertension Hallucinations Tachycardia Confusion Hyperthermia Sedation Mydriasis Coma Dry, flushed skin Seizures Urinary retention Central

Peripheral

TABLE 50-3. Anticholinergic Signs and Symptoms Sinus tachycardia is a consistent finding following an antihistamine overdose with anticholinergic effects. Both hypotension and hypertension may occur.39 These findings probably relate more to the patient's age, volume status, and vascular tone than to a specific class of antihistamines. As a result of sodium channel blockade following a large diphenhydramine overdose, prolongation of both the QRS complexes and QT intervals may occur.31 , 50 , 52 , 62 Of note, postmortem findings are generally limited to pulmonary and visceral edema, suggesting cardiogenic death.33 Mydriasis develops at both therapeutic and toxic doses, with most patients describing blurred vision and/or diplopia. Both vertical and horizontal nystagmus occur in patients with diphenhydramine overdose. Other CNS effects include seizures, hallucinations, acute extrapyramidal

movement

disorders,

and

psychoses.13 , 30

Rhabdomyolysis can occur in patients with extreme agitation or seizures following an H1 antihistamine overdose. Rhabdomyolysis is commonly noted in patients who overdose with doxylamine, even in the absence of trauma or any of the other common, etiologies such as seizures, shock, or crush injuries.16 , 35 , 38 The mechanism is undefined. Rhabdomyolysis is reported as a rare adverse event following

diphenhydramine

overdose.11

Topical application of some antihistamines, particularly to children with skin lesions such as chickenpox, may produce classic systemic anticholinergic toxicity.43 Promethazine and other H1 antihistamines are associated with sudden infant death syndrome, although causality is not proven.49 Cetirizine, a second-generation H1 antihistamine, is suggested as safer for infant use, but further study is warranted.55 Other adverse effects include pancytopenia and jaundice. Elderly patients are more susceptible to adverse events because renal and hepatic dysfunction, which are more common in the elderly,

delays antihistamine metabolism.26 Several infants who died of diphenhydramine overdose had serum concentrations lower than expected for adults; the implications are unclear.3 All H1 antihistamines cross the placenta, and some are teratogenic in animals. Because of their antimuscarinic effects, first-generation antihistamines are generally contraindicated in patients with glaucoma or prostatic hypertrophy.

H2

Receptor

Antagonists

Acute toxic effects appear to be extremely rare, even after large (20 g) oral ingestions of H2 receptor antagonists.28 Patients may develop tachycardia, dilated and sluggishly reactive pupils, slurred speech, and confusion.57 , 63 Bradycardia, hypotension, and cardiac arrest have followed rapid intravenous administration of cimetidine in seriously ill patients.53 Famotidine and ranitidine produce even fewer dose-related toxicities in overdose. In addition, they are less likely than cimetidine to induce or inhibit the cytochrome P450 enzyme system,

thereby

producing

fewer

drug–drug

interactions.27 , 44

Management Patients who will develop severe complications may be indistinguishable from those who will have a benign course. The patient's vital signs and mental status must be monitored. The individual should be attached to on a cardiac monitor and observed for signs of sodium channel blockade (increased QRS duration and prolonged QTc interval), development of seizures, and dysrhythmias. Assessment of the serum acetaminophen concentration is important because many analgesics and cough and cold products contain acetaminophen. Other laboratory studies should be obtained as indicated by history or physical signs and symptoms, such as creatine kinase in patients with seizures or doxylamine overdose. Measurement of antihistamine concentrations in body fluid is not readily available and is generally unnecessary for clinical assessment

and management. A serum pregnancy test should be obtained in women of childbearing age with ingestions. Gastrointestinal decontamination using oral activated charcoal should be considered.21 Orogastric lavage may be indicated in patients with massive overdose of a first-generation H1 antihistamine. Serial assessments of the patient's vital signs, particularly temperature, and mental status should be made. The potential for clinical deterioration necessitates management of symptomatic patients in a monitored environment.

Specific H1

Therapy

Receptor

Antagonists

Hypotension generally responds to isotonic fluids (0.9% sodium chloride solution or lactated Ringer solution). If the desired increase in blood pressure is not attained, dopamine or norepinephrine can be titrated to achieve an acceptable blood pressure. In one instance, cardiogenic shock and myocardial depression resulting from a 10-g ingestion of pyrilamine maleate could be reversed only with an intraaortic balloon counterpulsation device.17 This approach is a rarely needed but potentially useful intervention. Agitation, psychosis, or seizure generally responds readily to titration of a benzodiazepine such as diazepam or lorazepam. Cooling via evaporative methods (tepid mist via spray bottle or similar device; fan) is generally sufficient, but patients with severe hyperthermia should receive more rapid cooling using an ice bath. Hyperthermic patients should be monitored for development of disseminated intravascular coagulation and other complications. Seizures should be treated with an intravenous benzodiazepine such as diazepam 10 mg (0.1–0.2 mg/kg in children) or lorazepam with repeated dosing as necessary. Recurrent seizures refractory to the benzodiazepine should be treated with phenobarbital, propofol, or general anesthesia. In addition, proper fluid management and urinary

alkalinization are nephrotoxicity.

necessary

to

prevent

myoglobin-induced

The sodium channel-blocking (type IA antidysrhythmic) properties of diphenhydramine may lead to wide-complex dysrhythmias that resemble cyclic antidepressant overdose (Chaps. 61 and 7 1 ). Hypertonic sodium bicarbonate can reverse diphenhydramineassociated conduction abnormalities.52 Cardioversion or pacing may be required for dysrhythmias. Type IA (quinidine, procainamide, disopyramide), IC (flecainide), and III (amiodarone, sotalol) antiarrhythmic drugs are contraindicated because of their capacity to prolong the QTc

interval.

Physostigmine can effectively reverse the peripheral or central anticholinergic syndrome if clinically indicated.41 In a retrospective comparison of physostigmine and benzodiazepines, physostigmine was found to be safer and more effective for treating anticholinergic agitation and delirium. 5 Physostigmine can reverse both peripheral and central anticholinergic effects (Table 50-3 ). Contraindications to physostigmine use include a wide QRS complex or bradycardia noted by electrocardiography, asthma, and pulmonary disease. P.790 The primary benefits of physostigmine use in patients with antihistamine overdose include restoration of gastrointestinal motility, elimination of agitation, and possible obviation of the need for CT scan or lumbar puncture if the patient regains a normal mental status and can provide a clear history. The anticipated benefits of physostigmine must outweigh the potential risks prior to its use. For physostigmine administration, the patient should be attached to a cardiac monitor, and secure intravenous access should be established. Physostigmine (1–2 mg in adults; 0.5 mg in children) should be administered by slow intravenous push with continuous monitoring of vital signs, breath sounds, and oxygen saturation by pulse oximetry. The initial dose of physostigmine can be repeated at 5- to 10-minute intervals if anticholinergic symptoms are not

reversed and cholinergic symptoms such as salivation, diaphoresis, bradycardia, lacrimation, urination, or defecation do not develop. When improvement occurs as a result of physostigmine, readministration of physostigmine at 30- to 60-minute intervals may be necessary. Alternatively, sedation with benzodiazepines may be appropriate once the diagnosis is confirmed. A dose of intravenous atropine that is half the dose of physostigmine should be available at the patient's bedside to treat cholinergic toxicity if it occurs (Antidotes in Depth: Physostigmine ).

H2

Receptor

Antagonists

Patients who overdose on an H2 antihistamine should receive 1 g oral activated charcoal per kilogram body weight at most if indicated. H2 antihistamine antagonists rarely result in significant toxicity and therefore do not warrant exposure to the risks of complications from orogastric lavage or emesis. Monitoring for uncommon complications and assessment of coingestants should be performed as clinically indicated.

Decongestants History

and

Epidemiology

Decongestants are sympathomimetic agents that act on αadrenergic receptors, producing vasoconstriction, shrinking swollen mucous membranes, and improving bronchiolar air movement. Ephedrine, the first agent of this class to be used pharmaceutically, is derived from Ephedra spp plants. Ephedrine was used in China for at least 2000 years before it was introduced into Western medicine in 1924. Phenylephrine was introduced into clinical medicine in the 1930s. Several topical imidazoline decongestants (see Figure 50-4 ) have since been developed for clinical use. Recreational use of ephedrine-containing stimulants is common, and

combinations of these compounds with caffeine or other herbs may be marketed as “herbal ecstasy― (Chap. 39 ). The sale of dietary supplements containing Ephedra (ephedrine alkaloids) was banned by the FDA in 2004 because of concerns over their cardiovascular effects, including increased blood pressure and irregular heart rhythm. Xenobiotics that contain chemically synthesized ephedrine, traditional Chinese herbal remedies, and herbal teas are not covered by the rule.15

Pharmacology

and

Pharmacokinetics

Decongestants are pharmacologically active following topical or oral administration. Absorption from the gastrointestinal tract is rapid, with peak blood concentrations occurring within 2–4 hours of ingestion. Oral decongestants can affect the cardiovascular, urinary, central nervous, and endocrine systems.4 The decongestants phenylephrine, pseudoephedrine, ephedrine, and phenylpropanolamine reduce nasal congestion by stimulating the αadrenergic receptor sites on vascular smooth constricts dilated arterioles and reduces blood vascular beds. The α1 -mediated decrease in lowers resistance to airflow. Prolonged topical

muscle.29 This process flow to engorged nasal volume ultimately administration may

produce rebound congestion upon discontinuation; possible mechanisms include desensitization of receptors and mucosal damage. This damage is thought to be caused by α2 -mediated arteriolar constriction resulting in decreased nutritional supply to the mucosa. Therefore, selective α1 agonists may cause less mucosal damage.

Figure

50-4. Structures of ephedrine and phenylpropanolamine.

Phenylephrine is a powerful α1 , 2 -adrenergic receptor agonist with very little β-adrenergic agonist activity. Pseudoephedrine and ephedrine are direct-acting nonspecific α1 , 2 - and β1 , 2 -adrenergic receptor stimulants. Pseudoephedrine is the D-isomer of ephedrine and has only 25% of the adrenergic receptor activity of ephedrine.9 Phenylpropanolamine is an α1 , 2 -adrenergic receptor stimulant devoid of β-adrenergic receptor activity. Phenylpropanolamine can directly stimulate α1 , 2 receptors and can indirectly stimulate these receptors by causing norepinephrine release (Table 50-4 ). The imidazoline (I) category of sympathomimetics are generally reserved for topical application and are used for their local effects in the nasal passages and the eye. The more common medications include oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, and naphazoline hydrochloride (Figure 50-5 ). The imidazolines are rapidly absorbed from the gastrointestinal tract and mucous membranes. The elimination half-lives of these agents range from 2–4 hours. Their vasoconstrictor effects are mediated by their actions as α-adrenergic agonists, with binding to α1 , 2 receptors on blood vessels. The α1 -mediated vasoconstriction is complemented by an additive effect of preferential binding to α 2 receptors located on resistance vessels regulating blood flow. In P.791 addition, these compounds show high affinity for imidazoline receptors, which are located in the ventrolateral medulla and some peripheral tissues. Stimulation of imidazoline receptors produces a sympatholytic effect that results in bradycardia and hypotension. All imidazoline preparations have a relatively rapid onset of action, with 60% of maximum effectiveness after only 20 minutes. Oxymetazoline is the only compound with a duration of action > 8 hours. The other preparations have an average duration of action of approximately 4 hours.25

Figure 50-5. Structures of the imidazoline decongestants, tetrahydrozoline, and oxymetazoline.

Ephedrine Sympathomimetic 3–5 h Î ±1 , 2 and β1 , 2 Naphazoline Imidazoline 8 h Î ±2 , I Oxymetazoline Imidazoline 6–7 h Î ±2 , I Phenylephrine

Sympathomimetic 1 h Î ±1 , 2 Phenylpropanolamine Sympathomimetic 12 h (sustained release) Î ±1 , 2 Pseudoephedrine Sympathomimetic 3–4 h Î ±1 , 2 and β1 , 2 Tetrahydrozoline Imidazoline 4–8 h Î ±2 , I Xylometazoline Imidazoline 5–6 h Î ±2 , I Decongestant

Class

Duration of Action

Receptor

Activity

TABLE 50-4. The Pharmacologic Characteristics of Decongestants The imidazoline decongestants such as oxymetazoline and naphazoline are pure central and peripheral α2 -adrenergic receptor agonists; tetrahydrozoline stimulates α2 receptors and H2 receptors. These medications are primarily used as nasal decongestants. Tetrahydrozoline is available without prescription as an ophthalmic preparation to decrease eye irritation and redness.

Clinical

Manifestations

Following a decongestant overdose, most patients present with CNS

stimulation, hypertension, tachycardia, or reflex bradycardia (in response to pure α-adrenergic agonist-induced hypertension only). Approximately 4–5 times the recommended dose of pseudoephedrine 9 but less phenylpropanolamine may be required to cause hypertension. 10 An increase in sinus dysrhythmias is reported in adults with ingestion of 120 mg pseudoephedrine and moderate exercise.4 Headache was the most common initial symptom (39%) reported by patients who later developed severe toxicity.36 In 45 patients who developed hypertensive encephalopathy from phenylpropanolamine ingestion, 24 patients developed intracranial hemorrhages, 15 developed seizures, and 6 died.36 In more severe exposures, seizures, myocardial infarction, bradycardia, atrial and ventricular dysrhythmias, ischemic bowel infarction, and cerebral hemorrhages are reported.6 , 12 In a review of 500 reports of adverse reactions from patients who had ingested ephedrine and associated stimulants as dietary supplements, 8 fatalities from myocardial infarction and cerebral hemorrhage were reported.7 Symptoms of toxicity from decongestants usually resolve within 8–16 hours. However, symptoms may persist for > 24 hours if a sustained-release product is ingested. Acute myocardial infarction is reported with therapeutic dosing of pseudoephedrine.40 When ingested, the imidazoline decongestants naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline are potent central and peripheral α2 -adrenergic and imidazoline receptor stimulants. In overdose, they can cause CNS depression, hypotension, bradycardia, and respiratory depression.24 , 46 Children are particularly sensitive to the effects of the imidazoline decongestants.

Management Extreme agitation, seizures, tachycardia, hypertension, and psychosis should initially be treated with administration of oxygen and intravenous benzodiazepines, expeditiously titrated upward to effect.

A patient who remains hypertensive or is believed to have chest pain of ischemic origin (ECG indicated) may be treated with phentolamine, an α-adrenergic antagonist, or nitroprusside, a venous and arterial vasodilator. A patient with a focal neurologic deficit or an abnormal neuropsychiatric examination following decongestant ingestion should be evaluated for cerebral hemorrhage by noncontrast head CT scan and, if indicated, subsequent lumbar puncture to exclude subarrachnoid hemorrhage.36 Patients who have overdosed on a decongestant generally should receive 1 g activated charcoal per kilogram body weight as a single dose. Activated charcoal administration may be beneficial several hours after ingestion of sustained-release decongestant preparations, and serial doses of activated charcoal may be considered in this context. Syrup of ipecac has no role, and orogastric lavage should be reserved only for life-threatening ingestions within the previous hour. Ventricular dysrhythmias from decongestant ingestions should be treated with standard doses of lidocaine or amiodarone. 66 Refractory dysrhythmias may require antiadrenergic therapy with propranolol, but only after pretreatment with phentolamine, if possible, or with strict expectant management of the patient's blood pressure. Patients who develop hypertension following propranolol should immediately receive phentolamine. Phenylpropanolamine ingestions may cause hypertension with a reflex bradycardia and atrioventricular block that is responsive to standard doses of atropine.68 Atropine must be used with caution because it can cause a dangerous increase in blood pressure as the reflex bradycardia reverses. Therefore, a directacting vasodilator such as phentolamine or nitroprusside is preferred because the stimulus for the bradycardia is corrected with reversal of the hypertension. Imidazoline-induced hypertension rarely requires therapy, but in the setting of symptomatic hypertension a shortacting α-adrenergic antagonist such as phentolamine may be administered.67 However, the hypertension is generally transient and

followed by hypotension that raises the risk of antihypertensive therapy.

Summary The popularity and availability of antihistamines and decongestants make them readily accessible for deliberate or unintentional ingestions in both adults and children. Recreational use of these agents may lead to exposure to substantial doses of these medications. Fortunately, nearly all patients exposed to excessive doses of members of these classes of medications that are currently available in the United States do well if they receive treatment early in P.792 the course of ingestion. Patients treated with activated charcoal, continuous assessment, supportive care, management of abnormal vital signs, electrocardiography, cardiac monitoring, and mental status have an excellent outcome with little risk of adverse sequelae. Familiarity with the more severe complications of antihistamine and decongestant overdoses results in early and appropriate interventions to reduce both morbidity and mortality from these exposures.

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44. Mills JG, Koch KM, Webster C, et al: The safety of ranitidine in over a decade of use. Aliment Pharmacol Ther 1997;11:129–137. 45. Nolen TM: Sedative effects of antihistamines: Safety, performance, learning, and quality of life. Clin Ther 1997;19:39–55. 46. Osterhoudt KC, Henretig FM: Sinoatrial node arrest following tetrahydrozoline ingestion. J Emerg Med 2004;27:313–314. 47. Paakkari I: Cardiotoxicity of new antihistamines and cisapride. Toxicol Lett 2002;127:279–284. 48. Paton DM, Webster DR: Clinical pharmacokinetics of H1receptor antagonists (the antihistamines). Clin Pharmacokinet 1985;10:477–497. 49. Ponsonby AL, Dwyer T, Couper D: Factors related to infant apnoea and cyanosis: A population-based study. J Paediatr Child Health 1997;33:317–323. 50. Rinder CS, D'Amato SL, Rinder HM, Cox PM: Survival in complicated diphenhydramine overdose. Crit Care Med 1988;16:1161–1162. 51. Sawyer D, Conner CS, Scalley R: Cimetidine: Adverse reactions and acute toxicity. Am J Hosp Pharm 1981;38:188–197. 52. Sharma AN, Hexdall AH, Chang EK, et al: Diphenhydramineinduced wide complex dysrhythmia responds to treatment with

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Antidotes in Depth - Physostigmine Salicylate

Antidotes in Depth Physostigmine

Salicylate

Mary Ann Howland Physostigmine is a carbamate that reversibly inhibits cholinesterases in both the peripheral nervous system and the central nervous system (CNS).44 The tertiary amine structure of physostigmine permits CNS penetration and differentiates it from neostigmine and pyridostigmine, which are quaternary amines and thereby have limited ability to enter the CNS. This action inhibits the metabolism of acetylcholine, thereby allowing acetylcholine to accumulate and antagonize the anticholinergic effects of xenobiotics such as atropine, scopolamine,51 and diphenhydramine. Although physostigmine previously was used as an antagonist to the anticholinergic effects of the tricyclic antidepressants and the phenothiazines, its use is no longer recommended because of a poor risk-to-benefit ratio given the potential for exacerbation of life-threatening cardiotoxicity. A review of 30 years of the literature reassessed and questioned the contraindication to physostigmine use for cyclic antidepressant ingestions. The review concluded that the safety of physostigmine use for seizures or cardiotoxicity was difficult to predict, but the

author still did not recommend physostigmine use in the setting of cyclic antidepressant toxicity.43 Similarly, physostigmine likely will have a poor risk-to-benefit ratio in the management of presumed γ-hydroxybutyrate (GHB) toxicity. A study in rats revealed that physostigmine did not effect arousal but increased the risk of physostigmine-induced toxicities of fasciculations and seizures.4 Atypical antipsychotics have complex pharmacologic effects. Although some atypical antipsychotics (eg, olanzapine) have significant antimuscarinic side effects, the benefit of treating these anticholinergic effects with physostigmine in the often confusing overdose setting must be weighed against the potential risks of exacerbating cardiotoxicity.45

History The history of physostigmine dates to antiquity and the Efik people of Old Calabar in Nigeria.17,20,23,44 The chiefs in those areas used a poisonous concoction made from the beans of an aquatic leguminous perennial plant found in the area to deliver the esere ordeal. Esere was the word used to represent both the bean and the ritual used to test the innocence or guilt of an accused person. They also believed that the esere had the power to detect and kill those persons practicing witchcraft. Supposedly, innocent persons quickly swallowed the poison, which caused immediate emesis.23 Vomiting allowed them to survive on their own or to be given an antidote of excrement in water. The guilty, however, hesitated swallowing, leading to speculation that sublingual absorption led to severe systemic symptoms without the benefit of vomiting. These persons were noted to develop mouth fasciculations and died foaming at the mouth. Daniell, a British medical officer stationed in Calabar, brought samples of the bean and the plant back to England in 1840.23 John Balfour, a professor of medicine and botany at the Edinburgh Medical School, is credited with characterizing the plant, which became known as Physostigma venenosum Balfour (family Leguminoseae) in 1857. The active

alkaloid isolated from the Old Calabar, or ordeal bean, by Jobst and Hesse in 1864 was named physostigmine. Independently, 1 year later Vee and Leven also isolated the active alkaloid and named it eserine. Christison performed the first toxicologic studies, including selfexperimentation with increasing doses of the seed. Fraser, Christison's student and later successor, originated the concept of antagonism from his experiments with physostigmine and atropine. Fraser plotted the dose relationships between the effects of atropine versus physostigmine on various organs such as the eye and the heart. He demonstrated, that up to a certain dose, atropine acted as an antidote to the lethal effects of physostigmine.17 Experiments with physostigmine paved the way for Anderson, to propose the existence of a transmitter as the mechanism of action of physostigmine in 1906. In the 1920s, Loewi proposed and then proved the theory of neurohumoral transmission. Stedman and Burger established the chemical structure of physostigmine in 1925. Julian and Pikl synthesized physostigmine in 1935. By this time, physostigmine was already used as a miotic agent for patients with glaucoma, as a treatment for patients with myasthenia gravis, as a reversal agent to the paralytic effects of curare, as an antidote to atropine, and as a prototypical insecticide. In summary, physostigmine, a prototypical carbamate insecticide, was instrumental in the development of a bioassay for acetylcholine, concepts of neurohumoral transmission, mapping of cholinergic nerves, the concept of antagonism, the kinetics of enzyme inhibition, and improved understanding of the blood–brain barrier.20

Chemistry and Affinity Cholinesterase

for

Figure 50-6A shows the general formula for carbamate inhibitors. Figures 50-6B and C show the chemical structures of

physostigmine (C15H 21O 2 N 3 ), a tertiary amine, and neostigmine, a quaternary amine. Like acetylcholine, physostigmine is a substrate for the cholinesterases (choline ester hydrolases) erythrocyte acetylcholinesterase and plasma cholinesterase. Both acetylcholine and physostigmine bind to the cholinesterase enzymes to form a complex. Then a part of the substrate known as the leaving group (ie, choline for acetylcholine) is removed, and the remaining acetylated (for acetylcholine) or carbamoylated (for physostigmine) enzyme is hydrolyzed, regenerating the enzyme and freeing the acetate or carbamate groups, respectively (Figures 109-2, 109-3, 109-4). For acetylcholine, the process is extremely quick, with a turnover time of 150 ms. In contrast, the half-life for hydrolysis of the carbamoylated enzyme is 15–30 minutes.44 The I 50 (molar concentration that inhibits 50% of the enzyme) of physostigmine is 2.3 × 10- 7 M for acetylcholinesterase, which is much weaker than for other carbamates at 1 × 10- 1 0 M or many organic phosphorus compounds at 1 × 10- 1 1 M.21 Only the Sisomer inhibits cholinesterases, with plasma cholinesterase just a little more sensitive than acetylcholinesterase.3 Newer xenobiotics used in patients with Alzheimer P.795 disease11 show selectivity for the CNS and for acetylcholinesterase. They include tacrine, donepezil, and galantamine, which are reversible cholinesterase inhibitors; metrifonate, an irreversible inhibitor; and rivastigmine, a pseudoirreversible or slowly reversible inhibitor. These xenobiotics and neostigmine22 have undergone limited study for reversal of anticholinergic poisoning.11,22,26,38

Figure A13-1. A: General formula for carbamate inhibitors. B: Structure of physostigmine. C : Structure of neostigmine.

Pharmacokinetics Physostigmine is poorly absorbed orally, with a bioavailability of Section I - Case Studies > C - Pharmaceuticals > Chapter 52 - Antineoplastics

Chapter

52

Antineoplastics Richard Y. Wang A 70-year-old woman was brought to the emergency department (ED) from an extended-care facility because of the sudden onset of epistaxis. Her vital signs were: blood pressure, 120/70 mm Hg; pulse, 100 beats/min; respiratory rate, 18 breaths/min; and temperature, 98.6°F (37°C). The patient stated that for the last 2 days she had dysphagia, progressive weakness, and intermittent shaking. She had a past medical history of rheumatoid arthritis and pulmonary emboli. Her medications include methotrexate (MTX) and Coumadin, which were both started within the last month for her underlying medical disorders. An anterior nasal packing was placed to stop the bleeding. Further examination of the oropharynx demonstrated several ulcers. The skin showed ecchymoses. Chest and abdominal findings were unremarkable. A large-bore IV line was established, and blood was drawn for a complete blood cell count (CBC) with platelets, international normalized ratio (INR), partial thromboplastin time (PTT), electrolytes, blood urea nitrogen (BUN), and creatinine. Blood was also sent for a serum MTX concentration and a type and cross-

match. The CBC showed hemoglobin, 8 g/dL; white cell count, 2000/mm3 (81% neutrophils, 13% lymphocytes, 1% monocytes, 5% eosinophils); platelet count, 3000/mm3 ; and INR, 2.0. PTT and renal function were normal. The extended-care facility was contacted, and it was discovered that the patient was inadvertently given methotrexate 2.5 mg daily for 1 month instead of once a week for 1 month. The patient was transfused with packed red blood cells, platelets, and fresh-frozen plasma. Prophylactic broad-spectrum antibiotics were initiated. Leucovorin 10 mg/m2 was started and administered every 4 hours IV. The serum MTX concentration was later determined to be zero and leucovorin therapy was discontinued. The white blood cell count (WBC) was lowest on day 3 of hospitalization and rose thereafter. Although overdoses of antineoplastic medications are infrequent, these events are of greater consequence than overdoses of many other medications because of their narrow therapeutic margin. From 1988 to 2003, the annual number of people exposed to antineoplastic agents reported to US poison control centers was about 1000 (Chap. 130 ). This figure represents about 1 per 1000 cases of pharmaceutical exposures, or 1 per 2000 cases of all exposures annually reported to US poison control centers. Twothirds of the people exposed to antineoplastic agents in these reports were adults, one-fourth were young children, and the remainder were adolescents. Between 1999 and 2003 there was an observable change in the annual trend of the proportion of exposures between adults and young children: From 1999 to 2002, the annual percent of exposures for adults increased to approximately 50–70%, and for children younger than 6 years old, this figure decreased from 30% to 20%. Children and adolescents between the ages of 6 and 19 years accounted for approximately 7% of the population annually exposed, and this frequency did not change between these years. The reasons for these observations are not apparent and further analysis is

warranted to define the causes of these trends. Approximately 10% of the annual exposures in this setting resulted in morbidity defined as moderate or major in severity. This was higher than expected because unintentional exposures occurred 8 times more frequently than intentional exposures. The mortality was about 1 per 1000 exposures. A review of the 2819 orders for cytotoxic agents at a pharmacy satellite showed that 93 orders (3%) contained at least 1 error in the dosage regimen and 442 (16%) contained at least 1 error in the instructions for drug preparation.89 Three of the errors in dosage regimen were classified as potentially lethal, 13 as serious, 5 as significant, and 72 as minor. Two of the potentially lethal overdoses of cisplatin were a result of errors in duration of administration (100 mg/m2 for 3–4 consecutive days instead of for 1 day). Lack of healthcare provider familiarity with the agent and its dosing was a major cause of these events. In another study evaluating drug errors, 49% occurred at the ordering/prescribing stage. This was most commonly caused by physicians who lacked knowledge of the drug and of the intended patient.162 Other areas in which errors occurred were during transcription and nurse administration. As more antineoplastics become available and their indications broaden, unintentional exposures and unintended dosing regimens (Chap. 134 ) will increase in number and frequency. Aside from unintentional exposures, additional factors leading to increased toxicity associated with antineoplastics include age, gender, comorbidities/compromised host state, and diminished renal and hepatic function. Diminished hepatic clearance caused by altered enzyme expression can be accounted for by age, gender, smoking status, and the concurrent use of other medications. Differences in gender can contribute to varying pharmacokinetic parameters, including bioavailability, distribution, metabolism, and elimination. In a study, women treated with 5-fluorouracil (5-FU) for colon cancer were found to have a 2-fold higher frequency of

drug-related toxicity than men.266 The manifestations included leukopenia, diarrhea, and stomatitis, which also was observed in other reports.211 , 251 Although the basis for this difference in toxicity between genders is not known, it may be P.806 because of a decreased 5-FU clearance from diminished dihydropyrimidine dehydrogenase activity in women.187 , 211 Dihydropyrimidine dehydrogenase inactivates more than 80% of fluorouracil by metabolizing it to 5-fluorodihydrouracil, and low activity of this enzyme can result in hematologic and gastrointestinal toxicity. Alkylating Busulphan Hyperpigmentation,

Dacarbazine Hypotension,

pulmonary

hepatocellular

fibrosis,

toxicity,

hyperuricemia

influenzalike

syndrome

Melphalan Pulmonary

fibrosis

Mustards Chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine Hemorrhagic cystitis, encephalopathy, pulmonary fibrosis Seizures, myocardial necrosis, hyponatremia MESNA; sodium bicarbonate; methylene blue(?) Nitrosourea Carmustine, lomustine, semustine Pulmonary fibrosis, hepatocellular toxicity, renal insufficiency

Platinoids Cisplatin Renal failure, peripheral neuropathy, hypomagnesemia, hypocalcemia, hyponatremia, ototoxicity Seizures, encephalopathy, ototoxicity, retinal toxicity Amifostine (nephrotoxicity); thiosulfate Carboplatin, iproplatin Myelosuppression, hypomagnesemia, hypocalcemia, hyponatremia

Procarbazine MAOI activity

Antimetabolite Methotrexate Mucositis, nausea, diarrhea, hepatocellular toxicity Mucositis, myelosuppression, renal failure Folinic acid (leucovorin); carboxypeptidase; thymidine Purine analogs Fludarabine Mercaptopurine Encephalopathy, muscle weakness cholestasis

Pentostatin Hepatocellular

toxicity

Thioguanine Hyperuricemia

Pyrimidine

analogs

Hyperuricemia,

pancreatitis,

Cytarabine Acute lung injury, neuropathy, cerebellar ataxia

Fluorouracil Cardiogenic shock,

cardiomyopathy,

neuropathy,

cerebellar

ataxia

Antimitotic Epipodophyllotoxin Etoposide, teniposide CHF, hypotension

Paclitaxel GI

perforation,

Vinca

peripheral

neuropathy,

dysrhythmias

alkaloids

Vinblastine, vincristine, vindesine Peripheral neuropathy, hyponatremia Encephalopathy, seizures, autonomic instability, myelosuppression Antibiotics Anthracycline Daunorubicin, doxorubicin, epirubicin, Congestive cardiomyopathy Dysrhythmias, CHF Dexrazoxane Bleomycin Pulmonary fibrosis

idarubicin

paralytic

ileus,

Dactinomycin Hepatocellular

toxicity

Mithramycin Flush

Mitomycin C Hemolytic uremic

syndrome

Mitoxantrone Congestive cardiomyopathy

Enzyme L-Asparaginase Hypersensitivity,

Class

pancreatitis

Antineoplastic

Adverse Effects

Overdose

Antidotes

TABLE 52-1. Classification of Antineoplastics and Their Effects At an individual level, genetic polymorphisms can contribute to differences in xenobiotic response with resultant toxicity by altering targets, transporters, and enzyme complexes. Such variations have been characterized for several enzymes that are involved in the metabolism of antineoplastic agents. Irinotecan and amonafide are two examples that are associated with toxicity.

Irinotecan is a topoisomerase I inhibitor that works through its active metabolite, SN-38, which can cause diarrhea and neutropenia at elevated levels.279 A genetic variant of uridine diphosphate glucuronosyltransferase (UGT1A1) containing the T7 allele glucuronidates SN-38 at a slower rate than other variants, resulting in increased SN-38 levels and toxicity.12 , 125 Another example is amonafide, which is a topoisomerase II inhibitor; and its active P.807 metabolite, N -acetyl amonafide is formed by N -acetyltransferase 2 (NAT2). People capable of “rapid acetylation― have a genetic variation of NAT2 and are more likely to develop myelotoxicity than are people with a slower rate of acetylation activity.215 There are additional polymorphisms in metabolism associated with antineoplastic agents; however, further work is necessary to define their clinical significance. Because of the narrow therapeutic index of the antineoplastic agents, the significance of such findings demonstrates the benefit of individual drug monitoring to maximize the therapeutic efficacy of the these agents while limiting host toxicity. Most antineoplastic agents can be grouped into one of these four categories: alkylating agents, antimetabolites, antimitotics, and antibiotics (Table 52-1 ). The antimetabolites are grouped by the substrates with which they interfere. Methotrexate is a folate antagonist; other drugs with similar but lesser toxicity include trimethoprim and pyrimethamine. The antimitotics are plant alkaloids and they exert toxic effects by interrupting microtubule assembly. Other naturally derived agents include the antibiotics and the enzyme L-asparaginase, which can be isolated from bacteria. The alkylating agents are more commonly used than other antineoplastic agents and cause covalent binding to nucleic acids, which inhibits DNA activity. These xenobiotics include the nitrogen mustards, platinoids, and nitrosoureas. The antimetabolites and the alkylating agents are cell-cycle active,

meaning that they only affect cells undergoing cell division. Some agents are phase specific; that is, they affect the cell only at a period during cell division. The cell cycle consists of the S phase (DNA replication) and the M phase (mitosis). DNA regulation and chromosomal separation occur during the mitosis. Vincristine is Mphase specific and cytarabine is S-phase specific, in their sites of action. A new class of antineoplastics inhibits topoisomerase I, which is necessary for DNA replication because it allows for reversible DNA single-strand breaks. Because the majority of the cases of antineoplastic overdoses involve the methotrexate, vincristine, mitoxantrone (related to the anthracyclines), mustards, and cisplatin, this discussion focuses on these xenobiotics. Other sources for information regarding these agents are the American Cancer Society (http://www.cancer.org/docroot/home/index.asp ) and the American Society of Health-System (http://www.ashp.org/ ).

Pharmacists

Methotrexate

Figure. No Caption Available.

Pharmacology Methotrexate (MTX) is an important therapeutic agent for a variety of cancers, such as non-Hodgkin lymphoma, lymphocytic leukemia, breast cancer, and small-cell lung carcinoma. Its immunosuppressive activity allows it to also be used for rheumatoid arthritis, organ transplantation, psoriasis,

trophoblastic diseases, and therapeutic abortion.52 , 133 Its therapeutic and toxic effects are based on its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase (DHFR) and thymidylate synthetase (Fig. 52-1 ). Thymidylate synthesis is inhibited by polyglutamic derivatives of methotrexate. DHFR reduces folic acid to tetrahydrofolate (FH4 ), which serves as an essential cofactor in the synthesis of purine nucleotides. These reduced folates are also required by thymidylate synthetase to serve as methyl donors in the formation of thymidylate. Thymidylate is then used for DNA synthesis. MTX is a structural analog of folate and competitively inhibits DHFR by binding to this enzyme's site of action. This stops reduced folate production, which is necessary for nucleotide formation and DNA/RNA synthesis.

Figure 52-1. Mechanism of methotrexate (MTX) toxicity. MTX inhibits DHFR activity, which is necessary for DNA and RNA synthesis. Leucovorin bypasses blockade to allow for continued

synthesis.

The bioavailability of methotrexate appears to be limited by a saturable intestinal absorption mechanism. At oral doses less than 30 mg/m2 , the absorption is 90%; at doses greater than 80 mg/m2 , the absorption is less than 10–20%.36 The weekly adult dose used for the treatment of psoriasis and rheumatoid arthritis is low and can be administered orally. However, the dose used to induce abortion is higher (50 mg/m2 ) and must be administered parenterally to achieve effective drug concentrations. MTX dosing regimens for chemotherapy are variable, but can be generally classified as low, moderate, and high doses. Conventional intravenous doses of up to 100 mg/m2 can be administered without leucovorin rescue. Doses of 1000 mg/m2 are considered potentially lethal. Much higher doses (2–3 g/m2 ) can be given when MTX is followed by leucovorin in order to prevent lifethreatening toxicity. Mortality from high-dose MTX is approximately 6%, and occurs primarily when patients' MTX levels are not monitored.86 , 255 , 275 MTX has a triphasic plasma clearance. The initial plasma distribution half-life is short—0.75 hours. The second half-life is 2–3.4 hours and represents renal clearance of the drug. The third phase has a half-life of about 8–10.4 hours and represents tissue redistribution into the plasma. This third phase can be prolonged in the setting of renal failure and is associated with bone marrow and gastrointestinal (GI) toxicity. The kidneys eliminate 50–80% of MTX unchanged within 48 hours of administration. At high doses, drug and insoluble drug metabolites 7-hydroxy methotrexate and 2,4-diamino-10-methyl pteroic acid accumulate and may precipitate in the renal tubules, causing reversible acute tubular necrosis. MTX is one-tenth as soluble at a pH of 5.5 as it is at a pH of 7.5.36 , 231 The serum concentration threshold for nephrotoxicity is 2.2 mmol/L at a urine pH of 5.5, and 22 mmol/L at a urine pH of

P.808 6.9. Patients who are either inadequately hydrated or not alkalinized are at risk for acute renal failure from high dose MTX treatment.3 , 92 , 135 MTX is excreted unchanged in the urine by both glomerular filtration and active tubular secretion. Folic acid blocks MTX renal reabsorption and can enhance elimination during leucovorin rescue.118 A small amount of MTX is metabolized intracellularly to polyglutamate derivatives, which inhibit DHFR and thymidylate synthetase and are believed to be responsible for the persistent cytotoxic effect of MTX. Toxicity of MTX depends more on the duration of exposure than the dose itself. Thus, greater toxicity is expected from a 7-g (approximately 4 g/m2 , adult) IV dose administered over 48 hours than from a 20 g (approximately 12 g/m2 , adult) IV dose administered over 24 hours.99 Patients with a plasma MTX concentration greater than 1.0 µmol/L at 48 hours posttreatment are considered at risk for bone marrow and gastrointestinal mucosal toxicity.255 Risk factors for MTX toxicity are impaired renal function (primary route of drug elimination), third compartment spacing, ascites, and pleural effusions, use of nonsteroidal antiinflammatory drugs (NSAIDs), age, folate deficiency, and concurrent infection.255 The contribution of NSAID use to MTX toxicity may be a result of diminished renal clearance of the drug.153

Clinical

Manifestations

In the course of MTX therapy, a variety of disorders can occur, resulting from either increased patient susceptibility to toxicity or excessive administration. The clinical manifestations of MTX toxicity include stomatitis, esophagitis, renal failure, myelosuppression, hepatitis, and central neurologic system dysfunction. In a group of 23 patients who received 45 courses of high-dose MTX therapy with leucovorin rescue, the commonly

observed signs included increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (81%), nausea and vomiting (66%), mucositis (33%), dermatitis (18%), leukopenia (11%), thrombocytopenia (9%), and creatinine elevation (7%).216 Nausea and vomiting, considered rare after low-dose cancer therapy (1000 mg/m2 ) and last for about 6–12 hours. Mucositis, characterized by mouth soreness, stomatitis, or diarrhea, usually occurs 1–2 weeks after therapy and can last for 4–7 days. Other gastrointestinal symptoms resulting from MTX therapy include pharyngitis, anorexia, gastrointestinal hemorrhage, and toxic megacolon.16 Hepatocellular toxicity, as described by increased AST (>1000), ALT (>1000), and hyperbilirubinemia, can be observed with both acute and chronic therapy.180 , 194 It is usually associated with high-dosage regimens. Laboratory abnormalities improve within 1–2 weeks of discontinuation of MTX. The mechanism is incompletely understood, but toxicity is attributed to reduced liver folate stores.19 Factors associated with hepatotoxicity are sustained high plasma levels, increased cumulative dosages, chronic therapy, and host factors such as increase in age, obesity, diabetes, and alcoholism.280 Pancytopenia usually occurs within the first 2 weeks after an acute exposure. There are several reports demonstrating the occurrence of pancytopenia in individuals receiving chronic MTX therapy for rheumatoid arthritis and psoriasis.74 , 147 , 180 , 222 When used in small IV doses of 40–60 mg/m2 , MTX is not associated with appreciable nephrotoxicity. However, at doses greater than 5000 mg/m2 (approximately 130 mg/kg for an adult), several investigators report severe kidney damage, with oliguria, azotemia, and renal failure.25 The renal function can normalize over time. Patients at risk for nephrotoxicity include the elderly, those with underlying renal disease defined as a glomerular

filtration rate of less than 50 mL/min, and those who receive concurrent drug therapy that can delay MTX excretion, which includes agents that reduce renal blood flow such as NSAIDs, the nephrotoxic agents cisplatin and the aminoglycosides, or weak organic acids such as salicylates and piperacillin.127 , 255 The neurologic complications associated with either high-dose systemic MTX therapy or intrathecal administration are the most consequential manifestations. The incidence of neurologic toxicity from high-dose MTX therapy is approximately 5–15%.136 The manifestations usually occur from hours to days after the initiation of therapy and include hemiparesis, paraparesis, quadraparesis, seizures, and dysreflexia.84 , 179 , 277 These events are reversible to varying degrees. The mechanisms remain unclear, but may be the result of direct toxicity to neuronal glial and endothelial cells and decreased neurotransmitter synthesis.2 Clinical findings occurring within several hours (usually within 12 hours) of therapy are attributed to chemical arachnoiditis, and they include acute onset of fever, meningismus, pleocytosis, and increased cerebrospinal fluid (CSF) protein concentration.119 Leukoencephalopathy is associated with the onset of behavioral disorders and progressive dementia from months to years after treatment and is irreversible.7 CSF analysis and computerized tomography of the brain may be normal or show demyelination of white matter (especially in the anterior and frontal lobes).7

Management In the event of an oral overdose of methotrexate, the initial concern should be gastrointestinal decontamination. Activated charcoal adsorbs methotrexate and should be administered as soon as possible to limit absorption.94 The administration of multiple-dose activated charcoal and cholestyramine84 , 242 can significantly decrease the elimination half-life of methotrexate by interrupting the enterohepatic circulation. 94 , 105 This can increase

MTX clearance when it is administered parenterally, but is of most benefit to patients with diminished renal creatinine clearance. Adequate hydration with 0.9% sodium chloride solution as well as urinary alkalinization with IV sodium bicarbonate (to urine pH 7–8) (Antidotes in Depth: Sodium Bicarbonate ) is also important to prevent renal failure in patients who receive inadvertent high doses. The CBC should be monitored on days 7, 10, and 14 because life-threatening complications, such as bleeding disorders and overwhelming sepsis, can occur.159 Patients presenting with meningismus or altered mental status following MTX therapy require an initial computed tomography (CT) scan of the brain and then CSF analysis for infection.145 Although not considered standard, the CSF may be assayed for MTX if excessive exposure to this compartment is suspected. The CSF MTX concentration is about 0.1 µmol/L and lasts for 48 hours after an IV MTX dose of 1500 mg/m2 , and 100 µmol/L for the peak therapeutic concentration after a 12-mg intrathecal MTX dose.198 Magnetic resonance imaging (MRI) of the brain may demonstrate a high signal throughout the pachymeningeal (dura mater) region, which is consistent with a chemical meningitis.93 MRI scans of the brain of patients with leukoencephalopathy shows hyperintense lesions in the white matter area.93 This is a finding similar to that in patients presenting with subacute neurologic symptoms following MTX therapy.179 P.809

Antidotes Folinic acid (leucovorin, N -5-formyl-tetrahydrofolate) rescue therapy allows higher doses of methotrexate to be administered therapeutically, as leucovorin limits bone marrow and gastrointestinal toxicity. The effectiveness of leucovorin depends on both the timing of administration and the dose. Leucovorin is most beneficial when administered within 1 hour of exposure, but

should still be given to patients who present in a delayed manner after an excessive exposure. The only complications associated with leucovorin administration are the possible drug interaction with anticonvulsants (phenobarbital, phenytoin, primidone) to lower seizure threshold at high leucovorin dosages219 and hypersensitivity reactions.120 The initial leucovorin dose to be administered should achieve a plasma concentration equal to or greater than that of the MTX. In this manner, the reduced folate antidote can successfully compete with MTX for active transport sites on the cell membrane, displace MTX from its intracellular binding site, and, most importantly, restore reduced folate stores to allow for continued purine and subsequent DNA/RNA synthesis.134 , 210 The lower doses of leucovorin used during MTX therapy are an attempt to protect normal body cells but not tumor cells. Under therapeutic circumstances delay leucovorin rescue as long as possible, administer the minimal effective dose, and discontinue therapy as soon as it is no longer necessary.25 It is important to adjust the leucovorin dose according to the actual plasma MTX level for an overdose situation, and not to continue at the original rescue dose for routine therapy (Antidotes in Depth: Folic Acid and Leucovorin [Folinic

Acid] ).146

Serum MTX levels should be monitored at 12, 24, and 48 hours postexposure so that leucovorin therapy can be adjusted accordingly. Generally, leucovorin therapy is continued in patients undergoing chemotherapy if the plasma MTX level is above 1.0 µmol/L (1 × 10+ 6 M) at 48 hours postexposure,255 and maintained until the level is below 0.1 µmol/L.264 However, for patients without cancer, the leucovorin therapy should be continued until the MTX level is less than 0.01 µmol/L, because DNA synthesis is impaired above this value.53 In patients with marrow toxicity, leucovorin therapy should be considered until marrow recovery occurs, even if serum MTX is no longer detectable,173 because intracellular MTX activity may still be

ongoing. It should be noted that trimethoprim, a folate antagonist, can cause false elevations with certain MTX assays (competitive protein binding technique, enzyme inhibition).22 Spectrophotofluorimetric analysis may misinterpret folinic acid for MTX and should not be used as the analytic method during leucovorin therapy.149 Thymidine is also used to rescue cells from the cytotoxic effects of MTX by what is called thymidylate salvage . 82 , 259 Thymidine can be converted to thymidine triphosphate by thymidine kinase, which is not inhibited by MTX, thus allowing for DNA synthesis. Thymidine rescue is not as effective as leucovorin.185 , 259 It is currently available under an investigational protocol (NCI 92-C0134) for use by patients with high serum MTX concentration, severe manifestations of toxicity (ie, mucositis, thrombocytopenia, neutropenia, and hepatic insufficiency), and renal insufficiency from the National Cancer Institute (e-mail: [email protected] ; tel: 888–624–1937 or 301–496–5725; fax: 301–881–8239). The investigational dose for thymidine is 8 g/m2 /d IV, and this treatment is used in conjunction with leucovorin and carboxypeptidase. Carboxypeptidase G2 (CPDG2 ) is a rescue agent that inactivates MTX by cleaving its terminal glutamate group.292 It is a recombinant bacterial (Pseudomonas ) enzyme that is well tolerated by patients undergoing high-dose MTX therapy.68 , 283 , 284 , 292 On its administration, serum MTX concentration decreases within 1 hour. Hypersensitivity reactions may occur because of this agent's bacterial origin. CPDG2 is available for compassionate (protocol No. NCI 92-C-0134) use by patients with high serum MTX concentration (at least 10 µmol/L more than 42 hours after initiation of MTX therapy) or under investigational protocol (NCI 92-C-0137) for intrathecal (IT) overdoses (≥100 mg IT MTX) from the National Cancer Institute (e-mail: [email protected] ; tel: 888–624–1937 or 301–496–5725; fax: 301–881–8239). Leucovorin and thymidine treatments are

continued during CPDG2 use because this enzyme does not enter the cell. The investigational dose for CPDG2 is 50 U/kg IV and repeat administration may be necessary if the MTX concentration remains greater than 1 µmol/L. It is essential that the highperformance liquid chromatography (HPLC) technique be used to assay for MTX concentration after CPDG2 therapy, because the enzymatic byproducts of MTX yield falsely elevated values with the routine enzyme immunosorbent assay method.292

Extracorporeal

Elimination

There are several reports of the use of hemodialysis and/or hemoperfusion for patients with MTX toxicity. Although the volume of distribution (0.6–0.9 L/kg) and protein binding (50%) suggest that methotrexate is dialyzable, clinical evidence suggests otherwise.250 In one report, less than 10% of an initial 0.7 g dose of methotrexate was cleared in 12 sessions of hemodialysis.261 The measured clearance was only 38 mL/min, which can be compared to 5 mL/min for peritoneal dialysis,111 0.28–24 mL/min for continuous venovenous hemodiafiltration,137 , 146 and 180 mL/min for normal renal clearance.167 Using plasma exchange transfusion to remove MTX is not recommended because of the drug's low degree of protein binding, which limits the efficacy of this procedure.25 , 146 , 261 Acute intermittent hemodialysis with a high-flux dialyzer membrane yielded an effective mean plasma MTX clearance of 92 mL/min in 6 patients with renal failure that was a result of either chronic disease or high-dose MTX therapy.278 These patients received high-dose MTX therapy and had a predialysis plasma MTX concentration ranging from 1.45 to 1813 µmol/L. The time of dialysis initiation after MTX treatment was from 1 hour to 6 days in this patient population. A plasma MTX concentration of 0.3 µmol/L was used as an end point for dialysis. The reported plasma MTX clearance by this technique closely approximates

normal renal MTX clearance and should be considered if it is available. Charcoal hemoperfusion removed more than 50% of methotrexate in 4 patients with impaired renal MTX clearance during high-dose MTX therapy.73 This was thought to have prevented severe skin and mucosal toxicity. Sequential hemodialysis and hemoperfusion were used for a patient with substantial MTX toxicity.105 These procedures decreased the half-life of elimination from 45 hours to 7.6 hours. In experimental animals, hemoperfusion significantly reduced the terminal half-life of methotrexate. In surgically anephric dogs, hemoperfusion decreased the half-life from more than 20 hours to 1.3 hours.126 Consequently, hemoperfusion is recommended over hemodialysis. In vitro studies indicate that the toxic effects of 100 µmol/L of MTX cannot be reversed by 1000 µmol/L of leucovorin.210 This suggests the need for hemoperfusion to lower persistent MTX P.810 plasma concentrations of greater than 100 µmol/L.217 It is important to perform hemoperfusion early, prior to distribution into tissues. Rebound of MTX levels from tissues may be expected after hemodialysis, which can begin at 2 hours postdialysis and plateau at 16 hours.98 , 111 , 278 If hemoperfusion is not available, and the patient is in renal failure and has a plasma MTX concentration greater than 8 µmol/L, hemodialysis may be considered until more definitive treatment, such as enzymatic cleavage, is available.73 Patients who are at the greatest risk for developing MTX toxicity despite leucovorin treatment should be considered for extracorporeal elimination because they are most likely to benefit from this procedure. This includes patients with progressively diminishing renal clearance.255 Although hemoperfusion is preferred over hemodialysis, hemodialysis can be used if it is the only choice available. Hemodialysis can offer the additional benefit

of correcting fluid and electrolyte disorders resulting from renal failure. Other treatment options, including leucovorin and urinary alkalinization, should be continued during extracorporeal MTX removal. Folic acid is water soluble and can be removed by hemodialysis.64 , 217 , 241 , 245 This is probably also applicable for leucovorin, and replacement doses of leucovorin postdialysis should be considered.

Granulocyte

Colony-Stimulating

Factor

The decision to use myeloid growth factors in patients with agranulocytosis depends on the severity and nature of the neutropenia, and the anticipated speed of recovery. Granulocytemacrophage colony-stimulating factor (GM-CSF) was used in a patient with a patient had a admission and promyelocytes,

chronic MTX overdose and pancytopenia.250 The serum MTX concentration of 1.25 µmol/L on was in renal failure. Bone marrow biopsy showed but no mature white cells, and a marked reduction

of megakaryocytes. Because of deteriorating conditions, GM-CSF (125 µg/m2 /d) was administered when the MTX level fell below the reference limit for toxicity. Seven days after the initiation of GM-CSF, the WBC count rose and reached normal values within 10 days. Typically, if promyelocytes and myelocytes are present in the bone marrow, neutrophil recovery will occur spontaneously in 4–7 days, following the withdrawal of the offending agent.91 However, when granulopoiesis is completely absent, neutrophil recovery cannot be expected for at least 14 days. Using granulocyte colony-stimulating factor (G-CSF) or GM-CSF can accelerate neutrophil recovery during cytotoxic antineoplastic therapy. When myeloid precursors are present in the bone marrow, G-CSF can accelerate neutrophil recovery in 1–4 days. If myeloid precursors are absent, neutrophil recovery with G-CSF may take longer, but can be expected to occur sooner than without G-CSF therapy. GM-CSF is indicated for use in neutropenic patients following induction antineoplastic therapy for acute myelogenous

leukemia because this agent enhances the response of macrophages, neutrophils, and eosinophils. Serum levels of the antineoplastic should be below detection before institution of GCSF to gain maximal response; typically, G-CSF is initiated 24 hours upon the completion of the treatment cycle. The initial dose is 5 µg/kg/d IV or subcutaneously (SC), and it is continued beyond the expected WBC nadir. This is usually a 2-week course; however, it can be prolonged with lomustine overdoses.1 , 263 The dose may be adjusted, depending on the patient's WBC response. Therapy can be discontinued when the post nadir absolute neutrophil count is greater than 10 × 103 cells/mm3 . Bone pain can be anticipated from the use of these agents, presumably because of the increase in cellularity in the marrow space. Additional side effects can be expected from GM-CSF therapy, including myalgia, fevers, and pericarditis. GM-CSF might produce a transient beneficial response in the WBC in patients with aplastic anemia.55 However, when the anemia was severe, the GM-CSF therapy was not effective. Another hematopoietic growth factor is erythropoietin (EPO), which is approved for use in patients with anemia associated with cancer chemotherapy treatment.100

Vincristine

and

Vinblastine

Figure. No Caption Available.

Pharmacology Vincristine and vinblastine are derived from the periwinkle plant (Catharanthus roseus ) and used for the treatment of leukemias, lymphomas, and certain solid tumors. Their mechanism of activity is similar to that of colchicine, podophyllotoxin, and the taxoids (eg, paclitaxel, docetaxel).69 , 78 These xenobiotics disrupt microtubule assembly from tubulin subunits by either preventing their formation or depolymerization, both of which are necessary for routine cell maintenance. Microtubules are responsible for several basic cellular functions including cell division, axonal transport of nutrients and organelles, and cellular movement. Mitotic metaphase arrest is commonly observed because of the inability to form spindle fibers from the microtubules. Cell death quickly ensues as a result of the interruption of these homeostatic functions, accounting for the clinical manifestations. The vinca alkaloids are primarily eliminated through the liver and have a terminal plasma half-life of about 24 hours.193 Patients with hepatic dysfunction are susceptible to toxicity. The capacity of vincristine to be bound by plasma proteins ranges from 50% to

8 0 % .208 Vincristine overdose is the most frequently reported antineoplastic overdose in the literature. This is because there are at least 4 different ways to misdose this agent, including confusing it with vinblastine, misinterpreting the dose, administering it by the wrong route, and confusing two different-strength vials. The normal dose of vincristine is 0.06 mg/kg, and a single dose is not to exceed 2.0 mg for either an adult or child.

Clinical

Manifestations

Despite their similarity in structure, vincristine and vinblastine differ in clinical toxicity. Vincristine produces less bone marrow suppression and more neurotoxicity than does vinblastine. During the therapeutic use of vincristine, myelosuppression occurs in only P.811 patients.115

5–10% of However, this effect is common in the overdose setting and when it occurs the need for replacement blood products and concern for overwhelming infection is apparent.172 The fall in cell counts begins within the first week and may last for up to 3 weeks. Other manifestations of acute vincristine toxicity are mucositis, CNS disorders, and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Central nervous system disorders are varied and unusual during therapeutic vincristine therapy because of the agent's poor penetrance of the blood–brain barrier.131 They are, however, more common when there is delayed elimination, damage to the blood brain–barrier, overdose, or inadvertent intrathecal administration. Generalized seizures from toxicity or secondary effects may occur from 1 to 7 days after exposure.121 , 141 , 144 , 256 Treatment with benzodiazepines or phenobarbital is usually successful, and phenytoin was used successfully in a patient with barbiturate hypersensitivity.144 Other manifestations are depression, agitation, insomnia, and hallucinations. Vincristine

stimulation of the hypothalamus may be responsible for the fevers and SIADH noted in overdosed patients.223 The fevers begin 24 hours after exposure and last 6–96 hours. Serum electrolytes need to be monitored, typically for 10 days. Autonomic dysfunction is observed, and it commonly includes ileus, constipation, and abdominal pain. Atony of the bladder, hypertension, and hypotension also can occur.144 Ascending peripheral neuropathies occur during vincristine therapy and can be limited by keeping the total for a single dose below 2 mg.246 Neuropathy may appear after an overdose, starting at about 2 weeks and lasting for 6–7 weeks. Paresthesias, neuritic pain, ataxia, bone pain, wrist drop, foot drop, involvement of cranial nerves III–VII and X, and diminished reflexes can be observed.281 The incidence of paresthesia increases with dose and is reported to be 56% in patients treated at doses between 12.5 and 25 µg/kg.115 At a dose of 75 µg/kg, the incidence of patients with a sensory disorder increased by 6-fold. The loss of reflexes, the earliest and most consistent sign of vincristine neuropathy, is maximal at 17 days after a single massive dose. Muscular weakness is a limiting point in therapy, and typically involves the distal dorsiflexors of the extremities, although laryngeal involvement is also reported.165 , 230 These severe neurologic symptoms may be reversed by either withholding therapy or reducing dosage upon manifestation of these findings.165 The mechanism of toxicity is not well understood, but appears to be related to inhibition of microtubular synthesis, which leads to axonal degeneration.103 , 196 A brain biopsy of a patient suffering a vincristine-related death showed neurotubular dissociation, which is characteristic of vincristine damage in experimental animals.40 , 57 Unlike the vinca alkaloids, Taxolinduced peripheral neuropathy is predominantly sensory and resolves faster with discontinuation of the offending agent.170 This is because of the different effects on microtubule assembly by these agents. Nerve conduction studies and the Achilles tendon

reflex are useful in monitoring patients for toxicity after exposure. Vincristine-induced myocardial infarctions are reported but their cause is not understood.175 , 247 , 257 , 289 It may be related to vinca alkaloid-induced platelet aggregation, coronary artery spasm, or increased sensitivity of myocardium to hypoxia.

Management Patients receiving an inadvertent amount of an IV dose of vincristine should be admitted to a cardiac-monitored bed and observed for 24–72 hours. 174 Seizures, dysrhythmias, and alterations in blood pressure can be expectantly managed, although prophylactic phenobarbital and benzodiazepine were used to prevent seizures in two patients.54 , 152 Calcium channelblockers (nifedipine and amlodipine) were used to control hypertension in a patient with vincristine overdose.54 Blood counts must be monitored daily, and G-CSF may be used to treat neutropenia.54 , 172 , 256 However, the red cell response from the use of erythropoietin may be limited because of the induction of metaphase arrest in the erythroblasts by these particular xenobiotics.177 If patients remain asymptomatic during the observation period, they can be discharged with followup for bone marrow suppression and SIADH; otherwise, depending upon the patients' clinical condition, continual observation for progression of neurologic symptoms is warranted.27 The symptoms of acute toxicity usually last for 3–7 days, and the neurologic sequelae may last for months before some resolution is observed. In a controlled clinical trial, for vincristine-induced peripheral neuropathy glutamic acid therapy had limited efficacy. Patients receiving vincristine therapy were given glutamic acid as 500 mg orally 3 times a day.132 It was observed that there was a decreased incidence in loss of Achilles tendon reflex and delayed

onset of paresthesias in the glutamic acid-treated group. No reported adverse effects with glutamic acid were observed in this investigation. Animal studies involving the administration of glutamic and aspartic acid to mice poisoned with either vinblastine or vincristine demonstrate increased survival and decreased sensorimotor peripheral neuropathy.39 , 66 , 130 The mechanisms of these observed effects with glutamic acid remain unclear, but several have been suggested, including glutamic acid's ability to competitively inhibit a common cellular transport mechanism for vincristine,37 , 63 its ability to assist in the stabilization of tubulin and promote its polymerization into microtubules,41 , 110 and the ability of glutamic acid to improve cellular metabolism by overcoming the inhibition by these agents in the Krebs cycle. 77 , 220 Although the role of glutamic acid in acute toxicity needs further study, it is not harmful and should be considered. Glutamic acid may be initiated as 500 mg orally 3 times a day and continued until the serum drug concentration is below toxicity.132 L-Glutamic acid is the preferred stereoisomer because it is biologically active and this product is available as a powder from various distributors in the United States. Leucovorin may shorten the course of vincristine-induced peripheral neuropathy107 and myelosuppression. 152 The mechanism is attributed to leucovorin's ability to overcome a vincristine-mediated block of dihydrofolate reductase and thymidine synthetase.107 However, neither leucovorin24 , 128 , 262 nor pyridoxine129 has been shown definitely to be effective. An initial experimental investigation evaluating the efficacy of antibody therapy to limit vinca alkaloid toxicity shows promise.108

Enhanced

Elimination

Vincristine is rapidly distributed to tissue stores and highly bound to proteins and red cells.48 Although elimination of vincristine is via the hepatobiliary system,48 there is no evidence demonstrating

the efficacy of multiple-dose activated charcoal in enhancing the elimination in the overdose setting. In more than 50% of children given vincristine IV, plasma concentrations were not detected 4 hours after administration.190 Such characteristics favor early intervention and methods other than hemodialysis. Double-volume exchange transfusion was performed at 6 hours postexposure in P.812 3 children who were overdosed with 7.5 mg/m2 of vincristine IV. 152 This procedure replaced approximately 90% of the circulating blood volume by exchanging twice the patient's blood volume. Of the 2 survivors, their respective postexchange serum vincristine concentrations were 57% and 71% lower than their preexchange concentrations. The amount of vincristine removed was not determined. Although these patients developed peripheral neuropathies, myelosuppression, and autonomic instability, the author noted that the duration of illness was shorter than previously reported. Thus, based on the pharmacokinetic profile of vincristine and these two reports, exchange transfusion in the child is the preferred method of enhanced elimination when the patient presents soon after the administration of the drug, and plasmapheresis is the preferred method in the adult. Plasmapheresis was attempted with vinca alkaloid overdoses.172 , 208 In an 18-year-old patient who received two 8-mg IV doses of vincristine at 12-hour intervals, the procedure was performed 6 hours after the second dose and 1.5 times the plasma volume was plasmapheresed.208 Postplasmapheresis serum vincristine concentration was 23% lower than the starting concentration. The patient survived with myelosuppression, neurotoxicity, and SIADH.

Anthracyclines

Figure. No Caption Available.

Pharmacology The antineoplastics derived from the bacterium Streptomyces are dactinomycin, daunorubicin, doxorubicin, bleomycin, mitomycin, and plicamycin. Only plicamycin crosses the blood–brain barrier. The terminal elimination half-life for doxorubicin is about 30 hours.104 Doxorubicin and daunorubicin are both eliminated by the liver and patients with hepatic dysfunction should have their dosage decreased. Delayed drug elimination contributes to increased drug area under the plasma drug concentration versus time curve (AUC) and peak serum concentration, which are associated with myelosuppression and cardiac toxicity, respectively.166 The mechanism of therapeutic action of the anthracyclines is attributed to DNA intercalation228 and activation of topoisomerase II.260 These xenobiotics are metabolized to active metabolites, which have lesser degrees of activity than their parent compounds. A typical dose schedule for daunorubicin is 30–60 mg/m2 daily for 3 days; for doxorubicin, 45–60 mg/m2 every 18–21 days. Daunorubicin and doxorubicin share many common indications for cancer therapy, but they differ in that doxorubicin is used in solid tumors such as breast carcinoma. The

red

anthracycline

antibiotics—dactinomycin

and

doxorubicin—are associated with cardiotoxicity, which limits their therapeutic use. The mechanism responsible for their therapeutic effects is different from that which causes cardiotoxicity.260 The mechanism of cardiac toxicity is believed to result from the formation of free radicals.191 Doxorubicin and dactinomycin are quinone derivatives and can be reduced to free radicals. These metabolites are extremely cytotoxic through the promotion of lipid peroxidation. Paraquat and bleomycin have similar mechanisms of toxicity. The limited efficacy of free radical scavengers (αtocopherol, N -acetylcysteine) for anthracycline cardiotoxicity led to an understanding of the importance of iron as a cofactor for these radical-producing reactions.192 The anthracyclines have a high affinity for metal ions. Doxorubicin has an iron (Fe3 + )binding constant of 10, 41 which is comparable to deferoxamine.96 The heart's increased susceptibility to free radicals is attributed to its lack of sufficient enzyme activity responsible for free radical scavenging.75

Clinical

Manifestations

The cardiotoxic manifestations can be divided into acute and chronic categories. The various findings described with acute toxicity include dysrhythmias, ST and T-wave changes on the ECG, diminished ejection fraction that usually resolves over 24 hours, and sudden death.42 , 252 , 288 Abnormal findings on the ECG are present in 41% of patients receiving doxorubicin.14 , 112 , 164 , 252 , 276 , 291 , 294 These are neither dose related nor associated with the development of cardiomyopathy. Acute pericarditis and myocarditis resulting in conduction defects and congestive heart failure are also reported.42 Animal studies with doxorubicin demonstrate beneficial effects of adrenergic antagonists for toxicity because of elevated levels of catecholamines,43 although the use of β-adrenergic antagonists in the potential setting of diminished cardiac output needs to be considered.

Significant cardiotoxicity results from elevated peak serum levels and accounts for the continuous and periodic infusions practiced in therapy. In cumulative doses, the anthracycline antibiotics cause a cardiomyopathy that results in congestive heart failure. The condition is irreversible and is associated with a 48% mortality.212 This drug-induced congestive heart failure is associated with pathognomonic changes on electron microscopy that can distinguish it from infectious and ischemic etiologies. These histologic changes include reduced number of myocardial fibrils, and mitochondrial and cellular degeneration.33 The potential mechanisms for cardiac failure include free radical damage and impaired intracellular calcium homeostasis. 206 The incidence of chronic cardiotoxicity for doxorubicin is between 1 and 10% when the cumulative dose is less than 450 mg/m2 , and becomes greater than 20% when more than 550 mg/m2 (comparable to dactinomycin, 950 mg/m2 ) is administered.274 At a cumulative dose of 720 mg/m2 for epirubicin, the incidence of cardiac dysfunction is reported to be 19%.186 The best way of monitoring cardiac function during therapy is to use radionuclide cineradiography to measure the left ventricular ejection fraction.6 Therapy should be discontinued when the ejection fraction falls below 50%. Two-dimensional echocardiography can demonstrate left ventricular wall thickening and fractional shortening from anthracycline overexposure. Newer techniques used to assess subclinical cardiac muscle pathology from these agents include cardiac-specific contractile protein troponin T and troponin I,168 and radionuclide-tagged monoclonal antibody imaging.49 In a small clinical trial of patients treated with doxorubicin, P.813 serum cardiac troponin T levels did not correlate with echocardiographic findings. 150 In 21 of 24 patients, the serum troponin T level was below detection and 9 patients had abnormal echocardiographic findings. Further studies are necessary to

determine the role of these new laboratory studies in clinical management. Factors associated with an increased risk for cardiotoxicity include mediastinal irradiation, preexisting cardiac disease in children, age more than 70 years, and the concomitant use of cyclophosphamide, paclitaxel, and other anthracycline agents.42 Children are at risk for developing increased left ventricular afterload from doxorubicin toxicity because of the drug's ability to inhibit myocardial growth, which can lead to a disproportionate ratio of left ventricular wall thickness to left ventricular chamber size.169 Fatalities are reported with minimum doses of 150–333 mg/m2 , and occur within 1–16 days after exposure.65 Myelosuppression and mucositis are other effects associated with the use of the anthracycline agents. They typically occur in 1–2 weeks, and patients recover.26 The white cells are affected more than either the red cells or platelets. Patients with diminished drug clearance (eg, liver failure) are at risk for the development of these findings. Mitoxantrone is recognized to be less toxic than doxorubicin and daunorubicin. Major organs of toxicity remain the heart, bone marrow, and gut. Gastrointestinal effects are less severe and less frequent with mitoxantrone than with doxorubicin.244 Four cases of mitoxantrone overdose are reported in the literature.109 , 244 Common to these events is a 10-fold error in dosing (100 mg/m2 instead of 10 mg/m2 ), early onset of nausea with vomiting, and myelosuppression with fever. Acute decreased cardiac contractility was observed by echocardiography in 1 patient who was asymptomatic.109 Otherwise, no patient developed dysrhythmias, congestive failure, ECG changes, or elevated creatine phosphokinase levels early after exposure. Three patients developed fatal congestive heart failure (CHF) from 1–4 months later.244

Management There are no specific antidotes for this class of agents except for dexrazoxane; thus, management is largely supportive. Monitoring for cardiotoxicity and pancytopenia is necessary. A baseline chest radiograph, electrocardiogram, and echocardiogram to determine left ventricular ejection fraction (at rest and/or with stress) are required. Endomyocardial biopsy and cardiac catheterization can assist in distinguishing other causes of cardiac dysfunction. Left ventricular function is the best predictor for cardiomyopathy.88 , 235 A 10% absolute decrease in the left ventricular ejection fraction (LVEF) or a drop in LVEF of 50% from baseline is a significant finding for the discontinuation of further anthracycline therapy.235 Although digoxin and furosemide should be used to manage acute CHF, a variable response can be expected.244 Digoxin and low-dose verapamil benefit patients treated with doxorubicin; however, this benefit may be limited by the severity of the disorder.95 , 282 At higher doses of verapamil, hypotension and heart block were observed, which limited further use.202 , 254 Dexrazoxane is a cardioprotectant that limits the effects of doxorubicin by chelating intracellular iron, which mediates the formation of free radical cellular damage. In clinical trials, patients receiving dexrazoxane had smaller decreases in LVEF per dose of doxorubicin, fewer histologic changes on cardiac biopsy, were better able to tolerate doxorubicin doses greater than 600 mg/m2 , and had a lower occurrence of serum cardiac troponin T elevations than did patients who were not pretreated with dexrazoxane.169 , 248 The current role of this chelator is to limit cardiotoxicity in patients receiving more than 300 mg/m2 of doxorubicin.238 It is administered 30 minutes before doxorubicin in a 10:1 ratio. Dexrazoxane increases the systemic clearance of epirubicin in a clinical trial, which may be an added benefit to patients with increased exposure. 23 Further investigations are required to determine the use of dexrazoxane in overdose exposures and with

other anthracycline agents.5 , 186 Other cardioprotectants under investigation include amifostine50 and monohydroxyethylrutoside. Monohydroxyethylrutoside is a semisynthetic flavonoid that can chelate iron and scavenge free radicals. In experimental models, monohydroxyethylrutoside decreased doxorubicin-induced cardiotoxicity as measured by ST segment elevation on the ECG268 and left ventricular function.122 Clinical trials are lacking with this agent.

Enhanced

Elimination

The anthracycline agents are highly protein bound and have a large volume of distribution, which make them unlikely candidates for hemodialysis. However, the early institution of hemoperfusion may enhance elimination. In clearance could be enhanced Factors determining this were and the use of a 2% acrylic

an animal model, plasma doxorubicin up to 20-fold with hemoperfusion.286 duration of therapy, rate of flow, hydrogel-coated cartridge. Three

patients with a doxorubicin overdose were treated with hemoperfusion, 1 with an Amberlite cartridge, and all had a rapid reduction in their serum levels.65 One survived a 10-fold error in dosing. In a patient with a mitoxantrone overdose of 98 mg IV, hemoperfusion was begun within hours, but in two trials, only 0.287 and 0.236 mg of drug were removed.109

Nitrogen

Mustards

Mechlorethamine

Pharmacology

The nitrogen mustard agents are cyclophosphamide, ifosfamide, chlorambucil, mechlorethamine, and melphalan. Their indicated uses include immunosuppression (eg, controlling graft-versus-host rejection, collagen vascular diseases) and chemotherapy. The tumoricidal activity of these xenobiotics is the result of the formation of reactive intermediates that bind to nucleophilic moieties on the DNA chain, which inactivates DNA synthesis. Unlike the other xenobiotics, cyclophosphamide and ifosfamide require mixed function oxidation to achieve their alkylating properties. Mechlorethamine is the original compound from which all of the others were derived. It is highly reactive when it comes in contact with water and undergoes rapid chemical transformation. Local reactions caused by mechlorethamine spillage (eg, extravasation) include tissue injury and thrombophlebitis (see Extravasational Injury below). Nonenzymatic hydrolysis is the major route by which these agents are metabolized, thus accounting for their relatively short elimination half-lives (ie, less than 3 hours). 31 Cyclophosphamide, P.814 ifosfamide, and chlorambucil have active metabolites, which prolongs

their

Clinical

alkylating

activity

after

administration.142

Manifestations

Chlorambucil and ifosfamide can produce altered mental status and seizures from therapeutic use or from an overdose.46 Both compounds undergo N -dechloroethylation to produce chloroacetaldehyde, which is purported to be a nervous system toxin.102 Encephalopathy occurs in 9% of patients receiving 5 g/m2 of ifosfamide, and is more frequent with oral than with IV administration because of the first-pass effect and increased chloroacetaldehyde production.181 Seizures are more commonly associated with chlorambucil. Acute overdoses reported in the literature are all from the oral route, and range in dosing from 1.5–6.8 mg/kg (therapeutic is 0.1–0.2 mg/kg).10 , 47 The

seizures occur within 6 hours, may appear as generalized tonic–clonic activity or staring spells, and can last for 24 hours. However, in one instance in which therapeutic dosing was increased, seizures occurred 17 hours later. This delay may be attributed to a lower serum concentration or a slower time to peak than in the overdose setting. A similar reasoning would explain why a patient with a chronic overdose of 4.1 mg/kg over 5 days did not sustain CNS toxicity.81 Patients with increased likelihood to seize are those with underlying seizure disorders or with nephrotic syndrome, which can alter pharmacokinetics.229 Electroencephalograms (EEGs) demonstrated multiple paroxysms of bilaterally symmetric 2–3-Hz spikes and slow high-voltage rhythmic slowing that progressed to slower bursts of rhythmic spike and wave discharge in a child with an acute overdose.47 Myelosuppression occurs in patients with both acute and chronic overdoses, and can present as late as 41 days postexposure. Recovery is expected within 1 week of the nadir, and G-CSF treatment may be necessary.140 Cyclophosphamide and its analog ifosfamide induce hemorrhagic cystitis from their irritating metabolite acrolein. This occurs in approximately 5–10% of patients who receive therapy.45 , 62 The incidence of cystitis does not appear to be related to the total dose and administration route, age, or gender. The course is usually self-limiting, although blood transfusions may be required. Free water retention is observed in patients receiving more than 50 mg/kg of cyclophosphamide.70 This effect is attributed to the activity of the alkylating metabolite on the renal tubule and is observed at 6–8 hours after drug administration. The patient experiences decreased urinary output, increased urine osmolality, and decreased serum osmolality. This is self-limiting, lasting for about 12–16 hours. In the overdose setting, cyclophosphamide can cause dysrhythmias, myocardial necrosis, and death. ECG changes are noted at doses of 120 mg/kg and heart failure and myocarditis at

doses greater than 150 mg/kg.13 , 188 An ordering error led to the death of 1 patient and to irreversible cardiac damage in another patient from cyclophosphamide overdose. These 2 patients received 6520 mg of the agent daily for 4 consecutive days, when the amount was to be divided over 4 days.225 The onset of heart failure can be sudden, and patients older than 50 years of age, and those with prior treatment with anthracyclines, are at greatest risk for cardiac toxicity.253

Management Recommendations for patients with an acute chlorambucil exposure include routine gastrointestinal decontamination, a 6hour observation, a baseline CBC and hepatic enzymes, and a followup CBC weekly for 4 weeks.269 Ifosfamide-induced encephalopathy can be managed with methylene blue (50 mg IV as a 1% solution), although the mechanism by which methylene blue acts is unknown.155 , 293 Seizures are reported to be more effectively managed with benzodiazepines and barbiturates than with phenytoin.10 , 34 , 287 When gross hematuria from cyclophosphamide or ifosfamide therapy persists, treatments reported to be effective in the literature can be considered. These treatments include electrocauterization, systemic vasopressin, 213 intravesical administration of silver nitrate,154 formalin,90 , 239 prostaglandin F - Î ± ,243 and hydrostatic pressure.116 Some of the preventive therapies that seem to reduce this occurrence include adequate hydration for dilution effect, frequent bladder emptying, IV administration of 2-mercaptoethane sulfonate sodium (MESNA), and intravesical N -acetylcysteine.45 The thiol group of N acetylcysteine is believed to directly interact with acrolein to limit its irritating effect on the bladder epithelium. MESNA is believed to work by inactivating acrolein to an inert thioether.117 The IV dose of MESNA is 20% of the cyclophosphamide or ifosfamide amount

(wt/wt) and administered during therapy and again at 4 and 8 hours. MESNA is used during standard-dose therapy for ifosfamide and high-dose therapy for cyclophosphamide. Patients with large exposures to cyclophosphamide require baseline ECGs and echocardiograms. Intravenous fluid restriction, digoxin, and furosemide were successfully used to treat a patient with cyclophosphamide-induced congestive cardiomyopathy.273

Platinoids

Figure. No Caption Available.

Pharmacology The cytotoxic effects of the platinum-containing compounds were first recognized in 1965; since then, many types have been derived. The ones of clinical significance are cisplatin, carboplatin, and oxaliplatin. 189 These xenobiotics were designed to reduce the incidence of nephrotoxicity and to counter drug resistance. Differences in chemical structure exist. Most notably, cisplatin is an inorganic and carboplatin an organic compound. Similarities exist in their mechanism of toxicity, which is the binding of platinum to DNA to form inter- and intrastrand bonds, which lead to DNA dysfunction and strand breakage. These xenobiotics are eliminated from the body primarily in the urine and at varying rates. The amount eliminated at 24 hours is 25% for cisplatin and 90% for carboplatin. Patients with decreased creatinine clearance

(2000 Hz) hearing loss is evident 2–3 days after exposure to doses greater than 500 mg/m2 .56

Management Renal protection and enhanced elimination of platinum are the two primary goals in the management of a cisplatin overdose. Expectant management for myelosuppression and neurotoxicity can follow. Sodium chloride diuresis both promotes the inactive anionic state of cisplatin and decreases the urine platinum concentration to limit nephrotoxicity during therapy.8 , 272 Hydration with 0.9% NaCl solution and an osmotic diuretic (eg, mannitol) should be administered to achieve a high urine output (eg, 1–3 mL/kg/h) for 6–24 hours postexposure. In the setting of nonoliguric renal failure, careful hydration is recommended to maintain urinary output, because platinum renal excretion is directly related to urinary flow, and independent of creatinine clearance.58 Aside from evaluating the BUN and creatinine, assessment of renal function can include the glomerular filtration, filtration fraction, and renal plasma flow.106 , 183 , 184 , 197 Amifostine and sodium thiosulfate are effective nephroprotectants. Amifostine's role is more preventative and is approved by the FDA for use to protect against cisplatin-induced nephrotoxicity. Unlike thiosulfate, amifostine is activated intracellularly by alkaline

phosphatase to scavenge free radicals, prevent cisplatin-DNA adduct formation, and facilitate DNA repair.151 The patient requires adequate hydration during amifostine infusion because hypotension can occur. Sodium thiosulfate is effective postexposure. Thiosulfate remains in the extracellular space to bind free platinum and limit cellular damage at the renal tubules. Little or no renal toxicity occurred in patients receiving as much as 270 mg/m2 of cisplatin when thiosulfate was given as an IV bolus of 4 g/m2 followed by infusion of 12 g/m2 over 6 hours.113 , 207 Thiosulfate may offer the additional benefit of limiting neurotoxicity and should be administered to all patients after an overdose.176 , 270 The use of thiosulfate is limited by the time in which it needs to be administered after exposure (ie, 1–2 hours). N -acetylcysteine and BNP7787 are being investigated as alternative rescue agents for cisplatin toxicity.242 Hemodialysis is ineffective in patients with cisplatin overdoses, likely as a result of this agent's high protein binding.44 However, in patients with renal failure, hemodialysis may be beneficial. Plasmapheresis was performed in 2 adults and there was a fall in blood serum platinum concentrations with clinical improvement. The first patient received an overdose of 280 mg/m2 and was plasmapheresed on day 12 of exposure.58 After 3 daily treatments, the serum platinum concentration decreased from 2900 to 200 ng/mL and the patient had noticeable improvement in gastrointestinal and visual symptoms. On day 20, the serum platinum concentration rebounded to 700 ng/mL and the symptoms worsened. Further plasmapheresis lowered the concentration to 290 ng/mL by day 27 and symptoms improved. The other patient received 300 mg/m2 of cisplatin and received 4 daily treatments of plasmapheresis starting on day 6 postexposure.143 The plasma serum platinum concentration declined from 2979 to 430 ng/mL and the patient became more awake and less nauseous. On day 11, platinum concentrations rebounded to 834 ng/mL and fell to 279 ng/mL on reinstitution of

plasmapheresis. The amount of platinum removed by 3 trials was 4622 µg. The author of the paper contends that plasmapheresis prevented the need for hemodialysis in renal failure. Thus, plasmapheresis appears to be effective in cisplatin overdose and should be instituted immediately after exposure. Patients who remain symptomatic days later also may benefit.

Intrathecal

Overdose

Intrathecal overdoses with vincristine, methotrexate, doxorubicin, daunorubicin, and cytarabine are reported in the literature.156 Common sources of error are confusing the IV for the intrathecal agent and misidentifying the strength of the solution vial in the preparation of the medication. These events are distressing because of the disastrous immediacy with which the intrathecal space. Removal the patient's only chance

consequences they bring and the agent must be removed from the of as much of the agent as possible is of having an acceptable prognosis (see

Chap. 19 ). Upon recognition of the occurrence, the patient needs to be placed in a gravity-dependent position to prevent upward flow of the agent towards the cisterna magnum. The upright position significantly delays the flow of an intralumbar administered agent to the cerebral ventricles, when compared with the flow in a patient lying flat or in the Trendelenburg position. 80 The lumbar puncture site needs to be maintained or reestablished so that as much of the CSF can be drained as possible. With an intrathecal MTX model, if 20 mL of CSF is removed within 30 minutes of administration, then 94% of the agent given is retrieved. 4 However, by removing the same volume at 3 hours, only 10% of the agent is recovered. CSF drainage can be accomplished in short time intervals, considering that CSF production is 30 mL/h. CSF exchange should be accomplished by lavaging the intrathecal space with lactated

P.816 Ringer solution. An equal volume of the CSF space should be used in each pass of the lavage, and 2–3 passes should be performed to complete the procedure. The volume of CSF in a child older than age 3 years approaches that of an adult (ie, 120 mL). For large exposures, CSF perfusion must follow. This is performed by passing solution through a ventriculostomy and out a lumbar drainage catheter. Lactated Ringer solution with 15–25 mL of fresh-frozen plasma added per liter of crystalloid is infused at 150 mL/h for 18–24 hours.79 , 290 The ventriculostomy and lumbar drain can then be removed. The thecal effluent can be collected to determine the amount of drug recovered. Depending on the antineoplastic involved, additional measures may be necessary. Intrathecal vincristine overdoses are devastating. Only 2 of 13 patients reported in the literature survived, and their survival was attributed to the CSF evacuation of this agent within minutes of exposure as described above.79 , 290 There is no indication for the intrathecal administration of vincristine or vinblastine. This mishap is usually the result of confusing vincristine with the other medications (eg, cytarabine, MTX) that are commonly dispensed for intrathecal use. Death follows a characteristic course, consisting of back pain, meningismus, lower-limb weakness, urinary difficulty, loss of deep tendon reflexes, encephalopathy, and respiratory failure. Alteration in mental status appeared earlier when vincristine was administered intraventricularly.182 Pathologic changes are most notable in the cerebellum, the brainstem, and the anterior horns of the spinal cord. 18 There are only 2 reported survivors from intrathecal vincristine, and the amount of vincristine recovered in one case was 95% of the 2 mg of vincristine that had been administered.79 Additional therapies provided in these cases were glutamic acid (10 g IV over 24 hours, then 500 mg orally 3 times a day),132 folinic acid (25 mg IV every 6 hours), and pyridoxine (50 mg IV every 8 hours). These therapies were continued for 1 week or until the neurologic

symptoms stabilized. Dexamethasone (4 mg/m2 IV every 6 hours) may be given for meningeal inflammation. The roles of these agents are unclear, but because of the seriousness of the situation, aggressive therapy should be offered. Intrathecal overdoses of MTX commonly occur because a more concentrated solution vial is mistaken for one that is less concentrated.249 , 163 Overdoses reported in the literature range as high as 650 mg and death is associated with amounts greater than 500 mg.249 The therapeutic intrathecal MTX dose, according to age, is 6 mg for a patient younger than 1 year old; 8 mg for a patient between the ages of 1 and 2 years; 10 mg between the ages of 2 and 3 years; and 12 mg for than 3 years of age.36 The neurotoxicity associated events includes chemical arachnoiditis, ascending

for a patient a patient older with these neuropathy,

encephalopathy, and seizures. The seizures can be treated with phenobarbital and benzodiazepines.163 , 221 Unlike intrathecal vincristine overdoses, the prognosis for an intrathecal MTX exposure is more favorable because of the different mechanism of action and the availability of rescue therapy. Two deaths are reported with intrathecal MTX overdose after the patients received amounts greater than 500 mg.85 , 249 CSF removal of MTX is still crucial, and for amounts less than 100 mg, CSF drainage may be adequate if performed within 30–60 minutes of administration.138 , 198 When a longer period of time has elapsed, or a larger amount is involved, CSF exchange is necessary, and possibly CSF perfusion as well. At amounts greater than 500 mg, CSF perfusion must follow because drainage and exchange cannot remove enough MTX to prevent significant toxicity. CSF decontamination should continue until the final CSF MTX concentration is about 100 µmol/L, which is a peak therapeutic level for a 12-mg intrathecal MTX dose.198 Large amounts of MTX administered intrathecally pass into the systemic circulation, which poses a threat to the bone marrow. Although there are no reports of myelosuppression resulting from such an

event, IV leucovorin is indicated. High-dose leucovorin rescue should be started upon recognition of the overdose. The following IV leucovorin regimen was used in a patient who received 600 mg of intrathecal MTX and survived: 1000 mg/m2 , followed by 100 mg/m2 every 3 hours until the plasma MTX concentration was less than 0.1 µmol/L.198 Leucovorin is not to be administered intrathecally because seizures with resultant death can occur, and the etiology of MTX-induced neurotoxicity is chemical irritation, not folate inhibition.138 Additional therapies are hydration and urinary alkalinization to prevent renal toxicity, and IV dexamethasone to lessen meningeal inflammation. Enzymatic agents that inactivate MTX are a new and promising form of rescue therapy for intrathecal overdoses. CPDG2 dramatically shortened the MTX CSF half-life in a patient with a 600-mg intrathecal overdose.198 The patient received the carboxypeptidase agent intrathecally, following CSF decontamination, and survived. Enzymatic cleavage may obviate the future need for CSF perfusion in large overdoses.

Extravasational

Injury

Extravasational injuries are among the most consequential local toxic events. When an antineoplastic leaks into the perivascular space, significant necrosis of skin, muscles, and tendons can occur with resultant loss of function. The initial manifestations may include swelling, pain, and a burning sensation that can last for hours. Days later, the area becomes erythematous and indurated and can either resolve or proceed to ulceration and necrosis.226 Sometimes, these early findings may be difficult to distinguish from other forms of local drug toxicity, such as irritation and hypersensitivity. Either the drug or its vehicle (ethanol, propylene glycol) can cause local irritation. The drugs associated with local irritation include fluorouracil, carmustine, bisantrene, cisplatin, and dacarbazine. The local irritation and hypersensitivity manifestations are self-limiting and typified by an immediate onset

of a burning sensation, pruritus, erythema, and a flare reaction of the vein in which the agent is being infused. Pretreatment with an antihistamine usually prevents some of the hypersensitivity manifestations upon subsequent administrations.271 Drugs reported to cause hypersensitivity reactions include daunorubicin, doxorubicin, idarubicin, and mitoxantrone. This event is typified by the presence of pruritus. Nevertheless, when local reactions cannot be differentiated, it is always best to presume extravasation and manage the situation accordingly. The occurrence of these inadvertent events appears to be about 50 times more frequent in the hands of the inexperienced clinician.123 Several factors are associated with extravasational injuries from peripheral intravenous lines, including (a) patients with poor vessel integrity and blood flow, such as the elderly, those who undergo numerous venipunctures, and radiation therapy to the site; (b) limited venous and lymphatic drainage caused by either obstruction or surgical resection; and (c) use of sites over joints, which increases the risk of dislodgments because of movement.124 , 226 Extravasational injuries from implanted ports in central venous vessels can occur from inadequate placement of the needle, needle dislodgment, fibrin sheath formation around the P.817 catheter, perforation of the superior vena cava, and fracture of the catheter.234 When extravasation from a port is suspected and radiographic studies are not diagnostic, a CT scan of the chest with a contrast dye study is necessary for evaluation.11 General Stop infusion and maintain intravenous cannula at the site. Aspirate extravsate from the site by accessing the original intravenous cannula. Irrigation of subcutaneous tissue at the site with normal saline by accessing the original intravenous cannula.

Minimizes amount of antineoplastic localized at the site. Apply dry cool compresses for 1 hour, every 8 hours for 3 days. Localizes area of involvement and diminishes cellular uptake of the antineoplastic. Elevate extremity and administer analgesia. Promotes drainage, prevent dependent edema, and for comfort. Specific Anthracyclines Dimethyl sulfoxide (DMSO)—55–99%. Applied topically and allowed to dry. Every 6–8 hours for 3–10 days. Free radical scavenger. Dexrazoxane 1000 mg/m2 , daily, on days 1 and 2, and then 500 mg/m2 on day 3: IV. Limits free radical formation. Mechlorethamine Sodium thiosulfate—Prepare a sterile 0.17 Msolution by mixing 4 mL thiosulfate 10% weight/volume with 6 mL water for injection. Infiltrate the site of extravasation. Prevents tissue alkylation. Mitomycin DMSO applied topically. Free radical scavenger. Vinca alkaloids and epipodophyllotoxins Hyaluronidase—Inject, intradermally or subcutaneously, 150–900 U into the site. Degrades hyaluronic acid to enhance systemic absorption. Dry warm compresses. Promotes systemic absorption. Therapy

Purpose/Mechanism

TABLE 52-2. Management of Extravasational Injuries 2 9

The factors associated with a poor outcome from extravasational injuries include (a) areas of the body with little subcutaneous tissue, such as the dorsum of the hand, volar surface of the wrist, and antecubital fossa, where healing is poor and vital structures are more likely to be involved; (b) concentration of extravasate; (c) increased volume and duration of contact with tissue; and (d) the type of agent.226 , 227 Vesicant agents, such as doxorubicin, daunorubicin, dactinomycin, epirubicin, idarubicin, mechlorethamine, mitomycin, and the vinca alkaloids, appear to result in more significant local tissue destruction. Mitomycin infusions can cause dermal ulcerations at venipuncture sites remote from the location of administration.205 The anthracycline antibiotics are associated with a higher incidence of significant injuries and delayed healing, which may be a result of their slow release from bound tissue into surrounding viable tissue. Doxorubicin extravasation is associated with local tissue necrosis in approximately 25% of cases. The extravasational injuries from taxanes appear similar to the vesicant agents, but are milder in response and longer in days to presentation.17 , 214 Prevention is the best form of therapy for these injuries. Specialized nursing care and the use of indwelling central venous catheters have limited the extent of these injuries.

Management The treatment for extravasational injuries is somewhat controversial, varying from conservative care to early surgical debridement and the use of selective antidotes.236 This uncertainty is a result of the limited number of clinical cases available for study and the discordance between animal studies and clinical findings. However, general management guidelines for an extravasation and their theoretical foundations exist (Table 522 ). 29 , 38 Once extravasation is suspected, the infusion should be

immediately halted. A physician should be notified and the xenobiotic, its concentration, and the approximate amount infused should be noted. The venous access should be maintained so that aspiration of as much of the infusate as possible can be performed and antidote can be administered, if indicated. Injection of normal saline into the catheter to dilute the extravasate may be beneficial.148 , 236 The intermittent local application of ice and elevation of the extremity should be done for 48–72 hours so as to limit further progression of the agent and the development of dependent edema. Cooling the area is believed to prevent cell injury by reducing the amount of xenobiotic absorbed by the tissue and lowering the cellular metabolic rate. It was demonstrated that, with just cold application and strict elevation, only 13 (11%) of 119 patients with mild extravasations required surgical intervention for their injuries.160 In the past, heat was recommended to disperse the agent, but investigations with mice treated with intradermal doxorubicin demonstrated that this practice increases the area of skin ulceration.76 , 160 However, dry, warm compresses are still recommended for the vinca alkaloids and etoposide to promote systemic uptake.29 This is combined with the local infiltration with hyaluronidase to enhance absorption (Table 52-2 ). The amount of hyaluronidase administered at the site ranges from 150–900 U, and the working concentration of the solution depends on the area to be treated. For extravasational injuries involving a small area, the initial solution of 150 U/mL may be adequate. Otherwise, the solution may be P.818 diluted by 10-fold with normal saline to increase the amount of volume that would be needed to treat a larger surface area. If the intravenous cannula is still accessible, 1 mL of hyaluronidase can be administered through the catheter. Wounds that are either cancerous or infected should not be treated with hyaluronidase. The wound should be observed closely for the first 7 days, and a

surgeon consulted if either pain persists or evidence of ulceration appears.226 However, in severe extravasations—where there is a high incidence of necrosis because of the type of drug (doxorubicin), the volume or concentration, and any area in which there may be significant long-term morbidity (over joints)—early surgical consultation is warranted. If tissue ulceration occurs, initial management can be with sterile dressings to prevent secondary infections. After the area of necrotic skin has evolved to the point where it can be clearly delineated from surviving tissue, surgical debridement may be beneficial to limit secondary infection. The use of intravenous fluorescein or other dye indicators can aid in identifying viable tissue.15 The patient may require surgical reconstruction or skin grafts depending on the extent of the injury. Antidotal therapy should be considered when the extravasate is known to respond poorly to conservative care. The vesicant-type agents are associated with a significantly worse outcome, and when the exposure is large, a more aggressive approach should be initiated. Otherwise, conservative supportive management may be adequate. The specific antidotal treatments can be divided into several categories based upon their mechanism of action, one of which is the reduction of the inflammatory response through the application of steroids. Hydrocortisone has been used in varying concentrations (50–200 mg) as either subcutaneous or intradermal injections for doxorubicin and the vinca alkaloids,20 , 123 , 161 , 267 and as a topical cream.148 Steroids may have only a limited role in doxorubicin-induced lesions because inflammatory cells are not found in predominance at the wound site.32 The addition of steroids to doxorubicin infusions, so as to limit morbidity if extravasation should occur, is not recommended because the drugs are chemically incompatible.265 A prophylactic approach is to inactivate the drug by affecting the pH of the environment. The administration of 5 mL of 8.4% sodium bicarbonate through the same IV line to decrease the DNA binding

of doxorubicin has been advocated.21 The use of sodium bicarbonate should be cautious and not be considered as routine treatment because its hyperosmolarity can cause tissue necrosis.97 Sodium thiosulfate is recommended for mechlorethamine extravasations, and is believed to work by inactivating the agent by reacting with the active ethylenimmonium ring.124 , 199 The site is infiltrated with sterile sodium thiosulfate solution and then ice compresses are applied intermittently for 48–72 hours.29 Finally, there are agents, such as dimethyl sulfoxide (DMSO), that scavenge the free radicals that are believed to cause tissue damage from doxorubicin. Dimethyl sulfoxide is beneficial for anthracycline extravasations in both animal and human clinical trials.30 , 71 , 161 , 199 , 258 The concentration of DMSO used ranged from 55–99% and was applied topically with intermittent cool compresses.29 , 161 , 198 Some of the other beneficial properties of DMSO are its antiinflammatory, analgesic, and vasodilatory effects, and its ability to promote systemic absorption of drug at local sites.171 The systemic administration of dexrazoxane was demonstrated to limit anthracycline-induced skin lesions in a murine model158 and used successfully in patients with doxorubicin157 and epirubicin139 , 157 extravasations. Dexrazoxane was given to these patients over 3 days and by the intravenous route at a starting dose of 1000 mg/m2 . Additional clinical evidence needs to be gathered to better define the dosing regimen for this type of therapy. Although the overall incidence of extravasations with antineoplastic agents is small, the associated morbidity from any one event may be significant. Prevention is the best form of therapy.

Antineoplastics

in

the

Workplace

A variety of workers are at risk for increased exposure to antineoplastics, including pharmacists, nurses, physicians, and others involved in the preparation and dispensation of these agents, and who may be exposed to the body fluids of patients

treated with these agents. Several studies demonstrate that these agents can be detected in the work environment and measured in workers,233 and there is concern about the possible genotoxic effects from these exposures.237 The worker may absorb these xenobiotics by either the dermal, inhalational, or gastrointestinal route. The factors determining the amount of worker exposure include the nature of the work, the amount of drug used, the frequency and duration of exposure, the physical and chemical nature of the drug, and the use of ventilated cabinets and personal protection equipment during the handling of these agents. The workplace guidelines for antineoplastics fall under the broader category of hazardous agents. A sample list of drugs considered as hazardous agents by National Institute for Occupational Safety and Health (NIOSH) is available for further information.51 NIOSH defines a drug as a hazardous agent if it is either carcinogenic, teratogenic, genotoxic, associated with developmental reproductive toxicity, or toxic to organs at low dose.

or

Regulatory and workplace recommendations for exposure levels and the waste management of these agents are available from various agencies and organizations. These recommendations are limited in scope because only a small number of xenobiotics or adverse health effects have been adequately studied, and many agents do not meet the current definition for inclusion. US Environmental Protection Agency (Resource Conservation and Recovery Act, 40 CFR §§260–279) regulates 9 antineoplastics (arsenic trioxide chlorambucil, cyclophosphamide, daunomycin, melphalan, mitomycin C, naphthylamine mustard, streptozocin, and uracil mustard) and the equipment and devices associated with their preparation or delivery, as well as their disposal, as hazardous waste.218 The current recommendations for worker safety with these agents in the workplace includes the proper management of the work environment (eg, storage, handling, preparation, administration, use of personal protection equipment, decontamination, waste disposal) and the institution of a medical

surveillance

program

with

approved

laboratory

testing.9 , 195

Summary The antineoplastics are a unique therapeutic class because their cytotoxicity is a direct effect. Medicine is challenged to carefully balance this measure so that there is limited damage to native cells, and thus the patient. Over the years, the number of antineoplastic exposures reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System has remained small; however, the consequences of toxicity to the patient in these reports were great. The majority of these occurrences were iatrogenic, involving misreading of the product label, and P.819 errors in dosing and transcription of orders (Chap. 134 ). A key element was the lack of familiarity of the healthcare provider with the use of these select xenobiotics. The number of antineoplastics and their indicated use have increased over the years and will continue in this fashion into the future, increasing the chance for medical error and patient toxicity. The clinical manifestations of toxicity can develop in various organ systems and are primarily determined by the mechanism of action, route of administration, and duration of exposure. The gut epithelium and bone marrow are extremely susceptible to toxicity because of their high mitotic activity. They are important because their failure will lead to overwhelming sepsis and death. Treatment remains primarily supportive in nature. New additions in this area include carboxypeptidase, the antidote for MTX, and G-CSF to limit the severity of neutropenia. Further work is necessary to define the role of erythropoietin in exposures resulting in anemia. Although cytoprotectants will continue to be developed, they cannot be relied on to rescue patients from exposures because their number will be few in comparison to the quantity of available antineoplastics and their effectiveness limited to pretreatment.

Thus, prevention is the best treatment, which can be accomplished by maintaining a heightened awareness when working with these agents, educating the patient and healthcare provider regarding their use, and providing increased skilled care.

Acknowledgment This chapter was written by Richard Y Wang in his private capacity. No official support or endorsement by the Centers for Disease Control and Prevention is intended or should be inferred. Paul Calabresi, MD, contributed to this chapter in a previous edition.

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membranes. Am J Kidney Dis 1996;28:846–854. 279. Wasserman E, Myara A, Lokiec F, et al: Severe CPT-11 toxicity in patients with Gilbert's syndrome: Two case reports. Ann Oncol 1997;8:1049–51. 280. Weinstein GD: Methotrexate. Ann Intern Med 1977;86:199–204. 281. Weiss HD, Walker MD, Wiernick PH: Neurotoxicity of commonly used antineoplastic agents. N Engl J Med 1974;29:75–81. P.825 282. Whittaker JA, Al-Ismail SA: Effect of digoxin and vitamin E in preventing cardiac damage caused by doxorubicin in acute myeloid leukemia. Br Med J 1984;288:283–284. 283. Widemann BC, Balis FM, Murphy RF, et al: Carboxypeptidase-G2 , thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. J Clin Oncol 1997;15:2125–2134. 284. Widemann BC, Hetherington ML, Murphy RF, et al: Carboxypeptidase-G2 rescue in a patient with high-dose methotrexate-induced nephrotoxicity. Cancer 1995;1;76:521–526. 285. Wilding G, Caruso R, Lawrence TS, et al: Retinal toxicity after high-dose cisplatin therapy. J Clin Oncol 1985;3:1683–1689.

286. Winchester JF, Rahman A, Tilstone WJ, et al: Will hemoperfusion be useful for cancer chemotherapeutic drug removal? Clin Toxicol 1980;17:557–569. 287. Wolfson S, Olney MB: Accidental ingestion of a toxic dose of chlorambucil. Report of a case in a child. JAMA 1957;165:239–240. 288. Wortman JR, Lucas VS, Schuster E, et al: Sudden death during doxorubicin administration. Cancer 1979;44:1588–1590. 289. Yancey RS, Talpaz M: Vindesine-associated angina and ECG changes. Cancer Treat Rep 1982;66:587–589. 290. Zaragoza MR, Ritchey ML, Walter A: Neurologic consequences of accidental intrathecal vincristine: A case report. Med Pediatr Oncol 1995;24:61–62. 291. Zbinden G, Brandle E: Toxicologic screening of daunorubicin, NSC-82151, Adriamycin, NSC-123127 and their derivatives in rats. Cancer Chemother Rep 1975;59:707–715. 292. Zoubek A, Zaunschirm HA, Lion T, et al: Successful carboxypeptidase G2 rescue in delayed methotrexate elimination due to renal failure. Pediatr Hematol Oncol 1995;12:471–477. 293. Zulian GB, Tullen E, Maton B: Methylene blue for ifosfamide associated encephalopathy. N Engl J Med 1996;332:1239–1240.

294. Zweier JL: Iron-mediated formation of an oxidized Adriamycin free radical. Biochim Biophys Acta 1985;839:209–213.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Antidotes in Depth - Leucovorin (Folinic Acid) and Folic Acid

Antidotes in Depth Leucovorin (Folinic Acid) and Folic Acid Mary Ann Howland

Pharmacology

Folinic

Acid

Folic acid, an essential water-soluble vitamin, consists of a pteridine ring joined to PABA (para-aminobenzoic acid) and glutamic acid.6 Folic acid is the most common pharmaceutical preparation of the many folate congeners that exist in nature and perform essential cellular metabolic functions. After absorption, folic acid is reduced by dihydrofolic acid reductase (DHFR) to tetrahydrofolic acid, which accepts 1-carbon groups.

Tetrahydrofolic acid serves as the precursor for several biologically active forms of folic acid, including 5-formyltetrahydrofolic acid, which is best known as folinic acid, leucovorin, and citrovorum factor. These biologically active forms of folate are enzymatically interconvertible and function as cofactors, providing the 1-carbon groups necessary for many intracellular metabolic reactions, including the synthesis of thymidylate and purine nucleotides, which are essential precursors of DNA.21,23,27,28,32 The minimum daily requirement of folate is normally 50 µg, but in pregnant women and nutritionally deprived, acutely ill patients, 100 to 200 µg may be required.6,7

Role

in

Methotrexate

Toxicity

Methotrexate, an antimetabolite, is a structural analog of folic acid, differing only in the substitution of an amino group for a hydroxyl group at the number 4 position of the pteridine ring (see Fig. 52-1). Methotrexate binds to the active site of DHFR, rendering it incapable of reducing folic acid to its biologically active forms, and incapable of regenerating the necessary active forms required for the synthesis of purine nucleotides and thymidylate. At physiologic pH the binding between methotrexate and DHFR is competitive, with an inhibition constant of about 1 µmol/L.25 Leucovorin is a reduced, active form of folate. As such, it does not require DHFR for enzymatic interconversion to the form required for purine nucleotide and thymidylate formation. Leucovorin rescue is the term used to describe the practice of limiting the toxic effects of high-dose methotrexate therapy. Folic acid would be ineffective to counteract methotrexate toxicity because DHFR would be unavailable to convert folic acid to the necessary reduced and active forms.

Role

in

Methanol

Toxicity

Administering folic acid to monkeys accelerates formate

metabolism.17 Pretreatment with folic acid or leucovorin decreased formate levels and the accompanying metabolic acidosis, without affecting the rate of methanol elimination.19 Leucovorin was still effective in hastening the elimination of formate when given 10 hours after methanol administration. Other studies demonstrate that rats and monkeys experimentally made folate-deficient develop methanol toxicity at lower methanol levels. 11 Total folate, leucovorin, and folate dehydrogenase (which increases leucovorin levels) are all diminished in the livers of methanol-poisoned humans.11 In an analysis8 of a single methanol-poisoned patient who was given hemodialyzed, the half-life of formate was methanol-poisoned patient treated without half-life was 2.8 hours.8 This comparative

folate and ethanol and 1.1 hours.20 In another folate, the formate data is inadequate to

draw definitive conclusions, but may support the therapeutic role of folate, in addition to that of fomepizole and hemodialysis.

Leucovorin

Pharmacokinetics

Leucovorin is naturally formed in the body as the active (l or –) isomer, whereas the commercial preparation consists of equal amounts of the inactive (d or +) and active (l or –) isomers. The pharmacokinetics of the racemic mixture of leucovorin and its active metabolite were studied after IV infusion, and as a constant infusion in normal human volunteers.15,29 During constant infusion, the steady-state concentration for the active isomer was 2.33 µmol, the half-life was 35 minutes, and the volume of distribution was 13.6 L. The active isomer is metabolized to an active metabolite (L-5-CH3-THF). A more recent study detected no adverse effects of the inactive isomer on the intracellular uptake of the active isomer and concluded that giving the active isomer provided no pharmacokinetic advantage over the racemic mixture.26 P.827

The pharmacokinetics of orally administered leucovorin was studied in healthy, fasted, male volunteers in single doses ranging from 20–100 mg, and 200 mg IV over 5 minutes as compared to 200 mg orally.16,22 Bioavailability decreased from 100% for the 20-mg dose to 78% for the 40-mg dose, and ultimately to 31% for the 200-mg dose. A microbiologic assay was used to measure total tetrahydrofolates (reduced and active folates). Normal plasma folate levels are approximately 0.05 µmol/L.9 The 200-mg oral dose produced a peak plasma concentration of 1.82 µmol/L, compared to 0.66 µmol/L for the 20-mg oral dose and 27.1 µmol/L for the 200-mg IV dose.16,22

Leucovorin Dosing Overdoses

for

Methotrexate

When a patient overdoses on methotrexate, a dose of leucovorin estimated to produce the same plasma concentration as the methotrexate dose should be given as soon as possible and, preferably, within 1 hour. One mole of methotrexate weighs 455 daltons and 1 mole of leucovorin calcium weighs 511 daltons. Because of the safety of leucovorin and because of the toxicity of methotrexate, underdosing leucovorin should be avoided. Although plasma concentrations are often closely followed in patients on diverse oncologic regimens,2,3 it is inappropriate to wait for a methotrexate plasma concentration before initiating treatment with leucovorin in the overdose setting, or in the treatment of tubal pregnancies.1 The toxic threshold for methotrexate is reported to be 1 × 10- 8 mol/L (0.01 µmol/L or 10 nmol/L).4 Normal plasma folate levels are in the range of 13–43 nmol/L. In a patient who is not receiving methotrexate therapeutically, there is no need to permit any methotrexate to remain unantagonized by leucovorin. For example, if a child unintentionally ingests one hundred 2.5-mg methotrexate tablets for a total dose of 250 mg, only part of this

dose is absorbed because methotrexate absorption is saturable.5 The bioavailability of methotrexate decreases from 100% with doses less than 30 mg/m 2 to approximately 10–20% with doses greater than 80 mg/m2 . In this case, it is safe to assume that a bioavailability of 50% would result in an absorbed dose of methotrexate of 125 mg. For this substantial exposure an intravenous dose of 125 mg of leucovorin could be given over 15–30 minutes. This dose of IV leucovorin should be repeated every 3–6 hours until the methotrexate concentration is less than 1 × 108 mol/L, and preferably zero. The methotrexate halflife may vary from 5–45 hours, depending on the dose and the patient's renal function. For this reason, leucovorin therapy should be continued for 12–24 doses (3 days) or longer if methotrexate concentrations are unavailable. Patients who may develop thirdspace storage in ascites or pleural effusions may also require leucovorin dosing for an extended period of time. Patients with bone marrow toxicity require more prolonged dosing because plasma half-lives of methotrexate do not reflect persistent intracellular concentrations. Unintentional overdose with intrathecal methotrexate is potentially quite serious and is dose dependent. In these cases, intravenous leucovorin should be administered. Intrathecal leucovorin was considered a major factor in the death of a child given a slightly higher dose of intrathecal methotrexate than was prescribed.10,14 Not all intrathecal methotrexate overdoses require aggressive intervention, but consultation with experienced hematologists/oncologists and medical toxicologists is warranted.12 An intravenous leucovorin dose of 100 mg/m2 every 3–6 hours should be effective, in all but the most severe overdoses. A constant intravenous infusion of 21 mg/m2 /h has been safely administered for 5 days. A transition to the oral administration of leucovorin depends on the plasma concentration of the methotrexate and whether adequate plasma concentrations of

leucovorin can be achieved by that route. In adults, a 200-mg oral dose produces a peak plasma concentration of 1.82 µmol/L as compared to 27.1 µmol/L with a 200-mg IV dose. Administration of activated charcoal precludes the subsequent administration of oral leucovorin. In addition to leucovorin, other modalities to treat methotrexate overdoses should be used (activated charcoal, urinary alkalinization), or considered (carboxypeptidase G, extracorporeal removal, and thymidine) (Chap. 52) .

Adverse

Effects

and

Safety

Issues

Reports of adverse reactions to parenteral injections of folic acid or leucovorin are uncommon; however, adverse reactions may include allergic or anaphylactoid reactions.6 Seizures are rarely associated with leucovorin administration.18 The calcium content of leucovorin warrants a slow intravenous infusion at a rate not faster than 160 mg/min in adults. Leucovorin should never be administered intrathecally.10,13,24,31

Dos i n g The routine dose of leucovorin for “leucovorin rescue― ranges from 10–25 mg/m2 IM or IV every 6 hours for 72 hours to 100 mg/m2 every 3 hours in patients with renal compromise. If administration to neonates is necessary, a benzyl alcohol-free preparation must be used because of the toxicity of benzyl alcohol in neonates (Chap. 53) .30 For methotrexate overdoses, a dose of leucovorin equal to that of the ingested methotrexate dose should be administered IV as soon as possible over 15–30 minutes, but not faster than 160 mg/min in adults. An intravenous leucovorin dose of 100 mg/m2 every 3–6 hours should be effective, in all but the most severe overdoses. This dose should be continued for several days, or until the MTX serum

concentration falls below 1 × 10- 8 mol/L and no bone marrow toxicity is evident. Either folic acid or leucovorin (folinic acid) should be administered parenterally at the first suspicion of methanol poisoning. No complications are reported with the use of 50–70 mg of IV folic acid every 4 hours for the first 24 hours, in the treatment of methanol-poisoned patients.20 The precise dose necessary is unknown, but 1–2 mg/kg every 4–6 hours is probably reasonable. The folic acid should be continued until the methanol and formate are eliminated. As the first dose is usually administered prior to hemodialysis, a second dose should be administered at the completion of hemodialysis, because hemodialysis will probably remove this highly water-soluble vitamin.

Availability Folic acid is available parenterally in 10-mL multidose vials with 1.5% benzyl alcohol in concentrations of 5 or 10 mg/mL, from a P.828 variety of manufacturers. Once opened, this vial must be kept refrigerated. Leucovorin (folinic acid) powder for injection is available in 50-, 100-, and 350-mg vials. Reconstitution with sterile water for injection—5 mL to the 50-mg vial, or 10 mL to the 100-mg vial—results in a final concentration of 10 mg/mL. Adding 17 mL of sterile water for injection to the 350-mg vial results in a final concentration of 20 mg/mL. Because of the calcium content, the rate of intravenous administration should not be faster than 160 mg/min in adults. Leucovorin is also available orally in a variety of strengths, including 5-, 10-, 15-, and 25-mg tablets.

Summary

Leucovorin (folinic acid) is the primary antidote for a patient who receives an overdose of methotrexate. Leucovorin is the biologically active, reduced form of folic acid, the synthesis of which is prevented by methotrexate. Only leucovorin (folinic acid) is an acceptable antidote for a patient with methotrexate toxicity, but either folic acid or leucovorin is acceptable for a patient poisoned by methanol. Following a methanol overdose, folic acid enhances the elimination of formate.

References 1. American College of Obstetricians and Gynecologists practice bulletin. Medical management of tubal pregnancy. Number 3, December 1998. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 1999;65:97–103. 2. Bleyer WA: New vistas for leucovorin in cancer chemotherapy.

Cancer

19898;63:995–1007.

3. Booser DJ, Walters RS, Holmes FA, Hortobagyi GN: Continuous-infusion high-dose leucovorin with 5-fluorouracil and cisplatin for relapsed metastatic breast cancer: A phase II study. Am J Clin Oncol 2000;23:40–41. 4. Chabner BA, Young RC: Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues. J Clin Invest 1973;52:1804–1811. 5. Gibbon BN, Manthey DE: Pediatric case of accidental oral overdose of methotrexate. Ann Emerg Med 1999;34:98–100.

6. Hillman RS: Hematopoetic agents: Growth factors, minerals and vitamins. In: Hardman JG, Limbird CE eds: Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp. 1487–1517. 7. Houben PF, Hommes OR, Knaven PJ: Anticonvulsant drugs and folic acid in young mentally retarded epileptic patients. A study of serum folate, fit frequency and IQ. Epilepsia 1971;12:235–247. 8. Jacobsen D, McMartin KE: Methanol and ethylene glycol poisonings: Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1:309–334. 9. Janinis J, Papakostas P, Samelis G, et al: Second-line chemotherapy with weekly oxaliplatin and high-dose 5fluorouracil with folinic acid in metastatic colorectal carcinoma: A Hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study. Ann Oncol 2000;11:163–167. 10. Jardine LF, Ingram LC, Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol 1996;18:302–304. 11. Johlin F, Fortman C, Nghiem D, et al: Studies on the role of folic acid and folate dependent enzymes in human methanol poisoning. Mol Pharmacol 1987;31:557–561. 12. Lampkin BC, Wells R: Intrathecal leucovorin after intrathecal methotrexate. J Pediatr Hematol Oncol 1996;18:249.

13. Lee ACW, Wong KW, Fong KW, So KT: Intrathecal methotrexate overdose. Acta Pediatr 1997;86:434–437. 14. Levitt M, Nixon PF, Pincus JH, et al: Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5formyltetrahydrofolate. J Clin Invest 1971;50:1301–1308. 15. Lonardi F, Jirillo A, Bonciarelli G, et al: Toxicity of laevoleucovorin and dose lowering. Eur J Cancer 1992;28A:1007–1008. 16. McGuire BW, Sia LL, Haynes JD, et al: Absorption kinetics of orally administered leucovorin calcium. NCI Monogr 1987;5:47–56. 17. McMartin KE, Martin-Amat G, Makar AB, et al: Methanol poisoning. V: Role of formate metabolism in the monkey. J Pharmacol Exp Ther 1977;201:564–572. 18. Metropol NJ, Creaven PJ, Petrelli N, et al: Seizures associated with leucovorin administration in cancer patients. J Natl Cancer Inst 1995; 87:56–58. 19. Noker PE, Eells MS, Tephly TR: Methanol toxicity: Treatment with folic acid and 5-formyltetrahydrofolic acid. Alcohol Clin Exp Res 1980;4:378–383. 20. Osterloh J, Pond S, Grady S, et al: Serum formate concentrations in methanol intoxication as a criterion for hemodialysis. Ann Intern Med 1986;104:200–203.

21. Patel R, Newman EM, Villacorte DG, et al: Pharmacology and phase I trial of high-dose oral leucovorin plus 5fluorouracil in children with refractory cancer: A report from the Children's Cancer Study Group. Cancer Res 1991;51:4871–4875. 22. Priest DG, Schmitz JC, Bunni MA, et al: Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously. J Natl Cancer Inst 1991;83:1806–1812. 23. Reynolds EH: Effects of folic acid on the mental state and fit-frequency of drug-treated epileptic patients. Lancet 1967;1:1086–1088. 24. Riva L, Conter V, Rizzari C, et al: Successful treatment of intrathecal methotrexate overdose with folinic acid rescue: A case report. Acta Paediatr 1999;88:780–782. 25. Salmon SE, Sartorelli AC: Cancer chemotherapy. In: Katzung BG, ed: Basic and Clinical Pharmacology, 7th ed. Norwalk, CT, Appleton & Lange, 1998, pp. 889–891. 26. Schleyer E, Rudolph KL, Braess J, et al: Impact of the simultaneous administration of the (+)- and (-)-forms of formyl-tetrahydrofolic acid on plasma and intracellular pharmacokinetics of (-)-tetrahydrofolic acid. Cancer Chemother Pharmacol 2000;45:165–171. 27. Smith DB, Racusen LC: Folate metabolism and the anticonvulsant efficacy of phenobarbital. Arch Neurol 1973;28:18–22.

28. Stover P, Schirch V: The metabolic role of leucovorin. Trends Biochem Sci 1993;18:102–106. 29. Straw JA, Newman EM, Doroshow JH: Pharmacokinetics of leucovorin (d l-5 formyltetrahydrofolate) after intravenous injection and constant intravenous infusion. NCI Monogr 1987;5:41–45. 30. Tenenbein M: Recent advancements in pediatric toxicology. Pediatr Clin North Am 1999;46:1179–1788. 31. Trinkle R, Wu JK: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol 1997;19:267–268. 32. Weh HJ, Bittner S, Hoffknecht M, et al: Neurotoxicity following weekly therapy with folinic acid and high-dose 5fluorouracil 24h infusion in patients with gastrointestinal malignancies. Eur J Cancer 1993;29A: 1218–1219.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > C - Pharmaceuticals > Chapter 53 - Pharmaceutical Additives

Chapter

53

Pharmaceutical

Additives

Sean P. Nordt Lisa E. Vivero

A 32-year-old man was brought to the emergency department (ED) after being confused and inarticulate at a motel by paramedics. The patient's tongue was b and he had urinary incontinence. In the ED, the patient had a blood pressure of

mm Hg, a pulse of 101 beats/min, respirations of 20 breaths/min, and a tempe 97.4°F (36.3°C). Physical examination revealed abrasions on the left side of his pupils were 6 mm, equal, and reactive to light; his lungs were clear to ausc and his abdomen was soft and nontender. A 12-lead electrocardiogram showed tachycardia, a rate of 102 beats/min, a PR interval of 200 msec, a QRS complex msec, and a QTc interval of 450 msec. An old ED chart revealed that the patient suffered a gunshot wound to the head and subsequently had developed a seizur disorder.

A loading dose of 1 g phenytoin equivalents of fosphenytoin was given intraven over 5 minutes. Immediately following the fosphenytoin, the patient became hypotensive with a blood pressure of 85/50 mm Hg. His heart rate decreased to beats/min, and his QRS interval widened to 140 msec. Atropine 1 mg was given intravenously, resulting in an increase in heart rate to 82 beats/min. Intravenou

sodium chloride solution at 1 L over 15 minutes was administered, which restor blood pressure to 140/60 mm Hg. Several minutes later the patient's QRS narro 100 msec without other intervention. Subsequently, it was realized that the nur unintentionally given phenytoin instead of fosphenytoin. The patient had an adv reaction to the rapid infusion of phenytoin, which contains 400 mg/mL of propy glycol.

History

and

Epidemiology

During the last century there were several US outbreaks of toxicity associated w pharmaceutical additives (Chap. 1 ). The 1937 Massengill sulfanilamide disaster most notorious of these epidemics. Diethylene glycol, an excellent solvent, also nephrotoxin, was substituted for the additives propylene glycol and glycerin in t formulation of a new sulfanilamide antibiotic because of a lower cost.25 , 58 , 65

result, more than 100 people died from acute renal failure.25 More recently, ou of acute renal failure occurred when diethylene glycol was used to solubilize acetaminophen in South Africa, Bangladesh, Nigeria, and Haiti.18 , 47 , 67 , 108

In December 1983, E-Ferol, a new parenteral vitamin E formulation, was introdu contained 25 U/mL of α-tocopherol acetate, 9% polysorbate 80, 1% polysorbat and water for injection. At the time, no premarketing testing was required for n formulations of an already-approved xenobiotic. Several months after its release

syndrome in low-birth-weight infants, characterized by thrombocytopenia, renal dysfunction, cholestasis, hepatomegaly, and ascites, was described. 1 , 95 Thirty deaths and 43 cases of severe symptoms were attributed to E-Ferol. Vitamin E thought to be the cause and E-Ferol was recalled from the market 4 months afte release. It is now believed that the polysorbate emulsifiers were responsible.1

More recently there has been concern over potential mercury toxicity from the preservative thimerosal, a mercury derivative that has been used in parenteral for 70 years. Although there are a few reports of toxicity from large oral and in thimerosal dosages, no evidence has yet shown toxicity to result from routine vaccination. Potential concerns of toxicity, particularly autism, have spurred on efforts to eliminate thimerosal from vaccines, wherever possible. Although these additive-related occurrences are rare, relative to the frequency

pharmaceutical additive use, they illustrate the potential of pharmaceutical add toxicity.

Pharmaceuticals are labeled specifically to focus attention on the active ingredie a product, thus giving the misimpression that additive ingredients are inert and unimportant. Additives, or excipients, as they are more properly termed, are n to act as vehicles, add color, improve taste, provide consistency, enhance stabi solubility, and to impart antimicrobial properties to medicinal formulations. Alth is true that most cases of excipient toxicity involve exposure to large quantities, prolonged or improper use, these adverse events are nonetheless related to the toxicologic properties of the excipient.

Prior to selecting the specific additives and quantity necessary for a drug formu the drug manufacturer must consider several factors, including the active ingre

physical form, its solubility and stability, the desired final dosage form and route administration, and compatibility with the dispensing container materials. The s active ingredient may require different excipients to impart appropriate pharm characteristics to different dosage forms, such as in long-acting and immediate

formulations. Similarly, multiple-dose injection vials containing the same active ingredients as single-dose vials specifically require the addition of a bacteriosta not necessary for single-dose vials. P.830

Unlike requirements for active ingredients, there is no specific FDA approval sys pharmaceutical excipients. As such, the FDA determines the amount and type of necessary to support the use of a specific excipient on a case-by-case basis. Un current practice, only excipients that were previously permitted for use in foods pharmaceuticals are defined as generally recognized as safe (GRAS), or “GR listed.― All components of a pharmaceutical product, including excipients, mu produced in accordance with current good manufacturing practice standards to purity. Recently, the Safety Committee of the International Pharmaceutical Exc Council developed guidelines for the toxicologic testing of new excipients.136 Be patent protection laws, it was not until very recently that manufacturers were to provide a list of inactive ingredients contained in all pharmaceutical products Although it is becoming easier to identify pharmaceutical additives in products, information on their effects and the mechanisms by which they cause adverse

are often unknown or difficult to obtain. Cardiovascular Chlorobutanol Propylene glycol Fluid and electrolyte Polyethylene glycol Propylene glycol Sorbitol Gastrointestinal Sorbitol Neurologic Benzyl alcohol Chlorobutanol Polyethylene glycol Propylene glycol Thimerosal Ophthalmic Benzalkonium chloride Chlorobutanol Renal Polyethylene glycol Propylene glycol

TABLE 53-1. Potential Toxicity by Organ System of Various Pharmace Excipients

This chapter summarizes the available literature on commonly used additives a with direct toxicities. Data on pharmacokinetics and mechanism of toxicity are where data are available. Although many additives are associated with hyperse reactions, including anaphylaxis, these are not discussed because of their nonpharmacologic basis. However, excipients should always be considered as p causative agents in patients developing hypersensitivity reactions (Table 53-1 )

Benzalkonium

Chloride

Figure. No Caption Available.

Benzalkonium chloride (BAC) or alkyldimethyl (phenylmethyl) ammonium chloride quaternary ammonium cationic surfactant composed of a mixture of alkyl benzy dimethyl ammonium chlorides. Although it is the most preservative in the United States, it is also considered ) .79 , 85 Benzalkonium chloride is also used in otic and small-volume parenterals. The antimicrobial activity of

widely used ophthalmic the most cytotoxic (Table nasal formulations, and i BAC includes Gram-posit

Gram-negative bacteria, and some viruses, fungi, and protozoa. Because of its onset of action, good tissue penetration, and long duration of action, BAC is pr over other preservatives. The concentration of BAC in ophthalmic medications u ranges from 0.004 to 0.01%.85 Ingestion of strong BAC solutions (greater than can be caustic (Chap. 98 ).

Ophthalmic

Toxicity

Corneal epithelial cells harvested from human cadavers within 12 hours of death exposed to a medium containing 0.01% BAC.134 The surfactant properties of BA resulted in intracellular matrix dissolution and loss of epithelial superficial layer Following exposure to the medium, mitotic activity ceased, and degenerative ch corneal epithelium were noted. During a 24-hour observation period, epithelial cytokinetic or mitotic activity did not occur. Patients with a compromised cornea epithelium may be at increased risk for the adverse corneal effects of BAC.134

Two case reports demonstrate the potential toxicity of BAC and the difficulty in recognizing it. A 36-year-old woman complained of decreased vision when she inadvertently switched from Lensrins, a contact lens cleaning solution, to Dacrio

isotonic boric acid solution, preserved with BAC. After 3 days, she had inflamm pain, and decreased visual acuity. Examination of the cornea revealed many su punctate erosions of the epithelium. An in vitro experiment identified significant of BAC to soft contact lenses.53 In the second case, a 56-year-old man diagnose keratoconjunctivitis sicca was treated with topical antibiotics and artificial tears containing BAC. Following 1 year of

P.831 continual use, the patient developed intractable pain, photophobia, and extensi breakdown of the corneal epithelium. Not suspecting the BAC-containing produc patient continued to use the artificial tears solution for another 9 years despite continued pain and decreasing visual acuity. Replacement with a preservative-fr solution resulted in resolution of pain, photophobia, and corneal changes.85 Artificial tears 0.005–0.01

(various)

Acular (ketorolac) 0.01 Betagan (levobunolol) 0.004 Betoptic (betaxolol) 0.01 Ciloxan (ciprofloxacin) 0.006 Cyclogyl (cyclopentolate) 0.01 Decadron (dexamethasone) 0.02 Garamycin (gentamicin) 0.01 Glaucon (epinephrine) 0.01 Isopto Carpine (pilocarpine) 0.01 Murocoll-2 (scopolamine/phenylephrine) 0.01

Mydriacyl (tropicamide) 0.01 Phenylephrine (various) 0.005–0.01 Ocuflox (ofloxacin) 0.005 Ocupress (carteolol) 0.005 Polytrim (polymyxin B sulfate/trimethoprim) 0.004 Timoptic (timolol) 0.01 Tobrex (tobramycin) 0.01 Visine (tetrahydrozoline) 0.01 Medication

Percent

(%)

TABLE 53-2. Benzalkonium Chloride Concentrations of Common Ophth Medications

Nasopharyngeal

and

Oropharyngeal

Toxicity

Human adenoidal tissue was exposed to oxymetazoline nasal spray preserved w at concentrations ranging from 0.005–0.15 mg/mL for 1–30 minutes.13 Irre and broken epithelial cells were seen with all concentrations, however, it was e earlier and more frequently with the higher concentrations. The number of beat ciliary bodies also decreased as the duration and the concentrations increased. Benzalkonium chloride may decrease the viscosity of the normal protective muc lining of the naso- and oropharynx, resulting in cytotoxicity.

Giving rats 1 of 3 nasal steroid sprays preserved with either 0.031% or 0.022% their right nostril twice daily for 21 days caused squamous cell metaplasia and a decrease in the number of goblet cells, cilia, and mucus.14 No histologic change

occurred in rats receiving the preservative-free steroid or in tissue exposed to sodium chloride solution administered into the left nostril as the control. Similar another study, epithelial desquamation, inflammation, and edema occurred when and 0.10% BAC was applied hourly to the nasal cavities of rats for 8 hours.81 N developed in the nasal cavities of rats receiving 0.01% BAC.

Benzyl

Alcohol

Figure. No Caption Available.

Benzyl alcohol (benzene methanol) is a colorless, oily liquid with a faint aromat that is most commonly added to pharmaceuticals as a bacteriostatic agent (Tabl In 1982, a “gasping― syndrome, which included hypotension, bradycardia respirations, hypotonia, progressive metabolic acidosis, seizures, cardiovascular

collapse, and death, was first described in low-birth-weight neonates in intensiv units.20 , 60 , 90 All the infants had received either bacteriostatic water or sodiu chloride solution containing 0.9% benzyl alcohol to flush intravenous catheters o parenteral medications reconstituted with bacteriostatic water or saline.20 , 60 T

syndrome occurred in infants who had received greater than 99 mg/kg of benzy (range, 99–234 mg/kg).60 The World Health Organization (WHO) currently es the acceptable daily intake of benzyl alcohol to be not more than 5 mg/kg body weight.22

Pharmacokinetics

In adults, benzyl alcohol is oxidized to benzoic acid, conjugated in the liver with and excreted in the urine as hippuric acid. The immature metabolic capacities o diminish their ability to metabolize and excrete benzyl alcohol.60 Preterm babies greater ability to metabolize benzyl alcohol to benzoic acid than do term babies,

unable to convert benzoic acid to hippuric acid, possibly because of glycine def This results in the accumulation of benzoic acid (Fig. 53-1 ).82 A fatal case of m acidosis was reported in a 5-year-old girl who had received 2.4 mg/kg/h diazep preserved with benzyl alcohol for 36 hours to control status epilepticus. Elevate benzoic acid levels were identified in serum and urine samples. The estimated d dosage of benzyl alcohol was 180 mg/kg. 60 , 86 Ativan (lorazepam) 2.0 0.02 Bacteriostatic water for 1.5 —

injection

Bacteriostatic saline for injection 1.5 — Bactrim, Septra (trimethoprim-sulfamethoxazole) 1.0 0.61b Bumex 1.0

(bumetanide)

0.03 Compazine (prochlorperazine) 0.75 0.01 Cordarone (amiodarone) 2.0 0.42b Lasix (furosemide) 0.9 0.04 Librium (chlordiazepoxide) 1.5 0.03 Methotrexate

0.9 0.01 Norcuron (vecuronium) 0.9 0.01 Tracrium (atracurium) 0.9 0.03 Valium (diazepam) 1.5 0.03 Vasotec (enalapril) 0.9 0.01 VePesid (etoposide) 3.0 0.14 Versed 1.0 0.01 Vistaril 0.9 0.01 a b

(midazolam)

(hydroxyzine)

Based on dosage for a 70-kg person. Based on 24-hour dosage. Medication

Percent

(%)

mL/Average

Dosea

TABLE 53-3. Benzyl Alcohol Concentration of Common Medications

Neurologic

Toxicity

Benzyl alcohol is believed to have a role in the increased frequency of cerebral intraventricular hemorrhages and mortality reported in very-low-birth-weight (V

infants (weight Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > D - Antimicrobials > Chapter 54 - Antibiotics, Antifungals, and Antivirals

Chapter

54

Antibiotics, Antivirals

Antifungals,

and

Christine M. Stork A 56-year-old man with a past medical history significant for lumbar spinal stenosis and a recent laminectomy for chronic back pain was admitted to the hospital for a trial of intrathecal morphine. Because of a medication error, the postoperative order for intravenous cefazolin was administered into the intrathecal catheter. The error was detected when the patient complained of back pain 13 hours after initiation of the infusion; an estimated total dose of 350 mg (2.5 mL/h × 13.5 h at 10 mg/mL) was infused. Soon thereafter, the patient developed generalized seizures, was intubated for airway support, and was treated using intravenous benzodiazepines, phenytoin, and phenobarbital (30 mg). Seizure activity resolved and the patient was extubated 5 days later.

History

and

Epidemiology

The majority of the adverse effects related to antibiotics occur as

a result of iatrogenic complications rather than intentional overdose. The origins of these complications are diverse and include dosing and decision errors, allergic reactions, adverse drug effects, and drug interactions. Prevention in the form of process improvements and information regarding population risk for adverse drug effects is required to minimize these untoward events. As dosing errors are commonly noted in neonates and infants treated with intravenous antibiotics, careful and constant diligence on the part of all healthcare providers is required to minimize such errors. Antibiotics are more commonly associated with anaphylactic reactions than are other medications. The reason for this is unclear, but it may be a result of their high frequency of use, repeated interrupted exposures caused by intermittent prescriptive use, or because of environmental contamination. A complete and clear allergy history is essential to minimize these reactions in patients being considered for antibiotic therapy. Many adverse effects attributed to antibiotics are difficult to predict even when given patient- and population-specific parameters. In some cases, a diluent or ancillary chemical constituent of the drug is responsible for the adverse effect, as recognized with the use of procaine penicillin G in patients with procaine allergy. Antibiotics are involved in many of the common and severe drug interactions, primarily through the inhibition of metabolic enzymes. Patients being considered for antibiotic therapy should be carefully assessed for the use of concomitant drug therapy that may be pharmacokinetically or pharmacodynamically affected by the chosen antibiotic.

Pharmacology

and

Toxicology

Antibiotic pharmacology is aimed at the destruction of microorganisms through the inhibition of cell-cycle reproduction or by directly altering a critical function within a microorganism.

Table 54-1 lists antibiotics and their associated mechanisms of antimicrobial activity. Often the mechanisms for toxicologic effects following acute overdose differ from the therapeutic mechanisms. Table 54-1 also lists the toxicologic effects and related mechanisms. Table 54-2 lists the pharmacokinetics of each class of drugs.

Antibacterials Aminoglycosides

Figure. No Caption Available.

P.844 P.845 Aminoglycoside antibiotics that are in current use include amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, and tobramycin.

Antibiotic Aminoglycosides Inhibit 30s ribosomal subunit Neuromuscular blockade —inhibits the release of acetylcholine from presynaptic nerve terminals and antagonist at acetylcholine receptors Renal toxicity/ototoxicity —forms an iron complex that inhibits mitochondrial respiration and causes lipid peroxidation Penicillins, cephalosporins, and other β-lactams Inhibit cell wall mucopeptide synthesis Seizures —agonist at picrotoxin binding site causing GABA antagonism Hypersensitivity —immune Other —see text Chloramphenicol Inhibits 50s ribosomal subunit and inhibits protein synthesis in rapidly dividing cells Cardiovascular collapse “Gray baby syndrome― Same as mechanism of action Fluoroquinolones Inhibit DNA topoisomerase and DNA gyrase Same as mechanism of action; binds to cations, particularly, magnesium, seizures Not entirely known; binds to cations, particularly, magnesium; tendon rupture, hyper- and hypoglycemia Linezolid Inhibits bacterial protein synthesis through inhibition of Nformylmethionyl-t RNA None clinically relevant MAOI activity: pressor response to tyramine; and serotonin syndrome with SSRI and possibly meperidine Macrolides and ketolides Inhibit 50s ribosomal subunit in multiplying cells Wide QTc —block delayed rectifier potassium channel

Not entirely known; cytotoxic effect; exacerbation of myasthenia gravis Sulfonamides Inhibit para -aminobenzoic acid and/or para -amino glutamic acid in the synthesis of folic acid None clinically relevant Hypersensitivity —metabolite is hapten leading to hemolysis/methemoglobinemia —exposure to UVB causes free radical formation, which results in an oxidant stress Tetracycline Inhibits 30s and 50s ribosomal subunits; binds to aminoacyl transfer RNA None clinically relevant Unknown Vancomycin Inhibits glycopeptidase polymerase in cell wall synthesis “Red-man syndrome―—anaphylactoid Unknown Antifungal Amphotericin B Binds with ergosterol on cytoplasmic membrane to cause pores to facilitate organelle leak Same as mechanism of action Nephrotoxicity —vehicle deoxycholate may be involved; nephrocalcinosis Triazoles and imidazoles Increase permeability of cell membranes None clinically relevant None clinically relevant ?CYP inhibition

Drug

Pharmacology of Antibiotic Effect

Acute Overdose Adverse Effect and Related Pharmacology

Chronic Administration Adverse Effect and Related Pharmacology

TABLE 54-1. Antibiotic and Antifungal Pharmacology

Antibiotic Aminoglycosides Parenteral 0.25 Renal 2–3 Penicillins, cephalosporins, Oral, parenteral Variable Renal (predominant)

and

other

β-lactams

Variable Chloramphenicol Oral, parenteral, otic 0.5–1.0 90% Hepatic, 10% renal 1.6–3.3 Fluoroquinolones Oral, parenteral Variable Renal 3–5 Ketolides Oral 2.9 L/kg 63% Renal, 37% hepatic (50% of which is CYP3A4)

10–13 Macrolides Oral, parenteral Variable Hepatic Variable Sulfonamides Oral, parenteral Variable Hepatic Variable Tetracyclines Oral Variable Hepatic 6–26 Vancomycin Parenteral 0.2–1.25 Renal 4–6 Antifungal

Amphotericin B Parenteral 4.0 Hepatic 360 Triazoles and imidazoles Oral Variable

Hepatic Variable

Drug

TABLE

Absorption

54-2.

Volume of Distribution (L/kg)

Antibiotic

and

Elimination Route

Antifungal

Halflife (h)

Pharmacokinetics

Kanamycin Neomycin Amikacin Gentamicin Tobramycin Streptomycin Amikacin Gentamicin Kanamycin Neomycin Streptomycin Tobramycin Cochlear

TABLE

Cochlear

54-3.

and

Vestibular

Predominant

Vestibular

Aminoglycoside

Renal

Toxicity

As aminoglycosides are only available in parenteral and ophthalmic forms, overdoses of aminoglycoside antibiotics are almost exclusively the result of dosing errors. Fortunately, overdoses are rarely life-threatening, and most patients can be safely managed with minimal intervention.24 , 92 , 122 , 147 The adverse effects of aminoglycosides are generally class based, although subtle differences may exist in the potency with which the adverse effects occur (Table 54-3 ).

Large intravenous doses of aminoglycosides are both sufficiently effective and safe for use in single daily doses.5 Rarely, acute aminoglycoside overdose results in nephrotoxicity, ototoxicity, or vestibular toxicity.140 , 168 In one reported case, postmortem analysis confirmed complete loss of hair cells in the inner and outer cochlear. Aminoglycosides may infrequently exacerbate neuromuscular blockade, particularly at times corresponding to high-peak serum aminoglycoside concentrations (Chap. 66 ).200 , 274 These effects relate to the ability of aminoglycosides to inhibit the release of acetylcholine from presynaptic nerve terminals. This effect is mediated by antagonism by the aminoglycoside of the presynaptic calcium channel, and may be a result of the ability of aminoglycosides to block postsynaptic acetylcholine receptors.2 , 111

Risk factors for enhanced neuromuscular blockade include patients with abnormal neuromuscular junction function, such as those with myasthenia gravis and botulism, and patients receiving concomitant neuromuscular blocking drugs.2

Adverse Effects Associated Therapeutic Use

with

Adverse effects, including nephrotoxicity and ototoxicity, correlate more closely with elevated trough serum concentrations of aminoglycosides than with elevated peak concentrations. 2 , 88 , 129 , 177 , 181 Less-common adverse effects associated with chronic aminoglycoside use include electrolyte abnormalities, allergic reactions, hepatotoxicity, anemia, granulocytopenia, thrombocytopenia, eosinophilia, retinal toxicity, reproductive dysfunction, tetany, and psychosis.61 , 65 , 134 , 153 , 247 , 262 When aminoglycosides are administered at high doses or during once-daily dosing, sepsislike reactions, including chills and malaise, can occur.48 This is likely a result of contaminants that are delivered to the patient during the infusion.

Nephrotoxicity The mechanism of nephrotoxicity and ototoxicity is inconclusive, but appears to include the ability of the aminoglycoside to form reactive oxygen species in the presence of iron. Mitochondrial respiration is inhibited, lipid peroxidation occurs, and stimulation of glutamate activated N -methyl-D-aspartate (NMDA) receptors may play a role.113 , 232 , 241 , 269 The incidence of nephrotoxicity with aminoglycoside therapy is estimated at 5–10%.10 Although the aminoglycosides are almost completely excreted prior to biotransformation in the kidney, a small fraction of filtered aminoglycoside is transported by absorptive endocytosis across the apical membrane of proximal tubular cells where it becomes sequestered within lysosomes. The aminoglycoside binds to and destroys phospholipids contained on brush border membranes in the proximal renal tubule.10 Clinically, acute tubular necrosis occurs after 7–10 days of standard-dose therapy. Laboratory abnormalities include granular casts, proteinuria, elevated urinary sodium, and increased fractional excretion of sodium. Usually the renal dysfunction is reversible; however, irreversible toxicity is reported.9 Functional renal injury occurs days prior to elevations in serum creatinine, and for this reason, a delay in diagnosis is common.233 Risk factors for the development of nephrotoxicity include increasing age, renal dysfunction, female sex, previous aminoglycoside therapy, liver dysfunction, large total dose, long duration of therapy, frequent doses, high trough levels, presence of other nephrotoxic drugs, and the presence of shock.10 , 183 , 209 Because the uptake of aminoglycosides into organs causing toxicity is saturable, appropriate once-daily high-dose regimens are less problematic than several lesser doses given in a single day.

Ot otox icity Ototoxicity can occur after acute or prolonged exposure to aminoglycosides. Both cochlear and vestibular dysfunction are correlated with high aminoglycoside trough concentrations.41 , 182 Because aminoglycosides bioaccumulate in the endolymph and perilymph spaces, they have prolonged contact time with sensory hair cells.146 Vestibular toxicity, caused by destruction of sensory receptor portions of the inner ear or destruction of hair cells in the utricle and saccule, occurs in 0.4–10% of patients.159 , 182 Symptoms include vertigo or tinnitus. Table 54-3 details the relative characteristic toxicity of various aminoglycosides. Full-tone audiometric testing may first show high-frequency hearing loss, which may subsequently progress. Given the inability of cochlear hair cells to regenerate, all hearing loss that develops is permanent. Electronystagmography is the diagnostic tool of choice for vestibular dysfunction, and up to 63% of patients with early findings of vestibular dysfunction may have improvement after discontinuation of the drug.133 Simultaneous administration of other xenobiotics capable of causing ototoxicity enhances ototoxicity of aminoglycoside antibiotics (Chap. 21 ). 36 , 146 , 254 Withdrawal of the offending xenobiotic is indicated in patients with either nephrotoxicity or ototoxicity caused by an aminoglycoside antibiotic. Supportive care is the mainstay of therapy. Experimental treatments in animal models include the use of deferoxamine, glutathione, and NMDA receptor antagonists in an attempt to chelate and/or detoxify a reactive intermediate.195 , 251 The antibiotic ticarcillin forms a renally eliminated complex with aminoglycosides in the blood to provide protection against tobramycin-induced renal toxicity. In humans, ticarcillin removes 50% more aminoglycoside in 48 hours than do 2 hemodialysis sessions.80 However, ticarcillin therapy is generally of limited value because in most instances the serum concentration of the aminoglycoside has decreased before any therapeutic measures

can be employed. The use of ticarcillin should be considered only early after large overdose in patients with either demonstrated toxicity or renal failure where the risks of toxicity are significant.

Penicillins

Penicillins

nucleus

P.846 Penicillin is derived from the fungus Penicillium and many semisynthetic derivatives have clinical utility. Penicillins, as a class, contain a 6-aminopenicillanic acid nucleus, composed of a β-lactam ring fused to a 5-member thiazolidine ring. Classic available penicillins include penicillin G, penicillin V, and the antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and dicloxacillin). Penicillins developed to enhance the spectrum of antibiotic efficacy, particularly against Gram-negative bacilli, include the second-generation penicillins (ampicillin, amoxicillin, bacampicillin, and mezlocillin), third-generation penicillins (carbenicillin and ticarcillin), and fourth-generation penicillins (piperacillin). Table 54-1 lists the pharmacologic mechanism of penicillins and Table 54-2 lists their pharmacokinetic properties. Acute oral overdoses of penicillin-containing drugs are usually not life-threatening. The most frequent complaints following acute overdose are nausea, vomiting, and diarrhea. Rarely, hyperkalemia resulting in electrocardiographic abnormalities occurs after the rapid intravenous infusion of potassium penicillin G to patients with renal failure.

Seizures occur in persons given large intravenous or intraventricular doses of penicillins. 35 , 136 , 150 , 175 , 241 More than 50 million units intravenously are generally required to produce seizures in adults. 239 Penicillin-induced seizures appear to be mediated through an interaction of the drug with the picrotoxin-binding site on the neuronal chloride channel near the γ-aminobutyric acid (GABA) binding site (Chap. 14 ). Binding of the penicillin produces an allosteric change in the receptor that prevents GABA from binding, resulting in a relative lack of inhibitory tone.66 Penicillin analogs (such as imipenem) also cause seizures in both animal models and humans, presumably through a similar mechanism.241 Treatment of patients who develop penicillin-induced seizures include GABA agonists such as the benzodiazepines and barbiturates, if needed. Patients who receive an intraventricular overdose may require cerebrospinal fluid exchange to attenuate seizure activity.150 There are rare reports of amoxicillin overdose resulting in frank hematuria and renal failure, and a single case report of penicillin-associated hearing loss.28 , 32 , 98

Adverse Effects Associated Therapeutic Use

with

Penicillins are associated with a myriad of adverse effects after therapeutic use, the most common of which are allergic reactions. Penicillins are commonly implicated in immune-related reactions such as bone marrow suppression, cholestasis, hemolysis, interstitial nephritis, and vasculitis.6 , 95 , 123 , 187 , 188 , 250 Rare effects include pemphigus after penicillin use and corneal damage after the use of methicillin. 20 , 278

Acute

Allergy

Penicillins are the pharmaceuticals most commonly implicated in

the development of acute anaphylactic reactions. Anaphylactic reactions are severe life-threatening immune-mediated (IgE) reactions involving multiple organ systems that occur most often immediately after exposure to a triggering agent. Table 54-4 lists the classifications of anaphylactic reactions. Anaphylaxis to penicillin is typically seen after IgE antibody formation, which can only occur after prior exposure to penicillin. Life-threatening clinical manifestations occurring after anaphylaxis can include angioedema, tongue and airway swelling, bronchospasm, bronchorrhea, cardiac dysrhythmias, cardiovascular collapse, and cardiac arrest.81 , 161 The pathophysiology of systemic anaphylaxis is complex and involves multiple pathways. IgE antibodies are cross-linked on the surface of mast cells and basophils, resulting in local and systemic release of preformed mediators of anaphylactic response, including leukotrienes C4 and D 4 , histamine, eosinophilic chemotactic factor, and other vasoactive substances, such as bradykinin, kallikrein, prostaglandin D2 , and platelet-activating factor. I Large local contiguous reaction (>15 cm) II Pruritus (urticaria) generalized III Asthma, angioedema, nausea, vomiting IV Airway (asthma, tongue swelling, dysphagia, respiratory distress, laryngeal edema) Cardiovascular (hypotension, may progress to cardiovascular collapse) Grade

Classification

Description

TABLE 54-4. Classification of Anaphylactic Reactions

The incidence of penicillin hypersensitivity is 5% overall, with 1% of penicillin reactions resulting in anaphylaxis. The risk for a fatal hypersensitivity reaction after penicillin administration is 2 per 100,000 (0.002%) patient exposures.268 All routes of penicillin administration can result in anaphylaxis; however, it occurs most commonly after intravenous administration. Treatment is supportive with careful attention to airway, breathing, and circulation. If the penicillin was ingested, the patient may theoretically benefit from oral activated charcoal 1 g/kg. This is unlikely to prevent anaphylaxis, as only a few molecules need be absorbed to trigger the immunologic response. Initial drug therapy for anaphylaxis includes epinephrine 0.01 mL/kg (up to 0.5 mL) of 1:1000 dilution subcutaneously (SC) every 10–20 minutes. Epinephrine, through β-receptor stimulation, results in bronchodilation and increased cardiac output. In addition, its α-receptor stimulation results in increased peripheral vascular tone. Oxygen and inhaled β2 -adrenergic agonists are warranted in severe cases, as are corticosteroids. H1 -receptor antagonists may be sufficient in patients with mild allergic reactions who do not have pulmonary manifestations or airway concerns. H 2 -receptor antagonism as a treatment for anaphylaxis is controversial. H2 -receptors, when stimulated in the peripheral vasculature, cause vasodilation; in the heart, cause positive inotropy, positive chronotropy, and coronary vasodilation; and in the lung, cause increased mucus production.227 Theoretically, H2 receptor antagonists can lead to a decrease in myocardial activity at a time when H1 -receptor stimulation is causing hypotension, coronary vasoconstriction, and bronchospasm. However, in vitro and animal models demonstrate decreases in coronary circulation and decreases in the overall anaphylactic response following administration of H1 blockers.16 , 23 Cimetidine and ranitidine are useful for the treatment of pruritus and flushing after acute allergic reactions involving the skin.164 , 179 Cimetidine, used

following anaphylaxis, may result in clinical improvement, particularly hypotension and tachycardia.73 , 279 There is 1 case, however, of chronic ranitidine administration which was postulated to result in heart block after an anaphylactic response to latex.203 Available data indicate that treatment using H2 -receptor antagonists should only be considered when other therapies have failed and the patient is adequately H1 -receptor blocked. Aminophylline, although mentioned in some references for the treatment of anaphylaxis, is inadequately studied and should not be routinely employed. Lastly, glucagon may be of some benefit, particularly in patients who are maintained on β-adrenergic antagonists.

Amoxicillin-Clavulanic

Acid

and

Hepatitis

Intrahepatic cholestatic hepatitis occurs 1–6 weeks after initiation of therapy with amoxicillin-clavulanate.7 , 54 , 114 The incidence of hepatotoxicity typically is estimated at 1.1–2.7 per 100,000

prescriptions.94 The mechanism of P.847

hepatotoxicity is not clear, but may be related to clavulanate, a β-lactamase inhibitor used to prevent the bacterial destruction of β-lactam antibiotics, or one of its metabolites. Treatment is supportive and clinical findings typically resolve after the discontinuation of therapy. However, prolonged hepatitis, ductopenia, and pancreatitis rarely occur.50 , 215

Jarisch-Herxheimer Syndrome

Reaction

and

Hoigne

The most common adverse effects occurring after administration of intramuscular procaine penicillin G are the Hoigne syndrome and the Jarisch-Herxheimer reaction.12 , 63 , 121 , 131 , 174 , 245 , 285 Both occur after the administration of large intramuscular or intravenous doses of penicillin G.93 , 106 Hoigne syndrome is

characterized by extreme apprehension and fear, illusions, or hallucinations; changes in auditory and visual perception; tachycardia; systolic hypertension; and, occasionally, seizures that begin within minutes of injection.267 These effects occur in the absence of signs or symptoms of anaphylaxis. The cause of this syndrome is unknown. Procaine is implicated as the causative agent because of this syndrome's similarity to events that occur after the administration of other pharmacologically similar local anesthetics.229 , 240 , 264 Hoigne syndrome is 6 times more common in males than females.244 The reason for this increased prevalence is unclear, but autosomal dominance and influences of prostaglandin and thromboxane A2 activity in this population may be responsible.12 The Jarisch-Herxheimer reaction is a self-limited reaction that develops within a few hours of antibiotic therapy for the treatment of early syphilis or Lyme disease. Clinical findings include myalgias, chills, headache, rash, and fever, which spontaneously resolve within 18–24 hours, even with continued antibiotic therapy.180 , 223 The pathogenesis of this reaction is likely an acute antigen release by lysed bacteria.193

Cephalosporins

Cephem

Nucleus

Cephalosporins are semisynthetic derivatives of cephalosporin C produced by the fungus Acremonium , previously called

Cephalosporium. Cephalosporins have a ring structure similar to that of penicillins. Cephalosporins are generally divided into first, second, third, and fourth generations based on their antimicrobial spectrum. First-generation cephalosporins include cefadroxil, cefazolin, cephalexin, cephapirin, and cephradine. Secondgeneration cephalosporins include cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime. Thirdgeneration cephalosporins include cefdinir, ceftazidime, cefixime, ceftibuten, cefoperazone, ceftizoxime, cefotaxime, ceftriaxone, and cefpodoxime. Finally, of the fourth-generation cephalosporins, cefepime is the first to be marketed. Effects occurring after acute overdose of cephalosporins resemble those occurring after penicillin exposure. Some cephalosporins have epileptogenic potential similar to penicillin.98 , 270 Case reports have demonstrated seizures after inadvertent intraventricular administration.34 , 156 , 280 Management guidelines for cephalosporin overdose are similar to those of penicillin overdose. Table 54-1 lists the pharmacologic mechanism of cephalosporins and Table 54-2 lists their pharmacokinetic properties.

Adverse Effects Associated Therapeutic Use

with

Cephalosporins rarely cause an immune-mediated acute hemolytic crisis.25 , 79 Cefaclor is the cephalosporin most commonly reported to cause serum sickness, although it can occur with other cephalosporins.143 , 167 Also like penicillins, cephalosporins are associated with chronic toxicity, including interstitial nephritis and hepatitis with first-generation agents.187 , 188 , 277 Cefepime is reported in a single case to cause reversible coma and nonconvulsive seizures. 1

Cross-Hypersensitivity

The cephalosporins contain a 6-member dihydrithiazine ring instead of the 5-member thiazolidine penicillin ring. The extent of cross-reactivity between penicillins and cephalosporins in an individual patient is largely determined by the type of penicillin allergic response experienced by the patient. The incidence of anaphylaxis to cephalosporins is between 0.0001% and 0.1%, with a 3-fold increase in patients with previous penicillin allergy.144 Ten percent of patients with prior penicillin-related anaphylactic reactions will have positive skin test for cephalosporin hypersensitivity.219 A negative skin test predicts a negative allergic response on oral cephalosporin challenge in penicillinallergic patients. Lastly, the incidence of delayed hypersensitivity reactions after cephalosporin use is 1–2.8% in the general population and 8.1% in those with prior penicillin delayed hypersensitivity. Cross-reactivity may be greater with the firstand second-generation cephalosporins that are more structurally similar to penicillin or that are contaminated by penicillin.8 Antibody binding after cephalosporin exposure occurs at the determinants located on the side-chain groups of the cephalosporin.14 In fact, IgE directed against a methylene substituent linking the side chain to the penicillin molecule has been identified.112 These determinants are quite distinct among cephalosporins, which cause the pattern of cross-hypersensitivity among cephalosporins to be much less well-defined than among the penicillins. Caution should be used when considering cephalosporins in penicillin- or cephalosporin-allergic patients; however, if a risk-to-benefit analysis demonstrates a clear benefit to the patient without equivalent alternatives, the cephalosporin should be given.

N

-methylthiotetrazole

Side-Chain

Effects

Cephalosporins containing an N -methylthiotetrazole (nMTT) side chain (moxalactam, cefazolin, cefoperazone, cefmetazole, cefamandole, cefotetan) have toxic effects unique to their group

structure. As these cephalosporins undergo metabolism, they release free nMTT, which is responsible for their effects (Fig. 54-1 ) .176 Free nMTT inhibits the enzyme aldehyde dehydrogenase and, in conjunction with ethanol, can cause a disulfiramlike reaction (Chap. 77 ).39 The nMTT side chain is also associated with hypoprothrombinemia, although a causal relationship is controversial.107 It is thought that nMTT depletes vitamin K-dependent clotting factors by inhibition of vitamin K epoxide reductase.197 In a study of children 1 month to 1 year of age who were maintained on a prolonged antibiotic regimen, a significant degree of vitamin K depletion was found.22 Treatment of patients suspected of hypoprothrombinemia caused by these cephalosporins consists of fresh-frozen plasma, if bleeding is evident, and vitamin K1 in doses required to resynthesize vitamin K cofactors (Chap. 57 ).

Figure 54-1. Characteristic structures emphasizing the nMTT side chain.

of

cephalosporins

P.848

Other

β-Lactam

Antibiotics

Figure. No Caption Available.

Included in this group are monobactams such as aztreonam and carbapenems such as imipenem and meropenem. Table 54-1 lists the pharmacologic mechanism of these drugs, and Table 54-2 lists their pharmacokinetic properties. Effects occurring after acute overdose of other β-lactam antibiotics resemble those occurring following penicillin exposure. Imipenem has epileptogenic potential in both overdose and therapeutic dosing (see Adverse Effects Associated with Therapeutic Use ). Management guidelines for other β-lactam overdoses are similar to those for penicillin overdoses.

Adverse

Effects

Associated

with

Therapeutic

Use

Imipenem, a member of the class of carbapenem compounds, can cause seizures in therapeutic doses.45 , 142 , 158 , 202 , 249 The risk factors for seizures include central nervous system disease, prior seizure disorders, and abnormal renal function.204 The mechanism for seizures appears to be GABA antagonism (similar to the penicillins) in conjunction with enhanced activity of excitatory amino acids. 71 , 255

Cross-Hypersensitivity Aztreonam is a monobactam that does not contain the antigenic components required for cross-allergy with penicillins, and generalized cross-allergenicity is not expected.230 However, aztreonam cross-reacts in vitro with ceftriaxone, thought to be the result of the similarity in their side-chain structure.207 Crossallergenicity has also been noted between imipenem and penicillin, although the incidence has yet to be determined.

Chloramphenicol

Figure. No Caption Available.

Chloramphenicol was originally derived from Streptomyces venezuelae and is now produced synthetically. Antimicrobial activity exists against many Gram-positive and Gram-negative aerobes and anaerobes. Table 54-1 lists the pharmacologic mechanism of chloramphenicol, and Table 54-2 lists its pharmacokinetic properties.

Acute overdose of chloramphenicol commonly causes nausea and vomiting. Effects are caused by its ability to inhibit protein synthesis in rapidly proliferating cells. Metabolic acidosis occurs as a result of the inhibition of mitochondrial enzymes, oxidative phosphorylation, and mitochondrial biogenesis.90 Infrequently, sudden cardiovascular collapse can occur 5–12 hours after acute overdoses. In case series, cardiovascular compromise was more frequent in patients with serum concentrations >50 µg/mL.90 , 145 , 185 , 205 , 260 Because levels are not readily available, all poisoned patients should be closely observed for at least 12 hours after exposure. Orogastric lavage may be useful for recent ingestions when the patient has not vomited, and activated charcoal 1 g/kg should be given orally. Extracorporeal means of eliminating chloramphenicol are not usually required because of its rapid metabolism (Table 54-2 ). However, both hemodialysis and charcoal hemoperfusion decrease elevated plasma chloramphenicol levels and may be of benefit in patients with large overdoses, or in patients with severe hepatic or renal dysfunction.89 , 178 , 246 Exchange transfusion also lowers chloramphenicol serum concentrations in neonates. 145 , 253 Surviving patients should be closely monitored for signs of bone marrow

suppression.

Adverse Effects Associated Therapeutic Use

with

Chronic toxicity of chloramphenicol is similar to that which occurs following acute poisoning. The classic description of chronic chloramphenicol toxicity is the “gray baby syndrome.―89 , 90 , 178 , 253 Children with this syndrome exhibit vomiting, anorexia, respiratory distress, abdominal distension, green stools, lethargy, cyanosis, ashen color, metabolic acidosis, hypotension, and cardiovascular collapse. The majority (90%) of a dose of chloramphenicol is metabolized via glucuronyl transferase, forming

a glucuronide conjugate. The remainder is excreted renally unchanged. Infants, in particular, are predisposed to the gray baby syndrome because they have a limited capacity to conjugate chloramphenicol and, concomitantly, a limited ability to excrete unconjugated chloramphenicol in the urine.101 , 276 Dose-dependent bone marrow depression occurs with high serum concentrations of chloramphenicol.127 , 128 , 238 Clinical manifestations usually occur after several weeks of therapy and include anemia, thrombocytopenia, leukopenia, and very rarely, aplastic anemia. Bone marrow suppression is generally reversible on

discontinuation P.849

of therapy. Chloramphenicol causes bone marrow suppression by inhibiting protein synthesis in the mitochondria of marrow cell lines.189 , 190 The development of aplastic anemia after chloramphenicol use is not dose related and generally occurs in susceptible patients within 5 months of treatment (Chap. 24 ). 77 , 282 The dehydro and nitroso bacterial metabolites of chloramphenicol cause human bone marrow cell line injury through inhibition of myeloid colony growth, inhibition of DNA synthesis, and inhibition of mitochondrial protein synthesis.138 Other adverse effects associated with chloramphenicol include peripheral neuropathy;141 , 211 neurologic abnormalities, such as confusion and delirium;162 optic neuritis;58 , 141 nonlymphocytic leukemia;243 and contact dermatitis.151

Fluoroquinolones

Ciprofloxacin

The fluoroquinolones are a derived group of antibiotics antimicrobial activity. The ciprofloxacin, clinafloxacin, gemifloxacin, grepafloxacin,

structurally similar, synthetically that exhibit a diverse spectrum of fluoroquinolones include balofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin,

moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, and trovafloxacin. Like other antimicrobials, the fluoroquinolones rarely produce life-threatening effects following acute overdose, and most patients can be safely managed with minimal intervention.11 Table 54-1 lists the pharmacologic mechanism of fluoroquinolones, and Table 54-2 lists their pharmacokinetic properties. Rarely, acute overdose of a fluoroquinolone results in renal failure or seizures. The mechanism of renal failure after fluoroquinolone exposure is controversial. In animals, ciprofloxacin and norfloxacin cause pathologic changes in the kidney, especially in the setting of neutral or alkaline urine.60 , 234 In humans, renal failure is reported after both acute and chronic exposure to fluoroquinolones. A hypersensitivity reaction is postulated to explain pathologic changes consistent with interstitial nephritis.125 , 187 , 188 , 217 , 281 Treatment includes discontinuation of the fluoroquinolone and supportive care. Improvement in renal function is usually noticed within several days.

Seizures are reported with ciprofloxacin and may be a result of the inhibition of GABA.248 , 263 Others postulate that the ability of fluoroquinolones to bind efficiently to cations, particularly magnesium, results in seizures. This hypothesis is related to magnesium's inhibitory role at the excitatory NMDA-gated ion channel (Chap. 14 ).72 , 235 Treatment is supportive, using benzodiazepines and, if necessary, barbiturates to increase GABAergic activity.

Adverse Effects Associated Therapeutic Use

with

Several fluoroquinolones are substrates and/or inhibitors of cytochrome CYP isozymes. This can result in drug interactions, which are especially important with drugs that have a narrow therapeutic

index.

Serious adverse effects related to fluoroquinolone use consist of central nervous system toxicity, as discussed, cardiovascular toxicity, hepatotoxicity, and articular/tendon toxicity. Fluoroquinolones cause prolongation of the QTc interval and may cause torsades de pointes.69 , 135 , 228 Although the mechanism of this effect is unclear, sequestering of magnesium, resulting in clinical hypomagnesemia, is postulated.235 Treatment of patients presenting with QTc interval prolongation is supportive, with careful attention to magnesium supplementation if necessary. The fluoroquinolones rarely result in potentially fatal hepatotoxicity.51 , 52 , 91 , 103 , 115 , 154 , 169 , 220 This adverse effect is most notable with trovafloxacin, although the reason for the increased risk associated with this particular fluoroquinolone is not clear. Consequently, trovafloxacin (Trovan) is now reserved only for the treatment of patients with life-threatening infections in whom the benefits are thought to outweigh the risks. In addition, the manufacturer has initiated a limited distribution

system that allows drug shipment only to pharmacies within inpatient healthcare facilities. Fluoroquinolones should be used with caution in children and pregnant women because of their potential adverse effects on developing cartilage and bone. Damage to articular cartilage is demonstrated in young dogs and rats, although the extent varies among different fluoroquinolones.42 , 257 There are very limited data regarding damage to articular cartilage as a result of using fluoroquinolones in humans; however, children given ciprofloxacin on a compassionate basis developed complaints of swollen, painful, and stiff joints after 3 weeks of therapy.137 All signs and symptoms abated within 2 weeks of discontinuation of therapy. However, 29 additional children treated with ofloxacin or ciprofloxacin showed no differences with respect to cartilage thickness, cartilage structure, edema, cartilage-bone borderline, or synovial fluid. Women who received quinolones during pregnancy had larger babies and more caesarean deliveries because of fetal distress than did controls.19 However, there were no congenital malformations, delay to developmental milestones, or musculoskeletal abnormalities found. Fluoroquinolones are also implicated as a cause of tendon rupture, which is reported to occur for up to 120 days after the start of treatment and even after the discontinuation of therapy.206 The fluoroquinolone should be discontinued in patients, particularly athletes who complain of symptoms consistent with painful and swollen tendons. Other adverse effects include acute psychosis, rash, tinnitus, eosinophilia, serum sickness, and, commonly, photosensitivity.40 , 108 , 186 , 252

Macrolides

and

Ketolides

Erythromycin

P.850 The macrolide antibiotics include various forms of erythromycin (base, estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycin, troleandomycin, and dirithromycin. Ketolides are similar in pharmacology to macrolides; telithromycin is the only available agent at this time. Table 54-1 lists the pharmacologic mechanism of macrolides and ketolides, and Table 54-2 lists their pharmacokinetic properties. Acute oral overdoses of macrolide antibiotics are usually not life threatening and symptoms which are generally confined to the gastrointestinal tract include nausea, vomiting, and diarrhea. Erythromycin lactobionate causes QTc interval prolongation and torsades de pointes after intravenous use.198 Oral erythromycin is also implicated in causing prolongation of the QTc interval and torsades de pointes, especially in patients concurrently taking cytochrome P450 (CYP) 3A4 inhibitors. 212 In vitro models demonstrate erythromycin's ability to slow repolarization in a concentration-dependent manner. 192 The cause of widened QTc interval was once thought to be from hypokalemia-induced

promotion of intracellular efflux of potassium.213 Current data, however, demonstrate that the QTc interval prolongation results from blockade of delayed rectifier potassium currents (Chap. 23 ) .222 QTc interval prolongation and torsades de pointes are common after intravenous erythromycin lactobionate.198 More pronounced widening occurs in patients with underlying heart disease and correlates with the infusion rate.110 Epidemiologic studies note an increased incidence of ventricular dysrhythmias in women treated with erythromycin.75 Although there is no acute overdose data regarding ketolide antibiotics, effects are expected to be similar to macrolide antibiotics.

Adverse Events Associated Therapeutic Use Drug

with

Interactions

Erythromycin is the prototypical macrolide and, as such, has received the most attention with respect to potential and documented drug interactions. Clarithromycin, erythromycin, and troleandomycin are all potent inhibitors of the CYP3A4 enzyme system; azithromycin does not inhibit this enzyme.64 Erythromycin inhibits cytochrome P450 after metabolism to a nitroso intermediate, which then forms an inactive complex with the iron (II) of cytochrome P450. Chapter 9 lists substrates for the CYP3A4 system. Clinically significant interactions occur with erythromycin and carbamazepine or cisapride.43 , 105 , 118 , 124 , 210 Inhibition of cisapride metabolism results in increased concentrations of the parent drug, which is capable of causing a widening of the QTc interval and causing torsades de pointes.30 , 201 Cases of carbamazepine toxicity are documented when combined with the use of erythromycin.118 Erythromycin also inhibits CYP1A2, producing clinically significant interactions with clozapine,

theophylline,

and

warfarin.218

Macrolides may also interact with the absorption and renal excretion of drugs that are amenable to intestinal P-glycoprotein excretion or interfere with normal gut flora responsible for metabolism. This may be part of the underlying mechanism of cases of macrolide-induced digoxin toxicity (Chap. 62 ).196

End-Organ

Effects

The most common toxic effect of macrolides after chronic use is hepatitis, which may be immune mediated.46 Erythromycin estolate is the agent most frequently implicated in causing cholestatic hepatitis.100 , 132 Large doses (>4 g/d) of macrolide antibiotics are also associated with reversible high-frequency sensorineural hearing loss.37 , 237 Renal impairment may be a risk factor.224 , 256 There are rare case reports in which ototoxicity did not resolve following discontinuation of therapy. 78 , 160 There are insufficient data concerning the ototoxic potential of the other macrolide antibiotics. Other, rare toxic effects associated with macrolides include cataracts after clarithromycin use in animals and acute pancreatitis in humans.83 , 266 Allergy is rare and reported at a rate of 0.4–3%.70 Telithromycin contains a carbamate side chain that may interfere with the normal function of neuronal cholinesterase. It should be used cautiously in patients with myasthenia gravis, particularly those patients receiving pyridostigmine, because of the risk of cholinergic crisis.259

Sulfonamides

Sulfamethoxazole

Sulfonamides antagonize para -aminobenzoic acid or para aminobenzyl glutamic acid, which are required for the biosynthesis of folic acid. Table 54-1 lists the pharmacologic mechanism of sulfonamides, and Table 54-2 lists their pharmacokinetic properties. Acute oral overdoses of sulfonamides are usually not life threatening and symptoms are generally confined to nausea, although allergy and methemoglobinemia occur rarely.87 Treatment is similar to acute oral penicillin overdoses.

Adverse Effects Associated Therapeutic Use

with

The most common adverse effects associated with sulfonamide therapy are nausea and cutaneous hypersensitivity reactions. Hypersensitivity reactions are thought to be caused by the formation of hapten sulfamethoxazole metabolites, N -hydroxysulfamethoxazole-NHOH and nitroso-sulfamethoxazole-NO. The degree of hapten binding is mitigated in vitro by cysteine and glutathione.191 The incidence of adverse reactions to sulfonamides, including allergy, is increased in HIV-positive patients and is positively correlated to the number of previous opportunistic infections experienced by the patient.157 This may be caused by a decrease in the mechanisms available for detoxification of free radical formation, as cysteine and glutathione levels are low in these patients.272 Whether supplementation with a glutathione precursor such as N -acetylcysteine will reduce the

incidence of these reactions is unknown.3 Methemoglobinemia and hemolysis also rarely occur.76 , 166 The mechanism for adverse reactions is not entirely clear. However, when sulfamethoxazole is exposed to ultraviolet B (UVB) radiation in vitro, free radicals are formed that can participate in the development of tissue peroxidation and hemolysis.284 This finding may be of particular importance in treating patients with glucose6-phosphate dehydrogenase (G6PD) deficiency caused by a decrease in reducing capabilities.4 The sulfonamides are associated with many chronic adverse effects. Bone marrow suppression is rare, but the incidence is increased in patients with folic acid or vitamin B12 deficiency, and in children, pregnant women, alcoholics, immunocompromised patients, as well as receiving other folate antagonists. Other hypersensitivity pneumonitis, stomatitis,

dialysis patients, and in those patients who are adverse effects include aseptic meningitis,

hepatotoxicity, renal toxicity, and central nervous system toxicity.26 P.851

Tetracyclines

Tetracyclines

Tetracyclines

are

derivatives

of Streptomyces cultures. Currently

available tetracyclines include demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, and tetracycline. Table 54-1 lists the pharmacologic mechanism of tetracyclines, and Table 54-2 lists their pharmacokinetic properties. Significant toxicity after acute overdose of tetracyclines is unlikely. Gastrointestinal effects consisting of nausea, vomiting, and epigastric pain have been reported.38

Adverse Effects Associated Therapeutic Use

with

Tetracycline should not be used in children during the first 6–8 years of life or by pregnant women after the 12th week of pregnancy because of the risk of development of secondary tooth discoloration in the children or developing children in utero. Other effects associated with tetracyclines include nephrotoxicity, hepatotoxicity, skin hyperpigmentation in sun-exposed areas, and hypersensitivity reactions.46 , 104 , 130 , 258 More severe hypersensitivity reactions, drug-induced lupus, and pneumonitis are reported after minocycline use, as are cases of necrotizing vasculitis of the skin and uterine cervix, and lymphadenopathy with eosinophilia.171 , 236 , 242 Demeclocycline rarely causes nephrogenic diabetes insipidus.47 Outdated older formulations, but not newer formulations, of tetracycline are reported to cause hypouricemia, hypokalemia, and a proximal and distal renal tubular acidosis.56

Vancomycin

Vancomycin

Vancomycin is obtained from cultures of Nocardia orientalis and is a tricyclic glycopeptide. Vancomycin is biologically active against numerous Gram-positive organisms. Table 54-1 lists the pharmacologic mechanism of vancomycin, and Table 54-2 lists its pharmacokinetic properties. Acute oral overdoses of vancomycin rarely cause significant toxicity and most cases can be treated with supportive care alone. Multiple-dose activated charcoal therapy decreases the half-life of vancomycin and can be considered for patients with large overdoses when the patient is expected to have prolonged clearance.152

Adverse Effects Associated Therapeutic Use

with

Patients who receive intravenous vancomycin may develop the “red man syndrome,― through an anaphylactoid reaction in which mast cells and basophils are directly degranulated without antibody mediation.96 Symptoms include chest pain, dyspnea, pruritus, urticaria, flushing, and angioedema.221 Signs and symptoms spontaneously resolve, typically within 15 minutes. Other symptoms attributable to red man syndrome include hypotension, cardiovascular collapse, and seizures.13 , 194 The incidence of red man syndrome appears to be related to the rate of infusion. The incidence is approximately 14% when 1 g is given over 10 minutes, whereas it is 3.4% when given over 1 hour.194 , 199 A trial in 11 healthy persons studied the relationship between intradermal skin hypersensitivity and the development of red man syndrome. Each of the 11 subjects underwent skin testing that was followed 1 week later by an intravenous dose of vancomycin 15 mg/kg over 60 minutes. Following intravenous vancomycin, all subjects developed dermal flare responses and erythema, and 10 of 11 subjects developed pruritus within 20–45 minutes. After the infusion was terminated, symptoms resolved within 60 minutes.208 The signs and symptoms of the red man syndrome are related to the rise and fall of histamine concentrations.117 , 163 Tachyphylaxis occurs in patients given multiple doses of vancomycin.116 , 271 Animal models demonstrated a direct myocardial depressant and vasodilatory effect of vancomycin.59 More serious reactions result when vancomycin is given via intravenous bolus, further supporting a rate-related anaphylactoid mechanism.21 Patients most often experience red man syndrome after vancomycin is administered intravenously. In rare cases, oral administration of vancomycin can also result in the syndrome.18 Treatment includes increasing the dilution of vancomycin and slowing intravenous administration. Antihistamines may be useful

as pretreatment, especially prior to the first dose.214 A placebocontrolled trial in adult patients studied the incidence of these symptoms in patients given 1 g of vancomycin over 1 hour, as well as the effect of diphenhydramine in the prevention of the syndrome.271 There was a 47% incidence of reaction without diphenhydramine and a 0% incidence with diphenhydramine. Chronic use of vancomycin may cause reversible nephrotoxicity, particularly in patients with prolonged excessive steady-state serum levels. 9 , 216 Concomitant administration of aminoglycoside antibiotics may increase the risk of nephrotoxicity.225 Vancomycin also causes, but rarely, thrombocytopenia and neutropenia.55 , 74

Antifungals Numerous antifungals are available. Toxicity related to the use of antifungals is variable and is based generally on their mechanism of action. P.852

Amphotericin

B

Figure. No Caption Available.

Amphotericin B is a potent antifungal derived from Streptomyces nodosus. Amphotericin B is generally fungistatic against fungi that contain sterols in their cell membrane. Table 54-1 lists the pharmacologic mechanism of amphotericin B, and Table 54-2 lists

its pharmacokinetic properties. Development of lipid and colloidal formulations of amphotericin B attenuate the adverse effects associated with amphotericin B.109 In these preparations, the amphotericin B is complexed with either a lipid or cholesteryl sulfate. On contact with a fungus, lipases are released to free the complexed amphotericin B, resulting in focused cell death.120 There are several case reports of amphotericin B overdose in infants and children. Significant clinical findings include hypokalemia, increased aspartate aminotransferase concentrations, and cardiac complications. Dysrhythmias and cardiac arrest have occurred following doses of 5–15 mg/kg of amphotericin B.31 , 57 , 148 Care should be employed in the doses of amphotericin B administered according to dosage form, as these are not interchangeable. For example, intravenous therapy for fungal infections includes a usual dose of 0.25–1 mg/kg/d of amphotericin B or 3–4 mg/kg/d of amphotericin B cholesteryl. The potential for significant dosage errors and their sequelae is readily apparent in this comparison.

Adverse Effects Associated Therapeutic Use

with

Infusion of amphotericin B results in fever, rigors, headache, nausea, vomiting, hypotension, tachycardia, and dyspnea.172 Pretreatment with acetaminophen, diphenhydramine, ibuprofen, and hydrocortisone is helpful in alleviating the febrile symptoms, as are slower rates of infusion and lower total daily doses.99 , 265 Doses greater than 1 mg/kg/d and rapid administration of drug in less than 1 hour are not recommended. Infusion concentrations of amphotericin B greater than 0.1 mg/mL can result in localized phlebitis. Slower infusion rates, hot packs, and frequent line flushing with dextrose in water may help to alleviate symptoms. Eighty percent of patients exposed to amphotericin B will sustain some degree of renal insufficiency (Chap. 27 ).44 Azotemia is

caused by distal renal tubule damage, which causes renal artery vasoconstriction as a consequence of alterations in tubular and vascular smooth muscle function.84 Studies in animals show depressed renal blood flow and glomerular filtration rate, and increased renal vascular resistance. It is unclear why this occurs, but at this time, renal nerves, angiotensin II, nitric oxide, and tubuloglomerular feedback are excluded.226 , 231 The toxic effects associated with amphotericin B may be caused by the vehicle deoxycholate.283 After large total doses of amphotericin B, residual decreases in glomerular filtration rate may occur even after discontinuation of therapy. This is hypothesized to be the result of nephrocalcinosis. Potassium and magnesium wasting, proteinuria, decreased renal concentrating ability, renal tubular acidosis, and hematuria also occur.15 , 172 Strategies to reduce renal toxicity after amphotericin B include intravenous saline or magnesium and potassium supplementation.29 , 85 , 119 Liposomal formulations of amphotericin B resulted in fewer patients with breakthrough fungal infections, infusion-related fever, rigors, or nephrotoxicity.273 However, chest pain is uniquely reported after use of the liposomal agent.139 Other adverse effects reported after treatment with amphotericin B include normochromic, normocytic anemia; decreased erythropoietin release; respiratory insufficiency with infiltrates; and, rarely, dysrhythmias, tinnitus, thrombocytopenia, peripheral neuropathy, and leukopenia.165 , 170 , 172 Exchange transfusion may be useful in neonates and infants and should be considered after large intravenous exposures. In adults, extracorporeal elimination is not expected to be useful because of the low water solubility and high blood–protein binding of the drug.

Azole Antifungals: Imidazoles

Triazole

and

Fluconazole

Common triazole antifungals include fluconazole, itraconazole, and voriconazole. Common imidazoles include clotrimazole, econazole, ketoconazole, and miconazole. Triazole antifungals are active to treat an array of fungal pathogens, whereas imidazoles are used almost exclusively in the treatment of superficial mycoses and vaginal candidiasis. Severe toxicity is not expected in the overdose setting. Hepatotoxicity, thrombocytopenia, and neutropenia are uncommon.27 Rare case reports implicate voriconazole in the development of toxic epidermal necrolysis.126 The majority of toxic effects noted after the use of these drugs result from their drug interactions. Fluconazole, itraconazole, ketoconazole, and miconazole competitively inhibit CYP3A4, the enzyme system responsible for the metabolism of many drugs. Table 54-5 lists other organ system manifestations associated with antifungal agents and other antibiotics.

Antibiotics Specific to the Treatment of Human Immune Deficiency Virus and Related Infections The evaluation and management of patients infected with the human immunodeficiency virus (HIV) and associated acquired immune deficiency syndrome (AIDS) is ever evolving at a rapid

and progressive pace. Medications used to manage this disorder have increased life expectancy in these patients dramatically as new, more powerful antiviral agents and drug combinations become available. Drug therapy for HIV commonly consists of a combination of agents from different classes (nucleoside reverse transcriptase inhibitor [NRTI], nonnucleoside reverse transcriptase inhibitor [NNRTI], and protease inhibitor) in order to take advantage of the unique mechanism that each drug offers in inhibiting viral replication and minimizing drug resistance. Resistance patterns to the typical agents used in attenuating viral replication and proliferation are a substantial issue and will continue to be addressed with yet more evolution in management in P.853 the foreseeable future. This section focuses on overdoses and major toxic effects from HIV-directed antiviral therapy, as well as from drugs that are specifically used in the management of opportunistic infections.17 Table 54-6 lists the common antibiotic agents used to treat HIV-related opportunistic infections, and Table 54-7 lists common adverse drug effects and overdose effects, if known, for antibiotics that are specific in their use for HIV-related infections. Antibiotics Bacitracin Immune Hypersensitivity reactions Clindamycin Immune Hypersensitivity reactions Gastrointestinal Nausea/vomiting/diarrhea Nervous Dizziness, headache, vertigo Colistimethate (colistin sulfate)

Renal Decreased function, acute tubular necrosis Nervous Peripheral paresthesias, confusion, coma, seizures, blockade Griseofulvin Renal Proteinuria, nephrosis Hepatic Increased liver enzymes Gastrointestinal Nausea/vomiting/diarrhea Immune Granulocytopenia Other Disulfiram reactions, increased Lincomycin Gastrointestinal Nausea/vomiting/diarrhea Immune Hypersensitivity Metronidazole Neurologic

neuromuscular

porphyrins

reactions

Peripheral neuropathy, seizures Gastrointestinal Nausea/vomiting Other Disulfiram reactions Nitrofurazone Immune Hypersensitivity reactions Other Ointment contains polyethylene glycols Nitrofurantoin

(renal

dysfunction)

Gastrointestinal Nausea/vomiting/diarrhea Hepatic Jaundice Immune Rash, acute and chronic pulmonary hypersensitivity Neurologic Peripheral neuropathy Novobiocin Immune Rash Gastrointestinal Nausea/vomiting/diarrhea Hematologic Pancytopenia/hemolytic anemia Polymyxin Neurologic Muscle weakness, B sulfate

seizures

Renal Azotemia, proteinuria Selenium sulfide Cutaneous Contact dermatitis Hair loss (rare) Silver sulfadiazine Cutaneous Contact dermatitis Hematologic Anemia, aplastic anemia Spectinomycin Immune Rash (rare) Antifungals

Benzoic acid Gastrointestinal Nausea/vomiting/diarrhea Carbol-fuchsin solution (phenol/resorcinol/fuchsin) Gastrointestinal Nausea/vomiting/diarrhea Gentian violet Gastrointestinal Nausea/vomiting/diarrhea Immune Rash (rare) Nystatin Gastrointestinal Nausea/vomiting/diarrhea Pradimicins (investigational) Unknown Unknown Salicylic acid Gastrointestinal

and

dermal

Higher concentrations are caustic Undecylenic acid and undecylenate salt Gastrointestinal Nausea/vomiting/diarrhea Drug

TABLE

Organ

System

Signs,

Symptoms,

Laboratory

54-5. Consequential Organ System Manifestations Associated with Antibiotics and Antifungals

It should be noted that adverse reactions to antibiotics occur at an increased rate in HIV-infected patients. The reason for this occurrence is unclear. Drug interactions related to pharmacokinetic and pharmacodynamic causes are common and problematic in the management of HIV-positive patients.

Specific

Antiretroviral

Nucleoside Inhibitors

Analog

Classes

Reverse

Transcriptase

The nucleoside analog reverse transcriptase inhibitors inhibit the reverse transcription of viral RNA into proviral DNA. Currently available P.854 agents include abacavir (ABC), emtricitabine (FTC), didanosine (ddI), lamivudine (3TC), stavudine (d4T), zidovudine (AZT, ZDV), and zalcitabine (ddC). Albendazole Microsporidiosis Amphotericin B Aspergillosis Coccidiomycosis Cryptococcus Histoplasmosis Leishmaniasis Paracoccidioidomycosis Penicilliosis Antimony (pentavalent) Leishmaniasis Atovaquone Pneumocystis jiroveci pneumonia Azithromycin Mycobacterium avium complex Clarithromycin Caspofungin Aspergillosis Clindamycin

Pneumocystis jiroveci pneumonia Toxoplasma gondii encephalitis Dapsone Pneumocystis jiroveci pneumonia Ethambutol Mycobacterium avium complex Fluconazole Coccidioidomycosis Histoplasmosis Flucytosine Cryptococcus Foscarnet Cytomegalovirus Fumagillin Microsporidiosis Ganciclovir Cytomegalovirus Itraconazole Histoplasmosis Leucovorin Pneumocystis jiroveci pneumonia Toxoplasma gondii encephalitis Nitazoxanide Cryptosporidiosis Microsporidiosis Paromomycin Cryptosporidiosis Pentamidine Pneumocystis jiroveci pneumonia Primaquine Pneumocystis jiroveci pneumonia Pyrimethamine Toxoplasma gondii encephalitis Rifabutin

Mycobacterium avium complex Sulfadiazine Toxoplasma gondii encephalitis TMX-SMX Pneumocystis jiroveci pneumonia Toxoplasma gondii encephalitis Isosporiasis Trimetrexate Pneumocystis jiroveci pneumonia Valganciclovir Cytomegalovirus Voriconazole Aspergillosis TMX-SMX = trimethoprim and sulfamethoxazole. Drugs

Opportunistic

Infection

TABLE 54-6. Antibiotics Used to Treat Common Opportunistic Infections 1 7

Albendazole No reported cases Increased AST/ALT, nausea, vomiting, and diarrhea. Hematologic toxicity; rare—encephalopathy, renal failure, rash Antimony (pentavalent) Acute tubular necrosis Acute tubular necrosis. Multiorgan system failure Atovaquone No clinical relevant effects in reported cases53 Rashes, anemia, leucopenia, increased AST/ALT Caspofungin No reported cases Phlebitis, headache, hypokalemia, increased AST/ALT, fever Flucytosine

No reported cases Bone marrow suppression, hepatotoxicity, nausea, vomiting, diarrhea, and rash Foscarnet No reported cases Azotemia, hypocalcemia and renal failure are most consequential; may also result in anemia, leukopenia, thrombocytopenia, fever, headache, seizures, genital and oral ulcers, fixed-drug eruptions, nausea, vomiting, diarrhea, headaches, seizures, coma, diabetes insipidus, hypophosphatemia, hypokalemia, and hypomagnesemia Fumagillin No reported cases Neutropenia and thrombocytopenia Ganciclovir No clinical relevant effects in reported cases149 Leukopenia, worsening of renal function; can also cause nausea, vomiting, diarrhea, increased AST/ALT, anemia, thrombocytopenia, headache, dizziness, confusion, seizures Nitazoxzanide No reported cases Hypotension, headache, abdominal pain, nausea, vomiting; may cause green-yellow urine discoloration Pentamidine 40 times dosing error in a 17-month-old child resulted in cardiac arrest275 Hypoglycemia (early) followed by hyperglycemia, azotemia; can cause hypotension, torsades de pointes, phlebitis, rash, StevensJohnson syndrome, hypocalcemia, hypokalemia, anorexia, nausea, vomiting, metallic taste, leukopenia, and thrombocytopenia Primaquine No reported cases Granulocytopenia, hemolytic anemia, methemoglobinemia, leukocytosis; potential for hypertension Pyrimethamine

No reported cases Agranulocytosis, aplastic anemia, thrombocytopenia, and leukopenia Rifabutin High doses(>1 g daily): arthralgia/arthritis Nausea, vomiting, diarrhea; can cause hepatotoxicity, neutropenia, thrombocytopenia, and hypersensitivity reactions Sulfadiazine Acute renal failure and hypoglycemia62 Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme; can cause headaches, depression, hallucinations, ataxia, tremor, crystalluria, hematuria, proteinuria, and nephrolithiasis Trimetrexate No reported cases; treat similar to methotrexate (Chap. 52 ) Myelosuppression, nausea, vomiting, histaminergic reactions Valganciclovir No reported cases; expect to be similar to ganciclovir Anemia, neutropenia, thrombocytopenia; nausea, vomiting, headache,

and

peripheral

Common Drugs

neuropathy

Overdose

Effects

Common Adverse Drug Effects

TABLE 54-7. Antibiotics Used in the Treatment of HIVRelated Infections 1 7

Acute

Overdose

Effects

Many intentional overdoses of reverse transcriptase inhibitors occur without major toxicologic effect. The most serious adverse effect anticipated after acute overdose of an NRTI is the development of a lactic acidosis, which appears to be more common in women.49 , 82 , 173 This occurs after incorporation of

the nucleoside analog into mitochondrial DNA by RNA polymerase, causing inhibition of DNA polymerase γ. This results in decreased production of mitochondrial DNA electron transport proteins, which ultimately inhibits oxidative phosphorylation (Chap. 13 ). Organ system toxicity follows in addition to the development of lactic acidosis. The reported mortality in patients with NRTI-associated lactic acidosis is 33–57%.82 Resolution of symptoms in survivors is 1–24 weeks. Patients with NRTI-associated lactic acidosis may recover more quickly after the use of cofactors such as thiamine, riboflavin, L-carnitine, vitamin C, and antioxidants.33 The indications for the use of these agents are unclear at this time; however, because of the relative lack of toxicity of these agents, they may be considered in an attempt to attenuate toxicity.

Chronic

Effects

Development of lactic acidosis is more commonly associated with therapeutic use of reverse transcriptase inhibitors than with acute overdose. The mechanism is likely identical to that described above. Other common adverse effects are somewhat agent specific and include hematologic toxicity after zidovidine,68 , 102 pancreatitis with didanosine,155 hypersensitivity after abacavir,67 and sensory peripheral neuropathy after zalcitabine, stavudine, and didanosine.184 P.855

Nonnucleoside Inhibitors

Reverse

Transcriptase

Nonnucleoside reverse transcriptase inhibitors (NNRTI) bind directly to reverse transcriptase enzymes enabling allosteric inhibition of enzymatic function.261 Delavirdine (Rescriptor), nevirapine (Viramune), and efavirenz (Sustiva) comprise the currently available agents.

There are no substantial acute overdose data on these drugs, although they generally appear to be safe in overdose. Treatment should include supportive care until more information is available. The NNRTIs are also limited in toxicity after chronic use. Nevirapine and delavirdine use commonly results in hypersensitivity reactions such as rash.67 Efavirenz is reported to result in dizziness and dysphoria. Otherwise, toxicity can result from the ability of these drugs to either inhibit or enhance CYP isozymes in the metabolism of other drugs.

Protease

Inhibitors

Protease inhibitors inhibit the vital enzyme (proteinase), which is required for viral replication.86 Currently available agents include amprenavir (Agenerase), indinavir (Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir), and saquinavir mesylate (Invirase). Data after protease inhibitor overdose are limited. A review of data submitted to the manufacturer of indinavir found that of 79 reports, the complaints were nausea, vomiting, abdominal pain, and nephrolithiasis. Protease inhibitors as a class commonly result in gastrointestinal symptoms and rash.86 A uniqe finding is an altered fat distribution pattern that, over time, results in central obesity, “buffalo hump,― breast enlargement, cushingoid appearance,

and

peripheral

wasting.86

Summary Adverse effects attributable to antibiotics are largely related to chronic administration, although, rarely, acute toxicity does occur. Acute toxic effects of antibiotics are more common after large intravenous administration, drug interactions, or iatrogenic overdose. Careful vigilance on the part of the healthcare provider will prevent the majority of acute toxic manifestations following antibiotic use.

References 1. Abanades S, Nolla J, Rodriguez-Campello A, et al: Reversible coma secondary to cefepime neurotoxicity. Ann Pharmacother 2004;38:606–608. 2. Adams SL, Mathews J, Grammer LC: Drugs that may exacerbate myasthenia gravis. Ann Emerg Med 1984;13:532–538. 3. Akerlund B, Tynell E, Bratt G, et al: N-Acetylcysteine treatment and the rise of toxic reactions to trimethoprimsulfamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected

patients.

J

Infect

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > D - Antimicrobials > Chapter 55 - Antituberculous Medications

Chapter

55

Antituberculous

Medications

Edward W. Boyer A 15-year-old girl who had recently emigrated from Vietnam began to seize while at school. Paramedics observed two additional seizures during transport to the emergency department (ED). On arrival at the hospital, her vital signs were: blood pressure, 122/50 mm Hg; pulse, 107 beats/min; respirations, 22 breaths/ min; and temperature 99.4°F (37.4°C). Physical examination revealed an obtunded young girl without signs of head trauma, who was minimally responsive to painful stimuli. Her pupils were 3 mm and sluggishly reactive. Her oropharynx showed no signs of trauma. The lungs were clear to auscultation, and she was tachycardic with no murmurs, rubs, or gallops appreciated on cardiac examination. Her abdomen was soft with normal bowel sounds. Her skin was warm, dry, and well perfused. There was an abrasion on her left forearm, but no other extremity injuries. A peripheral intravenous catheter was established, and she was placed on 100% oxygen via a nonrebreathing face mask. Pulse oximetry demonstrated an oxygen saturation of 100%. A bedside capillary glucose test revealed euglycemia. She received a total of 8 mg IV lorazepam in the

ED but had another seizure. Additional history obtained from family members revealed that the patient had started taking medicine for a “lung problem.― On the basis of this information, she was given 5 g of intravenous pyridoxine with cessation of seizure activity. Fifty grams of activated charcoal was instilled via nasogastric tube. Laboratory values were: a white blood cell count of 13,600/mm3 ; hemoglobin, 12.9 g/dL; platelets, 287 × 103 /mm3 ; sodium, 142 mEq/L; potassium, 3.7 mEq/L; chloride, 103 mEq/L; bicarbonate, 7 mEq/L; blood urea nitrogen (BUN), 7 mg/dL; creatinine, 0.6 mg/dL; serum glucose, 97 mg/dL; and anion gap, 29 mEq/L. Arterial blood gas revealed: pH 7.19; PCO2 , 33 mm Hg; PO2 , 105 mm Hg; and 98% oxygen saturation. Creatinine phosphokinase was 1067 U/L. Cerebrospinal fluid (CSF) showed 4 RBC (red blood cells) per mm3 and 33 WBC (white blood cells) per mm3 , with a normal Gram stain. Cerebrospinal glucose was 76 mg/dL and protein was 27 mg/dL. Serum titers for herpes simplex virus, equine encephalitis virus, and West Nile virus were negative, as were blood and CSF cultures. She was admitted to the intensive care unit (ICU), but her level of consciousness did not improve over the next 6 hours. An electroencephalogram that was performed because of persistent depression of consciousness showed no seizure activity. The toxicology service recommended that the patient be given an additional 5 g of intravenous pyridoxine. The patient's level of consciousness improved over the next 15 minutes, at which point she revealed that she ingested approximately 8 g of isoniazid in a suicide attempt. The remainder of her hospitalization was uneventful. A computerized tomography scan and magnet resonance image of the brain were normal. She was discharged from the medical service and transferred to a psychiatric facility.

History

and

Epidemiology

The global burden of tuberculosis is enormous. Approximately 2 billion people are infected with Mycobacterium tuberculosis; 7.96 million new cases are diagnosed each year. An estimated 1.87 million persons die worldwide from the infection annually.3 The introduction of isoniazid (INH)

into clinical practice in 1952 caused the number of US cases of tuberculosis (TB) to steadily decrease over the subsequent 30 years. However, between 1985 and 1991, there was a resurgence in TB cases in the United States, a result of, among other factors, the human immunodeficiency virus (HIV) epidemic, homelessness, deterioration in the healthcare infrastructure, and an increased number of foreign-born persons. Concurrently, multidrugresistant tuberculosis emerged as a serious health concern. Currently, onethird of newly diagnosed cases are resistant to INH and one-fifth are resistant to both INH and rifampin, formerly the two most effective drugs for treating tuberculosis. Containment strategies, such as aggressive case identification and directly observed therapy, were initiated to slow the spread of the infection.21 , 22 , 43 , 57 Subsequently, the number of reported cases in the United States in 1998 decreased by 31% from the peak incidence reported in 1992. Populations that remain at risk for tuberculosis are HIV-positive patients, the homeless, intravenous drug users, healthcare workers, prisoners, prison workers, and Native Americans. In addition, the tuberculosis rate in foreign-born persons is 4–6 times higher than for US-born persons. The birth countries generating the highest number of US tuberculosis cases are Mexico, the Philippines, and tuberculosis has reintroduction of in an increased

Vietnam.23 , 24 , 57 The emergence of multidrug-resistant forced the use of multidrug regimens, as well as the older antituberculous drugs. This approach likely results incidence of adverse drug effects. Multidrug antituberculous

regimens are associated with a 15% incidence of adverse events.3 Hepatotoxicity, peripheral neuropathy, and ocular neuropathy are often irreversible and potentially fatal. Moreover, many patients receiving antituberculous therapy are chronically ill and have an increased risk of suicidality and intentional overdose.

Figure

55-1. INH and related compounds.

P.862

Isoniazid Pharmacology Isoniazid (INH, or isonicotinic hydrazide) is structurally related to nicotinic acid (niacin, or vitamin B3 ), nicotinamide-adenosine dinucleotide (NAD), and pyridoxine (vitamin B6 ) (Fig. 55-1 ). The pyridine ring is essential for antituberculous activity. The mechanism of action of INH involves an interaction with InhA, a mycobacterial enzyme that functions as an enoylacyl carrier protein (enoyl-ACP) reductase.83 , 84 Isoniazid itself does not directly interact with the InhA enzyme. Instead, INH is a prodrug that undergoes metabolic activation by a mycobacterial catalase-reductase, known as KatG, to produce a highly reactive intermediate.85 , 118 This activated form of INH is either an anion or radical that is stabilized by the pyridine ring. This INH-derived species enters the binding site of InhA where it reacts with the reduced form of nicotinamide adenine dinucleotide (NADH).85 The covalently linked INH-NADH complex remains bound to the active site of InhA, irreversibly inhibiting the enzyme.73 , 83 Enoyl-ACP reductases catalyze the NADH-dependent reduction of the double bonds in the growing fatty acid chain linked to acyl carrier proteins. InhA is required for the synthesis of very-long-chain lipids known as mycolic acids (containing between 40 and 60 carbons) that are important

components of mycobacterial cell walls.

Pharmacokinetics

and

Toxicokinetics

When therapeutic doses of 5–15 mg/kg are administered orally, INH is rapidly absorbed, reaching peak plasma concentrations within 2 hours.54 , 80 , 81 Isoniazid diffuses into all body fluids with a volume of distribution of approximately 0.6 L/kg and has negligible binding to serum proteins. After the drug penetrates infected tissue, it persists in concentrations well above those required for bacteriocidal activity. Isoniazid is metabolized via a cytochrome P450-mediated process, with approximately 75–95% of INH renally eliminated as hepatic metabolites within 24 hours of administration.71 The primary metabolic pathway for INH is via N -acetylation performed by hepatocytes and gut mucosa. N Acetyltransferase, the enzyme responsible for this conversion, exhibits Michaelis-Menten kinetics, although the activity of an individual's enzymes is determined by an autosomal dominant inheritance pattern. Patients with the polymorphic forms of N -acetyltransferase are distinguishable phenotypically as slow and fast acetylators. The slow acetylation isoform is found in 50–60% of American whites and African Americans, whereas the fast acetylator isoenzymes are found in 90% of Asians and Inuits.36 These isoforms are distinguishable by the following characteristics: (a) Slow acetylators have less presystemic clearance, or first-pass effect, than do fast acetylators; (b) fast acetylators metabolize INH 5–6 times faster than slow acetylators; and (c) plasma INH concentrations are 30–50% lower in fast acetylators than in slow acetylators. The elimination half-life of INH is approximately 70 minutes in fast acetylators, and 180 minutes in slow acetylators. Twenty-seven percent of INH is excreted unchanged in urine by slow acetylators, as compared with excretion of 11% in fast acetylators. The clearance of INH averages approximately 46 mL/min.11 , 112 Isoniazid is transformed either via a stepwise process to acetylhydrazine and isonicotinic acid, or directly to hydrazine. In the first instance, INH is initially acetylated to acetylisoniazid and then hydrolyzed to acetylhydrazine. This intermediate may then be oxidized by hepatic

microsomes to reactive intermediates that damage hepatocytes.109 Figure 55-2 illustrates the metabolism of INH.

Mechanism

of

Toxicity

Toxic effects of INH are caused by two additive mechanisms. First, INH alters the metabolism of pyridoxine, the coenzyme needed for P.863 transamination, transketolization, and decarboxylation, biotransformation reactions. Isoniazid creates a functional deficiency of pyridoxine by at least two mechanisms (Fig. 55-3 ). Hydrazone INH metabolites inhibit pyridoxine phosphokinase, the enzyme that converts pyridoxine to its active form, pyridoxal-5′-phosphate.26 , 53 , 67 In addition, INH reacts with pyridoxal phosphate to produce an inactive hydrazone complex that is renally excreted.67 , 112 Urinary excretion of pyridoxine and its metabolites increases with increasing INH dosage, reflecting the effect of INH on pyridoxine metabolism. The consequences of pyridoxine depletion include impaired activity of pyridoxine-dependent enzyme systems, as well as a decrease in catecholamine synthesis. In addition, INH either replaces nicotinic acid in the synthesis of NAD or reacts with NAD to form inactive hydrazones. Isoniazid disrupts cellular through both of these mechanisms.

reduction/oxidation

capabilities

Figure 55-2. Metabolism of INH. Acetylator status is determined by polymorphism in N -acetyltransferase.

Figure 55-3. The effect of isoniazid on γ-aminobutyric acid (GABA) synthesis.

Second, isoniazid interferes with the synthesis and metabolism of γaminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. Two pyridoxine-dependent enzymes control GABA metabolism: glutamic acid decarboxylase (GAD) and GABA aminotransferase. The former catalyzes GABA synthesis, while the latter degrades the neurotransmitter. The inhibitory effects are greater on GAD, which leads to decreased GABA concentrations.7 , 114 Depletion of GABA is thought to be the etiology of INH-induced seizures. Structurally similar chemicals exert similar acute toxic effects. Monomethylhydrazine, a metabolite produced from gyromitrin isolated from the Gyromitra species (“false morel―) mushroom, and the hydrazines used in liquid rocket fuel, have a similar mechanism of action (Chap. 113 ). Isoniazid, a class C drug, crosses the placenta to enter the fetal compartment and produce umbilical cord blood concentrations comparable to maternal levels.113 Mammalian teratogen studies suggest that isoniazid is not a human teratogen, although fetal deformities following acute overdose of INH have been reported.63 , 112 Administration of INH to pregnant women was not associated with cancer in their offspring. Isoniazid readily enters breast milk, but breast-feeding during therapy is considered acceptable.90 , 112

Interactions with Other Drugs and Foods Isoniazid has an overall incidence of drug–drug interactions of 5.4%.69 , 94 Isoniazid potentially inhibits several cytochrome P450 (CYP)-mediated transformations, particularly demethylation, oxidation, and hydroxylation (Chap. 9 ). Clinically relevant adverse effects are documented with theophylline (CYP1A2), phenytoin (CYP2C9/CYP2C19), warfarin (CYP2C9/CYP2C19), valproate, and carbamazepine (CYP3A4).52 , 94 Therapeutic doses of INH induce expression of the CYP2E1 cytochrome subtype. It also binds to CYP2E1 simultaneously to decrease the metabolism of substrate. The binding of INH to the active site inhibits the degradation of the enzyme itself. Intracellular concentrations of CYP2E1 are therefore increased; after INH diffuses from the CYP2E1 active site, greater-than-normal amounts of cytochrome become available to metabolize potential substrates.94 CYP2E1 catalyzes the formation of NAPQI (N -acetyl-p -benzoquinoneimine), the acetaminophen metabolite responsible for toxicity.25 Consequently, INH use may increase the likelihood of acetaminophen-induced unstudied.25

hepatotoxicity,

although

this

is

Isoniazid has numerous food interactions. Isoniazid is a weak monoamine oxidase inhibitor, and tyramine reactions to foods and serotonin syndrome from meperidine are reported in patients taking INH. Clinical effects include flushing, tachycardia, and hypertension.31 , 40 , 62 , 102 Furthermore, INH inhibits the enzyme histaminase, leading to exacerbated reactions following the ingestion of histamine in scombrotoxic fish.4 , 50 , 52 , 94 Table 55-1 summarizes additional INH drug and food interactions.

Clinical Acute

Manifestations

of

INH

Toxicity

Toxicity

Isoniazid produces the triad of seizures refractory to conventional therapy, severe metabolic acidosis, and coma. These clinical manifestations may appear as soon as 30 minutes following ingestion.48 , 52 , 108 The case

fatality rate of a single acute ingestion may be as high as 20%.15 , 18 Although vomiting, slurred speech, dizziness, and tachycardia may represent early manifestations of toxicity, seizures may be the initial sign of acute overdose.66 Seizures may occur following the ingestion of greater than 20 mg/kg of INH, and invariably occur with ingestions greater than 35–40 mg/kg. Patients with underlying seizure disorders, however, may develop seizures at lower doses.15 Hyperreflexia or areflexia may herald INH-induced seizures. Patients may exhibit improvement in consciousness between seizures.30 , 77 Because GABA, the primary inhibitory neurotransmitter, is depleted in acute INH toxicity, seizure activity may persist until GABA concentrations are restored. Acute INH toxicity is often associated with a wide anion gap metabolic acidosis associated with a high serum lactate. Typically, serum pH ranges between 6.80 and 7.30, although survival in the setting of an arterial pH 6.49 was reported.48 Paralyzed animals poisoned with INH do not develop lactic acidemia, a finding that suggests the lactate arises from intense muscular activity.26 , 78 Although not borne out in clinical practice, the acidosis from INH-induced seizures has been described as resolving more slowly P.864 than the lactic acidemia from typical seizures, the mechanism for which may be the formation of NAD hydrazones that prevent the transformation of lactate to pyruvate. 26 , 113 Alternate explanations of INH-associated acidosis include the generation of acidic INH metabolites and enhanced fatty acid oxidation leading to increased serum ketoacids.78 , 112 INH Acute: seizures, acidosis, coma, hyperthermia, oliguria, anuria Chronic: elevation of liver enzymes, hepatitis, autoimmune disease (arthritis, anemia, hemolysis, eosinophilia), peripheral neuropathy, optic neuritis, vitamin B6 deficiency (pellagra) Rifampin, PZA, ethanol: hepatic necrosis Acetaminophen: hepatic necrosis Warfarin: increased prothrombin time

Theophylline: tachycardia, vomiting, seizures, acidosis Phenytoin: increased phenytoin levels Carbamazepine: altered mental status Meperidine: hypertension Lactose: decreased INH absorption Antacids: decreased INH absorption Red wine/soft cheese: tyramine reaction Fish (scombroid): flushing, pruritus Liver enzymes, ANA, CBC HIV enteropathy may decrease absorption; INH should not be given with lactose-containing drug formulations because lactose can form hydrazones and lower INH concentrations Rifampin Acute: diarrhea, periorbital edema Chronic: hepatitis, reddish discoloration of body fluids Protease inhibitors: decreased serum concentration of protease inhibitor Delavirdine: increased HIV resistance Cyclosporine: graft rejection Warfarin: decreased INR Oral contraceptives: ineffective contraception Methadone: opioid withdrawal Phenytoin: higher frequency of seizures Theophylline: decreased theophylline levels Verapamil: decreased cardiovascular effect If administered with HIV antiretroviral agents, viral titers should be followed. Liver enzymes; monitor serum concentrations of drugs (ie, pheny- toin, cyclosporine) or clinical markers of efficacy (ie, coagulation times) Interactions of rifampin with several HIV medications are very poorly described; changes in dosing or dosing interval for both rifampin and antiretroviral drugs may be required; has teratogenic effects Ethambutol Chronic: optic neuritis, loss of red-green discrimination, loss of peripheral vision

Visual acuity, color discrimination Contraindicated in children too young for formal ophthalmologic examination Pyrazinamide Chronic: hepatitis, decreased urate excretion INH: increased rates of hepatotoxicity (when extended courses or high dose pyrazinamide used) Liver enzymes Courses of therapy of 2 months or less recommended Cycloserine Chronic: depression, paranoia, seizures, megaloblastic anemia INH: increased frequency of seizures CBC, psychiatric monitoring Ethionamide Chronic: orthostatic hypotension, depression Cycloserine: may increase CNS effects Follow clinical signs of orthostasis para -Aminosalicylic acid Chronic: malaise, GI upset, elevated liver enzymes, hypersensitivity reactions, thrombocytopenia Liver enzymes, CBC Capreomycin Chronic: hearing loss, tinnitus, proteinuria, sterile abscess at IM injection sites Audiometry, renal function tests

Drug

Major Adverse Reactions

Drug Interactions–Clinical Effect

Monitoring

Comments

TABLE 55-1. Adverse Reactions and Drug Interactions of Antituberculous Drugs Protracted coma typically occurs with acute severe INH toxicity. Coma may last as long as 24–36 hours and persist beyond the termination of seizure activity as well as the resolution of acidemia. The etiology of coma is unknown.48 Additional sequelae from acute INH toxicity include renal failure, hyperglycemia, glycosuria, and ketonuria, along with hypotension and hyperpyrexia.6 , 19 , 112

Chronic

Toxicity

As a consequence of a myriad of INH-induced biochemical changes, chronic, therapeutic INH use is associated with a variety of adverse effects. The most disconcerting is hepatocellular necrosis. Although asymptomatic elevation of aminotransferases is common in the first several months of treatment, laboratory testing may reveal the onset of hepatitis up to 1 year after starting INH therapy. In 1978, following several deaths among patients receiving INH therapy, the US Public Health Service reported the incidence of clinically evident hepatitis as 1% of those taking INH; of that subgroup, 10% died, for an overall mortality of 0.1%.17 , 60 Research performed since the resurgence of TB, however, identified a considerably lower rate of hepatotoxicity. Clinically relevant hepatitis occurred in only 11 patients in a population of 11,141 persons receiving INH, an incidence of 0.1%.76 Additional studies suggest that the death rate from INH hepatotoxicity is only 0.001% (2 of 202,497 treated patients).88 The decrease in mortality from INH-associated hepatitis may be a P.865 result of improved surveillance protocols allowing for earlier cessation of therapy or decision analysis concerning continued use of INH.

Isoniazid-induced hepatitis can arise via two pathways.34 The first involves an autoimmune mechanism resulting in hepatic injury that is thought to be idiopathic. 9 , 101 , 112 , 117 The association of hepatitis with lupus erythematosus, hemolytic anemia, thrombocytopenia, arthritis, vasculitis, and polyserositis supports an immunologic process.9 , 101 , 112 , 117 However, symptoms commonly found in autoimmune disorders such as fever, rash, and eosinophilia are usually absent, and rechallenge with isoniazid often fails to provoke recurrence of hepatocellular injury.34 The second, more common mechanism involves direct hepatic injury by INH or its metabolites. The metabolite believed responsible for hepatic injury is acetylhydrazine, which arises from the acetylation of INH followed by its hydrolysis. 74 Hepatotoxicity is associated with chronic overdosage, increasing age, comorbid conditions such as malnutrition, and combinations of antituberculous drugs that may serve as cytochrome inducers. Overt hepatic failure often occurs if INH therapy is continued after onset of hepatocellular injury.34 , 35 , 38 , 47 , 72 , 97 The incidence of hepatitis is 2–4 times higher in pregnant women than in nonpregnant women.39 Peripheral neuropathy and optic neuritis are known adverse drug effects of chronic INH use. Neurotoxicity is probably caused by pyridoxine deficiency aggravated by the formation of pyridoxine-INH hydrazones.36 Peripheral neuropathy, the most common complication of INH therapy, presents in a stocking-glove distribution that progresses proximally. Although primarily sensory in nature, myalgias and weakness may occur.98 Peripheral neuropathy is generally observed in severely malnourished, alcoholic, uremic, or diabetic patients; it is also associated with slow acetylator status, an effect which leads to increased INH levels and, consequently, increased pyridoxine depletion.42 Optic neuritis presents as decreased visual acuity; visual field testing may reveal central scotomata.44 , 52 Isoniazid is also associated with such findings of CNS toxicity as ataxia, psychosis, hallucinosis, and coma.1 , 10 , 41 , 87

Diagnostic

Testing

Acute INH toxicity is a clinical diagnosis that may be inferred by history

and confirmed by measuring serum INH concentrations.93 Acute toxicity from INH has been defined as a serum INH concentration greater than 10 mg/L 1 hour after ingestion, greater than 3.2 mg/L 2 hours after ingestion, or greater than 0.2 mg/L 6 hours after the ingestion.77 Because serum INH concentration measurements are not widely available, clinicians cannot rely on serum concentrations to confirm the diagnosis or initiate therapy. Because of the risk of hepatitis associated with chronic INH use, hepatic aminotransferases should be regularly monitored once therapy is started.

Management Acute

Toxicity

The initial management requires termination of seizure activity, fluid resuscitation, and stabilization and correction of vital signs with maintenance of a patent airway. Clinicians should consider the administration of sodium bicarbonate to treat severe acidemia with a pH Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > D - Antimicrobials > Antidotes in Depth - Pyridoxine

Antidotes in Depth Pyridoxine Mary Ann Howland

Figure. No Caption Available.

Pyridoxine (vitamin B6 ), a water-soluble vitamin, is administered as an antidote for overdoses of isonicotinic acid hydrazide (isoniazid, INH), hydrazine, methylated hydrazines, and perhaps

ethylene glycol. With the exception of ethylene glycol, all of the named xenobiotics produce seizures by the competitive inhibition of pyridoxal-5′-phosphate (PLP) Pyridoxine overcomes this inhibition. Also, the administration of pyridoxine may enhance the less-toxic pathway of ethylene glycol metabolism to form benzoic and hippuric acid, as opposed to oxalic acid.6 Hydrazine and methylated hydrazines (1,1-dimethylhydrazine [UDMH], monomethylhydrazine [MMH]) are used as rocket fuels, and MMH is also found in Gyromitra esculenta mushrooms.3

History Pyridoxine deficiency was first identified in 1926 and was mistakenly attributed to the absence of vitamin B2 . 33 Ten years later, the deficiency was fully characterized and attributed to vitamin B6 . 22 A rare genetic abnormality that produced pyridoxineresponsive seizures in newborns was recognized in 1954.5

Chemistry The active form of pyridoxine is the phosphate ester of pyridoxal (PLP).27 Pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, an aminomethyl form are all naturally occurring related compounds that are metabolized by the body to PLP.27 Pyridoxine was chosen by the Council on Pharmacy and Chemistry to represent vitamin B6 . 27 Pyridoxine hydrochloride was chosen as the commercial preparation because of its stability.47

Pharmacology PLP is an important cofactor in more than 100 enzymatic reactions, including decarboxylation and transamination of amino acids, and the metabolism of tryptophan to 5-hydroxytryptamine and methionine to cysteine.21,27 Iatrogenic pyridoxine deficiency in animals produces seizures associated with reduced

concentrations in the brain of PLP, glutamic acid decarboxylase, and γ-aminobutyric acid (GABA).15

Pharmacokinetics Pyridoxine is not protein bound, has a volume of distribution of 0.6 L/kg, and easily crosses cell membranes; in contrast PLP is nearly entirely plasma protein bound.47 Pyridoxine is rapidly metabolized at extrahepatic sites to pyridoxal, PLP, and 4-pyridoxic acid, with only 7% excreted unchanged in the urine.47 After intravenous infusion of 100 mg of pyridoxine over 6 hours, PLP concentration increases rapidly in serum and in erythrocytes.47 Pyridoxal rises from 37 nmol/L to 2183 nmol/L in serum and from undectable to 5593 nmol/L in erythrocytes, with peak levels achieved at the end of the infusion.47 Oral pyridoxine in doses of 600 mg is 50% absorbed within 20 minutes of ingestion by a first-order process with rapid achievement of peak plasma concentrations of pyridoxine, PLP, and pyridoxal.46 The concentration of PLP appears to be tightly controlled in the serum and related to alkaline phosphatase activity.22,46 Oral doses of pyridoxine from 10–800 mg result in PLP concentrations of 518–732 nmol/L 4 hours after ingestion.46 Chronic alcoholics have lower baseline PLP serum levels, as acetaldehyde enhances the degradation of PLP in erythrocytes, through stimulation of an erythrocyte membranebound phosphatase that hydrolyzes phosphate-containing B6 compounds.26

Mechanism of Hydrazide- and Hydrazine-Induced Seizures The antidotal role of pyridoxine in the management of INH and methylated hydrazines like MMH poisoning is based on the interference of these xenobiotics with the normal use and function of pyridoxine as a coenzyme. INH produces a syndrome resembling

cerebral vitamin B6 deficiency, which results in seizures. Specifically, INH and other hydrazides and hydrazines inhibit the enzyme pyridoxine phosphokinase that converts pyridoxine to PLP.21 In addition, hydrazides directly combine with PLP, causing inactivation through the production of hydrazones that are rapidly excreted by the kidney.21 PLP is a coenzyme for L-glutamic acid decarboxylase that facilitates the synthesis of GABA from Lglutamic acid. Animal studies suggest that this interference with PLP disrupts the formation of GABA.21,43 The decreased GABA formation reduces cerebral inhibition, which may contribute in part to the seizures resulting from exposure to INH and methylated hydrazines.35,45

Animal

Studies

In a dog model of INH-induced toxicity, pyridoxine reduced the severity of seizures, increased the time to seizure, and prevented the mortality of a previously lethal dose of INH in a dosedependent fashion.12,13 Lower molar ratios prevented deaths and higher molar ratios prevented both deaths and seizures.13 When used as a single agent, phenobarbital, pentobarbital, phenytoin, ethanol, and diazepam were ineffective in controlling seizures and mortality, but when combined with pyridoxine, each protected the animals from seizures P.873 and death.12 Other small-animal experiments have documented the effectiveness of pyridoxine against MMH-induced seizures when used alone21,29,40 and when used in combination with diazepam.18 Anticonvulsant efficacy is also demonstrated in cat36 and monkey38 models. Rat studies with intraperitoneal dimethylhydrazine (UDMH) also demonstrate the protective effects of pyridoxine given intraperitoneally 90 minutes later.14 Pyridoxine prevented seizures and death in a model that produced 94% mortality and 100%

seizures without pyridoxine.14 When intraperitoneal UDMH and pyridoxine IV 20 minutes later were administered to rats 17% died at 24 hours, as compared to a 100% mortality without pyridoxine.14 Other studies in dogs and monkeys also demonstrate the effectiveness of pyridoxine in preventing seizures and mortality, and in treating seizures.4 Pyridoxine IM protected the monkeys from death and stopped the seizures caused by an IV UDMH dose.

Human

Data

Clinical experience with the use of pyridoxine for INH overdose in humans demonstrates favorable results.3,11 Rapid seizure control with no morbidity or mortality was achieved when the ratio in grams of pyridoxine administered to INH ingested ranged from 0.14 to 1.3, although in practice, most patients receive approximately gram-for-gram amounts. In 5 patients, the use of gram-for-gram amounts of pyridoxine resulted in the complete control of seizures and a resolution of the metabolic acidosis.42 In 8 patients with intentional INH overdoses, basic poison management, intensive supportive care, and a mean dose of 5 g of pyridoxine IV resulted in no fatalities.8 Seizures were controlled in a 22-month-old boy given 100 mg of IV pyridoxine, after an estimated INH ingestion of 5 g.41 Variable results are reported when relatively small doses of pyridoxine are used.28 Seizures were reported in 2 patients following the ingestion of INHpyridoxine combination tablets, although the actual amount of pyridoxine ingested was not noted.39 In addition to controlling seizures, the administration of pyridoxine also appears to restore consciousness. Two patients, who remained obtunded for as long as 72 hours after the apparent resolution of the seizures, were reported to awaken immediately after 3–10 g of IV pyridoxine was administered.10 A third patient who was lethargic awakened with IV pyridoxine. This work

suggests that mental status abnormalities associated with INH overdose, and conceivably hydrazine overdoses, may be responsive to pyridoxine and also may require repetitive dosing.11,42 Patients treated with large doses of pyridoxine awaken more rapidly even after experiencing sustained seizure activity or status epilepticus. MMH poisoning can be encountered in a variety of clinical situations. In the aerospace industry, where MMH is used as a rocket propellant, percutaneous or inhalational poisoning may occur. Ingestion of the false morel mushroom, G. esculenta, can also produce toxicity when its major toxic compound, gyromitrin, is metabolized to MMH (Chap. 113) . The neurologic effects of MMH poisoning are similar to those of INH toxicity and include seizures and respiratory failure. Severe liver damage similar to INH-induced hepatotoxicity is also described.15 As in the case of INH hepatotoxicity, there is no evidence that MMH-induced hepatotoxicity can be treated by administration of pyridoxine.9 A patient who was exposed to hydrazine became comatose 14 hours later and remained comatose for 60 hours until 25 mg/kg of pyridoxine aroused him.23 Another case report describes improvement in the mental status of a confused, lethargic, and restless man who had ingested a mouthful of hydrazine and was treated with a 10-g dose of pyridoxine.20 This improvement developed over 24 hours and may have been unrelated to pyridoxine therapy. A severe sensory peripheral neuropathy lasting for 6 months developed 1 week following the overdose and was most likely a result of the hydrazine ingestion and not the pyridoxine. Six patients exposed to an Aerozine-50 (hydrazine and UDMH) spill were effectively treated with pyridoxine after developing twitching, clonic movements, hyperactivity, or GI symptoms.17

Ethylene

Glycol

PLP is a cofactor in the conversion of glycolic acid to nonoxalate compounds (Chap. 103). Patients poisoned with ethylene glycol should receive 100 mg/d of pyridoxine IV in an attempt to shunt metabolism preferentially away from the production of oxalic acid. This approach is supported by an animal model6 and by the study of primary hyperoxaluria,19 but has not been studied adequately in humans with ethylene glycol poisoning.31

Safety

Issues

Pyridoxine is clearly neurotoxic to animals and humans when administered chronically in supraphysiologic doses. 23,24,32 Delayed peripheral neurotoxicity occurred in patients taking daily doses of 200 mg to 6 g of pyridoxine for 1 month.30,34,35 Healthy volunteers given 1 or 3 g/d developed a small- and large-fiber distal axonopathy, with sensory findings and quantitative sensory threshold abnormalities occurring after 1.5 months in the highdose and 4.5 months in the low-dose regimens. Once symptoms occurred, the pyridoxine was immediately stopped, but symptoms progressed for 2–3 weeks, leading to speculation that it took time for the reversal of neuronal metabolic manifestations.7 Pyridoxine may also induce a sensory neuropathy when massive doses are administered, either as a single dose or over several days.1,25,41 Ataxia occurred in dogs receiving 1 g/kg of pyridoxine.41 Larger doses of pyridoxine produce incoordination, ataxia, seizures, and death.41 Death after pyridoxine administration was sometimes delayed for 2–3 days.41 Two patients treated with 2 g/kg of IV pyridoxine (132 and 183 g, respectively) over 3 days developed severe and crippling sensory neuropathies.1 One year later, both patients were unable to walk. Inadequate information is available to determine the maximal single acute nontoxic dose in humans; however, there appears to be a wide margin of safety. Doses of pyridoxine ranging from

70–375 mg/kg or doses equivalent to the milligram-per-kilogram historical dose of ingested INH have been administered without adverse effects.42

Dos i n g Considering all of the available data, a safe and effective pyridoxine regimen for INH overdoses in adults is 1 g of pyridoxine for each gram of INH ingested, to a maximum of 5 g or 70 mg/kg. Initial doses of pyridoxine in children probably should not exceed 70 mg/kg.42 These doses are sufficient in the majority of patients, but the dose can be repeated if necessary. The best way to administer pyridoxine in a patient after an INH overdose has not been P.874 established. For a patient who is actively seizing, pyridoxine may be given by slow IV infusion at approximately 0.5 g/min until the seizures stop or the maximum dose has been reached. When the seizures stop, the remainder of the dose should be infused over 4–6 hours to maintain pyridoxine availability while the INH is being eliminated. The dose should be repeated if seizures persist or recur, or if the patient exhibits mental status depression. In the intravenous pyridoxine, pyridoxine should be administered orally.33 For hydrazine and methylated hydrazines (ie, MMH, UDMH) poisoning, there is no established dose.45 Using the same dosage regimen as for INH is theoretically reasonable, but has never been tested in humans. Pyridoxine should not be the sole agent used for INH or MMH poisoning. A benzodiazepine should be used with pyridoxine in an attempt to achieve synergistic control of seizures. If the seizures do not respond to both of these measures, they can be repeated, followed by intravenous agents such as propofol, pentobarbital, or phenobarbital, and, if necessary, neuromuscular blockade and

general anesthesia. When neuromuscular blockade is achieved without extinguishing the central nervous system (CNS) seizure activity, irreversible neuronal damage may result. Although metabolic acidosis is probably a result of the seizures and should therefore resolve once the underlying condition is controlled, severe or refractory metabolic acidosis may require appropriate quantities of sodium bicarbonate.

Availability Pyridoxine HCl is available parenterally at a concentration of 100 mg/mL in 1-mL ampules from various manufacturers. Thus a 5-g IV dose of pyridoxine requires fifty 1-mL ampules containing 100 mg/mL. This is an exception to the rule that appropriate doses of medications rarely require multiple dosages of this magnitude. This also emphasizes the necessity of keeping an adequate supply available in the emergency department, as well as in the pharmacy. Oral pyridoxine is available in many tablet strengths from 10–500 mg from various manufacturers.

References 1. Albin R, Albers J, Greenberg H, et al: Acute sensory neuropathy-neuronopathy 1987;37:1729–1732.

from

pyridoxine

overdose.

Neurology

2. Alvarez EG, Guntupalli KK: Isoniazid overdose: Four case reports and review of the literature. Intensive Care Med 1995;21:641–644. 3. Andary C, Bourrier MJ: Variations in the monomethylhydrazine content in Gyromitra Mycologia 1985;77:259–264.

esculenta.

4. Back KC, Pinkerton MK, Thomas AA: Therapy of acute UDMH intoxication. Aerosp Med 1963;34:1001–1004. 5. Baxter P: Pyridoxine-dependent seizures: A clinical and biochemical conundrum. Biochim Biophys Acta 2003;1647:36–41. 6. Beasley UR, Buck WB: Acute ethylene glycol toxicosis: A review. Vet Hum Toxicol 1980;22:255–263. 7. Berger AR, Schaumberg HH, Schroeder C, et al: Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: A prospective study of pyridoxine neurotoxicity. Neurology 1992;42:1367–1370. 8. Blanchard P, Yao J, McAlpine D, et al: Isoniazid overdose in the Cambodian population of Olmsted County, Minnesota. JAMA 1986;256:3131–3133. 9. Braun R, Greeff U, Netter KJ: Liver injury by the false morel poison gyromitrin. Toxicology 1979;12:155–163. 10. Brent J, Vo N, Kulig K, Rumack BH: Reversal of prolonged isoniazid-induced coma by pyridoxine. Arch Intern Med 1990;150:1751–1753. 11. Brown CV: Acute isoniazid poisoning. Am Rev Respir Dis 1972;105:206–216. 12. Chin L, Sievers ML, Herrier RN, et al: Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs. Toxicol Appl Pharmacol

1981;58:504–509. 13. Chin L, Sievers ML, Laird HE, et al: Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dogs. Toxicol Appl Pharmacol 1978;45:713–722. 14. Cornish HH: The role of B6 in toxicity of hydrazines. Ann N Y Acad Sci 1969;166:136–145. 15. Dakshinamurti K, Paulose CS, Viswanathan M, et al: Neurobiology of pyridoxine. Ann N Y Acad Sci 1990;585:128–144. 16. Franke S, Freimuth U, List PH: Uber die Giftigkeit der fruhjahrslorchel Gyromitra (Helvella) esculenta. Fr Arch Toxicol 1967;22:293–332. 17. Frierson WB: Use of pyridoxine HCl in acute hydrazine and UDMH intoxication. Ind Med Surg 1965;34:650–651. 18. George ME, Pinkerton MK, Bach KC: Therapeutics of monomethylhydrazine intoxication. Toxicol Appl Pharmacol 1982;63:201–208. 19. Gibbs DA, Watts RWE: The action of pyridoxine in primary hyperoxaluria. Clin Sci 1970;38:277–286. 20. Harati Y, Niakan E: Hydrazine toxicity, pyridoxine therapy and peripheral neuropathy. Ann Intern Med 1986;104:728–729. 21. Holtz P, Palm D: Pharmacological aspects of vitamin B6 .

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1964;16:113–178.

22. Jang YM, Kim DW, Kang TC, et al: Human pyridoxal phosphatase. Molecular cloning, functional expression, and tissue distribution. J Biol Chem 2003;278:50040–50046. 23. Kirlin JK: Treatment of hydrazine induced coma with pyridoxine. N Engl J Med 1976;294:938–939. 24. Krinke G, Schaumburg HH, Spencer PS, et al: Pyridoxine megavitaminosis produces degeneration of peripheral sensory neurons (sensory neuropathy) in the dog. Neurotoxicology 1980;2:13–24. 25. Krinke G, Naylor DC, Skorpil V: Pyridoxine megavitaminosis: An analysis of the early changes induced with massive doses of vitamin B6 in rat primary sensory neurons. J Neuropathol Exp Neurol 1985;44:117–129. 26. Lumeng L, Li T: Vitamin B6 metabolism in chronic alcohol abuse. J Clin Invest 1974;53:693–704. 27. Marcus R, Coulston AM: Water-soluble vitamins. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, eds: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp. 1760–1761. 28. Miller J, Robinson A, Percy AK: Acute isoniazid poisoning in childhood. Am J Dis Child 1980;134:290–292. 29. O'Brien RD, Kirkpatrick M, Miller PS: Poisoning of the rat by

hydrazine and alkylhydrazines. 1964;84:371–377.

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30. Parry G, Bredesen D: Sensory neuropathy with low dose pyridoxine. Neurology 1985;35:1466–1468. 31. Parry MF, Wallach R: Ethylene glycol poisoning. Am J Med 1974;57:143–150. 32. Perry TA, Weerasuriya A, Mouton PR, et al: Pyridoxineinduced toxicity in rats: A stereological quantification of the sensory neuropathy. Exp Neurol 2004;190:133–144. 33. Scharman EJ, Rosencrance JG: Isoniazid toxicity: A survey of pyridoxine availability. Am J Emerg Med 1994;12:386–388. 34. Schaumburg H: Sensory neuropathy from pyridoxine abuse. N Engl J Med 1984;310:198. 35. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse: A new megavitamin syndrome. N Engl J Med 1983;309:445–448. 36. Shouse MN: Acute effects of pyridoxine hydrochloride on monomethylhydrazine seizure latency and amygdaloid kindled seizure thresholds in cats. Exp Neurol 1982;75:79–88. P.875 37. Starke H, Williams S: Acute poisoning from overdose of isoniazid: A case report. Lancet 1963;83:406–408.

38. Sterman MB, Kovalesky RA: Anticonvulsant effects of restraint and pyridoxine on hydrazine seizures in the monkey. Exp Neurol 1979;65:78–86. 39. Terman DS, Teitelbaum DT: Isoniazid self-poisoning. Neurology 1970;20:299–304. 40. Toth B, Erickson J: Reversal of the toxicity of hydrazine an analogues by pyridoxine hydrochloride. Toxicology 1977;7:31–36. 41. Unna IC: Studies of the toxicity and pharmacology of vitamin B6 (2-methyl, 3-hydroxy-4,5-bis-pyridine). Pharmacol Exp Ther 1940;70:400–407. 42. Wason S, Lacouture PG, Lovejoy FH: Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981;246:1102–1104. 43. Wood JD, Peesker SJ: The effect on GABA metabolism of isonicotinic acid hydrazide and pyridoxine as a function of time after administration. J Neurochem 1972;19:1527–1537. 44. Wood JD, Peesker SJ: A correlation between changes in GABA metabolism and isonicotinic acid. Hydrazide-induced seizures. Brain Res 1972;45:489–498. 45. Zelnick SD, Mattie DR, Stepaniak PC: Occupational exposure to hydrazines: Treatment of acute central nervous system toxicity. Aviat Space Environ Med 2003;74:1285–1291.

46. Zempleni J: Pharmacokinetics of vitamin B6 supplements in humans. J Am Coll Nutr 1995;14:579–586. 47. Zempleni J, Kubler W: The utilization of intravenously infused pyridoxine in humans. Clin Chim Acta 1994;229:27–36.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > D - Antimicrobials > Chapter 56 - Antimalarials

Chapter

56

Antimalarials G. Randall Bond

A 30-year-old man stumbled into the emergency department (ED) appearing to agitated. However, he was quite coherent. He complained of inability to see, dif a continuous ringing in his ears, and the sensation of “a train rushing throug

He stated that he took “a bunch of pills,― drank some wine, and went off before coming to the ED. On awakening approximately 6 hours later, he was una balance.

His mother related an extensive family, medical, and social history: The patient taking many medications. In addition, he took “water pills,― later identifie control hypertension. The patient, she said, took aspirin “for arthritis,― an for malaria.― She insisted that he used no illicit drugs and seldom drank alco packs of cigarettes per day. She further noted that he had been extremely dep loss of his unemployment benefits. In addition, he had had a quarrel on the day

Physical examination revealed a well-developed, talkative, anxious man, with th blood pressure, 100/40 mm Hg; pulse, 100 beats/ min; respiration, 18 breaths 97.2°F (36.2°C). The skin was warm, dry, anicteric, and without pallor or cy

Ophthalmic examination revealed fixed, widely dilated pupils (right eye 7 mm, le

unresponsive to light and accommodation. Assessment of visual acuity demonst of distant shadows but no perception of close objects. The fundi were easily vis were pale and flat. There was severe arteriolar constriction starting at the disc vessels. The veins appeared normal in diameter. The arteriovenous ratio was 1 movements were intact. Examination of the ears revealed normal tympanic membranes. The patient was fork on each side, but could not hear the ticking of a watch. The remainder of was normal except for a soft systolic ejection murmur.

Blood samples were drawn and an electrocardiogram (ECG) was obtained. An IV with dextrose 5% in water (D5 W), and 1 g/kg of body weight of activated char orally.

The initial laboratory data revealed a hematocrit of 37.6%; a hemoglobin of 12.1 blood cell count (WBC) of 8600/mm3 with 80% polymorphonuclear cells, 18% l monocytes, and 1% eosinophils. The platelet count and international normalized normal.

The electrolyte analysis revealed sodium, 143 mEq/L; potassium, 4.4 mEq/L; ch bicarbonate, 29 mEq/L; blood urea nitrogen (BUN), 9 mg/dL; and glucose, 65 m phosphokinase IU/L) were all salicylates. The waves in leads

(10,250 IU/L), lactic dehydrogenase (700 IU/L), and aspartate elevated. The urinalysis was normal, with a negative urine ferric ECG showed a normal sinus rhythm at 96 beats/min, an axis of II, III, and aVF. Peaked T waves were present in V2 to V4. The

were both normal. The chest radiograph was normal. The patient was admitted unit.

The ophthalmic and auditory symptoms rapidly resolved without any additional addition, the pupillary and funduscopic examination returned to normal. The fun vasculature and color within 24 hours. Blood pressure returned to normal by the abnormal auditory and visual findings entirely resolved within 48 hours. The pa subsequently discovered that he had taken ten (300-mg) quinine tablets, origina treatment of the Plasmodium falciparum malaria.

History

and

Epidemiology

The malaria parasite has caused untold grief throughout human history. Today,

population live in areas infection, and 1 million infected are 50 million year. In spite of using

where malaria is endemic. More than 300 million people die from the infection each year.122 Included among thos travelers from industrialized countries who visit the dev prophylactic medications (Table 56-1 ), 30,000 will acqu

The bark of the cinchona tree, the first effective remedy for malaria, was introd than 350 years ago. 107 The toxicity of its active ingredient, quinine, was noted use. In this century, the need to fight wars in malaria-infested areas, and the t pharmaceutical advances funded largely by the military during World War II (c amodiaquine, pyrimethamine) and later during the Vietnam conflict (mefloquine Chloroquine, hydroxychloroquine, primaquine, amodiaquine, mefloquine, and hal

related to quinine, but have different patterns of toxicity. Other xenobiotics used include the folate inhibitors proguanil and pyrimethamine (frequently used in co atovaquone), the sulfonamide sulfadoxine, or the sulfone dapsone, as well as te macrolides (Chap. 54 ). Quinine

sulfate

Not used 650 mg tid × 7 daysb Chloroquine phosphate 500 mg/wk as single dose 1000 mg STAT then 500 mg at 6 h, 24 h, and 48 h Hydroxychloroquine sulfate 400 mg/wk as single dose Rarely used Primaquine phosphate 30 mg of base/d × 14 daysc 30 mg of base/d × 14 days Halofantrine Not used 500 mg q6h × 3 doses, repeat in 7 days Amodiaquine Not used 10 mg of base/kg/d × 3 days Mefloquine

250 mg/wk as single dose 750 mg STAT, then 500 mg 8 h later Pyrimethamine-sulfadoxine Not used 75 mg pyrimethamine + 1500 mg sulfadoxine as single dose Artemisinin Not used 10 mg/kg × 7 days Artesunate Not used 2 mg/kg PO BID on day 1 then 2 mg/kg/d × 6d o r

2.4 mg/kg IV on day 1 then 1.2 mg/kg/d IV or PO × 6 days Artemether Not used 3.2 mg/kg IM on day 1 then 1.6 mg/kg/d IM or PO × 6 days Artemether-lumefantrine Not used 80 mg artomether + 480 mg lumefantrine at 0, 8, 24, 36, 48, and 60 h Doxycycline 100 mg/day 100 mg BIDe

Proguanil-atovaquone 100 mg proguanil + 250 mg atovaquone once per day 400 mg proguanil + 1000 mg atovaquone per day × 3 days Proguanil-chloroquine 200 mg proguanil + 100 mg chloroquine once per day Not used a Choice, duration, and dosage may vary with malarial species and frequency of geographic area. b Usually with doxycycline, tetracycline, or clindamycin for chloroquine-resistant c After leaving P. vivax or P. ovale area. d Often with mefloquine 15 mg/kg in a shorter course.

e

With quinine sulfate for chloroquine-resistant cases. Drug

Prophylactic

Dose

(Adult)

Upper Dose Range, Treatment (Adult

TABLE 56-1. Common Adult Doses of Antimalarials Used Worldwide

P.877 With the introduction of each new xenobiotic, resistance developed, particularly Asia, and Africa.104 , 107 In some places, quinine is again the first-line therapy In the last two decades, the search for active agents has returned to a natural herb qinghaosu.58 , 116 Artemisinin, the active ingredient, is widely used in are resistant malaria.116 With increased leisure travel, a greater number of North A prophylactic agents with potential toxicity.

Quinine

Figure. No Caption Available.

In addition to its use as an antimalarial, quinine is also available in small amoun been used for muscle cramps and, because of an extremely bitter taste similar t adulterant in drugs of abuse.

Pharmacokinetics

and

Toxicodynamics

Quinine is rapidly and almost completely absorbed orally (Table 56-2 ). Peak pl achieved within 3 hours, with 85–95% of quinine protein bound, primarily to a glycoprotein.99 , 113 The apparent volume of distribution is 1.8–4.6 L/kg.54 Pe concentrations are achieved at 3–6 hours. The average therapeutic plasma ha 9–15 hours. In overdose, the elimination half-life is approximately 25–26 h kidneys, and muscles metabolize 80% of the ingested dose to a variety of hyd Approximately 20% is excreted unaltered in urine. Quinine passes transplacentall milk.

If high doses of cinchona alkaloids are ingested during pregnancy, resultant oxy induce abortion or premature labor. Because of this mechanism, in the past quin

commonly as an abortifacient (Chap. 28 ). 69 Chloroquine continues to be used f parts of the developing world.6 , 86

Quinine and quinidine are optical isomers and share similar pharmacologic effec and antimalarials. Because of the tissue toxicity of quinine, intravenous quinidine States when a parenteral form is needed to treat severe or resistant malaria. Q effects on

P.878 the GI tract and stimulates the center in the brainstem responsible for nausea a the cardiac and endocrine toxicity of quinine can be attributed to its effects on channels. Bioavailability (%) 76 80 74 >85 Low, varies >95 90 Time to peak (oral) 1–3 h 2–5 h 1–3 h 8–24 h

4–7 h 2–6 h 3–6 h Protein bound (%) 93 50–65 — 98 — 87 70–80 Volume of distribution (L/kg) 1.8–4.6 >100 3 15–40 >100 3 0.5–1 Half-life 9–15 h 40–55 d 5–7 h 15–27 d 1–6 d 3–4 d 21–30 h Urinary excretion 20 55 4 100 L/kg.107 Whole-blood chloro reflects tissue distribution and correlates with mortality.22 About half of the ing eliminated in the urine, as much as 70% as the parent molecule, and the remain

hepatic metabolites.54 , 62 An exceedingly long half-life, averaging 41 days, wa Hydroxychloroquine has a similarly rapid absorption and a half-life of 40 days in However, half-life in overdose is reported to be 15–30 hours.47

Pathophysiology

Like quinine, chloroquine has a small toxic-to-therapeutic margin. Severe chloro usually associated with ingestions of 5 g or more in adults, or with serum conc µg/mL. The cardiovascular effects of chloroquine and hydroxychloroquine are s quinine, including QRS prolongation, atrioventricular (AV) block, ST- and T-wav U waves, and QTc interval prolongation, but other features of cinchonism, are u xenobiotics have low toxicity when used in therapeutic doses. Because of this, first-line drug for malaria prophylaxis and treatment in areas where Plasmodium changes are not described with prophylactic doses but occur rarely with daily do

hydroxychloroquine for arthritis. The variation in individual risk for this manifest understood. Recent evidence suggests an early, pathological role for membrano the ganglion cells of the retina.70 Melanin granules are also noted in the pigmen the retina, but this occurs late.58 , 70 A related process involving skin melanin i pruritus frequently noted in Africans who use these drugs (8–20%).58

In some hosts, amodiaquine metabolism produces a quinone imine metabolite th hapten to induce a hypersensitivity reaction.16 This has led to reduced use of a prophylactic agent, particularly among Western travelers. Nonetheless, the drug tropical countries for treatment of acute and chronic malaria.

Clinical

Manifestations

Symptoms usually occur within 1–3 hours of ingestion.88 The range of sympto chloroquine toxicity is quite similar to quinine, but the frequencies of various m Nausea, vomiting, diarrhea, and abdominal pain are less common than with qui depression often occurs. Apnea, hypotension, and cardiovascular compromise ca

Hypotension is a more prominent feature than with quinine.45 Electrocardiographi associated with chloroquine use include QRS prolongation, AV block, ST- and T increased U waves, and QTc interval prolongation, but these are less frequent t Significant hypokalemia is invariably associated with the cardiac manifestations

results

from

direct

chloroquine-induced

intracellular

shifts.

The neurologic manifestations include CNS depression, dizziness, headache, and dystonic reactions occur.77 Transient parkinsonism has been reported following

The ophthalmic manifestations are infrequent in acute toxicity, usually less con in nature. 45 , 58 More severe and irreversible vision and hearing changes are d with the use of chloroquine and hydroxychloroquine as antiinflammatory agents neuropathy, and cardiomyopathy also are described in this context.5 , 114 Derma hypersensitivity reactions similar to those associated with quinine are described oxidant stress from chloroquine may result in hemolysis in patients with gluco dehydrogenase (G6PD) deficiency (Chap. 24 ). Acute hydroxychloroquine toxicity is similar to chloroquine toxicity.47 , 63 Side

doses include nausea and abdominal pain, hemolysis in G6PD-deficient patients, damage, sensorineural deafness, and hypoglycemia.10 , 46 , 98 Hypersensitivity myocarditis and hepatitis, are described.34 , 61 P.881

One report of amodiaquine toxicity suggests that neurologic toxicity including muscle stiffness, dysarthria, syncope, and seizures may occur.45 Amodiaquine is hypersensitivity hepatitis and neutropenia in prophylactic use, but not therapeu overdose experience reported.

Management

Early, aggressive management of severe chloroquine toxicity decreased the fatal from 91% to 9%. 88 The protocol involves the use of epinephrine for chloroquin and myocardial depression, and diazepam for possible direct cardiovascular effec minimize CNS-based cardiac excitation.89 Other experiences validate this appro

Patients should receive early endotracheal intubation and mechanical ventilation used to facilitate intubation, its use immediately preceded sudden cardiac arrest after chloroquine overdose.22 An adequate FiO2 , tidal volume, and ventilatory Orogastric lavage should be performed for patients with recent and substantial charcoal should be administered. During decontamination, 2 mg/kg IV diazepam minutes, and then 1–2 mg/kg/d for 2–4 days. Simultaneously, epinephrine should be given IV with D5 W, and adjusted incrementally until a systolic blood

100 mm Hg is achieved. Even after this initial therapy, some patients may man cardiovascular compromise and require additional epinephrine and other catech complex width is increased, sodium bicarbonate should be administered as for q potassium concentrations should be monitored and potassium supplementation aggressive replacement therapy is discouraged, because hypokalemia represents total-body potassium depletion.21 , 45 , 47

Because chloroquine and hydroxychloroquine have high volumes of distribution, binding, and long terminal elimination half-lives, enhanced elimination procedure , 45

Primaquine Pathophysiology

Primaquine causes RBC oxidant stress. Clinically insignificant methemoglobinemi Methemoglobinemia and hemolysis can occur in normal individuals given high d toxicity of primaquine in therapeutic use has been hemolysis in G6PD-deficient contraindicated in pregnant women because the fetal G6PD status is unknown. suppression can occur.

Clinical

Manifestations

Overdose with primaquine is rarely reported. Nausea, headache, and abdominal A case of extreme, iatrogenic overdose (1260 mg followed by 15 mg/d for 5 da hallucinations, abdominal cramps, nausea, jaundice, hepatitis, and black urine.5 7.4 mg/dL. Aminotransferases peaked at aspartate aminotransferase (AST) 3309 aminotransferase (ALT) 2654 IU/L. Renal function, hemoglobin, and white blood reported. Resolution occurred over 1 month.

Management

In the event of overdose, therapy should be directed at minimizing absorption decontamination, reversing significant methemoglobinemia with methylene blue Antidotes in Depth: Methylene Blue ), supporting adequate circulating red cell m

necessary, and preventing hemoglobin-induced renal injury by maintaining adeq alkalinizing the urine to a pH greater than 6, if necessary (Chap. 10 , Antidotes Bicarbonate , and Antidotes in Depth: Activated Charcoal ).

Mefloquine Pharmacokinetics

and

Toxicodynamics

Mefloquine is slowly absorbed (Table 56-2 ). 96 Absorption is enhanced with food protein bound and has a very large volume of distribution (22 L/kg).49 , 96 Hepa in an inactive metabolite, with a terminal elimination half-life of 18 days, but variation occurs.96 Because it has such a long half-life, it may take several wee state, delaying the onset of toxic manifestations.

Clinical

Manifestations

Common effects with prophylactic and therapeutic dosing include nausea, vomit

These effects are noted particularly in children and older adults, or with high th are expected in acute overdose.90 , 116

Mefloquine has a mild cardiodepressant effect—less than that of quinine or qu

clinically significant in prophylactic dosing or with therapeutic administration. W neither the PR interval nor the QRS complex is prolonged, but QTc prolongation Clinically insignificant bradycardia is common.58 , 74 Reports of torsades de poin increase in QTc and risk of torsades de pointes are increased when mefloquine chloroquine, or, most particularly, with halofantrine.58 , 73 , 74 Risk is also assu acute overdose. The long half-life of mefloquine, about 18 days, means that par taken with therapeutic use of these xenobiotics when breakthrough malaria occ prophylaxis, or within 28 days of mefloquine therapy. Given the lack of alternat quinine is often used.

During prophylactic use, many patients experience insomnia, an alteration in dre dizziness, headache, fatigue, mood alteration, and vertigo.96 , 110 In only 2–1 effects significant enough to cause the traveler to “feel sick― or to chang 97 Intolerance occurs more commonly in women.7 , 79 , 110 Seizures occur very and therapeutic use.83 , 92 In many of these cases, there is a history of previou

first-degree relative, or other risk factors. Other neuropsychiatric symptoms, in “clouded― consciousness, toxic encephalopathy, anxiety, depression, giddin delirium with psychosis, comprise the bulk of serious adverse event reports. The related to the serum or CNS concentration. The frequency of hallucinations and about 1:10,000 with prophylaxis to as high as

P.882 1:200 with therapeutic In at least one case report, the severe n manifestations of mefloquine were reversed with physostigmine, suggesting a etiology.102 Risk of CNS toxicity is increased by administration of quinine or chl mefloquine. A self-resolving postmalaria neurologic syndrome including confusio tremor is associated with therapeutic use of mefloquine for severe malaria. 60 , dosing.25 , 90

The effect of mefloquine on the pancreatic potassium channel is much less than resulting in only a mild increase in insulin secretion.26 , 27 Symptomatic hypogly reported as an effect of mefloquine alone in healthy individuals, but has occurr of alcohol and in a severely malnourished patient with AIDS.4 , 27 , 58 In overdo

accompanied by alcohol use or recent starvation, this hypoglycemia may be sig

Rare events reported with prophylaxis include urticaria, alopecia, erythema mu necrolysis, myalgias, mouth ulcers, neutropenia, and thrombocytopenia.64 , 74 , likely hypersensitivity reactions. It is unclear which, if any, would be significant large dose ingestion. ARDS was linked to therapeutic dosing in 1 case.108

In therapeutic use, mefloquine is associated with an increased incidence of still quinine and a group of other antimalarial medications.75 Mefloquine was not, ho increased incidence of abortion, low birth weight, mental retardation or congen implications for an overdose in the absence of malaria are not clear, but fetal m instituted.

In contrast, the consequences of excessive dosing are not only severe, but pro permanent. Two cases of daily mefloquine overdosing resulted in confusion, ag speech difficulties, and high-frequency hearing loss in 1 case, and nausea, fatig depression, disorientation, and paresthesia in the other. In the first case, resolu year, except for residual hearing loss.56 In the second case, symptoms persisted another case, a man ingested 5.25 g of mefloquine over 6 days.15 Symptoms in myalgia, vertigo, visual accommodation difficulties, mild hypotension (90/50 mm beats/min) with occasional ventricular premature complexes, minimal increase in

and prolonged INR. His symptoms resolved over 5 days, except for the weaknes 2 months. The INR corrected over 2 weeks. In this case, cardiovascular symptom significant than were neurologic symptoms. A fourth man ingested mefloquine 3 3250 mg, and sulfadoxine-pyrimethamine 175 mg/3500 mg—2.5 times the usu each—over 3 days.18 He suffered encephalopathy that was unresolved 8 mont patient took mefloquine 2 g over 2 days (the usual therapeutic dose is 1250 mg malaria.72 At presentation he experienced nausea, constipation, and abdominal p headache, vertigo, insomnia, anxiety, confusion, hallucinations, and paranoia. He findings. ECG and laboratory findings were normal. No other drugs were detected elevated mefloquine level of 1.8 µg/mL (upper limit of therapeutic 1 µg/mL). with only supportive care.

Management

In overdose, supportive care is the primary therapy. Decontamination with activ indicated if the patient presents soon after the ingestion. Specific monitoring fo hypoglycemia, and liver injury should be provided. Patients should be followed f nerve complications.

In 2 renal-failure patients taking mefloquine, prophylactic hemodialysis did not Given the large volume of distribution and high degree of protein binding of m unlikely to be effective.

Halofantrine Pharmacokinetics

and

Toxicodynamics

Halofantrine is slowly and incompletely absorbed (Table 56-2 ).17 , 45 It is meta metabolite, N -desbutylhalofantrine. 17 The half-life of halofantizine is 1–6 day the QTc interval is proportional to the dose and serum halofantrine concentratio percent of children receiving a therapeutic course of halofantrine will have a QT msec.101

Clinical

Manifestations

The primary toxicity from therapeutic and supratherapeutic doses is torsades de fibrillation associated with prolongation of the QTc interval.23 , 39 , 73 , 106 Palpi and syncope may occur. First-degree heart block is common, but bradycardia is QTc interval duration is related to serum concentration, dysrhythmias would be Dysrhythmias are also likely in the context of combined overdose or combined/ with other drugs that cause QTc interval prolongation, particularly mefloquine.5

Other side effects, including nausea, vomiting, diarrhea, abdominal cramping, h headedness, which frequently occur in therapeutic use, are also expected in ov frequently described side effects—pruritus, myalgias, and rigors—can occur. In seizures, minimal liver enzyme concentration elevation, and hemolysis are desc

Whether these manifestations are related to halofantrine or to the underlying m

Management

Management of halofantrine overdose should also focus on decontamination, su monitoring for QTc interval prolongation and associated dysrhythmias. Treatment prolonged QTc interval and torsades de pointes is discussed above under Quinin

Proguanil,

Pyrimethamine,

Sulfadoxine,

Dapson

Atovaquone Pharmacokinetics

and

Toxicodynamics

Proguanil, pyrimethamine, sulfadoxine, and dapsone all interfere with folate me used in combination. Proguanil (chloroguanide) may be used alone, but is often (Lapdap), chloroquine, or the antiparasitic atovaquone (Malarone) for prophylax the de novo pyrimidine synthesis that is necessary for protozoal survival and re unnecessary in mammalian cells. Based on the relative side-effect profile, many physicians are

P.883 switching from mefloquine to atovaquone/proguanil for routine antimalarial pro Atovaquone and proguanil may now be the most common antimalarial agents us Pyrimethamine is used in combination with sulfadoxine (Fansidar) or with dapso growing malarial resistance has limited the usefulness of these two drug combi

for pharmacokinetic profile). Genetic polymorphism is described in the metabolis dapsone.48 , 87 This may be the cause of the significant hypersensitivity reactio dapsone.87

Clinical

Manifestations

Information on proguanil overdose is limited. The side effects of proguanil duri nausea, diarrhea, and mouth ulcers.58 Because of interference with folate, mega rare complication. Folate supplementation may be required in pregnancy and re neutropenia, thrombocytopenia, rash, and alopecia are also noted.25 In a single hypersensitivity hepatitis was described.25 When used to treat malaria, atovaq vomiting, sometimes severe, in a significant portion of patients (15–45%).90 associated with elevated liver function tests.90

Atovaquone alone, primarily used to treat Pneumocystis carinii in AIDS patients tolerated.78 Side effects include maculopapular rash, erythema multiforme (ra complaints, and mild aminotransferase elevations. Three cases of 3- to 42-fold dosing have been reported.20 No symptoms occurred in 1 case (at 3 times ther

Rash occurred in another, and in the third case, methemoglobinemia was attribu overdose of dapsone.

Dapsone and the sulfonamides have a long history of causing idiosyncratic reac neutropenia, thrombocytopenia, eosinophilic pneumonia, aplastic anemia, neurop 90 The rare occurrence of life-threatening erythema multiforme major, associate sulfadoxine prophylaxis, has limited the use of this combination for prophylaxis.

Acute ingestion of dapsone may result in nausea, vomiting, and abdominal pain dapsone produces RBC oxidant stress leading to methemoglobinemia and, to a sulfhemoglobinemia (Chap. 122 ). 19 , 59 The onset of hemolysis may be either delayed.121 Other symptoms, particularly tachycardia, dyspnea, dizziness, visu seizure, syncope, and coma resulting from end-organ hypoxia, can occur.19 , 45 described in overdose include hepatitis and peripheral neuropathy.45

Overdose of pyrimethamine alone is rare. In children, it results in nausea, vomi seizures, fever, and tachycardia.1 , 45 Blindness, deafness, and mental retardati Seizures were attributed to sulfadoxine-pyrimethamine in an overdose of 12 tabl dose is 3 tablets taken once).72 Chronic high-dose use may be associated with

requiring folate replacement (Chap. 24 and Antidotes in Depth: Folic Acid and ) .1

Management

Folate supplementation should be considered after overdose of proguanil or pyr in Depth: Folic Acid and Leucovorin [Folinic Acid] ). Other efforts should include

Following dapsone ingestion, clinically significant methemoglobinemia should be blue (Antidotes in Depth: Methylene Blue ). Sulfhemoglobinemia is irreversible, insignificant portion of total hemoglobin. Both hemodialysis and multidose activ elimination of dapsone during therapy.71 , 121 Multidose activated charcoal is ro the treatment of dapsone overdose.3 Required support may include RBC transfu alkalinization if hemolysis is extensive (Antidotes in Depth: Sodium Bicarbonate

Artemisinin

and

Derivatives

Artemisinin

Pharmacokinetics

and

Toxicodynamics

Artemisinin and its derivatives: artemether, arteether, dihydroartemisinin, and the Chinese herb qinghaosu. They were introduced in the 1980s in China for the and since then millions of doses have been used in Asia and Africa.

The parent drug artemisinin has poor solubility and limited bioavailablilty.82 Der

absorption and some may be used parenterally, but are rapidly degraded.82 Arte half-life. Because these xenobiotics have a short half-life, prolonged courses of prevent recrudescence of malaria. To provide a shorter, more effective treatmen emergence of malarial resistance, artemesinins are frequently used in combinat Recently the oral combination drug artemether/lumefantrine was introduced. Ch evaluating a combination of artemisinin and naphthoquine.112

The efficacy and toxicity of artemisinin is thought to be a result of the ability o core to form intracellular free radicals, particularly in the presence of heme. In brainstem nuclei is consistently produced following prolonged, high-dose and p These findings are associated with prolonged CNS exposure to parenteral depo f xenobiotics.35 , 90 Embryonic loss has also been observed in animals.90

Clinical

Manifestations

In contrast to the experience with animals, the experience of more than 8000 shows that these xenobiotics have a very low incidence of side effects.90 Low-fre include nausea, vomiting, abdominal pain, diarrhea, and dizziness.

Prospective studies have failed to identify an increased incidence of adverse ne particularly related to the brainstem.51 , 90 Rare reports of adverse CNS effects suggest the possibility of CNS depression, seizures, or P.884

cerebellar symptoms following intentional self-poisoning. In children with cerebra incidence of seizures and a delay to recovery from coma were noted in a compa neurologic difference was noted in long-term follow-up. In an artemether–quin adults with severe malaria, recovery from coma was also prolonged in the artem number ( Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > E - Cardiopulmonary Medications > Chapter 57 - Anticoagulants

Chapter

57

Anticoagulants Mark Su Robert S. Hoffman A 66-year-old man presented to the emergency department with a complaint of 24 hours of lower abdominal pain that radiated to his left groin. The pain had increased in intensity and resulted in syncope. His past medical history was significant for atrial fibrillation, hypertension, congestive heart failure, colonic polyps, diverticulosis, cataracts, and sciatica. His medications included warfarin 2.5 mg daily, oxybutynin chloride 2 mg twice daily, labetalol 300 mg three times daily, quinapril 40 mg daily, rofecoxib 25 mg daily, and zolpidem 10 mg as needed for sleep. On physical examination, he was awake and alert, but ill appearing and pale. Vitals signs were blood pressure, 101/38 mm Hg; pulse, 92 beats/min; respiratory rate, 18 breaths/min; temperature, 98.6°F (37°C); symptomatic orthostasis was present. Examination of the head, eyes, ears, nose, and throat was unremarkable. His chest was clear to auscultation bilaterally, and heart examination revealed an irregularly irregular rate. The patient's abdomen was noted to be moderately distended and tender in the left upper quadrant and left flank with scrotal edema. Rectal examination and

testing for occult blood were negative. The skin and extremities were normal, with no evidence of petechiae or ecchymoses. The patient was immediately given 100% oxygen via a non-rebreather mask, treated with intravenous 0.9% sodium chloride via 2 large-bore catheters, and blood was drawn for laboratory studies. An electrocardiogram demonstrated atrial fibrillation, at a rate of approximately 100 beats per minute, without evidence of acute myocardial ischemia or infarction. Initial laboratory studies showed a white blood cell (WBC) count of 14,000/mm3 , hemoglobin 10.3 g/dL, hematocrit 32.1%, and platelets 317,000/mm3 . The initial prothrombin time (PT) was 66.7 seconds (international normalized ratio [INR] of 5.7), and activated partial thromboplastin time (PTT) was 81.4 seconds. Urinalysis revealed a specific gravity of 1.025; small bilirubin; trace ketones; 100 mg/dL protein; and no red blood cells. After discovering the patient's coagulopathy, he was given 10 mg of vitamin K 1 subcutaneously. He was also given 4 units of fresh-frozen plasma based on his weight and then taken emergently for a noncontrast abdominal computed tomography (CT) scan of the abdomen, which revealed a large retroperitoneal hematoma, extending from the inferior pole of the spleen into the pelvis (Fig. 57-1 ). On repeat abdominal computed tomography scan with contrast 3 hours later, the retroperitoneal hematoma was noted to have increased in size. The patient was admitted to the surgical intensive care unit where his repeat coagulation studies were significant for a PT of 27 seconds, an INR of 2.3, and a PTT of 56.2 seconds. His hematocrit decreased to 22.6%, and he received an additional 6 units of fresh-frozen plasma and 6 units of packed red blood cells prior to surgery. Intraoperatively, a large hematoma with clots was evacuated and although no active bleeding was visualized at the time, the retroperitoneal blood was believed to originate from his psoas muscles. The patient had an uneventful course postoperatively and was discharged home 5 days later.

History

and

Epidemiology

Anticoagulants have numerous clinical applications, including the treatment of coronary artery disease, cerebrovascular events, deep venous thrombosis, and

pulmonary

embolism.

The origins and discovery of anticoagulants are extraordinary.1 , 18 , 74 , 128 The discovery of modern-day oral anticoagulants originated following investigations of a hemorrhagic disorder in Wisconsin cattle in the early 20th century that resulted from the ingestion of spoiled sweet clover silage. The hemorrhagic agent, eventually identified as bishydroxycoumarin, would be the precursor to its synthetic congener warfarin (named after the W isconsin A lumni R esearch F oundation). This knowledge also led to the use of warfarin as a rodenticide. “Superwarfarins― were subsequently developed as selective pressure caused rats to develop genetic resistance to warfarin. These potent agents permitted either small, repetitive ingestions or single, larger ingestions to successfully function as rodenticides. Like warfarin, the origins of the anticoagulant heparin are equally fascinating. A medical student initially attempting to study ether-soluble procoagulant agents derived from porcine intestines, P.888 serendipitously found that, over time, these apparent “procoagulants― actually prevented the normal coagulation of blood. The phospholipid anticoagulant responsible for this effect would later be identified as an early form of heparin. Shortly thereafter, the water-soluble mucopolysaccharide termed heparin (because of its abundance in the liver) was then discovered. Unfractionated heparin is a mixture of polysaccharide chains with varying molecular weights. Following the identification of the active pentasaccharide segment of heparin in the 1970s, multiple low-molecular-weight heparins were isolated and synthetic forms created.

Figure 57-1. Abdominal CT scan illustrating a large left-sided retroperitoneal hematoma in a patient with an INR of 5.7 presenting with left flank pain radiating to the groin.

In the late 19th century, human urine was noted to have proteolytic activity with a specificity for fibrin. A substance found to be an activator of endogenous plasminogen leading to the consumption of fibrin, fibrinogen, and other coagulation proteins was isolated and purified and given the name urokinase. Streptokinase, a protein produced by β-hemolytic streptococci, tissue plasminogen activator (t-PA), and other synthetic thrombolytic agents were later discovered. Although known to exist for many years, ancrod (Arvin; a purified derivative of snake venom) and hirudin (a product of leeches) only recently gained attention as naturally occurring antithrombotic therapeutic agents. The diversity of these anticoagulant and fibrinolytic agents has led to everincreasing use in many fields of medicine. Warfarin is the most common oral anticoagulant in use today because of its uses in patients with cerebrovascular disease, cardiac dysrhythmias, and thromboembolic disease.

During the period of 1999–2003, the total number of cases of reported warfarin exposures to the Toxic Epidemiologic Surveillance System was 11,544 with 22 deaths (Chap. 130 ). Throughout this time, there was a general trend toward an increasing number of reports. Additionally, because the common problem of excessive warfarin effects leading to hemorrhage is poorly quantitated as an adverse drug reaction, it frequently goes untabulated. Thus, as long as warfarin continues to be routinely prescribed, it is likely that the incidence of adverse drug events will increase. Physicians must be cognizant of the complications of warfarin and other anticoagulants, as well as their various therapeutic modalities, while balancing the potential for their risk and benefits.

Physiology Balance

Between

Coagulation

and

Anticoagulation An understanding of the normal function of the coagulation pathways is essential to appreciate the etiology of a coagulopathy. This section summarizes the critical steps of the coagulation cascade. For additional detail, the reader is referred to Chap. 24 and several reviews.64 , 125 , 151 Coagulation consists of a series of events that prevent excess blood loss and assist in the restoration of blood vessel integrity. Although the traditional understanding of the events that occur in the coagulation cascade,49 , 110 a s discussed below, adequately describe in vitro events, the current understanding emphasizes some distinct differences that occur in vivo. 64 , 125 , 151 Despite these differences, an understanding of the traditional model is most useful for interpreting the results of diagnostic tests of coagulation. Within the cascade, coagulation factors exist as inert precursors and are transformed into enzymes when activated. Activation of the cascade occurs through one of two distinct pathways, the intrinsic and extrinsic systems (Fig. 57-2 ).49 , 110 Once activated, these enzymes catalyze a series of reactions that ultimately converge and lead to the generation of thrombin and the

formation of a fibrin clot. The intrinsic pathway is activated by the complexation of factor XII (Hageman factor), with high-molecular-weight kininogen (HMWK) and prekallikrein, or vascular subendothelial collagen. This results in sequential activation of factor XII, active kallikrein, active factors IX to XI, and prothrombin (factor II) (Fig. 57-2 ). Prothrombin is converted to thrombin in the presence of factor V, calcium, and phospholipid. The integrity of this system is usually evaluated by determining the partial thromboplastin time (PTT). In the extrinsic, or tissue factor-dependent pathway, a complex is formed between factor VII, calcium, and tissue factor, which is released following injury. A calcium and lipid-dependent complex is then created between factors VII and X. The factor VII-X complex subsequently converts prothrombin to thrombin, which promotes the formation of fibrin from fibrinogen (Fig. 57-2 ). The integrity of this pathway is usually assessed by determining the prothrombin time (PT or INR). Activation of factor X provides extrinsic coagulation pathways. activate both factors IX and X between the two pathways.137 process of coagulation X .67 , 114 , to form a

the important link between the intrinsic and Additional evidence that tissue factors can suggests that there are more interrelations Furthermore, cell surfaces facilitate the

clotting. Platelets are also known to interact with proteins of the cascade through surface receptors for factors V, VIII, IX, and 168 As a final step, factor XIII assists in the cross-linking of fibrin stable thrombus.

Antithrombin III (AT), protein C, and protein S serve as inhibitors, maintaining the homeostasis that is required to prevent spontaneous clotting and keep blood fluid. Protein C, when aided by protein S, inactivates two plasma factors, V and VIII.27 , 41 , 64 AT complexes with all the serine protease coagulation factors (factor Xa, factor IXa, and contact factors, including XIIa, kallikrein, and HMWK), except factor VII.27 , 64 , 151 Thrombolytic agents such as streptokinase, urokinase, anistreplase, and recombinant tissue plasminogen activator (rt-PA) enhance the normal processes that lead to clot degradation.125

Thrombosis is initiated when exposed endothelium or released tissue factor leads to platelet adherence and aggregation, the formation of thrombin, and cross-linking of fibrinogen to form fibrin P.889 This results in a hemostatic plug or thrombus formation. Thrombus formation, in turn, leads to generation of plasmin from plasminogen, which causes fibrinolysis and eventual dissolution of the hemostatic plug.43 , 44 Thus the fibrinolytic system may be thought of as a natural balance against unregulated coagulation. Thrombolytic therapy increases fibrinolytic activity by accelerating the conversion of plasminogen to plasmin, which actively degrades fibrin.43 , 44 Following the administration of thrombolytic agents, a consequential drug-induced coagulopathy ensues, and fibrin degradation products are elevated secondary to the rapid turnover of strands.64 , 125 , 151

clot.

Figure 57-2. The figure presents a schematic overview of the coagulation and fibrinolytic pathways and indicates where phospholipids on the platelet surface interact with the coagulation pathway intermediates. Arrows are not shown from platelets to phospholipids involved in the tissue factor VIIa and

the factor IXa –VIIIa interactions to avoid confusion. Interactions of selected venom proteins are indicated in the black boxes. The diagram is not complete with reference to the multiple sites of interaction of the SERPINS (serine protease inhibitors) to avoid overcrowding.115 PL = platelets; XL = cross-linked.

Development

of

Coagulopathy

Impaired coagulation results from decreased production or enhanced consumption of coagulation factors, the presence of inhibitors of coagulation, activation of the fibrinolytic system, or abnormalities in platelet number or function. Platelets are involved in the initial phases of clotting following blood vessel injury by assisting in the formation of the fibrin plug. For the purposes of this chapter, a discussion of platelet-related abnormalities is excluded. Some of this information can be found in Chap. 24 . Decreased production of coagulation factors results from congenital and acquired etiologies. Although congenital disorders of factor VIII (hemophilia), factor IX (Christmas factor), factor XI, and factor XII (Hageman factor) are all reported, their overall incidence is still quite low. Clinical conditions that result in acquired factor deficiencies are much more common and result from either a decrease in synthesis or activation. Factors II, V, VII, and X are entirely synthesized in the liver,64 , 125 , 151 making hepatic dysfunction a common cause of acquired coagulopathy. In addition, factors II, VII, IX, and X require postsynthetic activation by an enzyme that uses vitamin K as a cofactor,173 , 178 , 179 such that vitamin K deficiency (from malnutrition, changes in gut flora secondary to xenobiotics, or malabsorption), or inhibition of vitamin K cycling (from warfarin, as will be described), is capable of impairing coagulation. Excessive consumption of coagulation factors usually results from massive activation of the coagulation cascade. Massive activation occurs during severe hemorrhage, or disseminated intravascular coagulation. The latter results from infection, such as sepsis, and from conditions that introduce tissue factor into the blood, such as neoplasms, snake envenomations, stagnant

blood flow, diffuse endothelial injury secondary to hyperthermia, ruptured aortic aneurysm, or aortic dissection. The hallmark of a consumptive coagulopathy is a depressed level of fibrinogen with an elevation of fibrindegradation products. This combination suggests the rapid turnover of fibrin in the coagulation process. In the other coagulopathic conditions, the failure to activate the coagulation cascade is associated with normal or high fibrin levels and low fibrin-degradation products because of limited clot formation. Inhibitors of the coagulation cascade (circulating anticoagulants) are of two types: immunoglobulin and nonimmunoglobulin. Immunoglobulins, which are often antibodies to existing coagulation factors, may occur without obvious cause. They may be part of a systemic autoimmune disorder or as a result of repeated transfusions with exogenous factors (as occurs in hemophilia).77 , 105 , 163 The clinical syndromes associated with antibody inhibitors are similar to those associated with deficiencies of the particular coagulation factors involved. Antibodies to factors V, VII to XI, and XIII are described in the literature. 22 , 163 Alternatively, nonimmunoglobulin neutralizers of coagulation occur in conditions associated with rapid white blood cell turnover.22 These lysosomal cationic proteins are neutralizers that P.890 compete with coagulation factors for negatively charged phospholipid membrane surfaces. Although they prolong in vitro coagulation times, they are rarely responsible for clinical coagulopathy because of the excess of phospholipid surface area available in vivo.77 , 105

Oral

Anticoagulants

Warfarin and “Warfarinlike― Anticoagulants Oral anticoagulants can be divided into two groups: (a) hydroxycoumarins, including warfarin (commonly called by its trade name Coumadin), difenacoum, panwarfarin, warficide, coumachlor, coumafuryl, fumasol, prolin, ethyl biscoumacetate (Tromexan), phenprocoumon, dicumarol

bishydroxycoumarin, and acenocoumarin (Sintrom); and (b) indanediones, including chlorophacinone, pindone, pivalyn, diphacinone, diphenadione, phenindione, and anisindione. Regardless of the classification, the mechanism of action involves inhibition of the vitamin K cycle. Vitamin K is a cofactor in the postribosomal synthesis of clotting factors II, VII, IX, and X (Fig. 57-3 ). The vitamin K-sensitive enzymatic step that occurs in the liver involves the γ-carboxylation of 10 or more glutamic acid residues at the amino terminal end of the precursor proteins, to form a unique amino acid γcarboxyglutamate.54 , 173 , 178 , 179 These amino acids chelate calcium in vivo, which allows the binding of the four vitamin K-dependent clotting factors to phospholipid membranes during activation of the coagulation cascade.198 Vitamin K is inactive until it is reduced from its quinone form to a quinol (or hydroquinone) form in hepatic microsomes. This reduction of vitamin K must precede the carboxylation of the precursor factors. The carboxylation activity is coupled to an epoxidase activity for vitamin K, whereby vitamin K is oxidized simultaneously to vitamin K 2,3-epoxide (Fig. 57-3 ).178 , 198 This inactive form of the vitamin is converted back to the active form by two successive reductions.54 , 112 , 141 In the first step, an epoxide reductase (known as vitamin K 2,3-epoxide reductase) uses reduced nicotinamide adenine dinucleotide (NADH) as a cofactor to convert vitamin K 2,3-epoxide to a quinone form.133 , 178 Subsequently, the quinone is reduced to the active vitamin K quinol form (see Antidotes in Depth: Vitamin K 1 ) .

Figure 57-3. The vitamin K cycle. Dotted lines represent pathways that can be blocked with warfarin and warfarinlike anticoagulants. The aliphatic side chain (R) of vitamin K is shown below the metabolic pathway.

Warfarin is a racemic mixture of R warfarin and S warfarin enantiomers. In rodents, S warfarin is 3–6 times more potent than R warfarin at producing hypoprothrombinemia.30 In humans, S warfarin may only be about 1.5 times as potent as R warfarin.31 Warfarin and all warfarinlike compounds inhibit the activity of vitamin K 2,3-epoxide reductase, as can be demonstrated by the

observation of elevated levels of vitamin K 2,3-epoxide, in orally anticoagulated subjects.39 , 201 Additional evidence suggests that another enzyme, vitamin K quinone reductase, is also inhibited by warfarin and its related compounds (Fig. 57-3 ).54 , 57 This reduction in the cyclic activation of vitamin K subsequently inhibits the formation of activated clotting factors.

Pharmacology

of

Warfarin

Orally ingested warfarin is virtually completely absorbed, and peak plasma concentrations occur approximately 3 hours after drug administration.177 Because only the free warfarin is therapeutically active, concurrent administration of xenobiotics that alter the level of free warfarin, either by competing for binding to albumin or by inhibiting warfarin metabolism, may markedly influence the anticoagulant effect.14 , 62 , 177 Table 57-1 lists the xenobiotics that interfere with or potentiate warfarin's effects. Although vitamin K regeneration is altered almost immediately, the anticoagulant effect of warfarin, as well as other oral anticoagulant agents, is delayed until the existing stores of vitamin K are depleted and the active coagulation factors are removed from circulation. Because vitamin K turnover is rapid, this effect is dependent on factor half-life (t1 / 2 ), with factor VII (t1 / 2 ~5 hours) P.891 depleted most For a prolongation of the INR to occur, factor levels must fall to approximately 25% of normal values. Assuming complete rapidly.62

inhibition of the vitamin K cycle, this not originally anticoagulated, at least are required before warfarin's effect does not occur and hence, the onset Acetaminophen Allopurinol Amiodarone Anabolic steroids Aspirin Carbenicillin Clarithromycin

suggests that in most patients who are 15 hours (three factor VII half-lives) is evident.62 In fact, complete inhibition of coagulation is even further delayed.

Cephalosporins Chloral hydrate Cimetidine Clofibrate Cyclic antidepressants Disulfiram Erythromycin Ethanol Fluconazole HMG-CoA Reductase Inhibitors Isoniazid Ketoconazole Metronidazole Nonsteroidal anti-inflammatory Omeprazole

agents

Phenytoin Propafenone Propoxyphene Quinidine Quinolones Sulfonylureas Tamoxifen Tetracycline Thyroxine TrimethoprimSulfamethoxazole Vitamin E Antacids Barbiturates Carbamazepine Cholestyramine Colestipol Corticosteroids Griseofulvin Oral contraceptives

Phenytoin Rifampin Vitamin K Potentiation

Antagonism

TABLE 57-1. Common Drug Interactions With Warfarin Anticoagulation Because the half-life of warfarin in humans is 35 hours, its duration of action may be as long as 5 days.30 , 62 , 177 On average, it takes approximately 6 days of warfarin administration to reach a steady-state anticoagulant effect. R warfarin is metabolized by isozymes CYP1A2 and CYP3A4, and S warfarin is metabolized by CYP2C9 of the hepatic microsomal P450 enzyme system. R warfarin is metabolized by side-chain reduction to secondary alcohols that are subsequently excreted by the kidney, whereas S warfarin is metabolized by hydroxylation to 7-hydroxy warfarin, which is excreted into the bile.62 , 177 The elimination of S warfarin is more rapid than that of R warfarin.31 The therapeutic dose of warfarin is established for both adults and children. Typical adult recommendations are to give a starting dose of 5 mg/d with subsequent doses based on nomograms, computer programs, and/or clinical experience.65 Previous recommendations of initiating with a “loading― dose appear to be unnecessary.3 Wide variability of maintenance dosing also exists, depending on, for example, individual responsiveness, comorbid health conditions, and age. For children, the suggested starting dose of warfarin is 0.2 mg/kg, followed by continued loading over 3 days, followed by a daily maintenance dose to maintain the INR between 2 and 3.124 , 148

Pharmacology

of

Long-acting

Anticoagulants

Within the coumarin group are two 4-hydroxycoumarin derivatives—difenacoum and brodifacoum. These agents differ from warfarin by their longer, higher-molecular-weight polycyclic hydrocarbon side chains (Fig. 57-4 ). Together with chlorophacinone, an indandione derivative, they

are

known

as

“superwarfarins,―

or

long-acting

anticoagulants.

Long-acting anticoagulants were designed to be effective rodenticides in warfarin-resistant rodents.109 Their mechanism of action is identical to that of the traditional warfarinlike anticoagulants, as demonstrated by the measurement of increased concentrations of vitamin K 2,3-epoxide after longacting anticoagulant administration.28 , 29 , 32 , 106 , 140 The ability of these xenobiotics to perform as superior rodenticides is attributed to their high lipid solubility and concentration in the liver.106 , 109 , 140 They also may saturate hepatic enzymes at very low levels, as demonstrated by zero-order elimination following overdose. 32 These factors make them about 100 times more potent than warfarin on a molar basis.106 , 109 , 140 In addition, they have a longer duration of action than the traditional warfarins.106 , 109 , 140 For example, to obtain 100% lethality in a mouse, more than 21 days of feeding with a warfarin-containing rodenticide (0.025% anticoagulant by weight of bait) is required.109 Similar efficacy can be achieved with a single ingestion of brodifacoum (0.005% anticoagulant by weight of bait).109

Figure 57-4. Structural comparison of prototypical short-acting (warfarin) and long-acting (brodifacoum) anticoagulants.

Many animals have been poisoned with long-acting anticoagulants, either secondary to the unintentional ingestion of rodenticides, or intentionally for scientific investigation. In rats, the half-life of brodifacoum is reported to be 156 hours.8 The half-life in dogs is reported to be between 6 and 120 days.202 Horses intentionally poisoned with brodifacoum had a half-life of 1.22 days.24 The veterinary literature is replete with reports of fatalities and of animals that remained anticoagulated in excess of 1 month.126 , 175 Likewise, many cases of intentional overdose of long-acting anticoagulants in humans are also described in the literature. Table 57-2 summarizes these cases. These patients' clinical courses are characterized by a severe coagulopathy that may last weeks to months, often accompanied by consequential blood loss. The most common sites of bleeding are the

gastrointestinal and genitourinary tracts. Although initial parenteral vitamin K 1 doses as high as 400 mg have been required for reversal,34 daily oral vitamin K1 requirements may be in the range of 50–100 mg. Recent experience in both animals and humans suggests that parenteral vitamin K1 therapy might not be required (see Antidotes in Depth: Vitamin K1 ) .32 , 202 It should also be noted that although ingestions of these xenobiotics are the most common route of exposure and subsequent cause of toxicity, dermal absorption of certain xenobiotics can occur, resulting in a significant coagulopathy.172 Patients with unintentional ingestions must be distinguished from those with intentional ingestions, because the former individuals demonstrate a low likelihood of producing coagulation abnormalities and have only rare morbidity or mortality. Prolongation of the INR is unlikely with a single small ingestion of a superwarfarin rodenticide. Clinically significant anticoagulation is even rarer. In a combined pediatric case series, prolongation of the INR occurred in only 8 of 142 children (5.6%) reported with single small ingestions of long-acting anticoagulants.17 , 94 , 96 , 170 Only 1 child in this group was reported to have “abnormal prolonged bleeding,― but this required no medical attention.170 In a single case report, a 36-month-old child developed a coagulopathy manifested by epistaxis and hematuria, with anticoagulation persisting for more than 100 days after a presumed, but unwitnessed, single unintentional ingestion of brodifacoum.183 Clinically significant coagulopathy can result, however, following small repeated ingestions. Two children reportedly became poisoned by repeated ingestions of a long-acting anticoagulant. One child presented with a neck hematoma that compromised his airway, and the other with a hemarthrosis.70 Similarly, a 7-year-old girl required multiple hospitalizations over a 20-month period following repeated nonsuicidal ingestions of brodifacoum.195 Finally, a 24month-old child who presented with unexplained bruising and a PT >125 seconds, P.892 was the victim of brodifacoum poisoning because of a Munchausen syndrome by proxy.7

Babcock7 2 Brodifacoum Purpura 9 mo Baker10 42 M Brodifacoum Upper and lower extremity swelling; multiple ecchymoses PT > 100 “Several weeks― 11 Barlow (Reingestion) 17 F Difenacoum None GI bleeding 15 5 wk 42 d Barnett12 27 F Brodifacoum Hemoptysis 7 — Basehore13 Unknown Brodifacoum Epistaxis, hematuria, 5 — Berry20 57 F

death

Brodifacoum Wound bleeding — Bruno12 52 M Brodifacoum Hematuria, oral bleeding 6 46 d Burucoa34 20 F Chlorophacinone Hematuria 8 49 d 60 F Chlorophacinone Hematuria, menorrhagia 7 25 d 23 M Chlorophacinone Oral bleeding 6 132 d Butcher35 M Difenacoum Hematuria 6 10 wk Canser36 61 F

Brodifacoum Ecchymoses, GI/vaginal

bleeding

>14 wk Chong38 20 M Brodifacoum Oral bleeding, hematuria 2 8 mo Chow40 27 F Bromadiolone Bruising, menorrhagia, epistaxis, PT 35.6 s

petechiae

3 wk Corke47 26 M Brodifacoum Hematuria,

oral

bleeding,

>5 wk Exner56 25 F Brodificoum Hemoptysis 7 >8 mo Helmuth78 25 M Brodifacoum CNS bleeding, death >6 —

mesenteric

hematoma

Hoffman82 30 M Brodifacoum Hematuria, GI 10 64 d Hollinger84 38 M Brodifacoum Hematuria 11 114 d Hui88 76 M Brodifacoum Hematuria, >10 >3 mo Huic89 35 F Unknown Epistaxis,

GI

bleeding

bleeding

hematomas,

metrorrhagia

>6 wk Jones93 17 M Brodifacoum Hematuria >10 55 d Kruse99 25 M Brodifacoum Upper GI bleeding; fatal CNS bleed

4 15 wka LaRosa103 17 M Brodifacoum Mucosal and skin bleeding PT 48 s >1 year Lipton108 31 F Brodifacoum Abortion 6 300 da McCarthy119 41 M Difenacoum Ecchymoses, hematuria, >10

GI

bleeding

>7 moa Murdoch129 37 F Chlorophacinone None 4 3 mo Palmer139 15 F Brodifacoum Pulmonary hemorrhage, — Rauch146 26 M

death

Brodifacoum Calf hematoma, hematemesis 9 24 moa 37 F Brodifacoum Ecchymoses >8 6 mo 42 M Brodifacoum Hematuria, epistaxis >4 >3 mo Ross 154 62 M Brodifacoum Hematuria 4 3 mo Routh155 29 F Brodifacoum Death 9 — Seidelman161 24 M Unconfirmed None >12 >37 d Sheen164 39 M

Brodifacoum Hematuria >12 >152 d Soubiron171 51 F Difenacoum Multiple hematomas, ecchymoses; >7 >9 d Swigar180 52 M Unconfirmed Compartment syndrome

spontaneous

hemoperitoneum

>82 d Tecimer181 37 M Brodifacoum Hematuria, occult GI bleeding 8 17 d Tsutaoka184 23 M Brodifacoum Mild gingival bleeding; hematuria and flank pain (26 days later) 37.8, 189 >30 days Walker191 71 M Bromadiolone Acute coronary syndrome; upper GI bleeding 7.0 —

Wallace 192 36 M Brodifacoum Upper GI bleeding 10 — Weitzel196 20 F Brodifacoum Melena, menorrhagia, hematuria >4 >11 mo 25 M Brodifacoum Epistaxis, compartment syndrome >4 100 d 37 M Brodifacoum Hematuria >5 >150 d a Denotes possible repeat ingestion.

Reference

TABLE

Age (y), Sex

57-2.

Xenobiotic

Intentional

Complications

Long-acting

Most patients (usually children) coagulation profile following an the risk of coagulopathy is low authors recommend supportive

Initial PT/INR

Anticoagulant

Duration of Coagulopathy

Overdoses

are entirely asymptomatic and have a normal acute unintentional exposure. Knowing that and that it takes days to develop, most care only.95 , 170 Despite the fact that

significant toxicity from superwarfarins is rare, it should be recognized that the reported benign courses of pediatric exposures may be misleading. Multiple retrospective studies suggest that children with unintentional acute exposures do not require any followup coagulation studies.33 , 127 , 142 , 165 However, this conclusion and approach to management may be an unjustified attempt to decrease the cost of “unnecessary― coagulation studies. There are clearly insufficient data to justify this conclusion, as many of these “exposed― children were never documented to have ingested longacting anticoagulants (see Chap. 130 ). We recommend that clinicians continue to manage these children as possible significant exposures, and that all children be followed up with daily INR P.893 studies for at least 48 hours. A baseline INR study may also be performed to determine if a child has been chronically ingesting the superwarfarin.

Clinical

Manifestations

Typical warfarin rodenticides contain only small concentrations of anticoagulant, 0.025% (or 25 mg of warfarin per 100 g of product). Using the data previously listed, a 10-kg child would require an initial dose of 2.5 mg of warfarin (or 10 g of rodenticide). These quantities are far greater than those that occur in typical “tastes.― Thus, single unintentional ingestions of warfarin-containing rodenticides pose virtually no threat to either normal or anticoagulated patients.95 In contrast, intentional and large unintentional ingestions of pharmaceutical-grade anticoagulants have the potential to produce a coagulopathy and consequential bleeding. In one study describing 12 patients with surreptitious ingestion of oral anticoagulants, 9 were healthcare professionals.134 These patients presented with bruising, hematuria, hematochezia, and menorrhagia, the typical manifestations of impaired coagulation. Hemorrhage into the neck with resultant airway compromise is a rare but life-threatening complication that has occurred.25 Although intentional ingestions of warfarin-containing products are uncommon, adverse drug events resulting in excessive anticoagulation and bleeding frequently occur. The risk of hemorrhage during oral anticoagulant

therapy depends on a myriad of factors, including the intensity of anticoagulation, patient characteristics, and comorbid conditions such as hypertension, renal insufficiency, hepatic dysfunction, malignancy, length of anticoagulant therapy, and indications for anticoagulation—cerebrovascular disease, prosthetic heart valves, atrial fibrillation, ischemic heart disease, and venous and arterial thromboembolism. Although the significance of each of these clinical conditions varies among different reports, most studies demonstrate that there is a greater incidence of bleeding complications with increasing INR,42 increasing intensity (or variation) of coagulation, advanced age, a history of previous bleeding episodes while on therapeutic warfarin, drug interactions, impaired liver function, and dietary changes.60 , 62 , 72 , 76 , 145 , 200 Clearly, the most serious complication of excessive anticoagulation is intracranial hemorrhage, which is reported to occur in as many as 2% of patients on long-term therapy.62 This complication is associated with a fatality rate as high as 77%.117 An Outpatient Bleeding Risk Index was created and shown to be more accurate than physician judgment in classifying patients according to the risk of major bleeding.21 The index was based on 4 independent risk factors: age 65 years or older; history of cerebrovascular accident; history of gastrointestinal bleeding; and history of recent myocardial infarction, hematocrit 1.5 mg/dL, or diabetes mellitus. The sum of the number of risk factors successfully predicted major bleeding at 48 months to be 3% in low-risk (0 risk factors), 12% in intermediate-risk (1–2 risk factors), and 53% in high-risk (3–4 risk factors) patients. Because physicians had little ability to accurately estimate the probability of bleeding, use of the Outpatient Bleeding Risk Index seems appropriate to improve awareness and treatment of these high-risk patients. In a study of 32 patients who developed life-threatening hemorrhage while on warfarin therapy, most patients had multiple risk factors including excessive anticoagulation.200 The gastrointestinal tract was identified as the source of bleeding in 67% of the patients.200 Sixty-six percent of patients were given vitamin K1 , 50% were given fresh-frozen plasma (FFP), and 7% were given both therapies.200

Laboratory

Assessment

Established screening tests are helpful for diagnosis. Four studies—PT (INR), PTT, thrombin time, and fibrinogen concentration—are usually adequate. Prothrombin time is calculated by adding standardized thromboplastin reagent (phospholipid and tissue factor) to a sample of the patient's citrated plasma (the citrate removes calcium to prevent clotting). Calcium is then introduced and the time to clotting measured. With the exception of factor X, the PT is unaffected by the presence or absence of factors VIII to XIII, platelets, prekallikrein, and HMWK. An individual's PT was formerly expressed as a ratio (PT observed-to-PT control). Because this ratio is directly affected by both laboratory methodology and the source of the thromboplastin reagent used, the generated results suffered from significant variability. Thus, a standard, the INR, was developed in an attempt to limit interlaboratory variability.79 , 131 The INR is derived by raising the PT ratio to a power value known as the International Sensitivity Index (ISI): (PT ratio)I S I . The ISI is a measure of responsiveness of the particular thromboplastin to warfarin. Although the use of the INR does not completely eliminate variability,80 , 130 it does improve the potential for standardized interpretation and limits interinstitutional variations. It should be noted that in patients taking oral anticoagulants, the INR is extremely effective at monitoring the extent of anticoagulation. However, in patients with acute fulminant hepatic failure of various etiologies, the INR is extremely variable and occasionally misleading as a consequence of the variability in thromboplastins.150 This may be less of a problem in the United States because of the use of recombinant human preparations of thromboplastin, which results in greater consistency.37 The partial thromboplastin time is measured by adding kaolin or celite to citrated plasma in order to activate the “contact― components of the intrinsic system. This mixture is then recalcified and the time to clotting observed. Some tests use phospholipids in the reagent to activate the remaining coagulation factors, thereby giving rise to the term activated partial thromboplastin time (aPTT). Because the PTT and aPTT are essentially interchangeable, the term PTT is used hereafter to represent the concept. The PTT is not affected by alterations in factors VII, XIII, or platelets.

The thrombin time, determined by adding exogenous thrombin to citrated plasma, evaluates the ability to convert fibrinogen to fibrin, and is thus unaffected by abnormalities of factors II, V, VII to XIII, platelets, prekallikrein, or HMWK. Finally, either a fibrinogen level or a determination of fibrin degradation products will help distinguish between problems with clot formation and consumptive coagulopathy. An evaluation of the combination of normal and abnormal results of these tests usually determines a patient's clotting abnormality (Table 57-3 ). Inhibitors can be diagnosed by “mixing studies,― because only a small percentage of the coagulation factors present in normal plasma are necessary to have normal clotting studies. If the patient with an abnormal PT or PTT suffers from even a severe factor deficiency, restoration of that factor activity to 50% of normal will completely normalize the PT or PTT. Thus the presence of an abnormal PT or PTT that will not correct by incubation of the patient's plasma with an equal volume of normal plasma is diagnostic of an inhibitor of coagulation. Heparin-induced anticoagulation results in an elevated PTT that corrects when mixing studies are performed. More sophisticated P.894 studies can be used to identify specific coagulation-factor deficiencies. The reader is referred to one of several standard references for a more detailed discussion of the approach to patients with abnormal coagulation studies.152 PT normal, PTT prolonged, bleeding Deficiencies of factors VIII, IX, XI Von Willebrand disease PT normal, PTT prolonged, no bleeding Deficiencies of factor XII, prekallikrein, inhibitor syndrome PT prolonged, PTT normal Deficiency of factor VII Warfarin therapy (early) Vitamin K deficiency (mild)

high-molecular-weight-kininogen

Liver

disease

(mild)

PT and PTT prolonged, thrombin time normal, fibrinogen normal Deficiencies of factors II, V, IX; vitamin K deficiency (severe) Warfarin therapy (late) PT and PTT prolonged, thrombin time abnormal, fibrinogen normal Heparin effect Dysfibrinogenemia PT and PTT prolonged, thrombin time abnormal, fibrinogen abnormal Liver disease Disseminated intravascular coagulation Fibrinolytic therapy Crotaline envenomation TABLE 57-3. Evaluation of Abnormal Coagulation Times Although warfarin levels may be useful to confirm the diagnosis in unknown cases and to study drug kinetics,73 , 132 the routine use of simple and inexpensive measures such as INR determination seems more appropriate.

Laboratory Evaluation Anticoagulants

of

Long-acting

For patients who have ingested long-acting anticoagulants and who are considered likely to develop a coagulopathy, baseline coagulation studies are not usually helpful, but they may provide information about chronic exposures. If the history is reliable and the patient is healthy, baseline studies can be avoided. Serial INRs at 24 and 48 hours should identify all patients at risk of coagulopathy.170 Depending on the social situation, these studies can be obtained while the patient remains in the home setting. In contrast, all patients with intentional ingestion of long-acting anticoagulants should be presumed to be at risk for a severe coagulopathy. In

fact, most patients do not seek medical care until bruising or bleeding is evident.11 , 32 , 34 , 38 , 56 , 78 , 82 , 93 , 94 , 96 , 99 , 108 , 129 , 155 , 180 These events often occur many days after ingestion, which obviates the need for gastric decontamination unless there is a suggestion of repetitive ingestion. These patients should be managed as described below. For patients who have suspected long-acting anticoagulant overdose, daily or twice-daily INR evaluations for 2 days should be adequate to identify most patients at risk for coagulopathy. Early detection through coagulation factor analysis may be preferred,73 however, and levels of long-acting anticoagulants can now be measured.59 , 100 , 132

General

Management

and

Antidotal

Treatment

Gastrointestinal decontamination should be performed on patients believed to have potentially significant life-threatening ingestions already present with significant bleeding. For patients who present hours of ingestion, gastric emptying is not indicated (see Chap. 8

who are unless they after a few ). Although

convincing data on the efficacy of either single- or multiple-dose activated charcoal (possible enterohepatic circulation) are lacking, at least a single dose of AC should be administered unless it is contraindicated. Oral cholestyramine can also be used to enhance warfarin elimination,147 but no studies are available that compare these two therapies or evaluate the role of combined activated charcoal and cholestyramine therapy. Although in animal models phenobarbital also enhances elimination, it is contraindicated in humans because of the decreased ability to reliably monitor the mental status of a patient who has the possibility of spontaneous intracranial hemorrhage and subsequent increased risk of falling. In addition to general supportive measures, the patient should be placed in a supervised medical and psychiatric environment that offers protection against external or self-induced trauma, and permits observation for the onset of coagulopathy. Blood transfusion is required for any patient with a history of blood loss or active bleeding who is hemodynamically unstable, has impaired oxygen transport, or is expected to become unstable. Although a transfusion of packed red blood cells is ideal for replacing lost blood, it cannot correct a

coagulopathy, and thus patients will continue to bleed. Whole blood contains both the cellular elements the patient is losing and the necessary coagulation factors to reverse the coagulopathy. Transfusion of whole blood may be considered in severe cases because whole blood contains many components, including platelets, white blood cells, and non–vitamin K-dependent factors. However, because whole blood contains only relatively small amounts of vitamin K-dependent factors, selective use of specific blood products is generally preferred. These products include packed red blood cells, FFP, cryoprecipitate or other factor concentrates, such as factor IX complex (Konyne 80), recombinant factor VIIA (rFVIIa), and prothrombin complex concentrate. Life-threatening hemorrhage secondary to oral anticoagulant toxicity should be immediately reversed with FFP, followed by vitamin K1 . FFP is rich in active vitamin K-dependent coagulation factors and will reverse oral anticoagulant-induced coagulopathy in most patients. In general, approximately 15 mL/kg of FFP should be adequate to reverse any coagulopathy.48 However, the specific factor quantities and volume of each unit may be varied, leading to an unpredictable response.113 A recent study comparing the efficacy of FFP and various clotting factor concentrates (prothrombin complex concentrate, factor VII concentrate, and Prothromplex T [factors II, VII, IX and X]) in rapid reversal of anticoagulation, showed that despite significant reduction in the INR, FFP had an extremely varied effect on factor IX repletion. These clotting factor concentrates not only significantly decreased the INR, but completely corrected it, and factor IX replacement was much more consistent.113 Furthermore, multiple FFP transfusions may also be required because of the rapid degradation of coagulation factors in the absence of vitamin K. P.895 Preliminary data using rFVIIa, a compound originally developed for the treatment of bleeding complications in patients with hemophilia, demonstrates it to be a useful pharmacologic therapy for bleeding secondary to warfarininduced excessive anticoagulation.52 , 123 There is also a single case report demonstrating efficacy at reversing severe bleeding caused by enoxaparin.87 Further experience with rFVIIa is necessary to determine its safety and

efficacy

in

anticoagulant-induced

hemorrhage.

Several issues influence the decision to administer vitamin K1 to a patient with a suspected overdose of a warfarinlike anticoagulant. Answers to the following questions should always be considered. Does the ingestion involve a warfarin-containing rodenticide or a pharmaceutical preparation? Is the ingestion unintentional or intentional? Does the patient require maintenance of therapeutic anticoagulation? Moreover, although vitamin K1 administration is required to reverse the blockade of coagulation factor activation, it cannot be relied on for the patient with acute and consequential hemorrhage (see Antidotes in Depth: Vitamin K1 ). Treatment with vitamin K1 takes several hours to activate enough factors to reverse the patient's coagulopathy,113 , 141 and this delay may be potentially fatal. Repetitive, large doses of vitamin K1 (on the order of 60 mg/d) may be required in some patients.73 , 134 If complete reversal of INR prolongation occurs or is desirable (as in most cases of life-threatening bleeding), and the patient's underlying medical condition still requires some degree of anticoagulation, they can then receive controlled anticoagulation with heparin once the bleeding is controlled and they are otherwise stable. Heparin anticoagulation was used without apparent bleeding complications in 25% of patients in one cross-sectional study.200 Vitamin K1 is preferable over the other forms of vitamin K; the other forms are ineffective93 , 129 , 133 , 185 and are potentially toxic.9 (Vitamins K3 [menadione] and K4 [menadiol sodium diphosphate] can cause oxidative stress on neonatal erythrocytes and produce hemolysis, hyperbilirubinemia, and kernicterus.) Parenteral administration of vitamin K1 (phytonadione) is traditionally preferred as initial therapy by many authors, but success also can be achieved with early oral therapy.32 In most cases reviewed, the patient was switched to oral vitamin K1 preparations for long-term care. Vitamin K1 can be administered intramuscularly, subcutaneously, intradermally, or intravenously. Although intravenous therapy has the most rapid onset of action of all routes of delivery, its use as the sole therapeutic agent is still associated with a delay of several hours112 , 141 and carries the added risk of anaphylactoid reactions.149 The use of low doses and slow rate

of administration reduces this risk,167 but we generally prefer that vitamin K1 be administered by other than the intravenous route (see Antidotes in Depth: Vitamin K1 ). In cases where oral administration is undesirable, for example, significant gastrointestinal hemorrhage, the subcutaneous route may be used, realizing that absorption may be erratic. Furthermore, if a patient is anticoagulated or overanticoagulated, administration of vitamin K1 by the intramuscular route may result in a large hematoma. Caution should be exercised if this route of administration is chosen. For patients with non–life-threatening hemorrhage, the clinician must consider whether anticoagulation is required for long-term care. In patients not requiring chronic anticoagulation, even small elevations of the INR may be treated with vitamin K1 alone to prevent a deterioration in coagulation status and reduce the risk of bleeding. Because in most cases, coagulopathy persists only for several days, there may be a rationale for prophylactic vitamin K1 administration in known warfarinlike anticoagulant ingestions in patients not requiring anticoagulation. In contrast to ingestions of warfarin, prophylactic vitamin K1 should never be given to asymptomatic patients with unintentional ingestions of long-acting anticoagulants because (a) if the patient is a child who develops a coagulopathy, it will last for weeks, and the 1 or 2 doses of vitamin K1 given will not prevent complications; (b) a gradual decline in coagulation factors occurs over the first day of anticoagulation, so no child would be expected to develop a life-threatening coagulopathy in 1 or 2 days; and (c) after vitamin K1 is administered, the onset of an INR abnormality will be delayed, which could impair the clinician's ability to diagnose any coagulation abnormality, possibly requiring the patient to undergo an unnecessarily prolonged observation period. For patients requiring chronic anticoagulation, The American College of Chest Physicians has issued guidelines for management of patients with elevated INRs (Table 57-4 ). Moreover, the use of a regression formula may assist in calculating the amount of oral vitamin K1 necessary to partially correct the INR, without completely discontinuing the oral anticoagulant. If validated, it would be extremely useful prior to minor surgery or dental procedures in patients requiring chronic anticoagulation, while theoretically decreasing the likelihood of thromboembolism.197

Treatment of Overdoses

Long-acting

Anticoagulant

Treatment of a patient with a long-acting anticoagulant overdose is essentially the same as the treatment of oral anticoagulant toxicity with certain exceptions. • 4.5 are also less reliable than values at or near the therapeutic range. b Although parenteral infusion of vitamin K 1 is recommended, we urge caution with this route of administration because there may not be an appreciable

difference in onset of therapeutic effect and, although rare, may cause severe anaphylactoid reactions. Adapted from American College of Chest Physicians Consensus Conference 2004 guidelines.3 INR

Recommendations

TABLE 57-4. Recommendations for Management of Elevated INR, with and without Bleeding, in Patients Requiring Chronic Anticoagulationa P.896 Long-acting anticoagulants are metabolized by the hepatic mixed-function oxidase system (cytochrome P450 [CYP]).8 , 133 In a rat model, the duration of coagulopathy was shortened by administering phenobarbital, a CYP3A4 inducer.8 Although a phenobarbital effect has never been systematically studied in humans, this approach was employed by several authors in isolated human cases of long-acting anticoagulant toxicity.34 , 93 , 108 , 183 , 195 Although these anecdotal reports suggest some improvement with phenobarbital therapy, the risks of producing sedation in a patient who might be prone to bleeding complications appear consequential. Patients with long-acting anticoagulant overdose should be followed until their coagulation studies remain normal while off therapy for several days. This usually requires daily or even twice-daily INR measurements until the INR is at the lower limit of the therapeutic range. Monitoring of serial INR measurements should allow for a gradual decrease in vitamin K1 requirement over time. Periodic coagulation factor analysis, however, may provide an early clue to the resolution of toxicity.82 The patient may require weeks to months of close observation for both psychiatric and medical management. Emphasis has been placed on determining a critical superwarfarin concentration below which anticoagulation does not occur.34 In one case report, brodifacoum was observed to follow zero-order elimination kinetics.32 If this type of toxicokinetics is consistent in the analysis of other long-acting anticoagulants, these laboratory measurements may prove more reliable than

the current empiric end points of therapy.

Parenteral

Anticoagulants

Heparin Conventional or unfractionated heparin is a heterogeneous group of molecules within the class of glycosaminoglycans.92 The heparin precursor molecule is composed of long chains of mucopolysaccharides, a polypeptide, and carbohydrates. The main carbohydrate components of heparin molecules include uronic acids and amino sugars in polysaccharide chains. Heparin for pharmaceutical use is extracted from bovine lung tissue and porcine intestines.160 As a therapeutic agent, heparin inhibits thrombosis by accelerating the binding of the protease inhibitor antithrombin III (AT) to thrombin (factor II) and other serine proteases involved in coagulation.111 , 153 Thus, factors IX to XII, kallikrein, and thrombin are inhibited. Heparin also affects plasminogen activator inhibitor, protein C inhibitor, and other components of coagulation. Heparin's therapeutic effect is usually measured through the activated PTT. The activated blood coagulation time (ACT) may be more useful for monitoring large therapeutic doses or in the overdose situation.101 Low-molecular-weight heparins (LMWHs) are 4000- to 6000-Dalton fractions obtained from conventional (unfractionated) heparin.63 As such, they share many of the pharmacologic and toxicologic properties of conventional heparin.26 The various LMWHs (e.g., Fraxiparine, enoxaparin, dalteparin) are prepared by different methods of depolymerization of heparin; consequently, they each differ to a certain extent regarding their pharmacokinetic properties and anticoagulant profiles. The major differences between LMWHs and conventional heparin are greater bioavailability, longer half-life, more predictable anticoagulation with fixed dosing, targeted activity against activated factor X, and less targeted activity against activated factor II. 26 , 63 As a result of this targeted factor X activity, LMWHs have minimal effect on the activated PTT, thereby eliminating either the need for, or the usefulness

of, such monitoring. As such, they are administered on a fixed-dose schedule. LMWHs have been investigated for prevention of thromboembolic disease after hip surgery and trauma, in patients with stroke or deep venous thrombosis, in pregnancy, and in other conditions where anticoagulation with heparin would otherwise be indicated (e.g., at the onset of oral anticoagulation therapy). Although these xenobiotics are presumed to have a minimal risk in pregnancy121 because they do not cross the placenta,61 , 176 they are not yet approved for treatment or prophylaxis of thromboembolic disease in pregnancy. Most studies demonstrate a lower incidence of embolization; however, there is still a trend toward increased bleeding.19 , 71 , 107

Pharmacology Because of heparin's large size and negative charge it is unable to cross cellular membranes. These factors also eliminate oral administration as a therapeutic route, and heparin must be administered by either subcutaneous injection or continuous intravenous infusion. Following parenteral administration, heparin remains in the intravascular compartment, in part bound to globulins, fibrinogen, and low-density lipoproteins, resulting in a volume of distribution of 0.06 L/kg in humans.55 , 135 Because of its rapid metabolism in the liver by a heparinase, heparin has a short duration of effect.111 Although the half-life of elimination is dose dependent and ranges from 1–2.5 hours, 111 , 118 , 135 the duration of anticoagulant effect is usually reported as 1–3 hours.111 Dosing errors or drug interactions with thrombolytic agents, antiplatelet drugs, or nonsteroidal antiinflammatory drugs may increase the risk of hemorrhage.76

Clinical

Manifestations

Intentional overdoses with heparin are rare.116 Most reported cases involve unintentional poisoning in hospitalized patients.66 , 69 , 116 , 138 , 159 These cases have involved the administration of large amounts of heparin as a consequence of misidentification of heparin vials, during the process of

flushing intravenous lines, and secondary to intravenous pump malfunction. Significant bleeding complications occurred in several cases, including 1 fatality.66 Although no overdoses of LMWHs are reported, LMWHs are renally eliminated and patients with severe renal insufficiency (creatinine clearance Section I - Case Studies > E - Cardiopulmonary Medications > Antidotes in Depth - Protamine

Antidotes in Depth Protamine Mary Ann Howland

History Protamine is a rapidly acting antidote that is used for reversing the anticoagulant effects of unfractionated heparin (UFH) and potentially low-molecular-weight heparin (LMWH). The antidotal property of protamine was recognized in the late 1930s, and it was approved for use as an antidote for heparin overdose in 1968.48 However, the largest body of literature pertaining to protamine originates from its use in neutralizing heparin following cardiopulmonary bypass and dialysis procedures.

Pharmacology The protamines are a group of simple basic cationic proteins found in fish sperm that bind to heparin to form a stable salt. Commercially available protamine sulfate is derived from the sperm of mature testes of salmon and related species. On hydrolysis, it yields basic amino acids, particularly arginine,

proline, serine, and valine, but not tyrosine and tryptophan. The effects of protamine sulfate and protamine chloride appear to be comparable.39 The molecular weight of heparin ranges from 3,000–30,000 daltons and is composed of approximately 45 monosaccharide chains. One milligram of protamine will neutralize approximately 100 U (1 mg) of UFH (mean molecular weight [MW] ~12,000 daltons). However, there is no proven method for neutralizing LMWH. Protamine neutralizes approximately 60% of the antifactor Xa activity of LMWH. Because the interaction of protamine and heparin is dependent on the MW of heparin, the lower-molecularweight heparin (mean MW 4500 daltons) has reduced protamine binding. This protamine-resistant fraction in LMWH is an ultralowmolecular-weight fraction with low sulfide charge.12 It is suggested that 1 mg enoxaparin equals ~100 antifactor Xa units. There are no human studies that have robust evidence either demonstrating or refuting a beneficial effect of protamine on bleeding related to LMWH. Within the first 8 hours following administration, the recommendation for reversal of the antithrombotic effect of LMWH is to administer 1 mg protamine per 100 antifactor Xa units of LMWH. A second dose of 0.5 mg protamine should be administered per 100 antifactor Xa units if bleeding continues.24 In animal studies, synthetic protamine variants were effective in reversing the anticoagulant effects of LMWH and are reported to be less toxic than protamine. These agents are not available for clinical use.24,29,59,60

Mechanism

of

Action

Heparin is a large electronegative substance that is rapidly complexed by the electropositive protamine, forming an inactive salt. Heparin is an indirect anticoagulant, requiring a cofactor. This cofactor formerly called antithrombin III, now referred to simply

as AT,24 alters its stereochemistry and thereby catalyzes the subsequent inactivation of thrombin and other clotting factors. Only about one-third of an administered dose binds to AT and this fraction is responsible for most of its anticoagulant effect.3,41 LMWH has a reduced ability to inactivate thrombin caused by lesser AT binding, but the smaller fragments of LMWH inactivate factor Xa almost as well as the larger molecules of UFH, allowing for equal efficacy. 24 Immunoelectrophoresis demonstrates that because of its net positive charge, protamine has a greater affinity for heparin than AT, producing a dissociation of the heparin–AT complex in favor of a protamine-heparin complex.49

Adverse Effects, Safety Issues

Risk

Factors,

and

Since the advent of cardiopulmonary bypass surgery, protamine has been routinely employed in the neutralization of heparin at the completion of the procedure. Millions of patients are exposed to protamine each year and approximately 100 deaths are reportedly associated with the use of protamine under these circumstances. It is largely in this setting that the adverse effects of protamine are also documented and studied.26,27,42 It is often difficult to separate the adverse effects caused by protamine from those of the protamine–heparin complex and those actually related to that of heparin. Adverse effects associated with protamine include both rate- and non–rate-related hypotension,15,16,17 a n d 18,20,31,34,53,56 anaphylactic30 and anaphylactoid reactions,33,44,46 bradycardia,1 thrombocytopenia,64 leukopenia, decreased oxygen consumption,61,63 acute lung injury,4,58 pulmonary hypertension,6 and anticoagulant effects.2 The mechanisms for these adverse effects are multifactorial. The strong net-positive charge of protamine may be responsible for some of the adverse effects and probably directly injures a variety of organelles, including platelets. 9,65 The protamine–heparin

complex activates the arachidonic acid pathway and the production of thromboxane is at least partly responsible for some of the hemodynamic changes, including pulmonary hypertension.6,11,25,45,65 Pretreatment with indomethacin limits these effects.11,25,45,65 Free protamine or protamine complexed with heparin can convert L-arginine to nitric oxide (formerly called endothelium-derived relaxing factor), which, in turn, causes vasodilation and inhibits platelet aggregation and adhesion.50 Protamine administered in the absence of heparin, or in an amount exceeding that necessary for heparin neutralization, can act as an anticoagulant and may inhibit platelet function, resulting in weaker clot formation.32,61 This anticoagulant effect may result from effects on factor VII and/or AT. Protamine in excess of heparin can enter the myocardium and decrease cyclic adenosine monophosphate (cAMP), causing myocardial depression.6 Protamine and protamine–heparin complexes can activate the complement pathway and contribute to vasoactive events.6,51 Protamine stimulates mast cells in the human heart and skin to release histamine.6 Risk factors for protamine-induced adverse reactions include prior exposure, which may occur during a previous P.908 surgery, history of nonprotamine medication allergy, a rapid rate of infusion, or a history of allergy to fish.51 A prospective study reported a 0.06% incidence of anaphylactic reactions to protamine in all patients undergoing coronary artery bypass, but a 2% incidence in diabetics using neutral protamine Hagedorn (NPH) insulin.7 The resultant elevation of histamine levels, the activation of complement, and elevated IgE, IgA, and IgG concentrations are also suggested as mechanisms for the adverse effects.40,57,66,67 Diabetic patients receiving daily subcutaneous injections of a protamine-containing insulin (NPH) have a 40–50% increased risk of adverse reactions.19,22,30,38,56 Occasionally, patients manifesting a protamine allergy are

presumed to have insulin allergy.37 In diabetic patients receiving protamine insulin injections, the presence of serum antiprotamine IgE antibody is a significant risk factor for acute protamine reactions. Only patients with previous exposure to protamine insulin injections had serum antiprotamine IgE antibodies. However, in the group without previous protamine insulin exposure, antiprotamine IgG antibody was noted as a risk factor for protamine reactions.67 Either naturally occurring cross-reacting antibodies, or perhaps previously unrecognized protamine exposure, was responsible for the generation of these IgG antibodies.

Alternatives to Protamine in Patients at High Risk for an Adverse Drug Reaction There are limited options for the reversal of heparin in patients who have previously experienced anaphylaxis following protamine therapy, or in patients who are expected to be at high risk for a protamine reaction. Clotting factors may be replaced, or exchange transfusion instituted in neonates, and protamine avoided, or protamine may be used while preparing to treat anaphylaxis expectantly. Several alternatives are under investigation and include the placement of heparin removal devices in the coronary artery bypass extracorporeal circuit, as well as the use of hexadimethrine, methylene blue, platelet factor 4, and heparinase as antidotes.7,36 Pretreatment with antihistamines and corticosteroids may be sufficient for immune-mediated mechanisms, but will probably not be beneficial for pulmonary vasoconstriction and non–immune-mediated anaphylactoid reactions.28

Dosing

in

Cardiopulmonary

Bypass

Protamine is most frequently used at the end of cardiopulmonary bypass operations to reverse the effects of heparin. There are many regimens used for protamine dosing, including (a) giving an arbitrary amount of protamine (eg, 0.2 mg/kg); (b) giving protamine in a ratio of 0.6–1.5:1 times the initial heparin dose, resulting in an activated coagulation time (ACT) of about 480 seconds; and (c) giving protamine in a ratio of 0.75–2.1:1 times the total operative heparin dose.68 Two additional methods of calculating the protamine dose to improve accuracy and avoid excess protamine are proposed.32,68 One advocates an initial protamine dose based on ACT, with subsequent doses based on the ratio of the change in thrombin time to the heparin-neutralized thrombin time. If this ratio is greater than 12 seconds, then 10-mg incremental protamine doses should be administered.32 The other uses a nomogram based on heparin activity in mg/kg versus ACT.68 Both methods demonstrate efficacy with 2-mg/kg doses of protamine, about one-half of the dose previously used. With these approaches, the ACT responded to protamine within 5 minutes, decreasing in value from between 550 and 700 seconds to a control of 150 seconds. Other investigators suggest a variety of monitoring methods and dosing schemas in this setting.13,23,54

Heparin Rebound and Redosing of Protamine A heparin anticoagulant rebound effect is noted after cardiopulmonary bypass and is attributed to the presence of detectable circulating heparin several hours after apparently adequate heparin neutralization with protamine. The incidence of heparin rebound and the need for additional protamine range from 4–42% depending on the neutralization protocol.21,43,52 It is likely that larger heparin doses may prolong the clearance of heparin, contributing to higher than expected heparin levels.52 When 300 U/kg of body weight doses of heparin were reversed at

the end of cardiopulmonary bypass with 3 mg/kg of protamine, a 14% incidence of small but detectable concentrations of circulating heparin was noted at 2 hours, which lasted less than 1 hour in all but 1 case.43 The prothrombin time was prolonged and thrombocytopenia was noted, but there was no increase in blood loss.

Dosing

Considerations

Approximately 1 mg of protamine will neutralize about 100 U (1 mg) of heparin (UFH). A limited number of studies suggest incomplete neutralization by protamine of the LMWHs enoxaparin, dalteparin, and tinzaparin. Present recommendations are to administer 1 mg protamine per 100 antifactor Xa units where 1 mg enoxaparin equals 100 antifactor Xa units. A second dose of 0.5 mg protamine should be administered per 100 antifactor Xa units if bleeding continues.14 A number of tests can directly measure heparin levels or indirectly measure heparin's effect on the clotting cascade.8,10,13 These tests may be helpful in determining the appropriate dose of protamine. Because excessive protamine can act as an anticoagulant, the dose chosen should always be an underestimation of that which is needed. In the case of unintentional overdose, the half-life of heparin should be considered, because half of the administered dose of heparin is eliminated within 60–90 minutes. In the case of an unintentional overdose without bleeding, the short half-life of heparin and the potential risks of protamine administration usually argue for a conservative approach of patient observation, rather than protamine reversal of anticoagulation. If protamine use is necessary to treat active bleeding, the dose must be administered intravenously over 15 minutes to limit rate-related hypotension.35,62

Dosing in the Overdose Setting

When faced with a patient believed to have received an overdose of an unknown quantity of heparin, the decision to use protamine should be determined by the presence of a prolonged activated partial thromboplastin time (aPTT) and the presence of persistent bleeding. P.909 In each circumstance, the potential risks of protamine use (especially in those who have had a prior life-threatening reaction to protamine as well as in a diabetic receiving a protaminecontaining insulin) and the risks of continued heparin anticoagulation should be evaluated. A baseline ACT, thrombin time, heparin-neutralized thrombin time, heparin activity, platelets, prothrombin time (PT)/partial thromboplastin time (PTT), hemoglobin, and hematocrit should be obtained. Because of the routine nature of heparin reversal following cardiopulmonary bypass, consultation with members of the bypass team may be helpful. An empiric dose of protamine may be suggested by the baseline ACT: (a) an ACT of 150 seconds necessitates no protamine; (b) an ACT of 200–300 seconds necessitates 0.6 mg/kg; and (c) an ACT of 300–400 seconds necessitates 1.2 mg/kg. These doses have not been tested outside the operating room. The ACT should be repeated 5–15 minutes following the protamine dose and in 2–8 hours (to evaluate the potential for heparin rebound), and further dosing should be based on these values. When the ACT is not available, 25–50 mg of protamine can be administered to an adult and adjusted accordingly. Repeat dosing in several hours may be necessary if heparin rebound occurs. The dose should be administered intravenously slowly over 15 minutes with resuscitative equipment immediately available. Neonates should not receive protamine that has been reconstituted with bacteriostatic water containing benzyl alcohol. Future interventions for bleeding following heparin may include activated factor VII and adenosine triphosphate. Activated factor

VII therapy was recently shown to be successful in treating postoperative bleeding in a patient with renal failure who was given LMWH and aspirin.47 Adenosine triphosphate completely reversed clinical bleeding related to LMWH in a rat model. These agents have not been FDA approved for clinical use in this setting.14

Availability Protamine is available either as a parenteral solution ready for injection or as a powder to be reconstituted with 5 mL of sterile or bacteriostatic water for injection. When the vials containing 50 mg of protamine are used, they should be shaken vigorously after the water is added. The final solution of either preparation contains 10 mg of protamine per mL.

Summary Protamine is an effective, rapidly acting antidote used to reverse the anticoagulant effect of unfractionated heparin, while its ability to reverse the effects of LMWH is less clear. This antidote should only be used for a prolonged aPTT in the presence persistent bleeding, since potential risks of its use include hypotension, anaphylactic reactions, dysrhythmias, leukopenia, thrombocytopenia and acute lung injury. Activated factor VII and adenosine triphosphate may be used in the near future to treat heparin-induced bleeding.

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1984;87:678–686. 56. Stewart WJ, McSweeney SM, Kellett MA, et al: Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization. Circulation 1984;70:788–792. 57. Stoelting RK, Henry DD, Verburg KM: Hemodynamic changes and circulating histamine concentrations following protamine administration to patients and dogs. Can Anaesth Soc J 1984;31:534–540. 58. Urdaneta F, Lobato EB, Kirby RR, Horrow JC: Noncardiogenic pulmonary edema associated with

protamine

administration during coronary artery bypass graft surgery. J Clin Anesth 1999;11:675–681. 59. Wakefield TW, Andrews PC, Wrobleski SK, et al: Effective and less toxic reversal of low-molecular weight heparin anticoagulation by a designer variant of protamine. J Vasc Surg 1995;21:839–849. 60. Wakefield TW, Andrews PC, Wrobleski SK: A [+18RGD] protamine variant for nontoxic and effective reversal of conventional heparin and low-molecular-weight heparin anticoagulation. J Surg Res 1996;63:280–296. 61. Wakefield TW, Bies LE, Wrobleski SK, et al: Impaired myocardial function and oxygen utilization due to protamine sulfate in an isolated rabbit heart preparation. Ann Surg 1990;212:387–393.

62. Wakefield TW, Mantler CB, Wrobleski SK, et al: Effects of differing rates of protamine reversal of heparin anticoagulation. Surgery 1996; 119:123–128. 63. Wakefield TW, Ucros I, Kresowik TF, et al: Decreased oxygen consumption as a toxic manifestation of protamine sulfate reversal of heparin anticoagulation. J Vasc Surg 1989;9:772–777. 64. Wakefield TW, Wrobleski SK, Nichol BJ, et al: Heparinmediated reduction of the toxic effects of protamine sulfate on rabbit myocardium. J Vasc Surg 1992;16:47–53. 65. Wakefield TW, Wrobleski BS, Wirthlin DJ, et al: Increased prostacyclin and adverse hemodynamic responses to protamine sulfate in an experimental canine model. J Surg Res 1991;50:449–456. 66. Weiss ME, Chatham F, Kagey Sobotka A, Adkinson NF: Serial immunological investigations in a patient who had a lifethreatening reaction to intravenous protamine. Clin Exp Allergy 1990;20:713–720. 67. Weiss ME, Nyhan D, Zhikang P, et al: Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. N Engl J Med 1989;320:886–892. 68. Wright SJ, Murray WB, Hampton WA, et al: Calculating the protamine-heparin reversal ratio: A pilot study investigating a new method. J Cardiothorac Vasc Anesth 1993;7:416–421.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > E - Cardiopulmonary Medications > Chapter 58 - Calcium Channel Blockers

Chapter

58

Calcium Francis

Channel

Blockers

DeRoos

Figure. No Caption Available.

A 40-year-old woman with a history of insulin-dependent diabetes

mellitus, coronary artery disease, and depression presented to the hospital with multiple nonspecific complaints, including “not feeling well,― dyspnea, weakness in the legs, and lightheadedness. Physical examination revealed a morbidly obese woman in no distress whose initial vital signs were: blood pressure, 120/70 mm Hg; heart rate, 100 beats/min; respiratory rate, 18 breaths/min; temperature 98.9°F (37.2°C). The lungs were clear to auscultation, and cardiac examination revealed normal S1 and S2 , and an S4 gallop, but no murmurs or rubs. Her abdomen was obese with active bowel sounds and no tenderness. Neurologic assessment revealed a normal mental status and no focal deficits. Because of the nonspecific complaints in a patient with significant medical conditions, a broad diagnostic evaluation was begun that included a rapid bedside glucose measurement, a urinalysis, electrolytes, renal function testing, liver enzymes, complete blood count, and an electrocardiogram (ECG). The ECG demonstrated a sinus rhythm at 100 beats/min, with normal PR and QRS intervals, left atrial enlargement, and evidence of an old anterior wall infarction (Fig. 58-1). There was no change from previous ECGs on file at the hospital. Approximately 4 hours into her evaluation and hospital stay, the patient complained of lightheadedness and weakness. Repeat physical examination revealed a slightly lethargic but arousable and cooperative woman. Her blood pressure was 70/30 mm Hg with a heart rate of 90 beats/min and regular. A repeat ECG revealed normal sinus rhythm and first degree heart block, with a PR interval of 240 msec (Fig. 58-2). At this time, she confided in the physician that the true reason for her visit was that she ingested 20 diltiazem (90-mg) tablets in a suicide attempt just prior to coming to the hospital. Initial therapy included boluses of 0.9% sodium chloride, calcium chloride (2 g intravenously), glucagon (1 mg intravenously), and intravenous infusions of dopamine and isoproterenol which resulted

in transient improvement in systolic blood pressure to 98 mm Hg. One hour after her initial hypotensive episode, the patient suffered a cardiac arrest with junctional rhythm of 65 beats/min and no measurable blood pressure (Fig. 58-3). With aggressive therapy, including cardiopulmonary resuscitation (CPR), endotracheal intubation, atropine (3 mg intravenously), high-dose intravenous infusions of dopamine and isoproterenol, and a glucagon bolus (5 mg intravenously), the systolic blood pressure returned to between 40 and 65 mm Hg with a heart rate of 50–60 beats/min. Over the next 3 hours multiple pharmacologic agents, including repeat boluses of calcium chloride and continuous infusions of glucagon (5 mg/h), amrinone (200-mg bolus then 800 mg/h), and phenylephrine were initiated, without improvement in blood pressure. During this period the patient's serum glucose had risen from 250–800 mg/dL and an insulin infusion was begun. Because of only limited improvement after multiple pharmacologic agents, a transcutaneous pacer was applied but was unable to capture. A transvenous right-ventricular pacemaker was then placed with intermittent capture at 70 beats/min, but the systolic blood pressure remained below 80 mm Hg. An intraaortic balloon pump (IABP) was placed, and within 15 minutes the blood pressure improved to 100/50 mm Hg. The patient was maintained on the IABP and transvenous pacemaker, and slowly weaned off the multiple inotropic agents and vasopressors over the next 24 hours. After a complicated 3-week hospitalization, the patient was discharged to an inpatient psychiatric facility with complete neurologic recovery.

Figure 58-1. This 12-lead electrocardiogram taken 2 hours postingestion of 1800 mg of sustained-release diltiazem demonstrates a sinus tachycardia at 100 beats/min with a normal QRS axis, normal intervals, left atrial enlargement, and an old anterior

wall

myocardial

infarction.

Figure 58-2. This 12-lead electrocardiogram, taken 6 hours postingestion of 1800 mg of sustained-release diltiazem, demonstrates first-degree heart block with a PR interval of 260 msec and no other changes as compared to the patient's previous electrocardiogram (Fig. 58-1) .

Figure 58-3. This 3-lead rhythm strip was obtained 9 hours postingestion of 1800 mg of sustained-release diltiazem, shortly after the patient became obtunded, hypotensive, and bradycardic. The electrocardiogram demonstrates a junctional bradycardia at 65 beats/min with widened QRS interval of 130 msec and possible inferior ischemia.

P.912 P.913 Calcium channel blockers (CCBs) were first used experimentally in the 1960s, and their use has steadily risen to the point where they are some of the most frequently prescribed cardiovascular drugs.47 Mirroring this widespread use, poisonings involving CCBs have also risen. The combination of compliance-improving sustained-release formulations and potent hemodynamic effects complicates the management of patients poisoned with these drugs. The hallmarks of toxicity include hypotension, from vasodilation and impaired myocardial contractility, and bradydysrhythmias. In severely

poisoned patients, no therapeutic intervention is demonstrated to be consistently effective. Management decisions must be made on an individual patient basis with careful assessment of the physiologic response to each treatment.

TABLE 58-1. Classification of Calcium Channel Blockers Available in the United States

Class

Specific

Compounds

Phenylalkylamine

Verapamil Verelan)

(Calan,

Isoptin,

Benzothiazepine

Diltiazem

(Cardizem,

Dilacor,

Tiazac)

Dihydropyridines

Nifedipine Isradipine

(Adalat, Procardia) (DynaCirc)

Amlodipine (Norvasc) Felodipine (Plendil) Nimodipine (Nimotop) Nisoldipine (Sular) Nicardipine (Cardene)

Diarylaminopropylamine ether

Bepridil

T-channel

None

blocker

Epidemiology

(Vascor)

(Mibefradil

withdrawn)

CCBs were first introduced to the US pharmaceutical market in the late 1970s. Currently, there are 10 CCB agents available in either regular or sustained-release formulations (Table 58-1). They are used for a variety of medical conditions, including hypertension, stable angina, dysrhythmias, migraine headaches, Raynaud phenomenon, and subarachnoid hemorrhage. In 1986, more than 1200 exposures and 7 deaths related to CCBs were reported to the American Association of Poison Control Centers. In 2003, those figures increased to 9650 exposures, including 2042 characterized by moderate to major toxicity, and an additional 57 deaths (Chap. 130). This significant rise in fatalities is most likely the result of the increased use and access to these drugs, although the introduction of sustained-release preparations in 1988 may also play a role.

Pharmacokinetics

and

Toxicokinetics

All CCBs are well-absorbed orally and undergo hepatic oxidative metabolism predominantly via CYP3A subgroup of the cytochrome P450 (CYP) enzyme system.45,62,119 Norverapamil, formed by Ndemethylation of verapamil is the only active metabolite and retains 20% of the parent compound's activity.78 Diltiazem is predominantly deacetylated into minimally active deacetyldiltiazem, which is then eliminated via the biliary tract.62 In overdose, these hepatic enzymes become saturated, reducing the P.914 potential control of the first-pass effect and increasing the quantity of active drug absorbed systemically. This saturation of drug metabolism contributes to the prolongation of the half-lives reported following overdose of various CCBs.19,43,44,146 All CCBs are highly protein bound.87,119 Volumes of distribution are large for verapamil (5.5 L/kg)120 and diltiazem (5.3 L/kg),119 and somewhat smaller for nifedipine (0.8 L/kg).93 Although not well-studied, the substantial protein binding and the large volumes of distribution make it unlikely

that extracorporeal drug removal with hemodialysis or hemoperfusion would be of any value in overdose. Several case reports offer clinical support for this conclusion.149,151,169 One interesting aspect of the pharmacology of CCBs is their potential for drug–drug interactions. CYP3A, which metabolizes most CCBs, is also responsible for the initial oxidation of numerous other drugs. Verapamil and diltiazem specifically compete for this isozyme and can decrease the clearance of many drugs including carbamazepine, cisapride, quinidine, various β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, cyclosporine, tacrolimus, most HIV-protease inhibitors, and theophylline.1,140 In June 1998, mibefradil, a structurally unique CCB, was voluntarily withdrawn following several reports of serious adverse drug interactions caused in part by mibefradil's potent inhibition of the CYP3A.7,104 Whereas other inhibitors of CYP3A4, such as cimetidine, fluoxetine, some antifungals, macrolide antibiotics, and even the flavonoids in grapefruit juice, may raise serum concentrations of several CCBs, the clinical significance of this effect remains unclear.1 In addition to affecting CYP3A, verapamil and diltiazem also inhibit Pglycoprotein–mediated drug transport into peripheral tissues. This inhibition results in elevated serum concentrations of drugs, such as cyclosporine and digoxin, which use this transport system.34,72 Unlike diltiazem and verapamil, nifedipine and the other dihydropyridines do not appear to affect the clearance of other agents via CYP3A or P-glycoprotein–mediated transport.2

Pathophysiology Calcium plays an integral part in excitation-contraction coupling and myocardial conduction (Fig. 58-4). Initially, Ca2 + is driven intracellularly down large concentration and electrical gradients through calcium-specific voltage-sensitive channels. These channels, specifically identified as L-type calcium channels, are located in the plasma membrane of all types of muscle cells81 and are composed of

homologous protein subunits, also found in some sodium and potassium channels.85 The α1 c subunit is the pore-forming portion of this channel and is where all CCBs bind to prevent Ca2 + transport.64 There are many other types of calcium channels, including N, P, T, Q, and R types, that can be found either intracellularly on the sarcoplasmic reticulum or on cell plasma membranes, particularly in neuronal and secretory tissue.153 They may be stimulated by cellular stretch (stretch-operated), specific neurohormonal binding (receptor-operated), or voltage changes (voltage-sensitive).144 Skeletal muscle depends exclusively on intracellular Ca2 + stores for excitation contraction coupling, so intracellular influx of Ca2 + does not add much to the total Ca2 + pool required for contraction. In cardiac and smooth muscle cells, however, this influx is critical. In smooth muscle, the rapid influx of calcium binds calmodulin, and the resulting complex stimulates myosin light-chain kinase activity.3 The myosin light-chain kinase phosphorylates, and thus activates, myosin, which subsequently binds actin, causing a contraction to occur (Fig. 58-4) .82,128 In myocardial cells, this slow Ca2 + influx creates the plateau phase (phase 2) of the action potential.125 The C a2 + then acts as a second messenger by binding to and opening a receptor-operated calcium channel on the sarcoplasmic reticulum which releases Ca2 + from the vast stores of the sarcoplasmic reticulum into the cytosol.73,74 This is often termed calcium-induced calcium release.40,183 Calcium then binds troponin C, which causes a conformational change that displaces troponin and tropomyosin from the actin allowing actin and myosin to bind, resulting in a contraction (Chap. 23; Fig. 58-4) .84

Figure 58-4. Normal contraction of myocardial cells. The L-type voltage sensitive calcium channels open to allow calcium ion influx during myocyte depolarization. These calcium ions cause the concentration-dependent release of more calcium ions from the sarcoplasmic reticulum that ultimately produce cardiac contraction.

In addition to its role in myocardial contractility, Ca2 + influx is also

important in myocardial conduction. Calcium influx plays an important role in the spontaneous depolarization (phase 4) of the action potential in the sinoatrial (SA) node.125 This Ca2 + influx also allows normal propagation of electrical impulses via the specialized myocardial conduction tissues particularly the atrioventricular (AV) node.147 After opening, the rate of recovery of these slow calcium channels, in both the SA and AV nodal tissue, determines rate of conduction.89,173 All commercially available CCBs exert their physiologic effects by antagonizing L-type voltage-sensitive calcium channels.83,175 The differences among their pharmacologic effects is related to a combination of specific receptor affinity and types of antagonism. This impairs Ca 2 + influx into muscle cells, particularly the myocardial and smooth muscle, which are dependant on this influx for normal function. In the vascular smooth muscle, the cytosolic Ca2 + concentration maintains basal tone and any P.915 decrease of Ca2 + influx results in relaxation and arterial vasodilation.77 In the myocardium, this impaired Ca2 + flow results in a decreased force of contraction. In addition, the delay in recovery of the slow calcium channels in the specialized SA and AV nodal tissue results in decreased heart rate and conduction.121 The CCBs currently available in the United States are classified into four structural groups (Table 57-1). Each group binds a slightly different region of the α1 c subunit of the calcium channel and thus has different affinities for the various L-type calcium channels, both in the myocardium and the vascular smooth muscle.111,123,124,166,175 For several reasons, verapamil, a phenylalkylamine, has the most profound inhibitory effects on the SA and AV nodal tissue, whereas diltiazem has less profound effects and dihydropyridines have little, if any, direct myocardial effects in therapeutic dosing.86,123,124 First, in therapeutic dosing, nifedipine does not alter the normal calcium channel recovery within the myocardium. 89,100 Second, not only do verapamil and, to a lesser extent, diltiazem impede Ca2 + influx and

channel recovery, but their blockade is potentiated as the frequency of channel opening increases.55,89,137 Finally, dihydropyridines bind the calcium channel best at less-negative membrane potentials. Because the resting potential for myocardial muscle (-90 mV) is lower than that of vascular smooth muscle (-70 mV), dihydropyridines bind preferentially in the peripheral vascular tissue.137 As a class, dihydropyridines have the most potent vasodilatory effects. Verapamil is the next most potent, followed by diltiazem. Consequently, verapamil is the most effective at decreasing heart rate, cardiac output, and blood pressure, whereas nifedipine produces the greatest decrease in systemic vascular resistance. Because nifedipine, and all the dihydropyridines, have little myocardial effect at therapeutic levels, the baroreceptor reflex remains intact and a slight increase in heart rate and cardiac output may occur.166 Isradipine is the only dihydropyridine whose inhibitory effect on the SA node is significant enough to blunt any reflex tachycardia.46 These receptor-binding differences among the CCB classes determine the potential therapeutic role of each. Verapamil and diltiazem are used in the management of hypertension, to reduce myocardial oxygen demand, to achieve rate control in atrial flutter and atrial fibrillation, and to abolish supraventricular reentrant tachycardias.2 Dihydropyridines are typically used to treat diseases with increased peripheral vascular tone such as hypertension, Raynaud phenomenon, Prinzmetal angina, esophageal spasm, vascular headaches, and post-subarachnoid hemorrhage vasospasm.24,51,158 Bepridil is unique because in addition to its calcium channel-blocking effects, it is a potent fast sodium channel and potassium channel blocker.66 This impairs both myocardial contractility and conduction and results in prolongation of the effective refractory period of the AV node, the action potential itself, and myocardial repolarization.66 Bepridil prolongs the QTc interval and may precipitate malignant ventricular dysrhythmias, including torsade de pointes.6,66 This dysrhythmogenic effect is potentiated in the setting of hypokalemia.

Bepridil is classified and used as an antidysrhythmic agent, but because of its dysrhythmogenic potential its use is limited to patients who are refractory to all other therapy.66

Clinical

Manifestations

The life-threatening toxicity of CCBs is manifest largely within the cardiovascular system and is an extension of their therapeutic effects. Myocardial depression and peripheral vasodilation occur, producing bradycardia and hypotension.152 Myocardial conduction may be impaired, producing AV conduction abnormalities, idioventricular rhythms, and complete heart block.12,42,68,75,105,113,131,139 Junctional escape rhythms frequently occur in patients with significant poisonings.17,28,36 The negative inotropic effects may be so profound, particularly with verapamil, that ventricular contraction may be completely inhibited.14,36,58 Patients may present initially asymptomatic but deteriorate rapidly into severe cardiogenic shock.157,177 Hypotension is the most common abnormal vital sign finding following an overdose.142,143 The associated clinical findings represent the degree of cardiovascular compromise and hypoperfusion of the patient's central nervous system. Early or mild symptoms include dizziness, fatigue, and lightheadedness, whereas more severely poisoned patients may manifest lethargy, syncope, altered mental status, coma, and death.29,60,68,99,131,148 Cases of seizures,60,68,116,134,162 cerebral ischemic events,150,155,179 ischemic bowel,54,56,161,178 and renal failure,113,139 occurring in the setting of CCB-induced cardiogenic shock, also are reported. Severe CNS depression is distinctly uncommon, and if respiratory depression or coma is present without severe hypotension, coingestants or other causes of altered mental status must be considered. Gastrointestinal symptoms, such as nausea and vomiting, are also uncommon.70 Although receptor selectivity is lost in overdose, and all CCBs can produce severe bradycardia, hypotension, and death,152 there are

some subtle variations in presentation, depending on the agent. The CCBs with the most significant myocardial effects, verapamil and, to a lesser extent, diltiazem, are associated with more negative inotropic and chronotropic effects.135,138 In a prospective, poison control center-based study, AV nodal block occurred much more frequently in the setting of verapamil poisoning.142 In contrast, nifedipine, because of its limited myocardial binding, may produce tachycardia or a “normal― heart rate initially, with bradycardia developing only in patients with more substantial ingestions.27,63,178,182 Deaths associated with dihydropyridines occur, although they are relatively uncommon.99,108,135 Numerous reports document hyperglycemia in patients with severe CCB poisoning.18,29,38,60,68,113,122,139,162,177 Insulin release from the β-islet cells in the pancreas is dependent on calcium influx via an L-type calcium channel.107,115 In CCB overdose, this channel is also antagonized, impairing normal calcium influx and reducing insulin release.31 The hyperglycemic effect may be exacerbated in a diabetic patient, or if glucagon is used as inotropic therapy (Chap. 4 8) .170 Acute pulmonary injury is also associated with CCB poisoning.18,50,63,71,80,109 Although the mechanism is unknown, precapillary vasodilation may cause an increase in transcapillary hydrostatic pressure.71,80 The elevated pressure gradient results in increased pulmonary capillary transudates and, ultimately, interstitial edema. Several factors, including the CCB involved, the dose ingested, the product formulation, and the patient's underlying cardiovascular health, may play a role in the ultimate degree of toxicity. Coingestion with other agents that have cardiovascular activity, such as βadrenergic antagonists and digoxin, may potentiate conduction abnormalities.23,48,79,101,188 The product formulation (immediate or regular vs. sustained release) affects the onset of symptoms and duration of toxicity. With regular-

release formulations, toxicity is often present within 2–3 hours of ingestion.13,143 With sustained-release products, however, initial signs or symptoms may be delayed for 6–8 hours, and delays P.916 reported.13,143,160,172

of up to 15 hours are In addition, with ingestion of sustained-release products, the drug's apparent half-life is prolonged and toxicity may last longer than 48 hours.9,12,36,103 Comorbidity and age are two factors that negatively impact on both morbidity and mortality in patients with CCB poisoning. Elderly patients, and those with underlying cardiovascular disease such as congestive heart failure, are much more sensitive to the myocardial depressant effects of CCBs.27,118 Even at therapeutic doses, these individuals may develop symptoms of mild hypoperfusion, such as dizziness and fatigue, much more frequently.59,69,75,127

Diagnostic

Testing

All patients with a suspected CCB ingestion should be attached to a cardiac monitor and have a 12-lead ECG performed to assess both their heart rate and rhythm, as well as the presence of any conduction abnormalities. Careful assessment of the degree of hypoperfusion, if any, may include a chest radiograph, pulse oximetry, and serum chemistry analysis for metabolic acidosis. Assays for various CCB serum concentrations are not routinely available and are not used to manage patients after overdose. If a patient presents with bradydysrhythmias of unclear origin, assessment of electrolytes, particularly potassium and magnesium, renal function, and a digoxin concentration may be helpful, although careful history taking often provides the most valuable clues. If hyperkalemia is present, cardioactive steroid poisoning should be considered, particularly in the absence of renal failure. Because calcium channel antagonist poisoning can impair insulin secretion from the pancreas, hyperglycemia may be detected.

Management Any patient with a suspected CCB ingestion should be immediately evaluated, even if there are no symptoms and the vital signs are normal. Intravenous access and continuous electrocardiographic monitoring should be initiated. A 12-lead ECG should be repeated at least every 1–2 hours for the first several hours. If the patient's condition normalizes, ECGs can be repeated at longer intervals subsequently. Initial treatment should begin with adequate oxygenation and airway protection (as clinically indicated), and aggressive gastrointestinal decontamination. If the patient is hypotensive and there is no evidence of congestive heart failure, an initial fluid bolus of 10–20 mL/kg of crystalloid should be given, and repeated as needed. Gastrointestinal

decontamination

is

a

critical

intervention.

Induced

emesis should be avoided because CCB-poisoned patients can rapidly deteriorate and become severely hypotensive. Orogastric lavage should be considered for all patients who present early (1–2 hours postingestion) after large ingestions, and for those patients who are critically ill. Although the effects of orogastric lavage in an overdose involving a sustained-release CCB have not been specifically studied, and although most of these formulations tend to be large and poorly soluble, because of their significant danger in overdose, orogastric lavage should still be strongly considered. When performing orogastric lavage in a CCB-poisoned patient, it is important to remember that lavage may increase vagal tone and potentially exacerbate any bradydysrhythmias.171 Pretreatment with a therapeutic dose of atropine may prevent this. All patients with CCB ingestions should receive 1 g/kg of activated charcoal orally. Multiple doses (0.5 g/kg) of activated charcoal (MDAC) without a cathartic should be administered to all patients with either sustained-release pill ingestions or signs of continuing absorption. Although data are limited, there is no evidence that MDAC increases CCB clearance from the serum.146,168 Rather, its efficacy may be a result of the

continuous presence of activated charcoal throughout the gastrointestinal tract, which adsorbs any active drug from its slowrelease formulation. Whole-bowel irrigation (WBI) with polyethylene glycol solution (1–2 L/h via nasogastric tube in adults, up to 500 mL/h in children) should be initiated for patients who ingest sustained-release products 20,167 and may be the most effective way of achieving gastrointestinal decontamination for ingestions involving these formulations.91 Dosing should be continued until the rectal effluent is clear. The importance of early initiation of MDAC and WBI, even for wellappearing patients with a history of sustained-release CCB ingestion, particularly children, cannot be overemphasized. It is imperative to minimize any absorption and prevent delayed cardiovascular toxicity, which can be profound and difficult to reverse. Several reports describe patients who presented with mild signs of poisoning, in whom gastrointestinal decontamination was not performed aggressively and who subsequently displayed severe toxicity. Pharmacotherapy should focus on maintenance or improvement of both cardiac output and peripheral vascular tone.88 Although many agents, including atropine, calcium, insulin, glucagon, isoproterenol, dopamine, epinephrine, norepinephrine, and phosphodiesterase inhibitors, have been used with reported success in CCB-poisoned patients, no single agent has consistently demonstrated total efficacy.68,135,138,142,143 Little prospective or basic research specifically evaluates effective treatment modalities. Therapy should begin with crystalloids and atropine, but more critically poisoned patients will not respond to these initial efforts, and inotropes and vasopressors will be needed. Although it would be ideal to initiate each agent individually and monitor the patient's hemodynamic response, in the most critically ill patients, multiple therapies should be administered simultaneously. A reasonable treatment sequence includes calcium followed by a catecholamine such as norepinephrine, high-dose insulin infusion, glucagon, and a

phosphodiesterase inhibitor. The evidence for the use of each of these drugs is discussed below.

Atropine Atropine is considered the drug of choice for patients with symptomatic bradycardia. In an early dog model of verapamil poisoning, atropine improved heart rate and cardiac output. 49 In one prospective study, 2 of 8 bradycardic CCB-poisoned patients also had an improvement in heart rate with atropine therapy. 142 Clinical experience, however, demonstrates atropine to be largely ineffective in improving heart rate in severe CCB-poisoned patients.29,38,74,138,148,157,179 Initial treatment with calcium might improve the efficacy of atropine.37,70,76 Given its availability, efficacy in mild poisonings, and safety profile, atropine should still be considered as initial therapy in patients with symptomatic bradycardia. Dosing should begin with 0.5–1.0 mg (0.02 mg/kg in children) IV every 2 or 3 minutes up to a maximum dose of 3 mg in all patients with symptomatic bradycardia. However, because of its limited efficacy in severely poisoned patients, treatment failures should be anticipated. In patients in whom WBI or MDAC will be used, the use of atropine must be P.917 carefully considered, weighing the potential benefits of improved heart rate, and thus cardiac output, against the anticholinergic effects potentially decreasing GI motility.

Calcium Pharmacologically, Ca2 + appears to be a logical choice to treat patients with CCB toxicity. Pretreatment with intravenous Ca2 +, prior to verapamil use for supraventricular tachydysrhythmias, prevents hypotension without diminishing the antidysrhythmic effects.33,156,180 This is also observed in the overdose setting where C a2 + tends to improve blood pressure more than it does the heart

rate. Although the exact mechanism is unclear, boluses of Ca2 + increase the extracellular Ca2 + concentration and increase the intracellular concentration gradient. This may drive Ca2 + intracellularly through unaffected calcium channels. Calcium salts are beneficial in experimental models of CCB poisoning.37,49,58 In verapamil-poisoned dogs, improvement in inotropy and blood pressure was demonstrated after increasing the serum [Ca2 +] by 2 mEq/L with an intravenous infusion of 10% calcium chloride at 3 mg/kg/min.58 Calcium ion reverses the negative inotropy, impaired conduction, and hypotension in humans poisoned by CCBs.21,57,61,63,105,106,110,112,126,127,136,181,184 Unfortunately, this effect is often short-lived and more severely poisoned patients may not improve significantly with calcium salt administration.26,29,38,43,50,53,74,146,151 Some authors believe that these failures might represent inadequate dosing.20,70,106 Unfortunately, the exact dosing of calcium salts is unclear. Reasonable recommendations for poisoned adults include an initial intravenous bolus of approximately 13–25 mEq of Ca2 + (10–20 mL of 10% calcium chloride or 30–60 mL of 10% calcium gluconate) followed by either repeat boluses every 15–20 minutes up to 3–4 doses or a continuous infusion of 0.5 mEq/kg/h of Ca2 + (0.2–0.4 mL/kg/h of 10% calcium chloride or 0.6–1.2 mL of 10% calcium gluconate).88,90,135 Careful selection of the calcium salt used is critical for dosing. Although there is no difference in efficacy of calcium chloride or calcium gluconate, 1 g of calcium chloride contains 13.4 mEq of calcium, which is more than 3 times the 4.3 mEq found in 1 g of calcium gluconate. Consequently, to administer equal doses of Ca2 +, 3 times the volume of standard calcium gluconate is required. If repeat dosing or continuous infusions are used, the serum [Ca2 +] and PO4 - 3 should be closely monitored to detect if hypercalcemia or hypophosphatemia develop. These concerns are not unfounded, and may in fact significantly limit Ca2 + therapy.99 Other adverse effects of intravenous Ca2 + include nausea,

vomiting, flushing, constipation, confusion, and angina.90 If there is any suspicion that a cardioactive steroid such as digoxin is involved in an overdose, Ca2 + should be avoided until after digoxin-specific Fab is administered because it may worsen digoxin toxicity (Chap. 6 2) .16

Inotropes

and

Vasopressors

Catecholamines are the next line of therapy in the treatment of CCB poisoning. Numerous case reports describe the success or failure of a wide variety of vasopressors, including epinephrine (success,8,26 failure,60,113), norepinephrine (success,68,122 failure113,116) , dopamine (success,9,39,179 failure8,26,35,53,60,113,122,177) , isoproterenol (success,52,113,131,139,169 failure8,28,60,177) , dobutamine (success,139 failure29,35,113), and vasopressin.49,97,165 Experimentally, no single therapy is consistently effective. This is not surprising given the significant variability in both the CCBs and the patients involved. Mechanistically, however, either stimulation of β1 adrenergic receptors on the myocardium or of α1 -adrenergic receptors on the peripheral vascular smooth muscle are the most logical targets, but which one depends upon the etiology of the hypotension. β-Adrenergic agonists activate adenylate cyclase via Gs protein.154 This results in formation of cyclic adenosine monophosphate (cAMP), which stimulates protein kinase A to phosphorylate the α1 subunit of various calcium channels (Fig. 58-6) .159 It is unclear whether this phosphorylation allows calcium channels to remain open longer,27,145 or if it opens dormant channels within the plasma membrane.21,90 In addition, protein kinase A also phosphorylates phospholamban, which improves calcium release from troponin after contraction.164 In the myocardium, this multifactorial increase in intracellular calcium results in improved chronotropy, dromotropy, and inotropy (Chap. 5 9) . In the peripheral vascular smooth muscle, α1 -adrenergic

receptor

agonists activate receptor-operated calcium channels. This opening of nonpoisoned calcium channels allows calcium influx (Fig. 58-5) ,145 which makes α1 -adrenergic agonists such as norepinephrine and phenylephrine logical choices if the hypotension is primarily the result of peripheral vasodilation, as would occur most typically with the dihydropyridine CCBs. Based on these pharmacologic mechanisms, norepinephrine appears to be an appropriate initial catecholamine to use in hypotensive CCB-poisoned patients. Its significant β1 -adrenergic activity combats P.918 the myocardial depressant effects, while its α1 -adrenergic effects increase peripheral vascular resistance. There is some theoretical concern about using pure β-adrenergic receptor agonists, such as isoproterenol and, to a lesser extent, dobutamine, because β2 adrenergic receptor agonist-induced peripheral vasodilation may worsen hypotension, particularly at high doses.

Figure

58-5. Myocardial toxicity of calcium channel blockers and

antidotal therapies. Calcium channel blockers reduce ion influx through the L-type calcium channel and thus reduce contractility. Mechanisms to increase intracellular calcium include recruitment of new or dormant calcium channels by increasing cyclic adenosine monophosphate (cAMP) either by stimulating its formation by adenylate cyclase (AC) with catecholamines or glucagon (see text), or by inhibiting its degradation with amrinone. Increasing the calcium concentration gradient across the cellular membrane to futher its influx, may improve contractility. The mechanism by which insulin therapy enhances inotropy is undefined. Phophodiesterase, PDE; protein kinase A, PKA.

Figure 58-6. Vascular toxicity of calcium channel blockers and antidotal therapies. Calcium's entry via voltage-sensitive channels initiates a cascade of events that result in actin–myosin coupling and contraction; this is inhibited by calcium channel blockers. Mechanisms to increase intracellular calcium include activation of receptor-operated calcium channels with α1 -adrenergic agonists or increasing the calcium ion gradient across the cellular membrane to further its influx.

Dopamine is predominantly an indirect acting pressor which acts by stimulating the release of norepinephrine from the distal nerve

terminal, and not by direct α- and β-adrenergic receptor stimulation.65 This may limit its effectiveness in severely stressed patients who may have catecholamine depletion.177 Published clinical experience of patients with severe CCB poisonings support these concerns.8,28,35,52,60,113,122,177 Improvement in blood pressure may be noted with dopamine at high dosing, when the drug has additional direct α- and β-adrenergic effects.65 The choice of a sympathomimetic drug is based on numerous factors, including the pharmacologic profile of each drug, the patient's underlying physiologic condition, and the physician's familiarity and comfort with the drug. If one sympathomimetic drug is unsuccessful, determining the cardiac output and systemic vascular resistance may be helpful in assessing whether the myocardial depressant or peripheral vasodilatory effects are responsible for the hypotension.138 This knowledge will help guide the subsequent choice of pharmacologic agents.

Insulin

and

Glucose

The most promising treatment for patients who are severely poisoned with CCBs may be hyperinsulinemia/euglycemia therapy. It is long known that high-dose insulin has positive inotropic effects.41 Although some indirect evidence suggests that increased Ca2 + entry may be involved,41,102 there is growing support for the hypothesis that improved myocardial use of carbohydrates is responsible for clinical improvement.96 Verapamil poisoning alters the normal metabolism of the myocardial cell, which primarily relies on fatty acids and forces carbohydrate dependence.95,97,98 At the same time, CCBs impede use of carbohydrates by inhibiting calcium-mediated insulin secretion from the β-islet cells in the pancreas,31,129 and by somehow increasing myocardial insulin resistance.96 In a canine model of verapamil toxicity, high-dose insulin, in conjunction with continuous dextrose infusion to maintain euglycemia, improved survival when compared to calcium, epinephrine, or glucagon.94,98 It

is postulated that although epinephrine and glucagon increase myocardial contractility, they do so at the expense of increased myocardial oxygen consumption, and that insulin improves overall myocardial efficiency. The use of insulin is particularly interesting, because severe CCB toxicity often produces significant hyperglycemia and insulin infusions are often initiated.38,162 There are now several reported cases of CCB-poisoned patients in whom adjuvant high-dose insulin therapy successfully improved hemodynamic function.17,117,187 Notably, there was little effect on heart rate in any of these patients, and in 1 patient, an improvement in ejection fraction from 10 to 50% was described.187 Reports of the failure of this treatment have also been published,30 but often represent initiation of therapy in terminally ill patients with multiple organ failure. Because of the promising animal evidence, the relative lack of other demonstrably effective therapeutics, the seriousness and potentially fatal nature of CCB poisoning, and the growing clinical successes with this therapy, early initiation of hyperinsulinemia/euglycemia therapy for CCB-poisoned patients is recommended. Based on the canine data and published clinical experience, if the serum glucose is Antidotes in Depth - Glucagon

Antidotes in Depth Glucagon Mary Ann Howland Glucagon molecular pancreas. discovery

is a polypeptide counterregulatory hormone with a weight of 3500 daltons, secreted by the α cells of the Glucagon was discovered in 1923, 2 years after the of insulin.8 Previously animal derived, the current FDA-

approved form is synthesized by recombinant DNA technology since 1998. Its traditional role was to reverse life-threatening hypoglycemia in diabetic patients who were unable to ingest dextrose in the outpatient setting. In medical toxicology, however, glucagon is used in the management of β-adrenergic antagonist and calcium channel blocker overdoses.

Mechanism

of

Action

Administration of 125I-labeled glucagon to cats demonstrates the presence of a specific glucagon receptor, and binding is closely correlated with activation of cardiac adenylate cyclase.25 A large number of glucagon binding sites are demonstrated, and as little as 10% occupancy produces near maximal stimulation of adenylate

cyclase. Glucagon receptors are identified in the human heart and brain, and resemble those on the pancreas.65 The binding of glucagon to its receptor results in coupling with two isoforms of the Gs protein, catalyzing the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the α subunit of the G s protein.24,53,70 One isoform is coupled to β agonists, while both isoforms are coupled to glucagon.70 The GTP-Gs units stimulate adenylate cyclase to convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).34,42 In addition, it now appears that in human atrial heart tissue glucagon, along with β2 agonists, histamine, and serotonin (but not β1 agonists), also activates Gi, which inhibits cAMP formation.29 Stimulation of glucagon receptors in the liver and adipose tissue increases cAMP synthesis, resulting in glycogenolysis, gluconeogenesis, and ketogenesis.34 Other properties of glucagon include relaxation of smooth muscle in the lower esophageal sphincter, stomach, small and large intestines, common bile duct, and ureters.21,24,32

Pharmacokinetics and Pharmacodynamics The volume of distribution of glucagon is 0.25 L/kg. The elimination half-life is 8–18 minutes, and the plasma, liver, and kidney extensively metabolize glucagon. After a single IV bolus, the effects of glucagon on the heart in human volunteers begin within 1–3 minutes, are maximal within 5–7 minutes, and persist for 10–15 minutes.48 The time to maximal glucose concentration is 5–20 minutes, with a duration of action of 60–90 minutes.19 Smooth muscle relaxation begins within 1 minute and lasts 10–20 minutes.19 Tachyphylaxis or desensitization may occur with continual dosing. Experimental heart preparations exposed to glucagon for varying

lengths of time demonstrated a decrease in the amount of cAMP generated.27,71 Calcium or isoproterenol administration after glucagon desensitization improved contractility and cAMP rose. Possible explanations for tachyphylaxis include uncoupling from the glucagon receptor and or phosphodiesterase (PDE) hydrolysis of cAMP.27,67,71,74 Other experiments demonstrated a transient effect of glucagon on contractility and hyperglycemia, also suggesting tachyphylaxis.23,28

Cardiovascular

Effects

Investigations of the mechanism of action of glucagon on the heart have been performed on cardiac tissue obtained from patients during surgical procedures and in a variety of in vivo and ex vivo animal studies. The results are often species specific and are affected by the presence or absence of congestive heart failure. The inotropic action of glucagon appears to be related to an increase in cardiac cAMP levels.13,34,42 Resulting positive inotropic2,17,40,48 and chronotropic2,13,17,30,32,40,42,48,68 actions of glucagon are very similar to those of the β-adrenergic agonists, except that they are not blocked by β-adrenergic antagonists.70 Although in some canine experiments glucagon was associated with ventricular tachycardia, glucagon was not found to be dysrhythmogenic in studies in patients with severe chronic congestive heart failure or myocardial infarction-related acute congestive heart failure, or in postoperative patients with myocardial depression.28,36,41,44 The effects of glucagon are markedly diminished as the severity and chronicity of congestive heart failure increases.48 Evidence now suggests an additional mechanism of action for glucagon, independent of cAMP, and dependent on arachidonic acid.59 Cardiac tissue metabolizes glucagon, liberating miniglucagon, an apparently active smaller terminal fragment.59,67 Mini-glucagon stimulates phospholipase A2 , releasing arachidonic

acid. Arachidonic acid acts to increase cardiac contractility through an effect on calcium. The effect of arachidonic acid, and therefore of mini-glucagon, is synergistic with the effect of glucagon and cAMP.58

Volunteer

Studies

The cardiovascular effects of glucagon were extensively studied in 21 patients with heart failure who were given varied doses and durations.49 Eleven patients who received 3–5 mg via IV bolus had increases in the force of contraction, as measured by maximum dP/dT (upstroke pattern on apex cardiogram), heart rate, cardiac index, blood pressure, and stroke work. There was no change in systemic vascular resistance, left ventricular enddiastolic pressure (LVEDP), or stroke index. Additionally, glucose increased by 50% and the potassium fell. A study of 9 patients demonstrated a 30% increase in coronary blood flow following a 50 µg/kg IV dose.44 Patients who received 1 mg via IV bolus also had an increase in cardiac index, but systemic vascular resistance fell, probably secondary to splanchnic and hepatic vascular smooth muscle relaxation.49 Patients who received an infusion of 2–3 mg/min for 10–15 minutes responded similarly to those who received the 3–5-mg IV P.943 boluses, but those patients receiving boluses experienced significant dose-limiting nausea and vomiting.49

Role in Overdoses Antagonists

with

β-Adrenergic

Overdoses with β-adrenergic antagonists are particularly dangerous and are manifested by hypotension, bradycardia, prolonged atrioventricular conduction times, depressed cardiac output and cardiac failure. Other noncardiovascular effects include

alterations in consciousness, seizures, and, rarely, hypoglycemia.1,11,14,16,22,66 Management is often complicated and many drugs, including atropine, isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, and various combinations, are used with variable success.15 Animal studies document the ability of glucagon to increase contractility, restore the sinus node function after sinus node arrest, increase atrioventricular (AV) conduction, and improve survival.38,48,56 Glucagon has successfully reversed bradydysrhythmias and hypotension in patients unresponsive to the aforementioned drugs, and should be administered early in the management of patients with severe overdoses.9,11,14,30,55,64 By increasing myocardial cAMP concentrations independent of the β receptor,34,42 glucagon is able to increase the inotropic2,17,40,48 and the chronotropic2,17,30,40,48,68 activity of the heart. Glucagon successfully reversed the bradycardia, low-output heart failure, and hypotension that developed in a premature newborn, presumably as a result of an inappropriately large prenatal dose of labetalol given to the mother. This neonate, delivered at 32 weeks gestation and weighing 1.8 kg, received 0.3 mg/kg glucagon intravenously initially and 5 additional doses of 0.3–0.6 mg/kg over the next 5 hours, with improvement in heart rate, blood pressure, and perfusion. Epinephrine and diuretics were also used.60

Combined Effects Phosphodiesterase Calcium

with Inhibitors

and

Strategies for enhancing the beneficial effects of glucagon have involved combining it with the phosphodiesterase III inhibitor (PDI III) amrinone (inamrinone) and its derivative milrinone and most recently rolipram (PDI IV). In a canine model of propranolol

toxicity, both amrinone (inamrinone) and milrinone alone were comparable to glucagon,38,57 but the combination of amrinone and glucagon resulted in a decrease in mean arterial pressure. A tachycardia occurred when milrinone was used with glucagon. 37,56 In an ex vivo model using strips of rat ventricular heart, rolipram enhanced the inotropic effect of glucagon and limited glucagon tachyphylaxis.27 The relationship between calcium and the chronotropic effects of glucagon was demonstrated in rats.6 Maximal chronotropic effects of glucagon are dependent on a normal circulating ionized calcium. Both hypocalcemia and hypercalcemia blunt the maximal chronotropic response.5,6

Role in Calcium Channel Blocker Overdose Calcium channel blocker overdoses produce a constellation of clinical findings similar to those recognized with β-adrenergic antagonist overdoses, including hypotension, bradycardia, heart block, and myocardial depression. Animal studies26,54,61,62,72,73 demonstrate the ability of glucagon to reverse the myocardial depression produced by nifedipine, diltiazem, and verapamil. Human case reports demonstrate similar benefit.10,12,43,46,47,63 Some authors suggest that the addition of amrinone to glucagon therapy is beneficial.69

Reversal

of

Hypoglycemia

Glucagon was once proposed as part of the initial treatment for all comatose patients.52 Glucagon stimulates the breakdown of glycogen to glucose in the liver by interacting with Gs . The theoretical rationale for this approach is only partially sound: Hypoglycemic patients may present in coma or with an altered mental status and hypoglycemia can be present concomitantly with

a drug overdose. Immediately restoring the patient's blood glucose level may be lifesaving. Glucagon, however, requires time to act and may be ineffective in a patient with depleted glycogen stores. Patients with type 2 diabetes are more likely to respond than are patients with type 1 diabetes. The intravenous administration of 0.5–1.0 g/kg of 50% dextrose in adults rapidly reverses hypoglycemia and does not rely on glycogen stores for its effect. Intravenous dextrose, therefore, is preferred over glucagon as the initial substrate to be given to all patients with an altered mental status presumed to be related to hypoglycemia (see Antidotes in Depth: Dextrose). Glucagon retains a role as a temporizing measure, until medical help can be obtained, in settings such as in the home, where IV dextrose is not an option. In patients with insulinoma, glucagon may actually worsen hypoglycemia, after an initial hyperglycemic response, as the result of a feedback rise in insulin.

Adverse

Effects

and

Safety

Issues

Side effects associated with glucagon include dose-dependent nausea, vomiting,41 hyperglycemia, hypoglycemia, and hypokalemia; relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon; and, rarely, urticaria, respiratory distress, and hypotension.18 The hyperglycemia is followed by an immediate rise in insulin, which causes an intracellular shift in potassium, resulting in hypokalemia.23,41,48 It is unclear whether stimulation of the Na+ - K+ -adenosine triphosphatase (ATPase) in skeletal muscle also contributes to the hypokalemia as occurs with β-adrenergic agonists.31,51 Glucagon can also increase the release of catecholamines in a patient with a pheochromocytoma, resulting in a hypertensive crisis,23 which can be treated with phentolamine.18 Continuous prolonged treatment with glucagon might lead to a dilated cardiomyopathy, as was reported in a patient with a

glucagonoma.4 Glucagon is a pregnancy category B drug.

Dos i n g An initial IV bolus of 50 µg/kg, infused over 1–2 minutes, is recommended (3–5 mg in a 70-kg person).16 If clinically acceptable, a longer duration of infusion may be used to limit vomiting. Higher doses may be necessary if the initial bolus is ineffective, and up to 10 mg can be used in an adult.25 Using too small a dose can potentially decrease systemic vascular resistance.49 In many cases, P.944 the bolus dose has 2–5 mg/h (up to be tapered as the regimen has never

been followed by a continuous infusion of 10 mg/h) in 5% dextrose in water, which can patient improves.1,24,25,50,55,66 This dosing been studied and is based on case reports.

Experimental heart preparations clearly demonstrate tachyphylaxis with continuous administration. Whether this occurs in humans is unclear, but might plead for repeated bolus infusions over 1–5 minutes rather than continuous infusion.27,71

Availability Glucagon (rDNA origin) by Eli Lilly and Company is available as a 1-mg (1-unit) lyophilized powder for injection, with an accompanying 1 mL of diluent in a disposable syringe.18 The diluent contains 12 mg/mL of glycerin water for injection, and hydrochloric acid, if needed, for pH adjustment. Glucagon (rDNA origin) as GlucaGen by Novo Nordisk A/S is available as a 1-mg (1-unit) lyophilized powder for injection. It should be reconstituted with 1 mL of sterile water for injection. Concentrations greater than 1 mg/1 mL should not be used. An adequate supply of glucagon in the emergency department is at least twenty 1-mg vials, with assurance of another 30 mg in the pharmacy.7,39

Summary Glucagon can produce positive inotropic and chronotropic effects despite β-adrenergic and calcium channel antagonism. Glucagon is beneficial in the treatment of patients with severe overdoses of βadrenergic antagonists and calcium channel blockers. The effects of glucagon may not persist and other therapies, such as insulin and dextrose, should also be considered (Chaps. 58 and 5 9). The relatively benign character of an IV bolus of glucagon in the patient with a serious overdose of a β-adrenergic antagonist or calcium channel blocker should lead the clinician to use glucagon early in patient management. Clinicians should be prepared for vomiting and the attendant risk for aspiration.

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6. Chernow B, Zaloga G, Malcolm D, et al: Glucagon's chronotropic action is calcium dependent. J Pharm Exp Ther 1987;241:833–837. 7. Dart RC, Goldfrank LR, Chyka PA: Combined evidence-based literature analysis and consensus guidelines for stocking of emergency antidotes in the United States. Ann Emerg Med 2000;36:126–132. 8. Davis S, Granner D: Insulin, oral hypoglycemic agents and the pharmacology of the pancreas. In: Hardman JG, Limbird LE, eds: Goodman & Gilman's The pharmacologuic basis of therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp. 1707–1708. 9. DeLima L, Khararasch E, Butler S: Successful pharmacologic treatment of massive atenolol overdose: Sequential hemodynamics and plasma atenolol levels. Anesthesiology 1995;83:204–207. 10. Doyon S, Roberts JR: The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993;22:1229–1233. 11. Ehgartner GR, Zelinka MA: Hemodynamic instability following intentional nadolol overdose. Arch Intern Med 1988;148:801–802. 12. Fant JS, James LP, Fiser RT, Kearns GL: The use of glucagon in nifedipine poisoning complicated by clonidine

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13. Farah A: Glucagon and the circulation. Pharm Rev 1983;35:181–217. 14. Fernandes CMB, Daya MR: Sotalol-induced bradycardia reversed by glucagon. Can Fam Physician 1995;41:659–665. 15. Frishman W: Beta-adrenoceptor antagonists: New drugs and new indications. N Engl J Med 1980;305:500–506. 16. Frishman W, Jacob H, Eisenberg E, Ribner H: Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 8. Self-poisoning with beta-adrenoceptor blocking agents: Recognition and management. Am Heart J 1979;98:798–811. 17. Glick G, Parmley W, Wechsler AS, Sonnenblick EH: Glucagon. Circ Res 1968;22:798–799. 18. Glucagon. Package Insert. Eli Lilly, Indianapolis, IN. 2003. 19. Glucagon. Package Insert. Novo Nordisk A/S, Princeton, NJ. 2003. 20. Golightly L, Smolinske S, Bennett M, et al: Pharmaceutical excipients. Med Toxicol 1988;3:128–165. 21. Hall-Boyer K, Zaloga G, Chernow B: Glucagon: Hormone or therapeutic agent. Crit Care Med 1984;12:584–589. 22. Heath

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features and therapy. Am J Emerg Med 1984;2:518–526. 23. Hendy GN, Tomlinson S, O'Riordan J: Impaired responsiveness to the effects of glucagon on plasma adenosine 3′5′-cyclic monophosphate in normal man. Eur J Clin Invest 1977;7:155–160. 24. Homcy CJ: The beta adrenergic signaling pathway in the heart. Hosp Pract 1991;26:43–50. 25. Illingworth RN: Glucagon for beta-blocker poisoning. Practitioner 1979;223:683–685. 26. Jolly S, Kipnis J, Lucchesi B: Cardiovascular depression by verapamil: Reversal by glucagon and interactions with propanolol. Pharmacology 1987;35:249–255. 27. Juan-Fita M, Vargas M, Kaumann A: Rolipram reduces the inotropic tachyphylaxis of glucagon in rat ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol 2004;370:324–329. 28. Kerns W II, Schroeder D, Williams C, et al: Insulin improves survival in a canine model of acute β-blocker toxicity. Ann Emerg Med 1997; 29:748–757. 29. Kilts JD, Gerhardt MA, Richardson MD, et al: [beta]2 Adrenergic and several other G protein–coupled receptors in human atrial membranes activate both Gs and Gi .. Circ Res 2000;87:635–637. 30. Kosinski EJ, Malidzak GS: Glucagon and isoproterenol in

reversing propanolol toxicity. Arch Intern Med 1973;132:840–843. 31. Kraus-Friedmann N, Hummel L, Radominska-Pyrek A, et al: Glucagon stimulation of hepatic Na+ , K+ -ATPase. Mol Cell Biochem 1982;44:173–180. 32. Larner J: Insulin and oral hypoglycemic drugs: Glucagon. In: Gilman AG, Goodman LS, Gilman A, eds: The Pharmacologic Basis of Therapeutics, 6th ed. New York, Macmillan, 1980, pp. 1497–1523. 33. Lawrence AM: Glucagon provocative test for pheochromocytoma. Ann Intern Med 1967;66:1091–1096. 34. Levey G, Epstein S: Activation of adenyl cyclase by glucagon in cat and human heart. Circ Res 1969;24:151–156. 35. Levey GS, Fletcher MA, Klein I, et al: Characterisation of Iglucagon binding in a solubilized preparation of cat myocardial adenylate cyclase. J Biol Chem 1974;249:2665–2673. 36. Lipski JI, Kaminsky D, Donoso E, Friedberg CK: Electrophysiological effects of glucagon on the normal canine heart. Am J Physiol 1972;222:1107–1112. P.945 37. Love JN, Leasure JA, Mundt DJ: A comparison of combined amrinone and glucagon therapy to glucagon alone for cardiovascular depression associated with propranolol toxicity in a canine model. Am J Emerg Med 1993;11:360–363.

38. Love JN, Leasure JA, Mundt DJ, Janz TG: A comparison of amrinone and glucagon therapy for cardiovascular depression associated with propanolol toxicity in a canine model. J Toxicol Clin Toxicol 1992;30:399–412. 39. Love JN, Tandy TK: β-Adrenoreceptor antagonist toxicity: A survey of glucagon availability. Ann Emerg Med 1993;22:151–152. 40. Lucchesi B: Cardiac actions of glucagon. Circ Res 1968;22:777–787. 41. Lvoff R, Wilcken D: Glucagon in heart failure and in cardiogenic shock—Experience in 50 patients. Circulation 1972;45:534–542. 42. MacLeod K, Rodgers R, McNeil J: Characterization of glucagon-induced changes in rate, contractility, and cyclic AMP levels in isolated cardiac preparations of the rat and guinea pig. J Pharmacol Exp Ther 1981;217:798–804. 43. Mahr NC, Valdes A, Lamas G: Use of glucagon for acute intravenous diltiazem toxicity. Am J Cardiol 1997;79:1570–1571. 44. Manchester JH, Parmley WW, Matloff JM, et al: Effects of glucagon on myocardial oxygen consumption and coronary blood flow in man and in dog. Circulation 1970;41:579–588. 45. Méry PF, Brechler V, Pavoine C, et al: Glucagon stimulates the cardiac Ca2 + current by activation of adenyl cyclase and inhibition of phosphodiesterase. Nature

1990;345:158–161. 46. Mullen JT, Walter FG, Ekins BR, Khasigian PA: Amelioration of nifedipine poisoning associated with glucagon therapy. Vet Hum Toxicol 1991;33:358. 47. Papadopoulos J, O'Neil M: Utilization of a glucagon infusion in the management of a massive nifedipine overdose. J Emerg Med 2000;18:453–455. 48. Parmley WW: The role of glucagon in cardiac therapy. N Engl J Med 1971;285:801–802. 49. Parmley W, Glick G, Sonnenblick E: Cardiovascular effects of glucagon in man. N Engl J Med 1968;279:12–17. 50. Peterson C, Leeder S, Sterner S: Glucagon therapy for beta-blocker overdose. Drug Intell Clin Pharm 1984;18:394–398. 51. Pettit GW, Vick RL, Kastello MD. The contribution of renal and extrarenal mechanisms to hypokalemia induced by glucagon. Eur J Pharmacol 1977;41:437–441. 52. Rappolt R, Inaba D, Gay G: NAGD regime (Naloxone [Narcan], activated charcoal, glucagon, doxapram [Dopram]) for the coma of drug related overdoses. Clin Toxicol 1980;16:395–396. 53. Rodell M: The role of hormone receptors and GTPregulatory proteins in membrane transduction. Nature 1980;284:17–22.

54. Sabatier J, Pouyet T, Shelvey G, Cavero I: Antagonistic effects of epinephrine, glucagon and methylatropine but not calcium chloride against atrioventricular conduction of disturbances produced by high doses of diltiazem, in conscious dogs. Fundam Clin Pharmacol 1991;5:93–106. 55. Salzberg M, Gallagher EJ: Propranolol overdose. Ann Emerg Med 1980;9:26–27. 56. Sato S, Tsuhi MH, Okubo N, et al: Combined use of glucagon and milrinone may not be preferable for severe propanolol poisoning in the canine model. J Toxicol Clin Toxicol 1995;33:337–342. 57. Sato S, Tsuhi MH, Okubo N, et al: Milrinone versus glucagon: Comparative effects in canine propranolol poisoning. J Toxicol Clin Toxicol 1994;32:277–289. 58. Sauvadet A, Rohn T, Pecker F, Pavione C: Synergistic actions of glucagons and miniglucagon on Ca2 + mobilization in cardiac cells. Cir Res 1996;78:102–109. 59. Sauvadet A, Rohn T, Pecker F, Pavione C: Arachidonic acid drives mini-glucagon action in cardiac cells. J Biol Chem 1997;272:12437–12445. 60. Stevens T, Guillet R: Use of glucagon to treat neonatal lowoutput congestive heart failure after maternal labetalol therapy. J Pediatr 1995;127:151–3. 61. Stone CK, May WA, Carroll R: Treatment of verapamil overdose with glucagon. Ann Emerg Med 1995;25:369–374.

62. Stone CK, Thomas SH, Koury SI, Low RB: Glucagon and phenylephrine combination vs glucagon alone in experimental verapamil overdose. Acad Emerg Med 1996;3:120–125. 63. Walter FG, Frye G, Mullen JT, et al: Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg Med 1993;22:1234–1237. 64. Ward DE, Jones B: Glucagon and beta-blocker toxicity. Br Med J 1976;2:151. 65. Wei Y, Mojsov S: Tissue-specific expression of the human receptor for glucagon-like peptide-I: Brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett 1995;358:219–224. 66. Weinstein R: Recognition and management of poisoning with beta-blocking agents. Ann Emerg Med 1984;13:1123–1131. 67. White CM: A review of potential cardiovascular uses of intravenous glucagon administration. J Clin Pharmacol 1999;39:442–447. 68. Whitehouse F, James T: Chronotropic action of glucagon on the sinus node. Proc Soc Exp Biol Med 1966;122:823–826. 69. Wolf LR, Spadafora MP, Otten EJ: Use of amrinone and glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993;22:1225–1228.

70. Yagami T: Differential coupling of glucagon and beta adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol 1995;48:849–854. 71. Yao L, Macleod KM, McNeill JH: Glucagon-induced desensitization: Correlation between cyclic AMP levels and contractile force. Eur J Pharmacol 1982;9:147–150. 72. Zaloga G, Malcolm D, Holaday J, et al: Glucagon reverses the hypotension and bradycardia of verapamil overdose in rats. Crit Care Med 1985;13:273. 73. Zaritsky A, Morowitz M, Chernow B: Glucagon antagonism of calcium blocker-induced myocardial dysfunction. Crit Care Med

1988;16:246–251.

74. Zeiders JL, Seidler FJ, Iaccarino G, et al: Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: Agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling. J Mol Cell Cardiol 1999;31:413–423.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > E - Cardiopulmonary Medications > Chapter 60 - Other Antihypertensives

Chapter

60

Other

Antihypertensives

Francis

DeRoos

Figure. No Caption Available.

Case 1 A 2-year-old boy was brought to the emergency department because of lethargy. The patient had no medical history, but shortly before this event he was playing with a bottle

of clonidine tablets. Physical examination revealed a lethargic but well-developed child whose initial vital signs were: blood pressure, 110/70 mm Hg; heart rate, 55 beats/min at rest and 80 beats/min with stimulation; respiratory rate, 16–20 breaths/min, with intermittent deep, sighing respirations; temperature, 97.9°F (36.6°C). The head and neck examination was significant for 2mm pupils that were slightly reactive to light. Lung and abdominal examinations were normal. Heart examination was notable for a regular bradycardia. Neurologic evaluation revealed a somnolent child with poor muscle tone and slight hyporeflexia. The gag reflex was intact. Of note, the patient became much more active, and at times agitated, with tactile stimulation, and he had strong, purposeful movements when intravenous access was initiated. Supplemental oxygen and an initial intravenous dose of 0.5 mg of naloxone, followed by a second dose of 1.5 mg, were administered without clinical response. Activated charcoal (12.5 g) was given via nasogastric tube. An electrocardiogram (ECG) revealed sinus bradycardia at a rate of 60 beats/min with no conduction abnormalities. Laboratory tests included an arterial blood gas with a PH 7.36, PCO2 of 42 mm Hg, and PO2 of 113 mm Hg. The patient was admitted to the pediatric intensive care unit for close observation and cardiac monitoring. Over the next 16 hours the patient's blood pressure remained stable, his heart rate increased to 90 beats/min, and his mental status returned to normal. As our understanding of the medical complications of chronic hypertension have grown along with the evidence supporting the conclusion that its treatment improves long-term morbidity and mortality, more and more antihypertensive drugs have become available. Two of the most popular classes of antihypertensives, calcium channel blockers and β-adrenergic antagonists, were discussed in Chaps. 58 and 5 9, but numerous other drugs are also marketed in the United States and are discussed here. Although overdoses involving these drugs are rarely reported,

either because of limited use (eg, the older agents such as reserpine, trimethaphan, and methyldopa) or limited toxicity (eg, diuretics and angiotensin II receptor antagonists), poisoning does occur. Most of the adverse effects and toxicity in overdose are exaggerated pharmacologic effects.

Clonidine and other Antihypertensives

Centrally

Acting

Clonidine is an imidazoline compound that was synthesized in the early 1960s. Because of its potent peripheral α2 -adrenergic agonist effects, it was initially studied as a potential topical nasal decongestant. However, hypotension was a common side effect, which redirected its consideration for other therapeutic applications.87 Clonidine is the best understood and the most commonly used of all the centrally acting antihypertensives, a group that includes methyldopa, guanfacine, and guanabenz. Although these drugs differ chemically and structurally, they all decrease blood pressure in a similar manner—by reducing the sympathetic outflow from the central nervous system. The imidazoline compounds, oxymetazoline and tetrahydrozoline, which are used as ocular topical vasoconstrictors and nasal decongestants, produce similar systemic effects when ingested87 (Chap. 50) . P.947 Since 1985, the increased efficacy and improved side-effect profiles of the newer antihypertensives have diminished the use of the α2 -adrenergic agonists in routine hypertension management. However, clonidine use is increasing as a result of a wide variety of applications, including attention deficit hyperactivity disorder (ADHD), peripheral nerve and spinal anesthesia, and as an adjunct in the management of opioid, ethanol, and nicotine withdrawal.94,107,113,116,194 In addition, abuse of clonidine may be a growing problem in opioid-dependant patients and it has been

used in criminal acts of chemical submission.17,129 Although clonidine exposure is relatively uncommon, it may cause significant toxicity, particularly in children. One report from 2 large pediatric hospitals identified 47 children requiring hospitalization for unintentional clonidine ingestions over a 5-year period.234 Significant clonidine poisoning resulting from formulation and dosing errors are also reported.181,210

Pharmacology

and

Pharmacokinetics

Clonidine is well absorbed from the gastrointestinal tract (approximately 75%) with an onset of action within 30–60 minutes. The plasma concentration occurs at 2–3 hours and lasts as long as 8 hours.48 Clonidine has 20–40% protein binding and an apparent volume of distribution of 3.2–5.6 L/kg.127 The majority of clonidine is eliminated unchanged via the kidneys.127 Guanabenz and guanfacine are structurally and pharmacologically very similar to each other. They are well absorbed orally, achieving peak levels within 3–5 hours, and both have large volumes of distribution (4–6 L/kg for guanfacine, 7–17 L/kg for guanabenz).92,204 Guanabenz is metabolized predominantly in the liver and undergoes extensive first-pass effect, whereas guanfacine is eliminated equally by the liver and kidney.92,204 Neither drug has significant active metabolites. Whereas clonidine, guanabenz, and guanfacine are all active drugs, with direct α2 -adrenergic agonist effects, methyldopa is a prodrug. It enters the CNS, probably by an active transport mechanism, before it is converted into its pharmacologically active degradation products.19 α-Methylnorepinephrine is the most significant of its metabolites, although α-methyldopamine and αmethylepinephrine may also be important.58,84,180 These metabolites are direct α2 -adrenergic agonists and impart their hypotensive effect just like the other centrally acting

antihypertensives. Approximately 50% of an oral dose of methyldopa is absorbed and peak plasma concentrations are achieved in 2–3 hours.148 However, because methyldopa requires metabolism into its active form, these concentrations have little correlation with its clinical effects. Methyldopa has a small volume of distribution (0.24 L/kg), with little protein binding (15%).148 It is eliminated in the urine, both as parent compound and after hepatic sulfation.154 Clonidine is available in both oral and patch form. The patch, referred to as the clonidine transdermal therapeutic system (TTS), allows slow, continuous delivery of drug over a prolonged period of time, typically 1 week. Similar delivery systems are effective in management of chronic pain with fentanyl and in the cessation of smoking tobacco with nicotine. This formulation, however, offers new clinical challenges. Each patch contains significantly more drug than is typically delivered during the prescribed duration of use. For example, a patch that delivers 0.1 mg/d of clonidine contains 2.5 mg total, whereas the 0.3 mg/d product contains 7.5 mg.28 Even after 1 week of use, between 35 and 50% and, in some instances, as much as 70%, of the drug remains in the patch.28,80 Puncturing the outer membrane layer or backing opens the drug reservoir and allows a significant amount of the drug to be released rapidly. In addition, patients do not perceive this delivery system as a medication, and may not exercise appropriate precautions. For example, discarding a used patch in an open wastebasket provides toddlers, who often are fascinated with stickers and other adhesive objects, an opportunity to remove the patch and apply, taste, or ingest it. Numerous reports of toxicity in both adults and children have resulted from dermal exposure, mouthing, or ingesting one clonidine patch, emphasizing this concern.28,38,80,85,110,174,175

Pathophysiology

Clonidine and the other centrally acting antihypertensives exert their hypotensive effects primarily via stimulation of presynaptic Î ±2 -adrenergic receptors in the brain.167,187,225 This central α2 adrenergic receptor agonism enhances the activity of inhibitory neurons in the vasoregulatory regions of the CNS, notably the nucleus tractus solitarius in the medulla, resulting in decreased norepinephrine release. This results in decreased sympathetic outflow from the intermediolateral cell columns of the thoracolumbar spinal tracts into the periphery1,224 and reduces heart rate, vascular tone, and, ultimately, arterial blood pressure.168,236 This centrally mediated sympatholytic effect is modulated by nitric oxide and γ-aminobutyric acid (GABA), which may explain some of the clinical variability that occurs among patients who have overdosed with clonidine.29,69,202,229 In therapeutic oral dosing, clonidine and the other centrally acting antihypertensives have little effect on the peripheral α2 receptors, the peripheral sympathetic nervous system, or the normal circulatory responses that occur with exercise or the Valsalva maneuver.147,158 However, when serum concentrations rise above 2 ng/mL, as in the setting of intravenous administration or oral overdose, peripheral postsynaptic α2 -adrenergic stimulation can occur, causing increased norepinephrine release and producing vasoconstriction and hypertension.36,42,150,212 This hypertension is short-lived, however, as the potent centrally mediated sympathetic inhibition becomes the predominant effect and hypotension ensues.4,47,121,134,192 Imidazoline-specific binding sites are identified both in the ventrolateral medulla of the brain and in other tissues, and may be important in the clinical effects of these agents.192,217 Direct stimulation of these receptors appears to lower blood pressure, independent of central α2 -adrenergic effects.20 Therefore, although their precise physiologic relationship has not been clearly elucidated, more evidence supports the concept that both imidazoline and α2 -adrenergic receptors modulate the ability of

clonidine, and presumably other centrally acting antihypertensives, to inhibit central norepinephrine release and the cardiovascular effects.21,81,143

Clinical

Manifestations

Although the majority of the published cases involve clonidine, the signs and symptoms of poisoning with any centrally acting antihypertensive are similar. The central nervous system (CNS) and cardiovascular toxicity reflect an exaggeration of their pharmacologic action. Common signs include CNS depression, bradycardia, hypotension, and, occasionally, hypothermia.6,165,197,221 Most patients who ingest clonidine, or the other similarly acting drugs, will manifest symptoms rapidly, typically within 30–90 minutes.234 The exception may be methyldopa, which requires metabolism to be activated, possibly delaying toxicity for hours.197,238 CNS depression is the most frequent clinical finding and can vary from mild lethargy to coma.38,74,132,134,144,146,152,157,173 In addition, P.948 severely obtunded patients may suffer from decreased ventilatory effort and hypoxia.4 Respirations may be slow and shallow, with intermittent deep sighing breaths. Various other terms are used to describe this phenomenon, including gasping, Cheyne-Stokes respirations, and periodic apnea.6,10,110,134,135 This hypoventilation is typically responsive to tactile stimuli alone, although mechanical ventilation may be required in severe cases.4,6,86,110,144 The associated CNS depression typically resolves over 12–36 hours,10,82,157 although prolonged coma is rarely reported.164 Other manifestations of this CNS depression include hypotonia, hyporeflexia, and irritability.36,134,207 The cranial nerve examination often demonstrates miotic pupils that may remain reactive to light.4,6,160,214 Two unusual case reports

describe seizures in the setting of clonidine poisoning,95,130 the mechanism of which is unclear. Hypothermia is associated with overdoses involving centrally acting antihypertensives.6,134,135,165 This is thought to be a consequence of α-adrenergic effects within the thermoregulatory center, although others suggest that these drugs activate central serotonergic pathways that alter normal thermoregulation.122,142 Although this phenomenon may last several hours, it rarely requires treatment and responds well to passive rewarming.36,165 Sinus bradycardia may occur in up to 50% of patients who ingest clonidine.207,234 Although usually associated with hypotension, it can be an isolated finding. Plausible explanations for this bradycardia include an exaggerated centrally mediated sympatholytic effect, a centrally mediated increase in vagal tone, or a direct stimulation of α2 -adrenergic receptors on the myocardium.44,118,224,235 Other conduction abnormalities, including first-degree heart block, Wenckebach block, 2:1 atrioventricular block, and complete heart block, are described both in overdose and after therapeutic dosing.68,109,157,189,191,222,235 It appears that very young patients and patients who have underlying sinus node dysfunction, concurrent sympatholytic drug therapy, or renal insufficiency are at greatest risk of developing bradydysrhythmias after central antihypertensive agent ingestion.24,207,216 Hypotension is the major cardiovascular manifestation of central antihypertensive toxicity.6,28,144,157,207,234 This typically occurs within the first few hours after exposure.61 Paradoxically, severe hypertension may be noted early in dosing, particularly during intravenous administration, or in massive overdoses.4,42,47,95,121,134,212 This is the result of peripheral α2 adrenergic agonism. Typically, as the central sympatholytic effects become predominant, the hypertensive effect is short-lived.95 However, in patients with massive ingestions, hypertension may be

protracted

and

require

pharmacologic

intervention.4,47,134,207

There is no clear association between the amount of any centrally acting antihypertensive ingested and the clinical manifestations. In children, clonidine ingestions as small as 0.2 mg have resulted in clinically severe poisoning.157 Fatalities from any of these agents are rare with few published reports within the Toxic Exposure Surveillance System (TESS) database (Chap 130) .197 This may be because these drugs effectively block all sympathetic outflow from the CNS and this physiologic effect is not essential for life. The CNS depression resulting in hypoventilation, hypoxia, and poor airway protection may be more pronounced in fatalities. As a result of Food and Drug Administration postmarketing surveillance and a case report that identified 4 deaths of children who received clonidine, a question was raised about whether there was an association between patients with ADHD who were being treated with combination clonidine-methylphenidate therapy and sudden death.27,56 However, close scrutiny of these cases revealed significant confounders and an investigation by the Food and Drug Administration concluded that there was inadequate evidence to confirm this association.56,171,211,233

Withdrawal Abrupt cessation of central antihypertensive therapy may result in withdrawal that is characterized by excessive sympathetic activity. Symptoms include agitation, insomnia, tremor, palpitations, and hypertension that begins between 16 and 48 hours after cessation of therapy.79,176,209 Ventricular tachycardia and myocardial infarction may occur in patients with clonidine withdrawal.16,149,166 The frequency and severity of symptoms appear to be greater in patients treated with higher doses for several months and in those with the most severe pretreatment hypertension.176 However, cases occur even when the dosing is gradually reduced.25,226 Although this phenomenon is associated

with all centrally acting α2 -agonists, it appears to be most prominent in the shorter-acting drugs such as clonidine and guanbenz.1,23,64,172,237 The mechanism for this hyperadrenergic phenomenon appears to involve an increase in CNS noradrenergic activity in the setting of decreased α 2 -receptor sensitivity.52 Reasonable treatment strategies include administering clonidine, via either the oral or intravenous route, followed by a closely monitored tapering of the dosing over several weeks, or benzodiazepines. Animal and human data suggest that βadrenergic antagonists, including labetalol, are harmful in the setting of clonidine withdrawal and their use is contraindicated.9,104

Diagnostic

Testing

Clonidine and other centrally acting antihypertensives are not routinely included in serum or urine toxicologic assays. Consequently, management decisions should be based on clinical parameters. No electrolyte or hematologic abnormalities are associated with this exposure. Because of the potential for bradydysrhythmias and hypoventilation, a 12-lead ECG and continuous cardiac and pulse oximetry monitoring are strongly recommended

during

the

assessment.

Management Appropriate therapy begins with particular focus on the patient's respiratory and hemodynamic status. Administration of activated charcoal is the primary mode of gastrointestinal decontamination in most ingestions. However, as in the initial case, in patients manifesting significant toxicity, the risks of placing a nasogastric tube and instilling activated charcoal may not exceed the potential benefits. Induction of emesis is contraindicated because of the possibility of rapid deterioration in mental status. Orogastric lavage has limited utility, because these drugs are rapidly

absorbed. Patients often present following the onset of symptoms rather than immediately after ingestion, and patients respond well to supportive care. In cases involving clonidine patch ingestions, whole-bowel irrigation appears to be an effective intervention.85 All patients with CNS depression should be evaluated for hypoxia and hypoglycemia. Respiratory compromise, including apnea, often responds well to simple auditory or tactile stimulation.4,6,86,110 Significant arousal during preparation for intubation often precludes the need for mechanical ventilation.4 Endotracheal intubation may be required, however, for the most severely poisoned

patients.

Isolated hypotension should initially be treated with intravenous boluses of crystalloid. Bradycardia is typically mild and P.949 usually does not require any therapy if adequate peripheral perfusion exists. If the bradycardia is severe, however, standard doses of atropine are often effective, but redosing may be required.4,6,132,207 Dopamine may be beneficial in patients with recalcitrant bradycardia or hypotension.4,6,28,70,132 Naloxone was probably first used in clonidine poisoning because of the similarity of its clinical findings to those of opioid toxicity, namely CNS and respiratory depression and miosis. Several clonidine-poisoned patients have had significant arousal after naloxone administration, as well as increased respiratory effort, heart rate, and blood pressure. 10,114,214 However, the exact reason for this physiologic response remains unclear. Animal models suggest that endogenous CNS opioids may modulate sympathetic outflow.54,103,192 This concept is supported by a clinical study in which clonidine was administered to hypertensive patients for 3 days resulting in a significant decrease in blood pressure. Subsequent administration of 0.4 mg naloxone parenterally reversed the decrease in blood pressure and heart rate in almost 60% of the patients.55 Because

of the short duration of effects of naloxone (20–60 minutes), redosing or continuous infusion may be required. As with some synthetic opioids, such as propoxyphene and fentanyl, clinical improvement may occur only after high doses (4–10 mg) of naloxone, 110,133 and some patients have no response regardless of dosing.11,132,234 If, in fact, naloxone acts as a nonspecific sympatholytic agent, it may also be beneficial in poisoning involving other α-adrenergic agents; however, there is a paucity of published clinical experience. In 1 adult with severe guanabenz poisoning, 7 mg of naloxone failed to improve her clinical status. 165 Rarely, naloxone administration in the setting of clonidine overdose can precipitate significant hypertension, so continuous hemodynamic monitoring is indicated.110,234 The use of α-adrenergic antagonists such as tolazoline and yohimbine, as specific antidotes for patients with α-adrenergic agonist overdoses, is controversial. Although some patients have had significant clinical improvements,144,157,178,188 tolazoline was ineffective in other patients.4,207 The adult dose is 5–10 mg intravenous infusion every 15 minutes, up to a total maximum of 40 mg.36 Given that tolazoline treatment is variably successful and that most physicians are unfamiliar with it, it cannot be recommended in the primary management strategy for centrally acting antihypertensive poisoning. The early onset hypertension is typically self-limited, and therapy should be cautiously undertaken, with the expectation that the hypertension will be self-limited. If hypertension is severe or prolonged, treatment with an infusion of sodium nitroprusside is appropriate.134 Other short-acting antihypertensives, such as esmolol, may exacerbate this paradoxical hypertension in a manner similar to that which occurs when these drugs are used in cocaine toxicity, by inducing unopposed α1 -receptor stimulation 47 (Chap. 74). Although oral nifedipine has been used, its lack of titratability and its unpredictable efficacy make its use inappropriate as well.

Other

Sympatholytic

Antihypertensives

Several other drugs also exert their antihypertensive effect by decreasing the effects of the sympathetic nervous system. Often termed sympatholytics, they can be classified as either ganglionic blocking agents, presynaptic adrenergic blocking agents, or α1 adrenergic antagonists, depending on their mechanism of action. These drugs are rarely used clinically and little is known about their effects in overdose.

Ganglionic

Blockers

Ganglionic blockers such as trimethaphan inhibit impulse transmission down both the postganglionic sympathetic and parasympathetic nerves, decreasing vascular tone, cardiac output, and blood pressure. These drugs were used more frequently in the 1950s and 1960s in Europe, but because of their significant side effects, they were quickly replaced with other drugs. Side effects stem from the unpredictable degree of sympathetic, as well as additional parasympathetic, blockade and include paralytic ileus, constipation, urinary retention, impotence, dry mouth, and blurred vision.154 Trimethaphan is the only ganglionic blocker available in the United States and it is administered intravenously. Although there are no cases of intentional overdose reported, there are cases of cardiopulmonary arrest associated with administration of continuous doses and with a 10-fold pediatric dosing error while treating hypertensive crisis.41,78 In overdose, the exaggerated hypotensive response should respond well to intravenous crystalloid boluses and, if needed, a direct-acting vasopressor such as norepinephrine.

Presynaptic

Adrenergic

Antagonists

Guanethidine

These drugs exert their sympatholytic action by decreasing norepinephrine release from presynaptic nerve terminals. Guanethidine and guanadrel interfere with the action potential that triggers norepinephrine release,194 whereas reserpine depletes norepinephrine and other catecholamines from the presynpatic nerve terminals, probably by direct binding and inactivation of catecholamine storage vesicles.65 Adverse effects of these drugs limit their clinical usefulness. These effects include a high incidence of orthostatic and exercise-induced hypotension, diarrhea, increased gastric secretions, and impotence.154 In addition, this hypotensive effect may be prolonged for as long as 1 week.106,195 Because of its ability to cross the blood–brain barrier, reserpine may also deplete central catecholamines and produce drowsiness, extrapyramidal symptoms, hallucinations, or depression.126 In overdose, an extension of their pharmacologic effects is expected. Severe orthostatic hypotension should be anticipated and treated with intravenous crystalloid boluses and a direct acting vasopressor. If reserpine is involved, significant CNS depression should also be anticipated.126

Peripheral

α1 -Adrenergic

Antagonists

The fourth group of sympatholytic agents is the selective α1 adrenergic antagonists, which include prazosin, terazosin, and doxazosin. The α1 receptor is a postsynaptic receptor primarily located on vascular smooth muscle, although they are also found in the eye and in the gastrointestinal and genitourinary tracts.39 In fact, this class of drugs provides first-line pharmacologic therapy for patients with urinary dysfunction secondary to benign prostatic hyperplasia. These drugs produce arterial smooth muscle relaxation, vasodilation, and lowering of the blood pressure. Although better tolerated than ganglionic blockers and peripheral adrenergic neuron blockers, these drugs may still produce significant

symptoms

of P.950

postural hypotension, including lightheadedness, syncope, or palpitations, particularly after the first dose or if the dosing is rapidly increased.15 Hypotension and CNS depression ranging from lethargy to coma are reported in overdose cases.120,124,186 In addition, priapism can occur.124,177 Treatment with supportive care, including intravenous fluid boluses and a vasopressor such as dopamine, was effective in the few overdose cases reported.120,124,137

Direct

Vasodilators

Nitroprusside

Hydralazine,

Minoxidil,

Diazoxide

Early work established that these drugs produce vascular smooth muscle relaxation independent of innervation or known pharmacologic receptors.49,111,112 More recently, this vasodilatory effect has been attributed to stimulation of nitric oxide release from vascular endothelial. The nitric oxide then diffuses into the underlying smooth muscle cells, stimulating guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP). This second messenger indirectly inhibits calcium entry into the smooth muscle cells, producing vasodilation.185 As this vasodilation occurs, the baroreceptor reflexes, which remain intact, produce an increased sympathetic outflow to the myocardium, resulting in an increase in heart rate and contractile force. Typically, these drugs are used therapeutically in patients with severe, refractory hypertension and in conjunction with a β-adrenergic antagonist to diminish the reflex tachycardia. Hydralazine, minoxidil, and diazoxide are effective orally, whereas sodium nitroprusside is only used intravenously. Minoxidil is also used topically, in a 2% solution, to promote hair growth, and significant poisoning has occurred in

suicidal adults who have ingested this formulation.141 Diazoxide, although previously used to rapidly reduce blood pressure in hypertensive emergencies, is rarely used for this indication now as a consequence of its poor titratability and its variable, and occasionally profound, hypotensive effect.111 Adverse effects associated with daily hydralazine use include several immunologic phenomenon such as hemolytic anemia, vasculitis, acute glomerulonephritis, and, most notably, a lupuslike syndrome.169 Minoxidil may cause electrocardiographic changes, both in therapeutic doses and in overdose. Sinus tachycardia, ST segment depressions, and T-wave inversions are reported.77,170,201 The significance of these changes is unknown; they typically resolve with either continued therapy or as other toxic manifestations resolve.77,201 The common toxic manifestations of these drugs are an extension of their pharmacologic action. Symptoms can include lightheadedness, syncope, palpitations, and nausea.3,131 Signs may be isolated to tachycardia alone,96,170,201 flushing, or alterations in mental status, which is related to the degree of hypotension.141 Based on American Association of Poison Control Centers annual poison data, it appears that in recent years, the majority of reported exposures to this class of drugs involve the topical formulation of minoxidil (Chap. 130) .53 After appropriate gastrointestinal decontamination, routine supportive care should be performed, with special consideration to maintaining adequate mean arterial pressure. If intravenous crystalloid boluses are insufficient, a peripherally acting αadrenergic agonist vasopressor such as norepinephrine or phenylephrine, is an appropriate next therapy. Dopamine and epinephrine should be avoided, to prevent an exaggerated myocardial response and tachycardia from β-adrenergic stimulation.

Nitroprusside Sodium nitroprusside exerts its vasodilatory effects after spontaneously releasing into the blood the vasodilator nitric oxide. The nitroprusside molecule also contains 5 cyanide radicals that, although gradually released, on occasion produce cyanide toxicity.153,190 Physiologic methemoglobin can bind the liberated cyanide. The binding capacity of physiologic methemoglobin is about 175 µg/kg of cyanide, corresponding to a little less than 500 µg/kg of infused sodium nitroprusside. These cyanide moieties are rapidly cleared, both by interacting with various sulfhydryl groups in the surrounding tissues and blood, and enzymatically in the liver by rhodanese, which couples them to thiosulfate-producing thiocyanate.59 This cyanide detoxification process in healthy adults occurs at a rate of about 1 µg/kg/min, which corresponds to a sodium nitroprusside infusion rate of 2 µg/kg/min.40,190 It is limited by the sulfur donor availability, so factors that reduce these stores, such as poor nutrition in infants and toddlers, critical illness, surgery, and diuretic use, place patients at risk for developing cyanide toxicity.40,99 Therefore, depending on the balance of cyanide release (eg, the rate of sodium nitroprusside infusion) and the rate of cyanide detoxification (eg, the sulfur donor stores), cyanide toxicity can develop within hours. Infusion of nitroprusside at a rate of more than 1.5 mg/kg, administered over a few hours, or more than 4 µg/kg/min, for more than 12 hours, may overwhelm the capacity of rhodanese for detoxifying cyanide. Signs and symptoms of cyanide toxicity include alteration in mental status, anion gap metabolic acidosis, and, in late stages, hemodynamic instability. (Chapter 121 has a complete discussion of cyanide.) One method of preventing cyanide toxicity from sodium nitroprusside is to expand the thiosulfate pool available for detoxification by the concomitant administration of sodium thiosulfate.35,40,75,99,190 Recommendations include infusing 500

mg sodium thiosulfate (the standard 50-mL bottle of 25% sodium thiosulfate found in the Cyanide Antidote kit). Unfortunately, the thiocyanate that is formed may accumulate, particularly in patients with renal insufficiency, and produce thiocyanate toxicity.59,99 Thiocyanate is almost exclusively renally eliminated with an elimination half-life of 3–7 days. It is postulated that a continuous sodium nitroprusside infusion of 2.5 µg/kg/min in patients with normal renal function could produce thiocyanate toxicity within 7–14 days, although it may be as short as 3–6 days or as little as 1 µg/kg/min in patients with chronic renal insufficiency who are not receiving hemodialysis.190 The symptoms of thiocyanate toxicity begin to appear at serum concentrations of 1 mmol/L (60 µg/mL), are very nonspecific, and may include nausea, vomiting, fatigue, dizziness, confusion, delirium, and seizures.59 Thiocyanate toxicity may produce life-threatening effects, such as hemodynamic and intracranial pressure elevation, when serum concentrations are above 200 µg/mL.40,59,75,218 An anion gap metabolic acidosis or hemodynamic instability does not occur with thiocyanate toxicity. Although cyanide or thiocyanate concentrations are not typically useful in the management of cyanide toxicity, they may be beneficial for P.951 monitoring critically ill patients who are at risk of thiocyanate poisoning. Hemodialysis is the treatment of choice for patient with severe clinical manifestations of thiocyanate toxicity.

Diuretics Diuretics can be divided into three main groups: (a) the thiazides and related compounds, including hydrochlorothiazide and chlorthalidone; (b) the loop diuretics, including furosemide, bumetanide, and ethacrynic acid; and (c) the potassium-sparing diuretics, including amiloride, triamterene, and spironolactone. Two other groups of diuretics—the carbonic anhydrase inhibitors,

such as acetazolamide, and osmotic diuretics, such as mannitol—are not used as antihypertensive agents. The thiazides produce their diuretic effect by inhibition of sodium and chloride reabsorption in the distal convoluted tubule. Loop diuretics, in contrast, inhibit the coupled transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle. Although their exact antihypertensive mechanism is unclear, an increased urinary excretion of sodium, potassium, and magnesium results from the use of loop diuretics. Potassiumsparing diuretics act either as aldosterone antagonists, such as spironolactone, or as renal epithelial sodium channel antagonists, such as triamterene, in the late distal tubule and collecting duct.100 The majority of toxicity associated with diuretics is metabolic and occurs during chronic therapy or overuse.232 Hyponatremia develops within the first 2 weeks of initiation of therapy in more than 67% of susceptible patients.203 Patients who are elderly, female, malnourished, or taking thiazides are at greatest risk.8 With severe hyponatremia (50 failure (to 9–12 hours).

Quinidine has substantial acute cardiotoxicity following overdose that includes conduction abnormalities and an increased QTc interval. “Quinidine syncope,â on therapeutic doses of quinidine experience paroxysmal, transient loss of cons frequently a result of torsades de pointes.40 , 64 , 124 Many of the ECG changes hypokalemia.

Because quinidine shares many pharmacologic properties with quinine (Chap. 56 that patients may occasionally suffer from cinchonism following either chronic o overdose. This syndrome includes abdominal symptoms, tinnitus, and altered m Quinidine also produces peripheral and cardiac antimuscarinic effects, which en the atrioventricular (AV) node. Thus, quinidine may actually exacerbate the ven

atrial flutter, explaining the need for rate control prior to chemical cardioversion quinidine.61 Furthermore, as with quinine, quinidine-induced blockade of K+ cha islet cells may cause uncontrolled insulin release, leading to hypoglycemia.102

Serum quinidine concentrations greater than 14 µg/mL are associated with ca evidenced by a 50% increase in either the QRS or QTc interval. However, in con procainamide, quinidine is associated with an increased QTc at both subtherape serum concentrations.40

Figure

61-3. Structures of the class IB antidysrhythmic agents lidocaine (and

tocainide,

mexiletine,

and

moricizine.

P.963

Disopyramide

Disopyramide (Fig. 61-2 ) is more likely than the other class IA antidysrhythmi inotropy and congestive heart failure. This effect may be noted both in patients dosing,125 and in those who overdose. This propensity may relate in part to dis block myocardial calcium channels.59 Disopyramide's mono-N -dealkylated meta most pronounced anticholinergic effects of the class, accounting for the occasion disopyramide to treat neurocardiogenic syncope.19

Electrophysiologic abnormalities similar to those associated with poisoning from can occur, including atrioventricular and intraventricular conduction abnormalitie pointes, and other ventricular dysrhythmias. Disopyramide frequently causes h

hypoglycemia through its antagonism of K+ channels in the pancreatic islet cells

Patients who overdose on disopyramide frequently develop classic anticholinerg including mydriasis, urinary retention, and gastrointestinal stasis.105 , 116 Letha hallucinations may be prominent.

Class

IA

Management

Management centers on assessment and correction of cardiovascular dysfunctio evaluation and intravenous line placement, the 12-lead ECG and continuous ECG paramount importance. Appropriate gastrointestinal decontamination is recomme patient is stabilized and should include whole-bowel irrigation if a sustained-rel involved.

For patients with widening of the QRS complex duration, bolus administration o hypertonic sodium bicarbonate is indicated. Depolarization is accelerated and th duration is reduced, by enhancing rapid sodium ion influx through the myocard

However, hypokalemia from the use of sodium bicarbonate may further prolong requiring careful monitoring of the serum K + and ECG. Class IA antidysrhythm is treated primarily with rapid 0.9% NaCL infusion, in order to expand the pati volume and to simultaneously increase myocardial contractility (ie, enhanced S

Hypotension in the setting of QRS complex duration prolongation may respond hypertonic sodium bicarbonate, which enhances inotropy by both accelerating d raising intravascular volume. Dopamine, dobutamine, isoproterenol, norepinephr balloon pump insertion may also be required, but their use has not been syste

Because disopyramide also blocks calcium channels, calcium administration is although evidence to support this antidotal effect is lacking. Glucagon effective depression in canine models, but it has not been evaluated in humans.95

Patients with stable ventricular dysrhythmias occurring in the setting of class I poisoning are usually treated with hypertonic sodium bicarbonate or lidocaine. A counterintuitive to administer another class I antidysrhythmic to a patient alread class I antidysrhythmic, there is sound theoretical and experimental literature to practice.135 That is, because lidocaine is a class IB drug with rapid on-off recep displace the “slower― class IA drug from the sodium channel, effectively blockade. Sodium bicarbonate enhances conduction through the myocardium, p termination of the ventricular dysrhythmia. Magnesium sulfate and overdrive pac

treating torsade de pointes.72 Drugs that must be avoided in treating patients associated with class IA poisoning include other class IA and IC drugs, as well antagonists and calcium channel blockers, all of which may exacerbate conduct

The roles of activated charcoal hemoperfusion, hemofiltration, and continuous hemodiafiltration are inadequately defined, but may be most beneficial for remo 83 There is no clinical evidence to support the use of hemodialysis or hemoperfu disopyramide poisoning.

Class IB Antidysrhythmics: Mexiletine, and Moricizine

Lidocaine,

Tocainid

Lidocaine Lidocaine

(Fig. 61-3 ), known internationally as lignocaine, is an aminoacyl amid

derivative of cocaine. Its predominant clinical uses are as a local anesthetic

P.964 and, for mechanistically similar reasons, as a drug to control ventricular dysrhy may prevent myocardial reentry by preferentially suppressing conduction in com Following an intravenous bolus, lidocaine rapidly enters the central nervous syst redistributes into the peripheral tissue with a distribution Lidocaine is 95% dealkylated by hepatic cytochrome P450 monoethylglycylxylidide (MEGX) and, subsequently, to the further metabolized to monoethylglycine and xylidide.123

half-life of approximat (CYP) 3A4 to an acti inactive glycine xylidid MEGX, although less po

channel blocker than the parent drug,13 may bioaccumulate because of its subs life.

Patients with lidocaine toxicity develop both central nervous system and cardio generally in that order. Because of its rapid entry into the brain, acute lidocain produces central nervous system dysfunction, particularly seizures, as its initia Concomitant respiratory arrest generally occurs. Shortly following the central n depression in the intrinsic cardiac pacemakers leads to sinus arrest, AV block, conduction delay, hypotension, and/or cardiac arrest.6 If the patient is supporte the drug distributes from the heart, and spontaneous cardiac function returns.

Nonmassive acute lidocaine toxicity is generally related to excessive or inappro

dosing. Common settings include intravenous administration when the intended subcutaneous, inadvertent excessive subcutaneous administration during lacerat swallowing of viscous oral lidocaine. The typical CNS manifestations of nonmass poisoning include drowsiness, weakness, a sensation of “drifting away,― diplopia, decreased hearing, paresthesias, muscle fasciculations, and seizures. Th these effects develop when serum lidocaine concentrations exceed 5 µg/mL an by paresthesias or somnolence. Any of these symptoms should, therefore, prom examine the patient's medication administration history or drug-infusion rate. A well as hypotonia in neonates, are reported to result from lidocaine toxicity and serum concentrations.108

Chronic lidocaine toxicity most commonly occurs as a therapeutic misadventure therapeutic infusions, generally in a critical care unit. Hepatic blood flow and h influence the rate of lidocaine metabolism, and only a small percentage is excre kidney. Consequently, toxicity following appropriate therapeutic dosing is most l

patients with congestive heart failure, shock, liver disease, or concomitant thera inhibitors such as cimetidine.91 , 127 Adverse reactions to lidocaine also increase decreasing body weight, and increasing infusion rate.33 Lidocaine toxicity occurs patients receiving infusions at 3 mg/min.117 Partly for this reason, lidocaine is used to prevent dysrhythmias in the immediate postmyocardial infarction period

When used as an antidysrhythmic, lidocaine must be administered parenterally t

first-pass hepatic metabolism associated with oral ingestion. However, numerou unequivocally demonstrate the toxicity associated with orally administered lido gastrointestinal tract absorption only one-third of the drug is bioavailable. Howe primary metabolite, MEGX, is nearly as toxic as lidocaine itself, substantial toxic following ingestion. Because of their small size and the relatively high concentra lidocaine (typically 4%), children seem overrepresented in reports of oral lidoca little as 15 mL of 2% viscous lidocaine in a 3-year-old child (estimate, 300 mg may cause seizures.57 , 114

It should be noted that when lidocaine is absorbed from the oropharynx, nong surfaces, skin, or subcutaneous tissues, hepatic metabolism is bypassed, resulti systemic bioavailability of the parent compound. Thus, seizures are reported wi application of lidocaine used for bronchoscopy,138 as well as intraureteral appli ureteroscopic stone extraction.99 Furthermore, deaths related to tumescent lipo

reported.107 In this technique, a large volume of dilute lidocaine is used to dist prior to liposuction. Although in some reports the cause of death was controver lidocaine concentrations were commonly elevated, and it is likely that lidocaine involved in the adverse events.68 , 107 Interestingly, proponents of this procedu lidocaine doses up to a maximum of 55 mg/kg are safe,97 whereas the convent limit for subcutaneous lidocaine with epinephrine is 5–7 mg/kg. Of significant recommended doses used for liposuction procedures do not consider the ability saturate the CYP3A4 hepatic microsomal enzymes. When saturation occurs, elim absorption and lidocaine toxicity may result. The high frequency of lidocaine-related medication errors relates in part to the

diverse “amps― of lidocaine designed for varying indications including re preparation of infusions, and local anesthesia.67 With the reduced emphasis on current advanced cardiac life support (ACLS) protocols, one important setting fo poisoning may be eliminated.27

Tocainide

Tocainide (Fig. 61-3 ) is indicated for the treatment of ventricular dysrhythmias for oral administration. Although a lidocaine analog, it does not undergo first-pa therefore almost 100% orally bioavailable. 77 Tocainide has pharmacologic effects

identical to lidocaine.77 , 112 Both renal failure and congestive heart failure pro considerably. The few overdoses reported with tocainide are associated with CN complications similar to those that occur with lidocaine overdose.10 , 34 , 122 The associated with hepatotoxicity and blood dyscrasias, which, although rare, have widespread

use.

Mexiletine

Mexiletine (Fig. 61-3 ), originally developed as an anorectic agent, was found to antidysrhythmic, local anesthetic, and anticonvulsant activity.23 It is currently a for the management of ventricular dysrhythmias. Its chemical structure and e properties are similar to those of lidocaine. Mexiletine, a base, is absorbed in th therefore, its absorption is increased when the gastric contents are alkalinized. failure and cirrhosis, as well as therapy with cimetidine or disulfiram, decrease mexiletine.76 Its metabolism, predominantly through CYP2D6, is accelerated by

phenobarbital,

rifampin,

and

phenytoin.76

Adverse therapeutic effects are primarily neurologic and are similar to those tha lidocaine. The few reported cases of mexiletine overdose describe prominent c

P.965 such as complete heart block, torsades de pointes, and Neurotox overdose includes self-limited seizures, generally in the setting of cardiotoxicity. case report described a patient with mexiletine poisoning who experienced stat any hemodynamic or electrocardiographic abnormalities.93 The use of other clas antidysrhythmics, such as lidocaine or tocainide, may potentiate the neurotoxici Mexiletine may produce a false-positive result on the amphetamine immunoassay asystole.31 , 47

Moricizine Moricizine

(Fig. 61-3 ) is a phenothiazine derivative that possesses the general

drugs, but is difficult to specifically subclassify. It depresses Na+ current in a m the other class IA drugs,30 but has other properties that more appropriately plac or IC. It is historically discussed as a class IB drug, as it is here. The parent dr extensive and rapid metabolism. Dose-related increases in PR and QRS intervals

hemiblocks, bundle-branch blocks, and sustained ventricular tachydysrhythmias. drug during the CAST II trial, in the setting of myocardial infarction, suggests th prodysrhythmic.63 Clinical experience with overdose of this drug is limited, but similar to other class I antidysrhythmics.

Class

IB

Management

The focus of the initial management for intravenous lidocaine-induced cardiac a cardiopulmonary resuscitation to allow lidocaine to redistribute away from the h setting, management of hemodynamic compromise includes fluid replacement a strategies. Resistant hypotension may require dopamine or norepinephrine adm insertion of an intraaortic balloon assist pump.50 Bradydysrhythmias typically do atropine, requiring the administration of dopamine, norepinephrine, or isoproter or insertion of a transvenous pacemaker may be useful,94 but the myocardium i electrical capture. Lidocaine-induced seizures, and those related to lidocaine an brief in nature and do not require specific therapy. For patients requiring treatm benzodiazepine generally suffices; rarely, a barbiturate is required.

Following oral poisoning by a class IB drug, administration of activated charcoa Enhanced elimination techniques are limited following intravenous poisoning beca time course of poisoning. Cardiopulmonary bypass, which does not directly enh

maintains hepatic perfusion, thereby allowing the lidocaine to be metabolized.49 may rarely be warranted following lidocaine overdose if liver failure or circulato use of other treatment modalities to be used. Hemoperfusion or hemodialysis m clearance of tocainide, but its indications remain unclear.134 Mexiletine's extensi its rapid metabolism make it a poor candidate for extracorporeal drug removal.

Class

IC

Antidysrhythmics:

Flecainide

and

Pro

Flecainide

Flecainide, a fluorobenzamide derivative of procainamide, is used orally to trea

and ventricular dysrhythmias, particularly atrial fibrillation. 2 , 71 Seventy-five pe metabolized hepatically by CYP2D6 to two major metabolites, one active and the remaining 25% is excreted renally.12 Thus, renal insufficiency, drug interactions heart failure all decrease its clearance. Additionally, alkaluria reduces its cleara

through enhanced tubular reuptake of nonionized drug. Patients using therapeut left ventricular dysfunction with worsening congestive heart failure. This is presu flecainide's negative inotropic effect, which itself may relate to its antagonistic channels. Furthermore, sudden dysrhythmic death may occur, particularly in pa ischemic

heart

disease.136

Reported overdose experience is limited to case reports that uniformly involve overdose. A 50% increase in QRS duration, a 30% prolongation of the PR interv in the QTc interval occurs with flecainide toxicity.88 The expected consequences electrophysiologic disturbances include bradycardia, premature ventricular contr ventricular fibrillation. 5 The combination of marked QRS and PR interval change minimal QTc interval prolongation, is characteristic of flecainide toxicity and con described with other antidysrhythmic agents.29

Propafenone

Propafenone bears a structural resemblance to propranolol,51 as well as similar

quantitative, electrophysiologic properties.87 Propafenone blocks fast inward sod weak β-adrenergic antagonist, and is an L-type calcium channel blocker.43 Bioa result of first-pass metabolism by CYP2D6 to 5-OH-propafenone, the primary a The long half-life allows the accumulation of parent compound, particularly in pa metabolizer pharmacogenetic variant of CYP2D6, which may cause excessive Πantagonism.78 , 119 The activity of a second metabolite, N -depropylpropafenone, Propafenone overdose produces sinus bradycardia, as well as ventricular dysrhy inotropy.45

Acute overdose typically produces wide complex tachycardia, right bundle-branc AV block, and prolongation of the QTc interval, as well as generalized seizures.6

administration of phenytoin to a child with propafenone poisoning was associate prolongation of the QRS interval, which initially responded to sodium bicarbonat subsequently developed bradyasystolic arrest.86 Massive overdose in a young ad the subsequent development of a mild cardiomyopathy and a left bundle-branch

Class

IC

Management

Initial stabilization should include standard management strategies for hypotens Additionally, therapy for hypotension, and for the electrocardiographic manifesta poisoning, includes intravenous hypertonic sodium bicarbonate to overcome the

blockade.70 An animal study documents the beneficial effects of hypertonic sod flecainide-induced ventricular dysrhythmias, and 3 reports of human overdose v narrowing in response to hypertonic sodium bicarbonate administration.18 , 53 , loading with hypertonic saline may be similarly effective, it remains unproved.

of flecainide is reduced by urinary alkalinization, suggesting that sodium chlorid may ultimately prove superior to sodium bicarbonate.89 The administration of ot antidysrhythmics is clearly contraindicated because of their additive blockade of However, amiodarone has been successful in the setting of ventricular fibrillatio therapy.120 The efficacy of an external or internal pacemaker may

P.966 be limited because of the drug-induced increased electrical pacing threshold of therapy with cardiopulmonary bypass32 or extracorporeal membrane oxygenatio and should be considered if readily available.

Extracorporeal removal is not expected to be beneficial for patients with flecaini

fact, has been unsuccessful. Although hemodialysis was successful in removing overdose, additional studies are needed to determine its clinical benefit.20

Class

III

Amiodarone,

Antidysrhythmics Dofetilide,

and

Ibutilide

The class III antidysrhythmics prevent and terminate reentrant dysrhythmias by potential duration and effective refractory period without slowing conduction vel or 1 of the action potential. This drug-induced effect on the action potential is g blockade of the rapidly activating component of the delayed rectifier potassium responsible for repolarization.

The class III antidysrhythmics in use today prolong repolarization of both the a Thus, common electrocardiographic effects of the class III drugs at therapeutic prolongation of the PR and QTc intervals and abnormal T and U waves. Chapter discussion of the pharmacologic mechanisms of this class. Chapters 23 and 5 9

Amiodarone

Amiodarone (Fig. 61-4 ) is an iodinated benzofuran derivative that is structurall thyroxine, and procainamide. Forty percent of its molecular weight is iodine. A of patients with out-of-hospital cardiac arrests, caused by refractory ventricula resulted in a higher rate of survival until hospital admission.36 Furthermore, the

the ACLS guidelines places tremendous emphasis on the early intravenous adm amiodarone.27 This, along with its ability to terminate or prevent atrial fibrillati increased use of this drug despite its association with potentially severe adverse few reported cases of amiodarone overdose.52

Figure 61-4. Structures of amiodarone (A ) compared with triiodothyronine (T 3 amiodarone is nearly 40% iodine by weight.

Although amiodarone has multiple pharmacologic effects, its efficacy as an anti primarily a result of its class III antidysrhythmic effects. It also has weak α-

antagonist activity and can block both L-type calcium channels and inactivated Amiodarone is slowly absorbed by the oral route and concentrates in the liver, tissue. Its oral bioavailability is extremely variable among individuals, as is its of approximately 66 L/kg.28 Steady-state pharmacokinetics may not occur for m

and the elimination half-life is 2 months. Amiodarone is metabolized via CYP3A4 desethylamiodarone, which has comparable activity to the parent compound.75 biliary excretion and virtually none is renally cleared.

The electrocardiographic effects of amiodarone differ, based on the route of dr Therapeutic oral doses prolong PR and QTc intervals but not the QRS complex. may produce a prolongation of the PR interval, but has few other electrocardio Ventricular dysrhythmias and sinus bradycardia are the most serious cardiac co therapeutic doses of amiodarone.137 Prodysrhythmic monomorphic and polymor tachycardias resistant to cardioversion and pharmacologic interventions are rep surprisingly uncommon, given the frequency and extent to which QTc interval Amiodarone's ability to compete for P-glycoprotein is responsible for several co effects, including elevated digoxin and cyclosporin levels and enhanced anticoa

of

warfarin.141

The diverse complications associated with long-term therapy do not occur follow intravenous use. Chronic therapy with oral amiodarone is associated with subst thyroid, corneal, hepatic, and cutaneous toxicity, organs in which it bioaccumul effects appear to be dose related, but because of the wide range of bioavailabi patterns among different patients, as well as the overlap between therapeutic a concentrations, therapeutic drug monitoring is of limited benefit. Pneumonitis, t consequential extracardiac adverse effect, effects up to 5% of patients taking th therapeutically. Amiodarone pneumonitis may develop within days of initiating typically occurs following years of therapy. Its occurrence may be dose related in those taking 95%

Plasma protein binding

25%

97%

Volume of distribution

6–7 L/kg (adults) 16 L/kg (infants) 10 L/kg (neonates) 4–5 L/kg (adults

0.6 L/kg (adults)

with renal failure)

Elimination

half-

1.6 days

6–7 days

Renal (60–80%), with limited hepatic

Hepatic metabolism

metabolism

(80%)

7%

26%

life

Route of elimination

Enterohepatic circulation

Figure 62-3. A. Normal depolarization. Depolarization occurs following the opening of fast Na+ channels; the rise in intracellular potential opens voltage-dependent Ca 2 + channels; and the influx of Ca2 + induces the massive release of Ca2 + from the sarcoplasmic reticulum, producing contraction. B . Normal repolarization. Repolarization begins with active expulsion of Na+ ions in exchange for K+ using an ATPase. This electrogenic (3 N a+ for 2 K+ ) pump creates an Na+ gradient that is used to

expel Ca2 + via an antiporter. The sarcoplasmic reticulum resequesters its Ca2 + load via a separate ATPase. C . Pharmacologic cardioactive steroids. Digitalis inhibition of the N a+ - K+ -ATPase raises the intracellular Na+ content, preventing the antiporter from expelling Ca2 + in exchange for Na +. The net result is an elevated intracellular Ca2 +, resulting in enhanced inotropy. D . Toxic cardioactive steroids. Excessive elevation of the intracellular Ca2 + elevates the resting potential, producing myocardial sensitization, and predisposes to dysrhythmias. The addition of exogenous Ca2 + may overwhelm the capacity of the sarcoplasmic reticulum to sequester this ion, resulting in systolic arrest. X = cardioactive steroid.

Drug interactions between digoxin and quinidine, verapamil, diltiazem, carvedilol, amiodarone, and spironolactone are common.19,22,43,66,91 These interactions occur because of a reduction of the protein binding of the cardioactive steroids, increasing their availability to the tissues; a reduction in excretion as a consequence of a decrease in renal perfusion; or as a result of interference with their secretion by the kidneys and intestines because of inactivation of P-glycoproteins. In approximately 10–15% of those patients receiving digoxin, a significant amount of digoxin is inactivated in the gastrointestinal tract by enteric bacterium, primarily Eubacterium lentum. Inhibition of this inactivation by the alteration of the gastrointestinal flora by many antibiotics, particularly the macrolide antibiotics, may result in increased bioavailability.71 Indeed, the use of certain antibiotics may produce as much as a 2-fold increase in serum cardioactive steroid concentration.90

Mechanisms of Action and Pathophysiology

Electrophysiologic

Effects

on

Inotropy

The cardioactive steroids increase the force of contraction of the heart (positive inotropic effect) by increasing cytosolic Ca2 + during systole. Both Na+ and Ca2 + ions enter and exit cardiac muscle cells during each depolarization and contraction. Sodium entry heralds the start of the action potential (phase 0) and carries the inward, depolarizing positive charge. Calcium subsequently enters the cardiac myocyte through L-type calcium channels during the plateau phase of the action potential, and this Ca2 + triggers the release of more Ca2 + into the cytosol from the sarcoplasmic reticulum. During repolarization and relaxation (diastole), Ca2 + is both pumped back into the sarcoplasmic reticulum by a local Ca2 +-ATPase and is pumped extracellularly by an Na+-Ca2 + antiporter and a sarcolemmal C a2 +-ATPase (Fig. 62-3; Chap. 23) .76 Cardioactive steroids inhibit active transport of Na+ and K+ across the cell membrane during repolarization by binding to a specific site on the extracytoplasmic face of the a subunit of the membrane Na+K +-ATPase. This inhibits the cellular Na+ pump activity, which decreases decreasing antiporter but rather

Na+ extrusion and increases Na+ in the cytosol, thereby the transmembrane Na+ gradient. Because the Na+-Ca2 + derives its power not from adenosine triphosphate (ATP) from the Na+ gradient generated by the Na+- K+ transport

mechanism,28 the dysfunction of the Na+- K+ -ATPase pump reduces C a2 + extrusion from the cell. The additional cytoplasmic Ca2 + enhances the Ca 2 +-induced Ca2 + release from the sarcoplasmic reticulum during systole and by this mechanism increases the force of contraction of the cardiac muscle.

Effects

on

Cardiac

Conduction

At therapeutic serum concentrations, cardioactive steroids also increase automaticity and shorten the repolarization intervals of the atria and ventricles (Table 62-2). There is a concurrent decrease in the rate of depolarization and conduction through the sinoatrial (SA)

and (atrioventricular) AV nodes, respectively. This is mediated both indirectly via an enhancement in vagally mediated parasympathetic tone, and directly by depression of this tissue. These changes in nodal conduction are reflected on the ECG by a decrease in ventricular response rate to suprajunctional rhythms and by PR interval prolongation (part of “digitalis effect―). The effects of cardioactive steroids on ventricular repolarization are related to the elevated intracellular resting potential caused by the enhanced availability of Ca2 +, and manifest on the ECG as QTc interval shortening and ST segment and T-wave forces opposite in direction to the major QRS forces. The last effect results in the characteristic scooping of the ST segments (the second part of which is referred to as digitalis effect) (Fig 62-4). Excessive increases in intracellular C a2 +, caused by excessive cardioactive steroid effects, result in delayed afterdepolarizations. These are fluxes in membrane potential caused by spontaneous Ca2 +-induced Ca2 + release, which is caused by the excess Ca2 +, and appear on the ECG as U waves. Occasionally, these may initiate a cellular depolarization that manifests as a premature ventricular contraction (Chap. 23) .27,58

TABLE

62-2.

Electrophysiologic Effects of Steroids on the Myocardium

Cardioactive

Atria and Ventricles

AV Node

ECG

Excitability

↑

—

Extrasystoles, tachydysrhythmias

Automaticity

↑

—

Extrasystoles, tachydysrhythmias

Conduction velocity

↓

↓

↑ PR interval, AV block

Refractoriness

↓

↑

↑ PR interval, AV block, decreased QTc interval

Hypokalemia

inhibits

Na+- K+-ATPase activity and contributes to the

pump inhibition induced by cardioactive steroids, enhances myocardial automaticity, and, as a consequence, increases myocardial susceptibility to cardioactive steroid-related dysrhythmias. This may be partly a result of decreased competitive inhibition between the cardioactive steroid and potassium at the N a+ - K+ -ATPase exchanger.93 Severe hypokalemia (5.0 mEq/L in setting of acute digoxin poisoning Chronic digoxin poisoning with dysrhythmias, significant gastrointestinal symptoms, or acute onset of significantly altered mental status, or renal insufficiency Serum digoxin concentration (SDC) ≥15 ng/mL at any time, or ≥10 ng/mL 6 h postingestion Ingestion of 10 mg in adult Ingestion of 4 mg in a child To aid in treatment of suspected cardioactive steroid poisoning without a confirmatory level Poisoning by nondigoxin cardioactive steroid Digoxin-specific Fab dosing (round up vial calculation)

Empiric therapy for acute poisoning: 10–20 vials (adult or pediatric) Empiric therapy for chronic poisoning:

Adult—3–6 vials Pediatric—1–2 vials

Class IA antidysrhythmics are contraindicated in the setting of cardioactive steroid poisoning because they may induce or worsen AV nodal block and decrease His-Purkinje conduction at slow heart rates, and because of their α-adrenergic receptor blockade and vagal inhibition significant hypotension and tachycardia may occur. Class IA antidysrhythmics are also prodysrhythmogenic and their safety in the setting of cardioactive steroid poisoning is unstudied. Additionally, quinidine reduces renal clearance of digoxin and digitoxin. In patients with symptomatic supraventricular bradydysrhythmias or high degrees of AV block, atropine 0.5 mg should be administered intravenously to an adult, or 0.02 mg/kg with a minimum of 0.1 mg to a child. Atropine should be titrated to block the vagotonic effects of the cardioactive steroid. The dose may be repeated at 5-minute intervals if necessary. Therapeutic success is unpredictable, because the depressant actions of cardioactive steroids are mediated only in part through the vagus nerve. The use of isoproterenol should be avoided in cardioactive steroid-induced conduction disturbances, as there may be an increased incidence of ventricular ectopic activity in the presence of toxic levels of cardioactive steroids.

Pacemakers

and

Cardioversion

External or transvenous pacemakers have limited indications in the management of cardioactive steroid poisoning since digoxin-specific Fab became available. In one retrospective study of 92 P.978 digitalis-poisoned patients, 51 patients were treated with cardiac pacing and/or digoxin-specific Fab, and the overall mortality rate was 1 3 % .111 Prevention of life-threatening dysrhythmias failed in 8% of

patients treated with immunotherapy and in 23% of patients treated with internal pacemakers. The main reasons for failure of digoxinspecific Fab was pacing-induced dysrhythmias and delayed or insufficient doses of digoxin-specific Fab. Iatrogenic complications of pacing occurred in 36% of patients. Thus, overdrive suppression with a temporary transvenous pacemaker should not be used to abolish ventricular tachydysrhythmias in the presence of cardioactive steroid poisoning.5,111 Pacemakers have limited utility and substantial risks in patients with cardioactive steroid toxicity making the use of digoxin-specific Fab first-line therapy.111 Transthoracic electrical cardioversion for atrial tachydysrhythmias, in the setting of digoxin poisoning, is both clinically and experimentally associated with the development of potentially lethal ventricular dysrhythmias. The dysrhythmias are similar to digoxin toxic rhythms,97 and related to the degree of toxicity, and the amount of administered current in cardioversion.97 In cardioactive steroidpoisoned patients with unstable rhythms, such as hemodynamically unstable ventricular tachycardia and ventricular fibrillation, cardioversion and defibrillation, respectively, are indicated.

Electrolyte

Therapy

Potassium Hypokalemia and hyperkalemia can exacerbate cardioactive steroid cardiotoxicity. When hypokalemia is noted in conjunction with tachydysrhythmias or bradydysrhythmias, potassium replacement should be administered with serial monitoring of serum potassium, because iatrogenic hyperkalemia is detrimental. In this setting, digoxin-specific Fab administration generally should not be used until the hypokalemia is corrected because the reinstitution of Na+- K+ATPase function may cause profound hypokalemia. In the presence of acute cardioactive steroid toxicity, when potassium exceeds 5.0 mEq/L, digoxin-specific antibodies are

indicated. When marked hyperkalemia develops in conjunction with ECG evidence of hyperkalemia, and if digoxin-specific Fab is not available immediately, an attempt should be made to lower the serum potassium with IV insulin, dextrose, sodium bicarbonate, and oral administration of the ion-exchange resin sodium polystyrene sulfonate. Similar caution, as stated above, should be applied to the subsequent administration of digoxin-specific Fab because of concern for profound hypokalemia. Calcium chloride is beneficial in most hyperkalemic patients, but in the presence of cardioactive steroid, poisoning by calcium salts may be disastrous, as intracellular hypercalcemia is already present. Although a 2004 study was unable to show an adverse effect,41 a number of experimental studies cite the additive or synergistic actions of calcium and cardioactive steroids on the heart, resulting in dysrhythmias,35,81,102 cardiac dysfunction59 (eg, hypercontractility, or the so-called stone heart, hypocontractility), and cardiac arrest.70,102,117 Furthermore, 3 case reports 7,62 of deaths in cardioactive steroid-poisoned patients following calcium administration support the withholding of calcium administration in the setting of hyperkalemia. The purported mechanism is augmented intracellular cytoplasmic Ca2 +, which results from an increased transmembrane concentration gradient that further inhibits calcium extrusion through the Na+-Ca2 + exchange and/or increased intracytoplasmic stores.57 This additional cytoplasmic calcium may result in altered contraction of myofibril organelles,59 less negative intracellular resting potential that allows delayed afterdepolarizations to reach firing threshold,45,57,81 altered function of the sarcoplasmic reticulum,59,93 or increased calcium interfering with myocardial mitochondrial function (see Chap. 23) .59 Although some investigators suspect that the rate of administration of the calcium may be a factor in the subsequent cardiac toxicity,70,81 calcium administration should be avoided, as there are better, safer, alternative treatments available for cardioactive steroid-induced hyperkalemia (eg, digoxin-specific Fab, insulin and sodium bicarbonate).7,35,62,81,102

Magnesium Hypomagnesemia may also occur in cardioactive steroid-poisoned patients, secondary to the contributory factors mentioned with hypokalemia, such as long-term diuretic use to treat congestive heart failure. Concomitant hypomagnesemia may result in refractory hypokalemia, despite potassium replacement. 120 The theoretical benefits of magnesium therapy include blockade of the transient inward calcium current, antagonism of calcium at intracellular binding sites, decreased cardioactive steroid-related ventricular irritability, and blockade of potassium egress from cardioactive steroid-poisoned cells. 3,30,53,87,98,108,120 Although hypomagnesemia increases myocardial digoxin uptake and decreases cellular Na+- K+ ATPase activity, there is conflicting evidence on whether magnesium “reactivates― activity.79,98,108

the

cardioactive

steroid-bound

Na+- K+-ATPase

The successful use of intravenous magnesium sulfate in the treatment of ventricular tachydysrhythmias, caused by digoxin toxicity, is reported, even in the presence of elevated serum magnesium levels.60 The mechanism of efficacy of magnesium may be its ability to suppress delayed afterdepolarizations, prolong refractory period by decreasing calcium uptake and potassium efflux,108 activate Na+- K+ -ATPase as an essential metallo-coenzyme, or antagonize digoxin at the sarcolemma Na+ - K+ -ATPase pump. However, this treatment is only temporizing, until digoxin-specific Fab is available for definitive therapy, and is not advocated as firstline therapy. The precise dosing of magnesium sulfate in cardioactive steroid-poisoned patients is not established.3,30,53,60,87,98,120 A common regimen uses 2 g of magnesium sulfate IV over 20 minutes in an adult (25–50 mg/kg/dose to a maximum of 2 g in a child). Following stabilization, an adult patient with severe hypomagnesemia may require a magnesium infusion of 1–2 g/h (25–50 mg/kg/h to a maximum of 2 g in a child), with serial monitoring of serum magnesium levels, telemetry, respiratory rate (observing for

bradypnea), deep-tendon reflexes (observing for hyporeflexia), and monitoring of blood pressure. Magnesium is contraindicated in the setting of bradycardia or atrioventricular block, preexisting hypermagnesemia, and renal insufficiency or failure.

Extracorporal

Removal

Forced diuresis,64 hemoperfusion,75,118 and hemodialysis118 are ineffective in enhancing the elimination of digoxin because of its large volume of distribution (4–10 L/kg), which makes it relatively inaccessible to these techniques. Because of its high affinity for tissue proteins, approximately 10 times less digoxin is found in the serum than is found at the tissue level, and of that amount, approximately 20–40% is protein-bound.55 Various investigations into new methods of extracorporal removal are under investigation. Plasmapheresis may have a role for removing retained Fab-digoxin complexes to prevent rebound toxicity after digoxin overdose treatment in anuric patients, but its usefulness has not been clearly defined.14,85 Additionally, there is a suggestion that hemoperfusion through a β2 -microglobulin adsorptive column might be useful for treating acute digoxin toxicity.53,113 P.979

Summary Digoxin and digitoxin are the most commonly prescribed members of the drugs classified as cardioactive steroids, which share common structural similarities and functions at the cellular level. Cardioactive steroids have a narrow therapeutic index. Signs and symptoms of cardioactive steroid toxicity range from subtle to profound. Both cardiac and noncardiac effects follow cardioactive steroid poisoning. Patients with acute toxicity often have a higher serum concentration of the drug and may present with profound nausea, vomiting, bradycardia, atrial and ventricular ectopy with block, or

hyperkalemia. Patients with chronic toxicity often have a lower serum concentration of cardioactive steroids and may present similarly, but more often the symptoms are more protean—loss of appetite, headache, weakness, nausea, alteration in mental status—all of which may be combined with similar ectopic rhythms as with acute toxicity. In addition to overt overdose, an elevation in the serum cardioactive steroid concentrations and an exacerbation of the clinical drug effect leading to toxicity may occur from drug interactions or from deterioriating metabolic processes such as with declining renal function, or from electrolyte abnormalities such as hypokalemia, and hypomagnesemia. A systematic approach toward treating patients using basic supportive and decontamination management techniques, supplemented by the early administration of digoxin-specific Fab immunotherapy can significantly reduce morbidity and mortality in these high-risk patients.

References 1. Banner W, Bach P, Burk B, et al: Influence of assay methods on serum concentrations of digoxin during Fab fragment treatments.

J

Toxicol

Clin

Toxicol

1992;30:259–267.

2. Bayer MJ: Recognition and management of digitalis intoxication: Implications for emergency medicine. Am J Emerg Med 1991;9 (Suppl 1):29–32. 3. Beller GA, Hood WB, Smith TW, et al: Correlation of serum magnesium level and cardiac digitalis intoxication. Am J Cardiol 1974;33:225–229. 4. Bismuth C, Gaultier M, Conso F, Efthymiou ML: Hyperkalemia in acute digitalis poisoning: Prognostic significance and therapeutic implications. Clin Toxicol 1973;6:153–162.

5. Bismuth C, Motte G, Conso F, Chauvin M: Acute digitoxin intoxication treated by intracardiac pacemaker: Experience in sixty-eight patients. Clin Toxicol 1977;10:443–456. 6. Blaustein MP: Physiologic effects of endogenous ouabain: Control of intracellular Ca2 + stores and cell responsiveness. Am J Physiol 1993;264:C1367–C1387. 7. Bower JO, Mengle HAK: The additive effect of calcium and digitalis. JAMA 1936;106:1151–1153. 8. Bristow MR, Port JD, Kelly RA: Treatment of heart failure: Pharmacologic methods. In: Braunwald E, Zipes D, Libby P, eds: Heart Disease. A Textbook of Cardiovascular Medicine, 6th ed. New York, WB Saunders, 2001, pp. 573–575. 9. Brubacher JR, Ravikumar PR, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 1996;110:1282–1288. 10. Carver JL, Valdes R: Anomalous serum digoxin concentrations in uremia. Ann Intern Med 1983;98:483–484. 11. Centers for Disease Control and Prevention: Deaths associated with a purported aphrodisiac. New York City, February 1993–May 1995. MMWR Morb Mortal Wkly Rep 1995;44:853–855. 12. Chern MS, Ray CY, Wu DL: Biological intoxication due to digitalis-like substance after ingestion of cooked toad soup. Am J Cardiol 1991;67:443–444.

13. Cheung K Hinds JA, Duffy P: Detection of poisoning by plantorigin cardiac glycoside with the Abbot TDx analyzer. Clin Chem 1989;35:295–297. 14. Chillet P, Korach JM, Vincent N, et al: Digoxin poisoning and anuric acute renal failure: Efficiency of the treatment associating digoxin-specific antibodies (Fab) and plasma exchanges. Int J Artif Organs 2002;25:538–541. 15. Cooke D: The use of central nervous system manifestations in the early detection of digitalis toxicity. Heart Lung 1993;22:477–481. 16. Critchley JA, Critchley LA: Digoxin toxicity in chronic renal failure: Treatment by multiple-dose activated charcoal dialysis. Hum Exp Toxicol 1997;16:733–735.

intestinal

17. Cummins RO, Haulman J, Quan L: Near-fatal yew berry intoxication treated with external cardiac pacing and digoxinspecific Fab antibody fragments. Ann Emerg Med 1990;19:38–43. 18. Dasgupta A, Wu S, Actor J, et al: Effect of Asian and Siberian ginseng on serum digoxin measurement by five digoxin immunoassays. Significant variation in digoxin-like immunoreactivity among commercial ginsengs. Am J Clin Pathol 2003;119:298–303. 19. De-Mey C, Brendel E, Enterling D: Carvedilol increases the systemic bioavailability of oral digoxin. Br J Clin Pharmacol 1990;29:486–490.

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relationship between twitch tension and intracellular sodium activity in sheep cardiac Purkinje fibers. J Physiol 1984;355:251–266. 28. Eisner DA, Smith TW: The Na-K pump and its effect in cardiac muscle. In: Fozzard HA, ed: The Heart and Cardiovascular System, 2nd ed. New York, Raven Press, 1991, pp. 863–902. 29. Eisner T, Wiemer DF, Haynes LW, Meinwald J: Lucibufagins: Defensive steroids from the fireflies Photinus ignitus and P . marginellus (Coleoptera: Lampyridae). Proc Natl Acad Sci U S A 1978;75:905. 30. French JH, Thomas RG, Siskind AP, et al: Magnesium therapy in massive digoxin intoxication. Ann Emerg Med 1984;13:562–566. 31. Friedman HS, Abramowitz I, Nguyen T, et al: Urinary digoxinlike immunoreactive substance in pregnancy. Am J Med 1987;83:261–264. 32. George S, Brathwaite RA, Hughes EA: Digoxin measurements following plasma ultrafiltration in two patients with digoxin toxicity treated with specific Fab fragments. Ann Clin Biochem 1994;31:380–381. 33. Giampietro O, Clerico A, Gregori G, et al: Increased urinary excretion of digoxin-like immunoreactive substance by insulindependent diabetic patients: A linkage with hypertension? Clin Chem 1988;34:2418–2422. 34. Gibb T, Adams PC, Parnham AJ, Jennings K: Plasma digoxin:

Assay anomalies in Fab-treated patients. Br J Clin Pharmacol 1983;16:445–447. P.980 35. Gold H, Edwards DJ: The effects of ouabain on heart in the presence of hypercalcemia. Am Heart J 1927;3:45–50. 36. Gorelick DA, Kussin SZ, Kahn I: Paranoid delusions and auditory hallucinations associated with digoxin intoxication. J Nerv Ment Dis 1978;166:817–819. 37. Graves SW, Adler G, Stuenkel C, et al: Increases in plasma digitalis-induced hypoglycemia. Neuroendocrinology 1989;49:586–591. 38. Graves SW, Brown BA, Valdes R: Digoxin-like substances measured in patients with renal impairment. Ann Intern Med 1983;99:604–608. 39. Graves SW, Valdes R, Brown BA, et al: Endogenous immunoreactive digoxin-like substance in human pregnancies. J Clin Endocrinol Metab 1984;58:748–751. 40. Graves SW: Endogenous digitalis-like factors. Crit Rev Clin Lab Sci 1986;23:177–200. 41. Hack JB, Woody JH, Lewis DE, et al: The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model. J Toxicol Clin Toxicol 2004;42:337–342. 42. Haddy FJ: Endogenous digitalis-like factor or factors. N Engl J Med 1987;316:621–622.

43. Hager WD, Fenster P, Mayersohn M, et al: Digoxin-quinidine interaction: Pharmacokinetic evaluation. N Engl J Med 1979;300:1238–1241. 44. Hastreiter AR, John EG, van der Horst RL: Digitalis, digitalis antibodies, digitalis-like immunoreactive substances, and sodium homeostasis: A review. Clin Perinatol 1988;15:491–522. 45. Hauptman PJ, Kelly RA: Digitalis. Circulation 1999;99:1265–1270. 46. Helfant RH, Scherlac BJ, Damata AN: Protection from digitalis toxicity with the prophylactic use of diphenylhydantoin sodium an arrhythmic-inotropic

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47. Henderson RP, Solomon CP: Use of cholestyramine in the treatment of digoxin intoxication. Arch Intern Med 1988;148:745–746. 48. Hilton PJ, White G, Lord A, et al: An inhibitor of the sodium pump obtained from human placenta. Lancet 1996;348:303–305. 49. Hobson J, Zettner A: Digoxin serum half-life following suicidal digoxin poisoning. JAMA 1973;223:147–149. 50. Hollman A: Plants and cardiac glycosides. Br Heart J 1985;54:258–261. 51. Isensee L, Solomon RJ, Weinberg MS, et al: Digoxin levels in dialysis patients. Hosp Physician 1988;24:50–52.

52. Jortani SA, Helm RA, Valdes R: Inhibition of Na,K-ATPase by oleandrin and oleandrigenen, and their detection by digoxin immunoassays. Clin Chem 1996;42:1654–1658. 53. Kaneko T, Kudo M, Okumura T, et al: Successful treatment of digoxin intoxication by hemoperfusion with specific columns for Î ²2 -microglobulin adsorption (Lixelle) in a maintenance haemodialysis patient. Nephrol Dial Transplant 2001;16;195–196. 54. Karkal SS, Ordog G, Wasserberg J: Digitalis intoxication: Dealing rapidly and effectively with a complex cardiac toxidrome. Emerg Med Rep 1991;12:29–44. 55. Katzung BG, Parmley WM: Cardiac glycosides & other drugs used in congestive heart failure. In: Katzung BG, ed: Basic and Clinical Pharmacology, 7th ed. Stamford, CT, Appleton & Lange, 1998, pp. 197–215. 56. Kelly RA, Smith TW: Endogenous cardiac glycosides. Adv Pharmacol 1994;25:263–288. 57. Kelly RA, Smith TW: Pharmacological treatment of heart failure. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, eds: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996, pp. 809–838. 58. Kelly RA, Smith TW: Recognition and management of digitalis toxicity. Am J Cardiol 1992;69:108–109. 59. Khatter JC, Agbanyo M, Navaratnam S, et al: Digitalis

cardiotoxicity: Cellular calcium overload as a possible mechanism. Basic Res Cardiol 1989;84:553–563. 60. Kinlay S, Buckley N: Magnesium sulfate in the treatment of ventricular arrhythmias due to digoxin toxicity. J Toxicol Clin Toxicol 1995;33:55–59. 61. Klausen T, Kjeldsen K, Norgaard A: Effects of denervation on sodium, potassium and [3 H] ouabain binding in muscles of normal and potassium depleted rats. J Physiol 1983;345:123–124. 62. Kne T, Brokaw M, Wax P: Fatality from calcium chloride in a chronic digoxin toxic patient (abstract). J Toxicol Clin Toxicol 1997;5:505. 63. Knight M, Glor R, Smedley SR, et al: Firefly toxicosis in lizards.

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69. Levy G: Gastrointestinal clearance of drugs with activated charcoal. N Engl J Med 1982;307:676–678. 70. Lieberman AL: Studies on calcium VI: Some interrelationships of the cardiac activities of calcium gluconate and scillaren-B. J Pharmacol Exp Ther 1933;47:183–192. 71. Lindenbaum J, Rund DG, Butler VP: Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. N Engl J Med 1981;305:789–794. 72. Lown B, Byatt NF, Levine HD: Paroxysmal atrial tachycardia with block. Circulation 1960;21:129–143. 73. Madan BR, Khanna NK, Soni RK: Effect of some arrhythmogenic agents upon the acetylcholine content of the rabbit atria. J Pharm Pharmacol 1970;22:621–622. 74. Mahdyoon H, Battilana G, Rosman H, et al: The evolving pattern of digoxin intoxication: Observations at a large urban hospital from 1980 to 1988. Am Heart J 1990;120:1189–1194. 75. Marbury T, Mahoney J, Juncos L, et al: Advanced digoxin toxicity in renal failure: Treatment with charcoal hemoperfusion. South Med J 1979;72:279–282. 76. McGary SJ, Williams AJ: Digoxin activates sarcoplasmic reticulum Ca2 + release channels: A possible role in cardiac inotropy. Br J Pharmacol 1993;108:1043–1050.

77. McRae S: Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. CMAJ 1996;155:292–295. 78. Miller JM, Zipes DP: Management of the patient with cardiac arrhythmias. In: Braunwald E, Zipes D, Libby P, eds: Heart Disease. A Textbook of Cardiovascular Medicine, 6th ed. New York, WB Saunders, 2001, pp. 726–727. 79. Nanji AA, Greenway DC: Falsely raised plasma digoxin concentrations in liver disease. Br Med J 1985;290:432–433. 80. Neff MS, Mendelssohn S, Kim KS, et al: Magnesium sulfate in digitalis toxicity. Am J Cardiol 1974;62:377–382. 81. Nola GT, Pope S, Harrison DC: Assessment of the synergistic relationship between serum calcium and digitalis. Am Heart J 1970;79:499–507. 82. Ordog GJ, Benaron S, Bhasin V, et al: Serum digoxin levels and mortality in 5,100 patients. Ann Emerg Med 1987;16:32–39. 83. Pace DG, Gillis RA: Neuroexcitatory effects of digoxin in the cat. J Pharmacol Exp Ther 1976;199:583–600. 84. Pond S, Jacos M, Marks J, et al: Treatment of digitoxin overdose with oral activated charcoal. Lancet 1981;2:1177–1178. 85. Rabetoy GM, Price CA, Findlay JWA, et al: Treatment of digoxin intoxication in a renal failure patient with digoxin-specific antibody fragments and plasmapheresis. Am J Nephrol

1990;10:518–521. 86. Radford DJ, Cheung K, Urech R, et al: Immunologic detection of cardiac glycosides in plants. Aust Vet J 1994;71:236–38. 87. Reisdorff EJ, Clark MR, Walter BL: Acute digitalis poisoning: The role of intravenous magnesium sulfate. J Emerg Med 1986;4:463–469. 88. Rich SA, Libera JM, Locke RJ: Treatment of foxglove extract poisoning with digoxin-specific Fab fragments. Ann Emerg Med 1993;22:1904–1907. P.981 89. Roberge RJ: Congestive heart failure and toxic digoxin levels: Role of cholestyramine. Vet Hum Toxicol 2000;42:172–173. 90. Rodin SM, Johnson BF: Pharmacokinetic interactions with digoxin. Clin Pharmacokinetic 1988;15:227–244. 91. Rose AM, Valdes R: Understanding the sodium pump and its relevance

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92. Rosen MR, Wit AL, Hoffman BF: Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J 1975;89:391–399. 93. Rosen MR: Cellular electrophysiology of digitalis toxicity. J Am Coll Cardiol 1985;2:22A–34A. 94. Rumack BH, Wolfe RR, Gilfinch H: Diphenylhydantoin treatment of massive digoxin overdose. Br Heart J 1974;36:405–408.

95. Safadi R, Levy T, Amitai Y, et al: Beneficial effect of digoxinspecific Fab antibody fragments in oleander intoxication. Arch Intern Med 1995;155:2121–2125. 96. Sameri RM, Soberman JE, Finch CK, et al: Lower serum digoxin concentrations in heart failure and reassessment of laboratory report forms. Am J Med Sci 2002;324:10–13. 97. Sarubbi B, Ducceschi V, D'Antonello A, et al: Atrial fibrillation: What are the effects of drug therapy on the effectiveness and complications of electrical cardioversion? Can J Cardiol 1998;14:1267–1273. 98. Seller RH: The role of magnesium in digitalis toxicity. Am Heart J 1971;82:551–556. 99. Selzer A: Role of serum digoxin assay in patient management. J Am Coll Cardiol 1985;5:106A–110A. 100. Shilo LM, Adawi A, Solomon G, Shenkman L: Endogenous digoxin-like immunoreactivity in congestive heart failure. Br Med J 1987;295:415–416. 101. Silber B, Sheiner LB, Powers JL, et al: Spironolactoneassociated digoxin radioimmunoassay interference. Clin Chem 1979;25:48–54. 102. Smith PK, Winkler AW, Hoff HE: Calcium and digitalis synergism: The toxicity of calcium salts injected intravenously into digitalized animals. Arch Intern Med 1939;64:322–328.

103. Smith SW, Shah RR, Herzog CA: Bidirectional ventricular tachycardia resulting from herbal aconite poisoning. Ann Emerg Med 2005;45:100. 104. Smith TW, Haber E, Yeatman L, et al: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797–800. 105. Smith TW: Pharmacokinetics, bioavailability and serum levels of cardiac glycosides. J Am Coll Cardiol 1985;5:43A–50A. 106. Smith TW: Digitalis. N Engl J Med 1988;318:358–365. 107. Somberg JC, Bounous H, Levitt B: The antiarrhythmic effects of quinidine and propranolol in the ouabain-intoxicated spinally transected cat. Eur J Pharmacol 1979;54:161–166. 108. Spechter MJ, Schweizer E, Goldman RH: Studies on magnesium's mechanism of action in digitalis-induced arrhythmias. Circulation 1975;52:1001–1005. 109. Springer M, Olson KR, Feaster W: Acute massive digoxin overdose: Survival without use of digitalis-specific antibodies. Am J Emerg Med 1986;4:364–369. 110. Sullivan JB: Immunotherapy in the poisoned patient. Med Toxicol 1986;1:47–60. 111. Taboulet P, Baud FJ, Bismuth C, et al: Acute digitalis intoxication: Is pacing still appropriate? J Toxicol Clin Toxicol 1993;31:261–273.

112. Torsti P: Acetylcholine content and cholinesterase activities in the rabbit heart in experimental heart failure and the effect of g-strophanthin treatment on them. Ann Med Exp Biol Fenn 1959;37(Suppl 4):4–9. 113. Tsuruoka S, Osono E, Nishiki K, et al: Removal of digoxin by column for specific adsorption of β2 -microglobulin: A potential use for digoxin intoxication. Clin Pharmacol Ther 2001;69:422–30. 114. Tuncok Y, Kozan O, Cavdar C, et al: Urginea maritima (squill) toxicity. J Toxicol Clin Toxicol 1995;33:83–86. 115. Valdes R, Graves SW, Brown BA, et al: Endogenous substances in newborn infants causing false-positive digoxin measurements. J Pediatr 1983;102:947–950. 116. Valdes R, Hagberg JM, Vaughan TE, et al: Endogenous digoxin-like immunoreactivity in blood is increased during prolonged strenuous exercise. Life Sci 1988;42:103–110. 117. Wagner J, Salzer WW: Calcium-dependent toxic effects of digoxin in isolated myocardial preparations. Arch Int Pharmacodyn 1976;223:4–14. 118. Warren SE, Fanestil DD: Digoxin overdose: Limitations of hemoperfusion-hemodialysis treatment. JAMA 1979;242:2100–2101. 119. Watson WA: Factors influencing the clinical efficacy of activated charcoal. Drug Intell Clin Pharm 1987;21:160–166.

120. Whang R, Aikawa J: Magnesium deficiency and refractoriness to potassium repletion. J Chron Dis 1977;30:65–68. 121. Wildicks EFM, Vermeulen M, van Brummelen P, et al: Digoxin-like immunoreactive substance in patients with aneurysmal subarachnoid hemorrhage. Br Med J 1987;294:729–732. 122. Withering W: An account of the foxglove and some of its medical uses: With practical remarks on dropsy and other diseases. Med Classics 1937;2:295–443. 123. Woolf AD, Wenger T, Smith TW, et al: The use of digoxinspecific Fab fragments for severe digitalis intoxication in children. N Engl J Med 1992;326:1739–1744.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > E - Cardiopulmonary Medications > Antidotes in Depth - Digoxin-Specific Antibody Fragments (Fab)

Antidotes in Depth Digoxin-Specific Antibody Fragments (Fab) Mary Ann Howland Digoxin-specific antibody fragments are indicated for the management of patients with toxicity related to digoxin, digitoxin, and all natural cardioactive steroids, such as oleander, squill, and toad venom. Digoxin-specific antibody fragments have an excellent record of efficacy and safety, and should be administered early in both established and suspected cardioactive steroid poisoning.

History The production of antibody fragments to treat patients poisoned with digoxin followed the development of digoxin antibodies for measuring serum digoxin concentrations by radioimmunoassay (RIA).11 The RIA technique permitted the correlation between serum digoxin concentration and clinical digoxin toxicity. In 1967, Butler and Chen suggested that purified antidigoxin

antibodies with a high affinity and specificity should be developed to treat digoxin toxicity in humans.11 The digoxin molecule alone, with a molecular weight of 780 daltons, was too small to be immunogenic. But digoxin could function as a hapten when joined to an immunogenic protein carrier such as albumin. These investigators immunized sheep with this conjugate to generate antibodies. The immunized sheep subsequently produced a mixture of antibodies that included antialbumin antibodies and antidigoxin antibodies. The antibodies were separated and highly purified to retain the digoxin antibodies, while removing the antibodies to the albumin and all other extraneous proteins. The antibodies that were developed have a high affinity for digoxin, and sufficient cross-reactivity with digitoxin to be clinically useful for the treatment of both poisonings. On the other hand, the specificity is so high that endogenous steroids, which resemble digoxin structurally, are not affected by antibody administration. Intact IgG antidigoxin antibodies reversed digoxin toxicity in dogs. Unfortunately, the urinary excretion of digoxin was delayed, and free digoxin was released after antibody degradation occurred. Furthermore, concern for hypersensitivity reactions also existed. To make these antibodies safe and effective in humans, whole IgG antidigoxin antibodies were cleaved with papain, yielding two antigen-binding fragments (Fab), with a molecular weight of 50,000 daltons each, and one Fc fragment.12 The Fc fragment does not bind antigen, but it does increase the potential for hypersensitivity reactions and was eliminated. The advantages of digoxin-specific antibody fragments when compared to whole IgG antibodies include larger volume of distribution, more rapid onset of action, smaller risk of adverse immunologic effects, and more rapid elimination.12,46,48 Ultimately, the first commercial product, Digibind, a relatively pure, very safe, and extremely effective Fab product, was produced. Another commercial product, DigiFab, is currently available.

Pharmacology Immediately following IV administration, digoxin-specific antibody fragments bind intravascular free digoxin. Unbound antibodies then diffuse into the interstitial space, binding free digoxin there. A concentration gradient is then established, which facilitates movement of the free intracellular digoxin, and digoxin that is dissociated from its binding sites (the external surface of Na+ - K+ adenosine triphosphatase [ATPase] enzyme) in the heart and in skeletal muscle, into the interstitial or intravascular spaces. 68 The dissociation rate constant of digoxin for Na+- K+-ATPase, therefore, affects the time course for binding to digoxin-specific antibody fragments and, consequently, the onset of action.50,69 The binding affinity of digoxin-specific antibody fragments for digoxin and digitoxin are about 109 –1011 M- 1 and 108 –109 M1,

and are greater than the affinity of digoxin or digitoxin for the N a+ - K+ -ATPase pump receptor.21

Pharmacokinetics The pharmacokinetics of Digibind versus DigiFab (previously named DigiTAb) were compared in human volunteers. 85 Each subject received 1 mg of digoxin intravenously as a 5-minute bolus, followed 2 hours later by a 30-minute intravenous infusion of 76 mg (equimolar neutralizing dose) of Digibind or DigiFab. Free and total digoxin (free plus digoxin-specific antibody fragment bound) were assayed using an ultrafiltration method over 48 hours. At 30 minutes after infusion of either digoxin-specific antibody fragment, the free digoxin serum concentration was below the level of detection of the assay and remained so for several hours. A few patients had free digoxin concentrations rebound to peak concentrations of 0.5 ng/mL at approximately 18 hours. The area under the plasma drug concentration versus time curve (AUC) for 2–48 hours, for free digoxin, was similar for both treatment groups. The elimination half-life of total digoxin

averaged 19.5 hours. The distribution half life was 1 hour for each digoxin-specific antibody fragments, and the volumes of distribution were 0.3 L/kg for DigiFab versus 0.4 L/kg for Digibind.21,22 The systemic clearance of DigiFab was higher than Digibind and accounted for the shorter elimination half life of DigiFab (15 hours versus 23 hours). 85 Urine sampling over the first 24 hours demonstrated mostly free digoxin and very little digoxin-specific antibody fragments. The authors postulate that during renal excretion, the digoxin-specific antibody fragmentsdigoxin complex is metabolized in the kidney by the proximal tubular cells, releasing free digoxin and unmeasured digoxinspecific antibody fragments metabolites. Similar findings were described by Smith and associates in 1976, following the first clinical use of digoxin-specific antibody fragments in a patient who gave a history of ingesting 90 (0.25 mg) digoxin tablets.75 Total serum digoxin concentration, which was 17.6 ng/mL before digoxin-specific antibody fragments were given, rose to 226 ng/mL one hour after the start of the digoxinspecific antibody fragments infusion and remained there for 11 hours, before falling over the next 44 hours, with a half-life of 20 hours.75 Fab concentrations peaked at the end of the infusion and then apparently exhibited a biphasic or triphasic decline, probably reflecting distribution into different compartments, as well as excretion and catabolism. Free serum digoxin concentrations were undetectable for P.984 the first 9 hours, then rose to a peak of 2 ng/mL at 16 hours, and fell to 1.5 ng/mL at both 36 hours and 56 hours at which time sampling stopped. An analysis of renal elimination based on an incomplete collection suggested that digoxin was excreted only in the bound form during the first 6 hours, but by 30 hours after Fab administration all digoxin in the urine was free digoxin. In order to better match availability of digoxin-specific antibody fragments to liberated digoxin, one study compared a loading dose

of digoxin-specific antibody fragments followed by an infusion to the total digoxin-specific antibody fragments dose infused over a short amount of time.65 The former strategy increased the ratio of digoxin bound to unbound digoxin-specific antibody fragments from 50 to 70%. 65 The authors hypothesized that too rapid an infusion regimen would permit digoxin-specific antibody fragments elimination to occur before they could optimally bind digoxin being redistributed from tissue sites.65 Digoxin takes several hours to distribute from the blood to the tissue compartment. As expected, a rodent model demonstrated that digoxin-specific antibody fragments were more effective when administered prior to complete distribution of digoxin.62 Once distribution is complete, increasing the dose of digoxin-specific antibody fragments improved efficacy as measured by comparing the area under the time-versus-concentration curve (AUC) of digoxin to that of the Fab-digoxin complex.62 Pharmacokinetic studies in patients with renal failure demonstrate that the half-life of digoxin-specific antibody fragments is prolonged 10-fold, with no change in the apparent Vd.79 Digoxinspecific antibody fragment serum concentrations remain detectable for 2–3 weeks. Total digoxin serum concentrations generally follow digoxin-specific antibody fragments. There is no evidence for dissociation of digoxin-specific antibody fragments-digoxin complex over time.86 In contrast, case reports demonstrate that free digoxin levels reappear up to 10 days following administration of digoxin-specific antibody fragments to patients with severe renal dysfunction, as compared to 12–24 hours in patients with normal renal function.27,41,52,53,71,73,79,80,81,86 In one series of patients with end-stage renal disease, the maximum average concentration of free digoxin was 1.30 ± 0.7 ng/mL and occurred at 127 ± 40 hours.81 The mechanism for this rebound is unclear. Following the peak, there is a slow decline that parallels the elimination of digoxin-specific antibody fragments.

Efficacy A large study evaluating adults and children with acute and chronic digoxin toxicity established the efficacy of digoxin-specific antibody fragments.1 Of the 150 patients treated, 148 were evaluated pretreatment for cardiovascular manifestations of toxicity: 79 patients (55%) had high-grade atrioventricular (AV) block, 68 (46%) had refractory ventricular tachycardia, 49 (33%) had ventricular fibrillation, and 56 (37%) had hyperkalemia. Ninety percent of patients had a response to digoxin-specific Fab within minutes to several hours of Digibind administration. Complete resolution of all signs and symptoms of digoxin toxicity occurred in 80% of cases. A partial response was observed in 10% of patients, and of the 15 patients who did not respond, 14 were moribund or actually found not to be digoxin toxic. The spectacular success of digoxin-specific antibody fragments for patients with digoxin toxicity is demonstrated by the fact that of the 56 patients who had cardiac arrest caused by digoxin, 54% survived hospitalization, as compared with 100% mortality before the advent of these fragments.1,5 Newborns, infants, and children have all been successfully treated with Digibind.5,39,70

Adverse

Effects

and

Safety

Digoxin-specific antibody fragments are effective, as well as very safe. Reported adverse effects include hypokalemia as a consequence of reactivation of the Na+- K+-ATPase, withdrawal of the inotropic or atrioventricular nodal blocking effects of digoxin leading to congestive heart failure or a rapid ventricular rate in patients with atrial fibrillation, and, rarely, allergic reactions.21,22 In the multicenter study of 150 patients, the only acute clinical manifestations were hypokalemia in 6 patients (4%), worsening of congestive heart failure in 4 patients (3%), and transient apnea in a several-hours-old neonate.1 There were no other reactions reported in any of the patients in this series. In a postmarketing

surveillance study of Digibind that included 451 patients, 2 patients with a prior history of allergy to antibiotics reportedly developed rashes.57 One of these patients developed a total body rash, facial swelling, and a flush during the infusion. The other experienced a pruritic rash. Two other adverse reactions (thrombocytopenia and rigors) were probably unrelated to the use of Digibind.57 One patient received Digibind on 3 separate occasions over the course of 1 year for multiple suicide attempts, with no adverse effects.8 During the clinical trials with DigiFab, 1 patient developed pulmonary edema, most likely caused digoxin effects.22 to the infusion of

bilateral pleural effusion, and renal failure, by the loss of the inotropic and chronotropic Phlebitis and postural hypotension were related DigiFab in two healthy volunteers.

Both products warn that patients with allergies to papain, chymopapain, or other papaya extracts may be at risk for an allergic reaction because trace amounts of these residues may remain in the digoxin-specific antibody fragments.22,48 Manufacturers of DigiFab state that because some literature suggests a resemblance between dust mite allergens and some latex allergens with the antigenic structures of papain, patients may exhibit cross-allergenicity. Patients with an allergy to sheep protein or those who have previously received ovine antibodies or ovine Fab may also be at risk for allergic reactions, although this is not reported.

Indications

for

Digoxin-Specific

Fab

Digoxin-specific antibody fragments are indicated for lifethreatening, or potentially life-threatening, digoxin, digitoxin, or other xenobiotic resulting in cardioactive steroid toxicity. 21 Patients with progressive bradydysrhythmias, including symptomatic sinus bradycardia, or second- or third-degree heart block unresponsive to atropine, and those patients with severe

ventricular dysrhythmias, such as ventricular tachycardia or ventricular fibrillation, should also be treated with digoxin-specific antibody fragments. Ventricular tachycardia with a fascicular block is likely to be a digoxin-toxic rhythm.47 Any patient with a potassium concentration exceeding 5 mEq/L that is attributable to a cardioactive steroid in the presence of other manifestations of digoxin toxicity should also be treated. Acute ingestions greater than 4 mg in a healthy child (or more than 0.1 mg/kg), or 10 mg in a healthy adult, require digoxin-specific antibody fragments, with the threshold lower in patients with significant medical P.985 illness. Serum digoxin concentrations are not representative of myocardial concentrations until tissue distribution takes place. Following ingestion, a time delay of 4–6 hours is usually required for digoxin to achieve distribution from the serum to the myocardium. Serum concentrations of ≥10 ng/mL, at steady state after an acute ingestion, are an indication for treatment with digoxin-specific antibody fragments. Because the elderly appear at greatest risk of lethality, the threshold for treating those older than 60 years of age should be lowered.7 Before the advent of digoxin-specific antibody fragments, mortality in patients older than 60 years of age was 58%, as compared to 8% in patients younger than 40 years of age, and to 34% in patients between the ages of 40 and 50 years of age.7 A rapid progression of clinical signs and symptoms, such as cardiac and gastrointestinal toxicity and an elevated or rising potassium level, in the presence of an acute overdose, suggests a potentially life-threatening ingestion and the need for digoxin-specific antibody fragments. In a patient with an unknown ingestion who is clinically ill with characteristics suggestive of poisoning by a cardioactive steroid, a calcium channel-blocking agent, or a β-adrenergic antagonist, digoxin-specific antibody fragments should be administered early in the management, and always prior to calcium use. If digoxin or another cardioactive steroid is involved, the effects can be

reversed, obviating the need to administer calcium and avoiding the danger of giving calcium to a cardioactive steroid-toxic patient. Cardioactive steroid toxicity causes intracellular myocardial hypercalcemia, and the administration of exogenous calcium may further exacerbate conduction abnormalities and potentially result in cardiac arrest, unresponsive to further resuscitation. Also, when it is difficult to distinguish clinically between digoxin poisoning and intrinsic cardiac disease, the administration of digoxin-specific antibody fragments can help establish the diagnosis. A recent computer-based simulation model compared the treatment of non-lifethreatening digoxin toxicity with standard therapy. The authors concluded that treatment with digoxinspecific antibody fragments could decrease length of hospitalization by 1.5 days.20

Onset

of

Response

In the multicenter study of 150 patients, the mean time to initial response from the completion of the digoxin-specific antibody fragments infusion (accomplished over 15 minutes to 2 hours) was 19 minutes (range, 0–60 minutes), and the time to complete response was 88 minutes (range, 30–360 minutes).16 Time to response was not affected by age, concurrent cardiac disease, or presence of chronic or acute ingestion.1

Dos i n g The dose of digoxin-specific antibody fragments depends on the total body load (TBL) of digoxin. Adult and pediatric patients receiving digoxin therapeutically who develop chronic digoxin toxicity require small doses of digoxin-specific antibody fragments because their total body burden of digoxin is smaller when toxicity develops. Children with acute overdoses require digoxin-specific

antibody fragments doses based on the amount of digoxin ingested, in a manner similar to adults with acute ingestions. Estimates of digoxin TBL can be made in three ways: (a) estimate the quantity of digoxin acutely ingested and assume 80% bioavailability (mg ingested × 0.8 = TBL); (b) obtain a serum digoxin concentration (SDC), and, using a pharmacokinetic formula, incorporate the apparent volume of distribution (Vd) of digoxin and the patient's body weight (in kg); or (c) use an empiric dose based on the average requirements for an acute or chronic overdose in an adult or child.

TABLE A19-1. Sample Calculation Based on History of Acute Digoxin Ingestion

Adult Weight: 70 kg Ingestion: Fifty (0.25-mg) digoxin tablets Calculation: 0.25 mg × 50 = 12.5 mg ingested dose 12.5 mg × 0.80 (80% bioavailability) = 10 mg (absorbed dose)

Child Weight: 10 kg Ingestion: Fifty (0.25-mg) digoxin tablets Calculation: Same as for adult. Child will require 20 vials

Each of these methods of estimating the dose of digoxin-specific antibody fragments has limitations. History of ingestion is often unreliable, and empiric doses based on averages may overestimate or underestimate Fab requirements. Using the pharmacokinetic

formula assumes a steady-state Vd of 5 L/kg. This is not accurate in the acute setting. In addition, the 5 L/kg Vd is a population average that varies both with each individual and in certain disease states, such as the decreases that occur in patients with renal disease and hypothyroidism.87 Sample calculations for each of these methods are shown in Tables A19-1, A19-2, and A19-3. Each vial of digoxin-specific antibody fragments contains 38 mg (Digibind) or 40 mg (DigiFab) P.986 of purified digoxin-specific antibody fragments that will bind approximately 0.5 mg of digoxin or digitoxin. If the quantity of ingestion cannot be reliably estimated, it is safest to use the largest calculated estimate. Alternatively, the clinician should be prepared to increase dosing, should resolution be incomplete.

TABLE A19-2. Sample Calculations Based on the Serum Digoxin Concentration (SDC)

Adult Weight: 70 kg SDC = 10 ng/mL Volume of distribution = 5 L/kg Calculationa :

No. of vials = 7 Child Weight: 10 kg

Serum digoxin concentration: 10 ng/mL Volume of distribution: 5 L/kg Calculationa :

No. of vials = 1 Quick Estimation (for Adults and Children)

a

1000 is a conversion factor to change ng/mL to mg/L.

TABLE A19-3. Empiric Dosing Recommendations

Acute Ingestion Adult: 10–20 vials Childa : 10–20 vials Chronic Toxicity Adult: 3–6 vials Childb : 1–2 vials a Monitor

for volume overload in very small children. b The prescribing information contains a table for infants and children, with corresponding serum concentrations.

Administration According to the manufacturer, Digibind should be administered IV over 30 minutes via a 0.22-micron membrane filter.21 The 38-mg

vial must be reconstituted with 4 mL of sterile water for IV injection, furnishing an isoosmotic solution. This preparation can be further diluted with sterile isotonic saline for injection (for small infants, addition of 34 mL to the 4 mL [for 38 mL total] achieves 1 mg/mL). After Digibind is reconstituted, it should be used immediately, or if refrigerated, it should be used within 4 hours.21 Although slow IV infusion over 30 minutes is preferable, Digibind may be given by IV bolus to a critically ill patient. Each vial of DigiFab should be reconstituted with 4 mL of sterile water for IV injection and gently mixed to provide a solution containing 10 mg/mL of digoxin-specific antibody fragments.22 The reconstituted product should be used promptly or, if refrigerated, it should be used within 4 hours. This preparation can be further diluted with sterile isotonic saline for injection. DigiFab should be administered slowly as an intravenous infusion over at least 30 minutes unless the patient is critically ill, in which case the DigiFab can be given by IV bolus. If a rate-related infusion reaction occurs, the infusion should be stopped and restarted at a slower rate. For infants and small children, the manufacturer recommends diluting the 40-mg vial with 4 mL of sterile water for IV injection and administering the dose undiluted using a tuberculin syringe. For very small doses, this preparation can be further diluted with an additional 36 mL of sterile isotonic saline for injection (for a total of 40 mL) to achieve a 1 mg/mL concentration.

Availability Digoxin-specific antibody fragments are available as Digibind or DigiFab. Vials contain 38 mg or 40 mg of purified lyophilized digoxin-immune ovine immunoglobulin fragments, respectively. Digibind is prepared using digoxin as the hapten. DigiFab is prepared using a digoxin derivative (digoxindicarboxymethoxylamine) as the hapten. Affinity chromatography is used to isolate and purify the digoxin-specific antibody

fragments

following

papain

digestion.

Measurement of Digoxin Serum Concentration after Digoxin-Specific Antibody Fragments Administration Many laboratories are not equipped to determine free serum digoxin concentrations. Therefore, after digoxin-specific antibody fragments are administered, total serum digoxin concentrations are no longer clinically useful, because they represent free plus bound digoxin.21,31,36,44,77 The type of test employed can either result in falsely high or falsely low serum concentrations, depending on which phase (solid or supernatant) is sampled.35,49 If the correct dose of digoxin-specific antibody fragments is administered, the free serum digoxin concentrations should be near zero. Free digoxin concentrations begin to reappear 5–24 hours or longer after Fab administration, depending on the antibody dose, infusion technique, and the patient's renal function. Newer commercial methods, employing ultrafiltration or immunoassays, make free digoxin measurements easier to perform and, therefore, more clinically useful, but they remain associated with errors in the underestimation or overestimation of the free digoxin level.30,37,54,60,78,82 Free digoxin concentrations are particularly useful in patients with severe renal dysfunction. Independent of the availability of these data, the patient's cardiac status must be carefully monitored for signs of recurrent toxicity. Other pitfalls in the measurement and utility of serum digoxin concentrations include endogenous and exogenous factors. Endogenous digoxinlike immunoreactive substances (EDLISs) have been described in infants, in women in the third trimester of pregnancy, and in patients with renal and hepatic failure.29,32,33,38,40,50,83,84 When EDLISs are free or weakly bound, as in these circumstances, they are measurable by the

typical RIA and can account for factitiously high reported serum digoxin concentrations in the absence of digoxin treatment. The role of EDLIS in the body has not been fully elucidated, but it does have an effect on both the Na+- K+-ATPase pump and the cardioactive steroid receptor site. 33 EDLISs are implicated as a causative factor in hypertension and renal disease. Exogenous factors relate primarily to measurement techniques and interpretation. 42 Digoxin is metabolized to compounds with varying levels of cardioactivity.45 Some metabolites cross-react and are measured by RIA, while others are not. The in vivo production of these metabolites varies in patients, and may depend on intestinal metabolism by gut flora as well as renal and liver clearance.

Role of Digoxin-Specific Antibody Fragments with other Cardioactive Steroids Digoxin-specific antibody fragments were designed to have highaffinity binding for digoxin and digitoxin. There are structural similarities, however, between all cardioactive steroids. In fact, RIA-determined digoxin concentrations have been reported in patients following poisoning with nondigoxin cardioactive steroids,27,47,61 suggesting that cross-reactivity exists between digoxin-specific antibody fragments and other cardioactive steroids. Thus, digoxin-specific antibody fragments may have some efficacy in all natural cardioactive steroid poisonings, including oleander, yellow oleander, squill, and toad venom.3,9,10,14,26,28,63 In vitro studies also suggest the binding affinity of Digibind for cardioactive steroids.18,19,58 P.987 The successful reversal, by Digibind, of cardiotoxicity resulting from ingestion of Nerium oleander was reported.72 This patient responded to 5 vials (200 mg) of Fab, but larger doses may be

required in other cardioactive steroid poisonings because of the lower affinity binding of Digibind for these toxins. DigiFab is expected to have similar affinity binding toward cardioactive steroids. Both products are polyclonal, contributing to their broad spectrum of affinity for nondigoxin cardioactive steroids. Treatment decisions should be based on empirical grounds, with initial therapy consisting of 10–20 vials. Subsequent doses can be based on clinical response.

References 1. Antman EM, Wenger TL, Butler VP, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin specific Fab antibody fragments: Final report of multicenter study. Circulation 1990;81:1744–1752. 2. Argyle JC: Effect of digoxin antibodies on TDX digoxin assay. Clin Chem 1986;32:1616–1617. 3. Barrueto F Jr, Jortani SA, Valdes R Jr, et al: Cardioactive steroid poisoning from an herbal cleansing preparation. Ann Emerg Med 2003;41:396–399. 4. Beller GA, Smith TW, Abelmann WH, et al: Digitalis intoxication: A prospective clinical study with serum level correlations. N Engl J Med 1971;284:989–997. 5. Berkovitch M, Akilesh MR, Gerace R, et al: Acute digoxin overdose in a newborn with renal failure: Use of digoxin immune Fab and peritoneal dialysis. Ther Drug Monit 1994;16:531–533. 6. Bismuth C, Gaultier M, Conso F, et al: Hyperkalemia in acute

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7. Borron S, Bismuth C, Muszynski J: Advances in the management of digoxin toxicity in the older patient. Drugs Aging 1997;10:18–33. 8. Bosse GM, Pope TM: Recurrent digoxin overdose and treatment with digoxin-specific Fab antibody fragments. J Emerg Med 1994;12:179–185. 9. Brubacher J, Lachmanen D, Ravikumar PR, Hoffman RS: Efficacy of digoxin specific Fab fragments (Digibind) in the treatment of toad venom poisoning. Toxicon 1999;37:931–942. 10. Brubacher J, Ravikumar P, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 1996;110:1282–1288. 11. Butler VP, Chen J: Digoxin specific antibodies. Proc Natl Acad Sci U S A 1967;57:71–78. 12. Butler VP, Schmidt DH, Smith TW, et al: Effects of sheep digoxin specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs. J Clin Invest 1977;59:345–359. 13. Butler VP, Smith TW, Schmidt DH, et al: Immunological reversal of the effects of digoxin. Fed Proc 1977;36:2235–2241. 14. Cheung K, Urech R, Taylor L, et al: Plant cardiac glycosides

and digoxin Fab antibody. J Pediatr Child Health 1991;27:312–313. 15. Colucci R, Choses M, Kluger J, et al: The pharmacokinetics of digoxin immune Fab, total digoxin and free digoxin in patients with renal impairment [abstract]. Pharmacotherapy 1989;9:175. 16. Curd J, Smith TW, Jaton J, et al: The isolation of digoxin specific antibody and its use in reversing the effects of digoxin. Proc Natl Acad Sci U S A 1971;68:2401–2406. 17. D'Angio RG, Stevenson JG, Lively BT, et al: Therapeutic drug monitoring: Improved performance through educational intervention.

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37. Jortani S, Pinar A, Johnson N, Valdes R: Validity of unbound digoxin measurements by immunoassays in presence of antidote (Digibind). Clin Chim Acta 1999;283:159–169. 38. Karboski JA, Godley PJ, Frohna PA, et al: Marked digoxin like immunoreactive factor interference with an enzyme immunoassay. Drug Intell Clin Pharm 1988;2:703–705. 39. Kaufman J, Leikin J, Kendzierski D, Polin K: Use of digoxin Fab immune fragments in a seven-day-old infant. Pediatr Emerg Care 1990;6:118–121. 40. Kelly RA, O'Hara DS, Canessa MG, et al: Characterization of digitalis like factors in human plasma. J Biol Chem 1985;260:11396–11405. 41. Koren G, Deatie D, Soldin S: Agonal elevation in serum digoxin concentrations in infants and children long after cessation of therapy. Crit Care Med 1988;16:793–795. 42. Koren G, Parker R: Interpretation of excessive serum concentrations of digoxin in children. Am J Cardiol 1985;55:1210–1214. 43. Lechat P, Mudgett-Hunter M, Margolies M, et al: Reversal of lethal digoxin toxicity in guinea pigs using monoclonal antibodies and Fab fragments. J Pharmacol Exp Ther 1984;229:210–215. 44. Lemon M, Andrews DJ, Binks AM, et al: Concentrations of free serum digoxin after treatment with antibody fragments. Br Med J 1987;295:1520–1521.

P.988 45. Lindenbaum J, Rund D, Butler VP, et al: Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. N Engl J Med 1981;305:789–794. 46. Lloyd BL, Smith TW: Contrasting rates of reversal of digoxin toxicity by digoxin: Specific IgG and Fab fragments. Circulation 1978;58:280–283. 47. Marchlinski FE, Hook BG, Callans DJ: Which cardiac disturbances should be treated with digoxin immune Fab (ovine) antibody? Am J Emerg Med 1991;9:24–34. 48. Marcus L, Margel S, Savin H, et al: Therapy of digoxin intoxication in dogs by specific hemoperfusion through agarose polyacrolein microsphere beads: Heart J 1985;110:30–39.

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Am

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52. Nollet H, Verhaaren H, Stroobandt R, et al: Delayed elimination of digoxin antidotum determined by RIA. J Clin Pharmacol 1989;29:41–45. 53. Nuwayhid N, Johnson G: Digoxin elimination in a functionally anephric patient after digoxin specific Fab fragment therapy. Ther Drug Monit 1989;11:680–685. 54. Ocal I, Green T: Serum digoxin in the presence of Digibind: Determination of digoxin by the Abbott AxSYM and Baxter Stratus II immunoassays by direct analysis without pretreatment of serum samples. Clin Chem 1998;44:1947–1950. 55. Ordog GJ, Benaron S, Bhasin V: Serum digoxin levels and mortality in 5100 patients. Ann Emerg Med 1987;16:32–39. 56. Osterloh J, Herold S, Pond S: Oleander interference in the digoxin radioimmunoassay in a fatal ingestion. JAMA 1982;247:1596–1597. 57. Postmarketing

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60. Rainey P: Digibind and free digoxin. Clin Chem 1999;5:719–721. 61. Renard C, Grene-Lerouge N, Beau N, et al: Pharmacokinetics of digoxin-specific Fab: Effects of decreased renal function and age. Br J Clin Pharmacol 1997;44:135–138. 62. Renard C, Weinling E, Pau B, Schermann JM: Time and dose-dependent digoxin redistribution by digoxin-specific antigen binding fragments in a rat model. Toxicology 1999;137:117–127. 63. Safadi R, Levy I, Amitai Y, Caraco Y: Beneficial effect of digoxin-specific Fab antibody fragments in oleander intoxication. Arch Intern Med 1995;155:2121–2125. 64. Savin H, Marcus L, Margel S, et al: Treatment of adverse digitalis effect by hemoperfusion through columns with antidigoxin antibodies bound to agarose polyacrolein microsphere beads. Am Heart J 1987; 113:1078–1084. 65. Schaumann W, Kaufmann B, Neubert P, et al: Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur J Clin Pharmacol 1986;30:527–533. 66. Schmidt DH, Butler VP: Immunological protection against digoxin toxicity. J Clin Invest 1971;50:866–871. 67. Schmidt DH, Butler VP: Reversal of digoxin toxicity with specific antibodies. J Clin Invest 1971;50:1738–1744.

68. Schmidt TA, Holm-Nielsen P, Kjeldsen K: Human skeletal muscle digitalis glycoside receptors (Na,KATPase)—Importance during digitalization. Cardiovasc Drugs Ther 1993;7:175–181. 69. Schmidt TA, Kjeldsen K. Enhanced clearance of specifically bound digoxin from human myocardial and skeletal muscle samples by specific digoxin antibody fragments: Subsequent complete digitalis glycoside receptor (Na,K-ATPase) quantification. J Cardiovasc Pharmacol 1991;17:670–677. 70. Schmitt K, Tulzer G, Hackel F, et al: Massive digitoxin intoxication treated with digoxin-specific antibodies in a child. Pediatr Cardiol 1994;15:48–49. 71. Sherron PA, Gelband H: Reversal of digoxin toxicity with Fab fragments in a pediatric patient with acute renal failure. Paper presented at Management of Digitalis Toxicity: The Role of Digibind, San Francisco, July 26–28, 1985. Burroughs Wellcome, sponsor. 72. Shumaik GM, Wu AU, Ping AC: Oleander poisoning: Treatment with digoxin-specific Fab antibody fragments. Ann Emerg Med 1988;17:732–735. 73. Sinclair AJ, Hewick DS, Johnston PC, et al: Kinetics of digoxin and anti-digoxin antibody fragments during treatment of digoxin toxicity. Br J Clin Pharmacol 1989;28:352–356. 74. Smith TW: New advances in the assessment and treatment of digitalis toxicity. J Clin Pharmacol 1985;25:522–528.

75. Smith TW, Haber E, Yeatman L, et al: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797–800. 76. Smith TW, Lloyd BL, Spicer N, et al: Immunogenicity and kinetics of distribution and elimination of sheep digoxin specific IgG and Fab fragments in the rabbit and baboon. Clin Exp Immunol 1979;36:384–396. 77. Soldin S: Digoxin: Issues and controversies. Clin Chem 1986;32:5–12. 78. Ujhelyi MR, Colucci RD, Cummings DM, et al: Monitoring serum digoxin concentrations during digoxin immune Fab therapy. Ann Pharmacother 1991;25:1047–1049. 79. Ujhelyi MR, Robert S: Pharmacokinetic aspects of digoxinspecific Fab therapy in the management of digitalis toxicity. Clin Pharmacokinet 1995;28:483–493. 80. Ujhelyi MR, Robert S, Cummings DM, et al: Disposition of digoxin immune Fab in patients with kidney failure. Clin Pharmacol Ther 1993;54:388–394. 81. Ujhelyi MR, Robert S, Cummings DM, et al: Influence of digoxin immune Fab therapy and renal dysfunction on the disposition of total and free digoxin. Ann Intern Med 1993;119:273–277. 82. Valdes R, Jortani S: Monitoring of unbound digoxin in patients treated with antidigoxin antigen-binding fragments: A model for the future? Clin Chem 1998;44:1883–1885.

83. Vasdev S, Johnson E, Longerich L, et al: Plasma endogenous digitalis-like factors in healthy individuals and in dialysis dependent and kidney transplant patients. Clin Nephrol 1987;27:169–174. 84. Vinge E, Ekman R: Partial characterization of endogenous digoxin-like substance in human urine. Ther Drug Monit 1988;10:8–15. 85. Ward SB, Sjostrom L, Ujhelyi MR. Comparison of the pharmacokinetics and in vivo bioaffinity of DigiTAb versus Digibind. Ther Drug Monit 2000;22:599–607. 86. Wenger TL: Experience with digoxin immune Fab (ovine) in patients with renal impairment. Am J Emerg Med 1991;9:21–23. 87. Winter ME: Digoxin. In: Koda-Kimble MA, Young LY, eds: Basic Clinical Pharmacokinetics, 3rd ed. Vancouver, WA, Applied

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > E - Cardiopulmonary Medications > Chapter 63 - Methylxanthines and Selective β2Adrenergic Agonists

Chapter

63

Methylxanthines Î ²2 -Adrenergic

and Selective Agonists

Robert J. Hoffman

Figure. No Caption Available.

A 17-year-old girl presented to the emergency department reporting that she ingested thirty-five (200-mg) tablets of caffeine approximately 2 hours earlier. She complained of nausea,

vomiting, and palpitations. Her vital signs were: blood pressure, 115/66 mm Hg; pulse 142 beats/min; respiratory rate, 20 breaths/min; and temperature, 100.2°F (37.9°C). The patient was attached to a cardiac monitor. She was anxious, disoriented, and cooperative. Significant physical findings included mydriasis, tachycardia, tremor, and diaphoresis. A 12-lead ECG demonstrated a sinus tachycardia, with frequent unifocal premature ventricular contractions (PVCs). Fifty grams of activated charcoal with sorbitol was given orally, but she immediately vomited. Metoclopramide (10 mg IV) was administered, and 30 minutes later 50 g of activated charcoal with sorbitol was orally administered again, but vomiting recurred. At admission the patient's serum electrolytes were: sodium, 140 mEq/L; potassium, 3.0 mEq/L; chloride, 107 mEq/L; bicarbonate, 16 mEq/L; BUN, 8 mg/dL; creatinine, 1 mg/dL; and glucose, 248 mg/dL. One liter of 0.9% NaCl solution was administered intravenously over 30 minutes, and potassium chloride (40 mEq IV) was administered twice by infusion over 1 hour. The patient's serum electrolytes 3 hours after admission and subsequent to potassium repletion were: sodium, 141 mEq/L; potassium, 2.8 mEq/L; chloride, 110 mEq/L; and bicarbonate, 17 mEq/L. The patient continued to have a sinus tachycardia with frequent unifocal PVCs, and the blood pressure decreased to 98/50 mm Hg. Two liters of lactated Ringer solution was administered by bolus over 1 hour, and the blood pressure increased to 108/56 mm Hg. Fifty grams of activated charcoal with sorbitol was orally administered again, this time without ensuing emesis. Approximately 4 hours after presentation P.990 and 6 hours after ingestion, a serum sample for a quantitative caffeine concentration was obtained. The treating institution lacked the capability to determine a quantitative caffeine concentration, and the blood sample was sent to a reference laboratory. Serum electrolyte assays were repeated at

approximately 7 hours postingestion. Although the bicarbonate had increased to 20 mEq/L, the potassium was still 2.8 mEq/L. The patient again received potassium chloride (40 mEq IV) by infusion over 1 hour. The severity and persistence of hypotension and hypokalemia combined with a lack of intensive care capabilities necessitated transfer to the intensive care unit in a nearby children's hospital. At the receiving institution, her vital signs had improved to blood pressure, 110/64 mm Hg; pulse, 110 beats/min; respiratory rate, 18 breaths/min; and temperature, 99.0°F (37.2°C). Fifty grams of activated charcoal without sorbitol was readministered. The patient experienced anxiety and agitation that responded to lorazepam (3 mg IV). She was awakened during the night to be reevaluated and to receive another dose of activated charcoal orally. Otherwise, the patient remained sedated through the night. She awoke in the morning with a normal mental status and reported feeling ill but much improved. Repeat electrolyte assays were normal except for a potassium of 3.1 mEq/L. Her serum caffeine concentration at that time, approximately 18 hours postingestion, was 88 µg/mL. Caffeine concentration assays were repeated twice that day, with results of 56 µg/mL and 40 µg/mL, at which time further assays were deemed unnecessary. Serum electrolyte assays repeated that evening, and at all subsequent times, were normal. The patient was discharged from intensive care and admitted to a psychiatric service. The serum sample for the 6-hour caffeine concentration drawn at the initial institution was later determined to be 149 µg/mL.

Figure 63-1. Metabolism of caffeine and other methylxanthines by the hepatic P450 enzyme system.

Methylxanthines, which include caffeine (1,3,7 trimethylxanthine), theobromine (3,7-dimethylxanthine), and theophylline (1,3dimethylxanthine), are so named because they are methylated derivatives of xanthine (Fig. 63-1 ). Members of this group of plant-derived alkaloids have very similar pharmacologic properties and cause similar clinical effects. Methylxanthines are used ubiquitously throughout the world, most commonly in beverages imbibed for their stimulant, mood elevating, and fatigue abating effects. Coffea arabica and related species are used to make coffee, a beverage rich in caffeine. Cocoa and chocolate are derived from the seeds of Theobroma cacao , which contains theobromine and, to a lesser extent, caffeine. Thea sinensis , a bush native to China but now cultivated worldwide, produces leaves from which various teas, rich in caffeine and containing small amounts of theophylline and theobromine, are brewed.

Selective β2 -adrenergic agonists have been developed for the treatment of bronchoconstriction. Their selectivity has improved therapy for bronchoconstriction, allowing avoidance of the adverse effects of epinephrine, an α- and β-adrenergic agonist, as well as isoproterenol, a β1 - and β2 -adrenergic agonist. All β2 adrenergic agonists have nearly identical clinical effects and the principal differences are their pharmacokinetics. This chapter does not examine each β2 -adrenergic agonist individually; rather, they are discussed as a class. The β2 -adrenergic agonists include albuterol, bitolterol, clenbuterol, formoterol, pirbuterol, salmeterol, terbutaline, and ritodrine. P.991

Epidemiology From 1998 to 2003, the American Association of Poison Control Centers (AAPCC) reported the following trends in methylxanthine exposures. Theophylline exposures decreased from 2609 involving 20 deaths in 1998 to 861 exposures and 10 deaths in 2003. Caffeine exposures decreased from 7390 exposures in 1998 to 6086 exposures of pharmaceutical and herbal caffeine in 2003, but increased from no deaths in 1998 to 5 deaths in 2003. The decrease in theophylline exposures presumably reflects continued decrease in use of theophylline as a therapeutic agent. The number of caffeine exposures, has essentially remained stable, reflecting steady use of caffeine, particularly caffeine in substances other than coffee, tea, and soft drinks. There were 11,397 selective β2 -adrenergic agonists exposures and 1 death in 1998, and 10,501 exposures and 1 death in 2003. The number of selective β2 -adrenergic agonists exposures has remained stable, presumably from consistent use of these agents, but death remained uncommon. Chapter 130 discusses poison exposure data. The overwhelming preponderance of caffeine consumed is in

beverages, and a lesser portion in foods and tablets or capsules. Users typically seek the stimulant and psychoactive effects of caffeine. Caffeine is also increasingly advocated for use as a weight-loss agent.15 , 72 The use of guarana, a plant with a very high caffeine content, for weight loss and athletic performance enhancement, has increased dramatically in recent years. With some scientific evidence demonstrating benefit in athletic performance, caffeine is advocated as a concentration97 , 156 and “energy― booster and as athletic performance enhancer.33 , 96 Despite the limited experience with overdose from these combination preparations, formulations containing caffeine/guarana combined with ephedrine/ma huang cause illnesses such as myocardial infarctions and death. 79 Formulations containing phenylpropanolamine and caffeine, also once marketed as an anorexiant diet aid, were removed from US markets because of adverse drug events, and a demonstrated lack of benefit from the inclusion of caffeine and a sympathomimetic agent for the purpose of appetite suppression.82 (Chapter 39 discusses dietary supplements.) Medicinally, caffeine is used to treat neonatal apnea and bradycardia syndrome; as an analgesic adjuvant, particularly when combined with relatively mild analgesics such as acetaminophen, aspirin, and ibuprofen; and as an adjuvant treatment for migraine headaches, as well as postlumbar puncture headaches. Theophylline, or its water-soluble salt aminophylline, is rarely used to treat respiratory conditions. Theophylline was used to treat reversible bronchospastic airway disease, particularly asthma and chronic obstructive pulmonary disease. Theophylline was once the mainstay of therapy for such diseases, but more selective agents with fewer side effects, such as albuterol and other selective β2 adrenergic agonists, are now more commonly used. However, because antiinflammatory and other beneficial effects of theophylline have been described, its role in the treatment of pulmonary disease may again expand.102 In neonates,

theophylline and aminophylline are used similarly to caffeine to treat neonatal apnea and bradycardia syndrome. The result of such treatment is increased respiratory rate, decreased apnea, increased cardiac chronotropy and inotropy, and increased cardiac output.31 Caffeine and theophylline toxicity may result from either iatrogenic or self-administration, and acute or chronic toxicity can occur in either circumstance. Chronic toxicity from caffeine is most typically described as a result of the frequent self-administration of caffeine. A particular syndrome associated with chronic caffeine use consisting of headache, palpitations, tachycardia, insomnia, and delirium is termed caffeinism . Chronic theophylline toxicity results from the use of theophylline as a medicinal therapeutic agent. Neonates receiving caffeine therapy may develop either acute or chronic caffeine toxicity.7 , 17 Most reported cases of theobromine poisoning occur in animals and typically result from small animals ingesting cocoa or chocolate.50 , 54 , 80 Theobromine has become an ingredient of numerous “energy― drinks used for stimulation and athletic enhancement. No reports of human toxicity exist, but it would not be unexpected if toxicity from these sources are soon reported. Use of β2 -adrenergic agonists is widespread. Adverse effects are associated with both therapeutic dosing and overdose. Excessive use of β2 -adrenergic agonists can result in tachyphylaxis, a phenomenon in which downregulation of receptors occurs and the effects from this drug diminishes as a result of excessive use.43 , 92 Consequently, patients may require higher doses to achieve the same clinical effect they previously experienced at lower doses, resulting in more profound systemic side effects. The most common manifestation of selective β2 -adrenergic agonist toxicity occurs in children who ingest oral albuterol. Toxicity of terbutaline and ritodrine are infrequent but well-reported.

Pharmacology Methylxanthines Methylxanthines cause the release of endogenous catecholamines, resulting in stimulation of β1 and β2 receptors. The resulting adrenergic agonism is important in both their therapeutic effects and in their toxicity.179 Levels of endogenous catecholamines are extremely elevated in patients with acute methylxanthines poisoning.21 Methylxanthines are structural analogs of adenosine and also function pharmacologically as adenosine antagonists. Adenosine believed to modulate histamine release and cause bronchoconstriction, which may explain the clinical efficacy of adenosine antagonists in the treatment of bronchospasm.

is

Additionally, adenosine antagonism results in release of norepinephrine, and to a lesser extent epinephrine. At supratherapeutic doses, methylxanthines also inhibit phosphodiesterase, the enzyme responsible for degradation of intracellular cyclic adenosine monophosphate (cAMP). Phosphodiesterase inhibition was long considered to be the primary therapeutic mechanism of the methylxanthines, but clinically significant elevations in cAMP levels are not achieved until serum methylxanthine levels are well above the therapeutic range. This likely occurs as a result of the structural similarity of cAMP and methylxanthines. cAMP is involved in the postsynaptic second messenger system of β-adrenergic stimulation. Thus, elevated cAMP levels cause clinical effects similar to adrenergic stimulation, including smooth muscle relaxation, peripheral vasodilation, myocardial stimulation, and CNS excitation.

Selective Selective

β2

-Adrenergic

Agonists

β2 -adrenergic agonists act quite specifically at β2 -

adrenergic receptors, resulting in an increase in intracellular cAMP. The effects of β2 agonism include relaxation of vascular, bronchial, and uterine P.992 smooth muscle, glycogenolysis in skeletal muscle, and hepatic glycogenolysis and gluconeogenesis. These receptors are located in other areas, such as type II alveolar cells, mast cells, and lymphocytes, but their significance is unknown. Selective β2 adrenergic agonists are characterized as either directly activating the β2 receptor, such as albuterol, being taken up into a membrane depot, such as formoterol, or interacting with a receptor-specific auxiliary binding site, such as salmeterol. These differences do not appear to be relevant in acute toxicity.95

Pharmacokinetics

and

Toxicokinetics

Caffeine Pharmacokinetics Caffeine is bioavailable by oral, intravenous, subcutaneous, intramuscular, and rectal routes of administration. Oral administration, which is by far the most common route of exposure, results in nearly 100% bioavailability of the drug. The presence of food in the gut does little to affect peak concentration. However, food in the gut does delay time until the peak plasma concentration is reached, which is typically 30–60 minutes in the absence of food. Caffeine rapidly diffuses into the total body water and all tissues, and readily crosses the blood–brain barrier and the placenta. The volume of distribution is 0.6 L/kg, and 36% is protein bound. Caffeine is secreted in breast milk. 177 Caffeine exhibits Michaelis-Menten kinetics and is metabolized via the microsomal cytochrome P450 (CYP) system, primarily by the isozyme CYP1A2. The major pathway involves demethylation to

1,7-dimethylxanthine (paraxanthine) followed by hydroxylation or repeated demethylation followed by hydroxylation. To a lesser extent, caffeine is also metabolized to 3,7-dimethylxanthine (theobromine) and 1,3-dimethylxanthine (theophylline). Neonates demethylate caffeine, producing theophylline, and also possess the unique ability to convert theophylline to caffeine by methylation.3 , 11 , 12 , 30 , 67 , By approximately 4–7 months of age, infants metabolize and eliminate caffeine in a manner similar to adults.10 All people metabolize some quantity of caffeine to active metabolites, including theophylline and theobromine. The degree to which this occurs is dependent on the age, cytochrome P450 enzyme induction status, and other factors. For this reason, there may be a role for assessment of serum theophylline concentration in the management of patients with suspected caffeine overdose, but such role is not clearly defined and obviously limited. Less than 5% of caffeine is excreted in the urine unchanged. The half-life of caffeine is highly variable and dependent on several factors. Generally speaking, younger patients, particularly infants, as well as patients with cytochrome P450 inhibition, such as pregnant patients and patients with cirrhosis, have longer caffeine half-lives than the 4.5-hour half-life in healthy, adult, nonsmoking patients.32 , 47 , 51 , 171

Toxicokinetics Caffeine toxicity is a dose-dependent phenomenon. Unfortunately, the range of toxicity reported in different references varies greatly, and no definite conclusions can be drawn regarding serum levels and symptomatology in overdose. Therapeutic dosing in adults is 100–200 mg orally every 4 hours; in neonates, a typical loading dose is 20 mg/kg, with daily maintenance dosing of 5 mg/kg. Based on case reports and series, lethal dosing in adults is estimated at 150–200 mg/kg, and death is associated with serum concentrations >80 µg/mL. Although numerous fatalities

occur with serum concentrations 400 µg/mL is also reported.175 Infants survive toxicity with greater serum concentrations of caffeine than are tolerated by children and adults.

Theophylline Pharmacokinetics Theophylline is approximately 100% bioavailable by the oral route. Many of the available oral preparations are sustained-release, designed to provide stable serum concentrations over a prolonged period with less-frequent dosing. Peak absorption generally occurs 6–10 hours after ingestion. However, following overdose of sustained-release preparations, the time to peak absorption may take twice as long as that of the immediate release preparations. Similar to caffeine, theophylline rapidly diffuses into the total body water and all tissues, readily crosses the blood–brain barrier and placenta, and is secreted into breast milk.14 , 104 , 190 , 192 Theophylline's volume of distribution is 0.5 L/kg, and 56% of it is protein bound. Theophylline is metabolized via the microsomal cytochrome P450 system, primarily by the isozyme CYP1A2. The major pathway is demethylation to 3-methylxanthine, in addition to being demethylated or oxidized to other metabolites. Less than 10% of theophylline is excreted in the urine unchanged. Similar to caffeine, the half-life of theophylline is highly variable, and is dependent on several factors. In healthy, adult, nonsmoking patients, the half-life is 4.5 hours. Theophylline's half-life in infants and the elderly, as well as in patients with cytochrome P450 inhibition, pregnant patients, and patients with cirrhosis, is longer than in healthy children and adult nonsmoking patients.88 ,

117 , 170

Factors that induce cytochrome P450, such as cigarette smoking, and others that inhibit cytochrome P450, such as exposure to cimetidine, erythromycin, and oral contraceptives, can significantly alter theophylline clearance.75 , 116 , 131 , 132 , 147 , 181 Decreased theophylline or caffeine metabolism or reversal of enzyme induction predisposes to the development of chronic toxicity.

Toxicokinetics Like caffeine, theophylline exhibits Michaelis-Menten kinetics.146 At higher doses and in overdose, it undergoes zero-order elimination, and only a fixed amount of the drug can be eliminated in a given time because of saturation of metabolic enzymes.144 Therapeutic serum concentrations of theophylline are 5–15 µg/mL; higher concentrations are considered toxic. Morbidity and mortality occur with relatively lower concentrations in chronic toxicity. Although morbidity and mortality are not always predictable based on serum concentrations, life-threatening toxicity, including seizures, ventricular dysrhythmias, and death, is associated with serum concentrations of 80–100 µg/mL in acute overdoses and serum concentrations of 40–60 µg/mL in chronic toxicity.

Theobromine As is the case with the other methylxanthines, theobromine is well absorbed from the gut, and is 80% bioavailable when administered in solution. It is bioavailable orally, intravenously, and rectally. Theobromine has 21% protein binding, a volume of distribution of 0.62 L/kg, and a plasma half-life of 6–10 hours.55 , 141 Theobromine undergoes hepatic metabolism by the CYP system similarly to P.993 caffeine

and

theophylline.29

Like the other methylxanthines,

theobromine is excreted in breast milk, and consumption of chocolate results in measurable concentrations in breast milk. Toxic concentrations of theobromine in animals are known, but comparable human data is lacking.

Selective

β2

-Adrenergic

Agonists

Pharmacokinetics These agents are used inhalationally, orally, and parenterally. They are bioavailable by both the inhalational and enteral route, and much of “inhaled― β2 -adrenergic agonists may actually be swallowed and absorbed from the GI tract. Absorption, distribution, and elimination vary among these agents. The halflife of albuterol is approximately 4 hours. Less than 5% crosses the blood–brain barrier. It is metabolized extensively in the liver, and excreted in urine and feces as albuterol and metabolites.2 Terbutaline is partially metabolized in the liver, mainly to inactive conjugates. With parenteral administration, 60% of a given dose is excreted in the urine unchanged.1

Toxicokinetics Ingestion of β2 -adrenergic agonists, which happens predominantly in young children treated with oral albuterol preparations, can cause significant symptomatology.101 For oral albuterol poisoning, 1 mg/kg appears to be the dose threshold for developing significant toxicity.186

Methylxanthine

Pathophysiology

Caffeine, theobromine, and theophylline affect the same organ systems and cause qualitatively similar effects.

It should be noted, however, that there are distinct differences in the activity and effects of the various methylxanthines, particularly in therapeutic dose. The major clinical effects at both therapeutic doses and in overdose result from adenosine antagonism, release of endogenous norepinephrine and consequent β-adrenergic receptor stimulation, and phosphodiesterase inhibition. Toxicity affects the gastrointestinal, cardiovascular, central nervous, and musculoskeletal systems, in addition to causing a constellation of metabolic derangements. Polypharmacy poisoning with methylxanthines and other agents that result in adrenergic stimulation, such as ephedrine, amphetamines, or cocaine, may be particularly severe.52 , 184 Theobromine toxicity is exceedingly rare. There are limited human data, and most published cases are actually veterinary. Animals with theobromine poisoning may experience emesis, incontinence, restlessness, excitement, tachycardia, seizures, coma and death. These characteristic symptoms, as well the pharmacologic similarity between theobromine and other methylxanthines, dictates that management principles for caffeine and theophylline be applied in cases of theobromine toxicity.

Toxicity Gas tr ointes tinal In overdose, methylxanthines cause nausea, and most significant acute overdoses result in severe and protracted emesis. Emesis occurs in 75% of cases of acute theophylline poisoning, whereas only 30% of cases of chronic poisoning are characterized by emesis.163 This emesis is often quite severe and may be difficult to control despite the use of potent antiemetics. This is especially evident with sustained-release theophylline preparations.5 Methylxanthines cause an increase in gastric acid secretion and smooth muscle relaxation. These factors contribute to the gastritis

and esophagitis reported in chronic methylxanthine users.42 Gastritis is noted in drinkers of decaffeinated coffee, so some of the adverse gastric effects associated with coffee drinking may be a result of ingredients other than caffeine alone.

Cardiovascular Methylxanthines are cardiac stimulants that result in positive inotropy and chronotropy. Dysrhythmias, particularly tachydysrhythmias, are common in methylxanthine overdose. As a result of their adenosine antagonism, supraventricular tachycardias (SVTs) commonly occur in overdose. Tachydysrhythmias, particularly ventricular extrasystoles, are uncommon following therapeutic doses, whereas they are common in overdose.39 , 124 , 157 In the setting of acute poisoning, generally benign sinus tachycardia is nearly universal in patients without antecedent cardiac disease. In any patient, particularly a patient with underlying cardiac disease, a sinus tachycardia can degenerate to a more severe rhythm disturbance, which is the most common cause of fatality associated with methylxanthines poisoning. Both atrial and ventricular dysrhythmias including SVT, multifocal atrial tachycardia, atrial fibrillation, premature ventricular contractions, and ventricular tachycardia, can result from methylxanthine toxicity.20 , 160 Electrolyte disturbances, particularly hypokalemia, may be a contributing factor in the development of dysrhythmias. Dysrhythmias occur more commonly and at lower serum concentrations in cases of chronic poisoning. Consequential dysrhythmias occur in 35% of chronic theophylline poisonings, but in only 10% of acute poisonings.160 These dysrhythmias occur at serum levels of 40–80 µg/mL in chronic theophylline overdoses, and most commonly at serum levels greater than 80 µg/mL in acute overdose. Neonates born to mothers who consumed >500 mg/d of caffeine are more likely to have dysrhythmias than are neonates born to mothers who consumed 100 µg/mL are usually associated with severe hypotension. In therapeutic doses, methylxanthines cause cerebral vasoconstriction, which is a desirable effect when caffeine is used to treat a migraine headache. However, in overdose, this effect likely exacerbates CNS toxicity by diminishing cerebral perfusion.119 Methylxanthines cause renal vasodilation, which, in addition to the increased cardiac output, results in a mild diuresis.133 It has been noted that dietary caffeine use is associated with a slight, but relevant, increase in blood pressure that may contribute to population levels of morbidity and mortality.91

Pulmonary Methylxanthines stimulate the CNS respiratory center, causing an increase in respiratory rate. For this reason, caffeine and theophylline are used to treat neonatal apnea syndromes. Caffeine and theophylline overdose can cause hyperventilation, respiratory alkalosis, respiratory failure, respiratory arrest, and acute lung injury. P.994

N europsychi atr ic

The stimulant and psychoactive properties of methylxanthines, particularly caffeine, elevate mood and improve performance of manual tasks.24 , 34 , 90 These stimulant effects are typically considered desirable, and are one reason why caffeine is so widely used. CNS stimulation is an effect sought by users of coffee, tea, cocoa, and chocolate, but CNS stimulation resulting from therapeutic use of theophylline is generally considered to be an undesirable side effect. Caffeine is an effective analgesic adjuvant, possibly because of the stimulant properties of the drug.123 , 125 , 154 , 155

Although at low doses methylxanthines improve cognitive performance and elevate mood, with increasing doses they result in adverse effects. Headache, anxiety, agitation, insomnia, tremor, irritability, hallucinations, and seizures can occur with caffeine or theophylline poisoning. In adults, caffeine doses of 50–200 mg result in increased alertness, decreased drowsiness, and lessened fatigue, and caffeine doses of 200–500 mg produce adverse effects. Children tend to develop CNS symptoms at lower serum theophylline concentrations than adults, and this excitation is a significant clinical disadvantage of theophylline use. Seizures are a major complication of methylxanthine poisoning. The additional methyl group possessed by caffeine (1,3,7trimethylxanthine) affords this agent greater CNS penetration relative to theophylline and theobromine, which are dimethylxanthines. Caffeine's ability to both promote and prolong seizures is well recognized, and caffeine has been used to prolong therapeutically induced seizures in electroconvulsive therapy.49 , 99 Seizures resulting from methylxanthines overdose tend to be severe and recurrent, and may be refractory to treatment. Antagonism of adenosine, the endogenous neurotransmitter responsible for halting seizures, contributes to the profound seizures associated with methylxanthine overdose.56 , 62 , 161 , 191

When studied prospectively, chronic theophylline toxicity results in seizures in 14% of patients, whereas 5% of acutely poisoned patients experience seizures. In cases of chronic and acute-onchronic toxicity, seizures are more likely to occur, and they typically occur at lower serum concentrations.135 Patients at extremes of age, younger than 3 years and older than 60 years, are also more likely to experience seizures with overdose.

Musculoskeletal Methylxanthines increase intracellular calcium content and increase striated muscle contractility, secondarily decreasing muscle fatigue. They also increase muscle oxygen consumption and increase the basal metabolic rate. These effects are sought by users of methylxanthines to enhance or improve athletic performance or lose weight.9 , 18 , 41 , 57 , 71 , 70 Theobromine has the most potent activity on the muscles, over 100 times that of caffeine, and theophylline has the least muscle-stimulating activity. All methylxanthines cause smooth muscle relaxation. Tremor is the most common adverse effect from methylxanthines. Skeletal muscle excitation, which hypertonicity, myoclonus, or even methylxanthine overdose.105 , 115 which rhabdomyolysis may result

may include fasciculation, rhabdomyolysis, can occur with , 137 , 149 , 189 Mechanisms by include increased muscle

activity, particularly from seizures, and direct cytotoxicity from excessive sequestered intracytoplasmic calcium. Interestingly, there are multiple case reports of compartment syndrome with rhabdomyolysis resulting from theophylline overdose.114 , 176

Metabolic Numerous metabolic derangements may result from acute methylxanthine toxicity, and are similar to other states of excess adrenergic agonism or increased metabolism.75 , 78 , 153 , 162

Severe hypokalemia can result from β2 -adrenergic stimulation.178 This results from influx of extracellular potassium into the intracellular compartment despite normal total body potassium content. Both electrocardiographic and neuromuscular complications of hypokalemia may develop. Other effects of β2 adrenergic agonist poisoning include hypomagnesemia, hypophosphatemia.28 , 101 , 183 Transient hypokalemia resulting from β2 -adrenergic agonism occurs in 85% of patients with acute theophylline overdose, and typically the serum potassium concentration falls to approximately 3 mEq/L.4 , 165 Stimulation of Na+ -K+ -adenosine triphosphatase (ATPase) results in a shift of serum potassium to the intracellular compartment of skeletal muscle. This hypokalemia is only a shift of potassium from the extracellular to the intracellular compartment, not a loss of potassium, and total body potassium stores are unchanged. The significance of hypokalemia in patients with methylxanthine overdose is unclear. Vomiting and renal losses do not contribute significantly to hypokalemia, but these may result in fluid loss. Hyperkalemia may result from overly aggressive repletion of potassium or from rhabdomyolysis. Metabolic acidosis with increased serum lactate levels is commonly noted as a complication of theophylline overdose.23 , 109 Tachypnea and respiratory alkalosis secondary to stimulation of the respiratory center may be contributory. Hyperglycemia, with serum glucose of approximately 200 mg/dL, is common and occurs in 75% of acute theophylline overdoses. Hypophosphatemia, hypomagnesemia, hypocalcemia, hypercalcemia, and ketosis may also result from methylxanthines toxicity.151 Hyperthermia caused by increased metabolic and muscle activity may result from caffeine and theophylline overdose. Leukocytosis, probably secondary to the high levels of circulating catecholamines, results from acute methylxanthine overdose. This phenomenon apparently lacks clinical significance.

In the absence of seizures or protracted emesis, chronic methylxanthine poisoning does not typically lead to metabolic derangements because such toxicity is an ongoing, compensated process.

Chronic

Toxicity

The major difference between acute and chronic toxicity is the duration of exposure to the drug. Patients with chronic toxicity may manifest subtle signs such as anorexia, nausea, palpitations, or emesis, although they may also present with seizures or dysrhythmias. The patient chronically receiving theophylline or caffeine has higher total body stores, and also often has underlying medical disorders, and may develop toxicity with a smaller amount of additional theophylline or caffeine. Chronic methylxanthine poisoning typically occurs in the setting of therapeutic use of theophylline, and caffeine or from products. Patients anorexia, nausea,

may occur with iatrogenic administration of frequent, chronic consumption of caffeinated often manifest subtle signs of illness, such as palpitations, or emesis. However, the initial

presentation in these patients, even with theophylline concentrations in the 40–60 µg/mL range, may be a seizure. In children chronically overdosed with theophylline, the peak serum theophylline concentration may fail to identify those who will progress to life-threatening toxicity. In the absence of protracted emesis or seizures, the initial electrolytes and blood gases are expected to be normal in patients with chronic methylxanthine toxicity.

Chronic

Use

An inconclusive link to cancer, heart disease, osteoporosis, hyperlipidemia, and hypercholesterolemia are associated with

caffeine P.995 use.60 , 63 , 74 , 145 , 187 containing

beverages

Excessive consumption of can cause hypokalemia.148

caffeine-

Debate centers on the psychiatric and cognitive effects of chronic theophylline use, particularly in children. 113 To date, evidence suggests that although theophylline may acutely result in excessive CNS stimulation and hyperactivity, chronic use of methylxanthines does not adversely affect children's cognitive development.19

Caffeinism Caffeinism is a syndrome of chronic toxicity resulting from excessive caffeine consumption. It may involve anxiety, palpitations, tremulousness, tachycardia, diuresis, headache, and diarrhea.180 Patients suffering caffeinism also experience withdrawal symptoms upon abstinence. The chronic toxicity from excessive caffeine use, caffeinism, is a distinctly different entity from caffeine withdrawal.

Caffeine

Withdrawal

Caffeine induces tolerance and a withdrawal syndrome, including headache, yawning, nausea, drowsiness, rhinorrhea, lethargy, irritability, nervousness, a disinclination to work, and depression, may result on abstinence.173 Caffeine withdrawal symptoms are described in neonates born to mothers with consequential caffeine use.121 The onset of caffeine withdrawal symptoms begins 12–24 hours after cessation of caffeine use, and lasts up to 1 week.73 In a double-blind trial, 52% of adults with moderate caffeine intake developed a withdrawal syndrome on caffeine abstinence.168

Reproduction Massive doses of methylxanthines are teratogenic, but the doses of typical use are not associated with birth defects. Decreased fecundity and adverse fetal outcome are noted in animals with chronic exposure to methylxanthines.64 , 68 , 120 Human studies of fertility, fetal loss, and fetal outcome produce divergent results, and the effects of methylxanthines use during gestation are unclear.87 , 94 , 126 , 130

Selective β2 -Adrenergic Pathophysiology

Agonist

Gastrointestinal Nausea and emesis are common adverse effects of selective β2 adrenergic agonist toxicity. Gastrointestinal symptoms of selective Î ²2 -adrenergic agonist toxicity are not as severe as those resulting from methylxanthine toxicity and are not expected to require antiemetic therapy.

Cardiac These drugs increase chronotropy and, in both therapeutic dose and overdose, result in tachycardia. Cardiac dysrhythmias, although described with β2 -adrenergic agonist poisoning, are usually supraventricular in origin and clinically inconsequential. Dysrhythmias other than sinus tachycardia should not be routinely attributed to β2 adrenergic agonist toxicity until other causes have been excluded. Myocardial infarction is associated with both albuterol and isoproterenol.58 Isoproterenol, once a common asthma therapy prior to widespread use of selective β2 -adrenergic agonists, has Î ²1 - and β2 -adrenergic agonist activity and is a well-reported

cause of myocardial infarction. Given the frequency of use of selective β2 -adrenergic agonists, as well as toxicity and adverse effects, it seems that myocardial infarction is unlikely to occur with toxicity, but these reports clearly warrant caution about the possibility. Elevation of the muscle fraction enzyme of creatine phosphokinase (CPK-MM) and of the myocardial band enzymes of creatine phosphokinase (CPK-MB) after large doses of β2 -adrenergic agonists, particularly terbutaline infusions and continuous albuterol nebulization, is well described.44 , 45 , 174 The clinical significance of increased CPK-MB and cardiac troponin in patients receiving terbutaline infusions is unclear and has not been demonstrated to correlate clinically with adverse effects.40

Metabolic Severe hypokalemia can result from β2

-adrenergic

stimulation

because of an influx of extracellular potassium into the intracellular compartment, despite normal total body potassium content. Both electrocardiographic and neuromuscular complications of hypokalemia may develop. This hypokalemia is only a shift of potassium from the extracellular to the intracellular compartment, not a loss of potassium, and total body potassium stores are unchanged. Other effects of β2 -adrenergic poisoning include hypomagnesemia and hypophosphatemia.

Diagnostic

Testing

An ECG, serum electrolytes, and a serum caffeine or theophylline concentration, as appropriate, are indicated in cases of suspected methylxanthine toxicity. Because toxicity is dose related in acute overdose, serum concentrations of caffeine and theophylline may be loosely applied as a correlate with toxicity. Some degree of methylation and demethylation of methylxanthines

may occur in patients of all ages, and one methylxanthine poisoning may result in a small elevation in the serum concentration of another methylxanthine metabolite. Overdose of caffeine may result in a spuriously elevated serum measurement for theophylline.59 , 95 However, the utility of a serum theophylline concentration in cases of caffeine toxicity is undemonstrated; consequently, at this time, such concentrations should not be obtained. Theophylline concentrations, and to a lesser extent caffeine concentrations, may be used to guide management of poisoning with the respective agents. For these concentrations to be maximally useful, it is important to know whether they reflect acute or chronic poisoning. In the setting of toxicity, serum methylxanthines concentrations should be obtained immediately and then serially every 1–2 hours until a downward trend is evident. Unfortunately, serum caffeine concentrations are usually readily available only in institutions in which neonates are therapeutically treated with caffeine. Serum theophylline concentration is a more readily available laboratory assay, and the greater clinical experience with theophylline in therapeutic dose and in overdose provides a more established correlation between serum theophylline concentration and symptomatology. Likewise, serum electrolytes, particularly potassium, should be monitored serially as long as the poisoned patient remains symptomatic and such values are in a range that may warrant treatment. Cardiac monitoring should continue until the patient is free of dysrhythmias other than sinus tachycardia, the patient has a decreasing serum methylxanthine level, and the patient is stable. In P.996 patients with systemic illness, hyperthermia, or increased muscle tone, assessing serum creatine phosphokinase (CPK) and urinalysis

to detect rhabdomyolysis are also indicated.

Management General Principles Decontamination

and

Gastrointestinal

After assuring adequacy of airway, breathing, and circulation, supportive care and maintenance of vital signs within acceptable limits are the mainstay of therapy for methylxanthine and selective β2 -adrenergic agonist toxicity. Decisions regarding gastrointestinal decontamination, including orogastric lavage, administration of activated charcoal, and whole-bowel irrigation, depend on the dosage and type of preparation involved, time since exposure, and the patient's physical condition. Activated charcoal is the only gastrointestinal decontamination that should be routinely considered for selective β2 -adrenergic agonist ingestions.

Emes is Induced emesis is not indicated for selective β2 -adrenergic agonist ingestion and should only rarely be considered for minimally symptomatic patients whose methylxanthine ingestions occurred less than 1 hour earlier. A simulated overdose, controlled, volunteer study with sustained-release theophylline was unable to demonstrate reduction of absorption of theophylline in patients treated with syrup of ipecac.130 Seizures are possible with any significant methylxanthine poisoning, and emesis in a patient experiencing a seizure is an obvious danger. Because the benefits of emetics are undemonstrated and emesis interferes with administration of activated charcoal, induced emesis is rarely considered for methylxanthine poisoning.6 , 158

Orogastric

Lavage

Orogastric lavage may be considered for patients with potentially toxic methylxanthine ingestions and in patients who require endotracheal intubation. Orogastric lavage may not be effective in removing theophylline tablets, probably because of the large size of the tablets relative to the lumen of the orogastric tube. Selective β2 -adrenergic agonist liquid ingestion that occurs within 1 hour prior to treatment may warrant aspiration through a nasogastric tube. Ingestion of sustained-release theophylline tablets is associated with the formation of bezoars that may be difficult to remove or dislodge. Treatment in such cases has included endoscopic removal.37

Activated

Charcoal

Activated charcoal may play an important role in the treatment of methylxanthine poisoning and selective β2 -adrenergic agonists present in the GI tract prior to absorption, limiting the absorption of a given dose. Although multiple-dose activated charcoal (MDAC) is helpful in the management of methylxanthine toxicity, it is not indicated for selective β2 -adrenergic agonist ingestion. MDAC enhances elimination of theophylline by gut dialysis. Such enhanced elimination by gut dialysis is not demonstrated, experimentally or otherwise, for caffeine or theobromine toxicity. Because caffeine is to some extent metabolized to theophylline, in cases of caffeine poisoning, MDAC would, at the very least, enhance elimination of theophylline metabolites. The pharmacologic similarity of the methylxanthines and the relative safety of MDAC therapy warrant the use of such treatment for any methylxanthine toxicity. MDAC is discussed in “Enhanced Elimination― later in this chapter.

Whole-Bowel

Irrigation

Treatment of patients with significant ingestions of sustainedrelease pills may include whole-bowel irrigation (WBI) with a balanced electrolyte solution to enhance gastrointestinal elimination (Antidotes in Depth: Whole-Bowel Irrigation and Other Intestinal Evacuants ). Polyethylene glycol electrolyte lavage solution used for WBI may displace theophylline already bound to charcoal.84 This may be a particular problem in patients who have taken several doses of activated charcoal prior to WBI, in which desorption of methylxanthines from activated charcoal can result in a bolus of methylxanthines available for gastrointestinal absorption. Also, WBI is experimentally demonstrated to provide no additional benefit to activated charcoal in treatment of sustained-released theophylline ingestion.36 Despite this data, WBI remains the recommended treatment of a patient with an ingestion of sustained-release theophylline.

Selecting

a

Method

of

Decontamination

The use of decontamination methods that involve more than minimal risk, specifically orogastric lavage, should only occur after careful consideration of the indications. Potentially life-threatening acute ingestions occurring not more than 1 hour earlier can be treated with orogastric lavage.

Treatment

of

Gastrointestinal

System

Toxicity Phenothiazine antiemetics are contraindicated in methylxanthine poisoning because they are typically ineffective and may lower the seizure threshold. Metoclopramide may be used, but a more potent 5-HT3 antagonist antiemetic such as ondansetron or granisetron may be required.48 , 142 , 152 Histamine (H2 ) blockers or proton pump inhibitors may be administered to any patient with

hematemesis. Cimetidine is contraindicated because it inhibits CYP450, delaying clearance of methylxanthines.

Treatment

of

Cardiovascular

Toxicity

Hypotension should initially be treated by administration of isotonic intravenous fluid, such as 0.9% sodium chloride solution or lactated Ringer solution, in bolus volumes of 20 mL/kg. If acceptable blood pressure cannot be maintained despite several fluid boluses, or if there are contraindications to fluid bolus, vasopressor therapy should be considered. Methylxanthine and selective β2 -adrenergic agonist toxicity may cause hypotension via β2 -adrenergic agonism, therefore administration of vasopressors with β2 -adrenergic agonist effects such as epinephrine, dobutamine, or isoproterenol are not preferable. A pure α-adrenergic agonist such as phenylephrine is the first-line pressor of choice in such a situation, although norepinephrine is also acceptable (Table 63-1 ). Hypotension may be refractory to treatment with intravenous fluid and vasopressor therapy, and in such cases the administration of a β-adrenergic antagonist may be warranted.53 Administration of a β-adrenergic antagonist to a hypotensive patient may seem counterintuitive. Methylxanthine-induced hypotension is to a significant extent mediated by β2 -adrenergic vasodilation. Nonselective β-adrenergic antagonists suppress β2 -adrenergic stimulation. In addition, β1 -adrenergic antagonism treats tachycardia and any decreased cardiac output that may result from inefficient cardiac P.997 activity. In canines with aminophylline-induced tachycardia and hypotension, administration of esmolol results in a return to normal heart rate and blood pressure, and does not exacerbate hypotension.65 Propranolol, esmolol, and metoprolol have been used successfully to treat methylxanthine-induced hypotension. 25 ,

139

It is most appropriate to use a β-adrenergic antagonist with a brief duration of action, such as esmolol at least initially, in such circumstances. In the event of an adverse reaction or side effect such as hypotension or bronchospasm, the duration of such a βadrenergic antagonist will be relatively brief. Ideally, any βadrenergic antagonist therapy should be preceded and accompanied by measurement of cardiac output and central venous blood pressure with a device such as a pulmonary artery catheter or a transcutaneous bioinpedance device.100 Cardiovascular Hypotension Vasopressors Phenylephrine Norepinephrine β-Adrenergic

antagonists

Relatively contraindicated in asthmatic Only with hemodynamic monitoring. Supraventricular dysrhythmias Calcium channel blockers β-Adrenergic antagonists Relatively contraindicated in asthmatic Only with hemodynamic monitoring. Ventricular dysrhythmias Antidysrhythmics Lidocaine

β-Adrenergic antagonists Relatively contraindicated in asthmatic Only with hemodynamic monitoring. Gastrointestinal Emesis Antiemetics

patients.

patients.

patients.

Metoclopramide Ondansetron Granisetron Hematemesis Proton pump inhibitors

H 2 antagonists Cimetidine may decrease clearance of methylxanthines and prolong toxicity. CNS Anxiety Benzodiazepine Agitation Barbiturates Seizure

prophylaxis

Propofol Seizures

Metabolic Metabolic acidosis Sodium bicarbonate Hypokalemia Potassium chloride

β-Adrenergic antagonists Not routinely recommended for this purpose.

Relatively

contraindicated

System

Indication

in

asthmatic

Therapeutics

patients. Comments

TABLE 63-1. Therapeutics for Methylxanthines and Selective β2 -Adrenergic Agonist Poisoning In situations where drug toxicity is not in question, adenosine or electrical cardioversion are the preferred treatment for SVT, but this is not so for SVT resulting from methylxanthine toxicity. Because of the antagonist effects, administration of adenosine should not be expected to convert a methylxanthine-induced SVT. However, even if adenosine is successfully used to convert an SVT, the effect is likely to be transient. Because methylxanthine toxicity has a global effect on the myocardium, cardioversion, which is effective in electrically “reorganizing― depolarization, is unlikely to work, as this SVT does not result from a single locus of aberrant electrical activity. Primary

treatment

for

methylxanthine-induced

SVT

includes

administration of benzodiazepines, which work to abate CNS stimulation and concomitant release of catecholamines. More focused pharmacologic therapy to treat SVT would be through administration of a such as diltiazem.

conduction-attenuating

calcium

channel

blocker

In animal models, treatment of acute theophylline toxicity with the calcium channel blockers verapamil, diltiazem, and nifedipine results in decreased cardiac-related deaths and prevents dysrhythmias, hypotension, myocardial necrosis, and seizures.185 In addition to their cardiovascular benefit, calcium channel blockers may also afford some neurologic protection and prevent seizures. In the nonasthmatic patient, methylxanthine-induced supraventricular tachycardia and other tachydysrhythmias may be treated by administration of a β-adrenergic antagonist.

Correction of hypokalemia may be crucial in methylxanthine poisoning associated with ventricular dysrhythmias. Hypokalemia is a well-described consequence of excess adrenergic agonism, including poisoning from methylxanthines and sympathomimetic P.998 agents. In the absence of associated dysrhythmia, the clinical significance of such hypokalemia is unclear. Such hypokalemia has been experimentally demonstrated to respond to treatment with β-adrenergic antagonists.

Treatment

of

Central

Nervous

System

Toxicity Administration of a benzodiazepine, such as diazepam or lorazepam, is appropriate treatment for anxiety, agitation, or seizure. The seizures associated with methylxanthine toxicity are severe and often refractory to treatment. Seizures not controlled with one or two therapeutic doses of a benzodiazepine should be treated with a barbiturate such as pentobarbital or phenobarbital, or another suitable sedative-hypnotic such as propofol. No delay should occur before administering such medications. Unsuccessful treatment of methylxanthine-induced seizures with any particular drug should quickly be abandoned in favor of treatment with an additional or more efficacious anticonvulsant. The administration of barbiturates may result in or exacerbate hypotension. Treatment of any aforementioned problem with benzodiazepines, barbiturates, or other sedative-hypnotic may require repeated dosing until clinical effect is achieved. Administration of phenobarbital to prevent seizures in theophylline-poisoned rabbits and mice increased survival by decreasing the incidence of seizures.46 , 69 Although historically phenobarbital was the recommended drug for such prophylaxis, use of a benzodiazepine, such as lorazepam, seems preferable. Patients at risk for seizure include patients older than 60 years or

younger than 3 years of age; those with chronic overdose and a serum concentration of 40–60 µg/mL; and acutely overdosed patients with serum levels >100 µg/mL. Phenytoin and fosphenytoin are of no benefit in controlling methylxanthine-induced seizures and they have no role in such treatment.83 , 118 Retrospective review of human cases demonstrated phenytoin to be ineffective in treating seizures in 21 of 22 cases.89 Phenytoin is ineffective in the treatment of seizures, results in the occurrence of seizures at an earlier time after overdose, and results in higher mortality when administered to

theophylline-poisoned

Treatment

of

mice.26

Metabolic

Derangements

Patients with symptomatic hypokalemia or hypocalcemia should be treated accordingly. Most cases of mild hypokalemia are well tolerated, but any patient with symptomatic hypokalemia, particularly those associated with ECG changes of T waves or QTc prolongation, should be treated. The frequency of ventricular dysrhythmias in methylxanthine poisoning, may be exacerbated by hypokalemia coupled with increased intrinsic catecholamine release. There is no specific level of hypokalemia that absolutely necessitates treatment. Cautious administration of potassium to treat symptomatic hypokalemia may be indicated, but this is distinct from higher doses of potassium used in total body potassium repletion. In cases of hypokalemia secondary to β-adrenergic agonism, after the β-adrenergic agonism returns to baseline, an efflux of potassium from the intracellular compartment occurs along with a concomitant rise of the serum potassium concentration. Overly aggressive attempts to correct hypokalemia may result in hyperkalemia after the β-adrenergic agonist effects abate. Acute methylxanthine-induced hypokalemia may be treated with potassium supplementation, but because of the nature of the

problem, excess β-adrenergic agonism, supplementation is typically ineffective.

potassium

Experimentally, administration of propranolol to theophyllinepoisoned dogs prevented or partially reversed hypokalemia, hypophosphatemia, hyperglycemia, and metabolic acidosis, as well as hypotension.98 Prevention or correction of the metabolic derangements associated with theophylline toxicity by administration of a β-adrenergic antagonist is congruent with the fact that these derangements, particularly hypokalemia, are the consequence of β-adrenergic agonism. The efficacy of βadrenergic antagonists as therapy for hypokalemia resulting from acute methylxanthine poisoning in humans has not been studied. The importance of treating hypomagnesemia, hypophosphatemia, and hypocalcemia must be addressed depending on the extent and clinical manifestation as they would for other patients experiencing them. As with hypokalemia, QTc prolongation is an absolute indication

for

treatment.

Hyperglycemia, likely resulting from increased circulating catecholamines, is common. This hyperglycemia does not necessitate treatment with any type of hypoglycemic agent, both because it is a transient effect and because, in other situations of hyperglycemia resulting from adrenergic agonism, a rebound hypoglycemia may occur.

Treatment

of

Musculoskeletal

Toxicity

The use of benzodiazepines is appropriate treatment for fasciculations, hypertonicity, myoclonus, or rhabdomyolysis. Rhabdomyolysis necessitates aggressive intravenous fluid therapy, possibly with sodium bicarbonate (Antidotes in Depth: Sodium Bicarbonate ).

Enhanced

Elimination

Fortunately, methylxanthine toxicity lends itself well to several methods of enhanced elimination, including gut dialysis with MDAC, charcoal hemoperfusion, and hemodialysis, as well as lesser-used methods such as continuous arteriovenous hemoperfusion (CAVHP), and plasmapheresis.16 , 106 , 112 Infants with methylxanthine poisoning may be too ill, unstable, or small to be treated with hemodialysis or hemoperfusion. Both MDAC and exchange transfusion are effective methods of enhanced elimination in infants, and may be the preferred method of treatment in these patients.136 , 138 , 166 , 164 The therapeutic effects of activated charcoal in such cases are much greater than simply limiting absorption of ingested methylxanthines. Activated charcoal, particularly MDAC, allows elimination of theophylline, by way of gastrointestinal dialysis.13 MDAC is extremely effective in enhancing elimination of theophylline.22 , 66 , 111 , 134 Experimentally in dogs, rabbits, and human volunteers, activated charcoal administered after IV aminophylline administration resulted in increased systemic clearance and decreased half-life of theophylline.86 , 103 , 122 , 140 The pharmacologic similarity of the methylxanthines suggest that MDAC may be effective in gut dialyzing caffeine or theobromine, and MDAC certainly will be effective in eliminating any theophylline generated from metabolism of caffeine or theobromine. The efficacy of MDAC, combined with the safety and ease with which this therapy can be administered, makes MDAC the mainstay of enhanced elimination in methylxanthine toxicity. Severe emesis associated with methylxanthine poisoning may result in intolerance of MDAC, and in case series has been shown to necessitate abandonment of MDAC for definitive enhancement of methylxanthine elimination by charcoal hemoperfusion (Antidotes in Depth: Activated Charcoal ).159 P.999 Charcoal hemoperfusion is an effective method of enhanced

elimination of methylxanthines, decreasing theophylline's half-life to 2 hours and increasing its clearance possibly up to 6-fold.35 , 129 , 150 , 188 Variations of charcoal hemoperfusion, including albumin colloid hemoperfusion, resin hemoperfusion, and charcoal hemoperfusion, in series with hemodialysis, are reported.38 , 85 , 107 , 143 , 172

Charcoal hemoperfusion in series with hemodialysis may be superior to either method alone because it extends the life of the charcoal hemoperfusion cartridge, increases overall methylxanthine extraction and clearance, and allows fluid and electrolyte abnormalities to be corrected. Charcoal hemoperfusion is typically less readily available and somewhat more complicated than hemodialysis, which may influence selection between charcoal hemoperfusion and hemodialysis as therapy options. Combined hemodialysis and MDAC is an easily performed regimen that provides superior theophylline clearance to hemodialysis alone. Although employed as an effective treatment modality, hemodialysis has always been less efficient than hemoperfusion in the extracorporeal removal of methylxanthines.8 , 108 , 110 , 169 Traditionally, hemodialysis was not preferred because methylxanthine elimination rates by hemodialysis were much lower than that those achieved by charcoal hemoperfusion and even lower than MDAC, a much safer, easier, noninvasive method. Improvement of hemodialysis equipment allows blood flow rates as much as 2 times greater than in the recent past, and has tremendously increased the potential rates of methylxanthine clearance by hemodialysis. As a result, the difference in elimination achieved by hemoperfusion and hemodialysis is insignificant. This fact, in combination with the ability of hemodialysis to correct fluid and electrolyte imbalances, the greater availability of hemodialysis, greater technical ease, and lower complication rates, are resulting in a paradigm shift from considering charcoal hemoperfusion to be the definitive treatment

for significant methylxanthine toxicity to one in which charcoal hemoperfusion and hemodialysis are considered equivalent treatment options.167 In the treatment of methylxanthine poisoning, the specific indications for therapy to enhance elimination are not agreed upon. Several studies and clinical experience are the basis for the following suggested indications for extracorporeal elimination by charcoal hemoperfusion, hemodialysis, combined charcoal hemoperfusion/hemodialysis or combined hemodialysis and MDAC. Most cases of methylxanthine toxicity and overdoses occur with theophylline, and theophylline concentrations tend to be both readily available and to correlate with toxicity. Therefore, many recommendations regarding hemoperfusion and/or hemodialysis for theophylline toxicity use serum theophylline concentration as a guideline. Serum concentrations may not be available in instances of caffeine poisoning and do not exist for theobromine poisoning. The clinical aspects of theophylline management guidelines can be generalized to all methylxanthines. When

indicated,

charcoal

hemoperfusion

and/or

hemodialysis

should be initiated while patients are still hemodynamically stable, or considered alternately, while they are stable. Charcoal hemoperfusion and/or hemodialysis therapy should be considered for chronic theophylline poisoning associated with a serum theophylline concentration >40–60 µg/mL or with a deteriorating clinical status. Charcoal hemoperfusion and/or hemodialysis should be performed any time a methylxanthine exposure results in a serum theophylline concentration >90 µg/mL and symptoms, regardless of clinical stability (Table 63-2 ). Any methylxanthine exposure resulting in a serum theophylline concentration >40 µg/mL that is associated with ventricular dysrhythmias, seizures, hypotension unresponsive to fluids, or emesis unresponsive to antiemetics should also be treated with charcoal hemoperfusion and/or

hemodialysis.

1 . Acute theophylline serum level >90 µg/mL and symptomatic 2 . Theophylline serum level >40 µg/mL and A . Seizures or B . Hypotension unresponsive to intravenous fluid or C . Ventricular dysrhythmias

TABLE 63-2. Methylxanthine Poisoning: Indications for Charcoal Hemoperfusion and/or Hemodialysis Seizures, dysrhythmias, or hemodynamic instability are not contraindications for extracorporeal drug removal. To the contrary, these events make administration of such therapy more critical to ensure survival of the patient.

Treatment

of

Chronic

Methylxanthine

Toxicity Treatment of chronic methylxanthine toxicity is determined by the patient's clinical status and by the efficacy of MDAC. The precise serum theophylline or caffeine concentration at which patients with chronic theophylline or caffeine toxicity should receive activated charcoal hemoperfusion or hemodialysis is controversial. For a hemodynamically stable patient without signs of life-threatening methylxanthine toxicity such as ventricular dysrhythmias or seizures, therapy with MDAC may be sufficient. If the serum theophylline or caffeine concentration does not decline following the administration of activated charcoal, or if the patient's clinical status deteriorates, charcoal hemoperfusion or hemodialysis is indicated.

Treatment

of

Acute-On-Chronic

Methylxanthine

Toxicity

Patients chronically receiving theophylline or caffeine who acutely overdose should be initially managed in the same manner as patients with acute overdose, although action concentrations for dialysis are the same as for chronic toxicity. Because total body stores of the methylxanthines are higher in patients who are chronically exposed, the threshold for toxicity may be reached at lower serum concentrations.

Summary Selective β2 -adrenergic agonists are widely used for the treatment of bronchospasm. Methylxanthines are ubiquitously used by cultures throughout the world. Selective β2 -adrenergic agonist toxicity results from medicinal use of these xenobiotics, and methylxanthine toxicity results from the use of xenobiotics as well as from consumption of methylxanthine-containing foods and beverages. There are significant differences in the clinical presentation and management of patients with acute and chronic methylxanthine poisoning. Supportive care and treatment of gastrointestinal, cardiovascular, CNS, metabolic, and musculoskeletal toxicities are the mainstay of therapy. The unique properties of methylxanthines necessitate specific therapies for the gastrointestinal, cardiovascular, and CNS toxicities of methylxanthines. With some unique exceptions, selective β2 adrenergic agonist toxicity is usually well tolerated and only requires supportive care. Methods of enhanced elimination, particularly extracorporeal elimination by activated P.1000 charcoal hemoperfusion, hemodialysis, or activated charcoal hemoperfusion and hemodialysis in series, as well as gut dialysis with MDAC, are effective treatments for methylxanthine toxicity.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > F - Anesthetics and Related Medications > Chapter 64 - Local Anesthetics

Chapter Local

64 Anesthetics

David R Schwartz Brian

Kaufman

A 30-year-old woman presented to the emergency department 4 hours after she had undergone a laser epilation treatment. In preparation for the procedure, 150 g EMLA (eutectic mixture of local anesthetics) cream (5 tubes) was applied to her lower extremities under occlusive dressings. One hour later, she began to experience light-headedness, dyspnea, tongue numbness, and muscular twitching. The only medications she was taking were sertraline and an oral contraceptive. On physical examination she was alert and in mild respiratory distress with both perioral and acral cyanosis, which was unresponsive to supplemental oxygen. Her vital signs were: blood pressure, 130/80 mm Hg; heart rate, 120 beats/min; respiratory rate, 20 breaths/min; temperature 98.6°F (37°C). Her height was 163 cm, and she weighed 74 kg. Her lungs were clear, and her heart sounds were normal. Her abdomen was soft and nontender with normal bowel sounds. Bilateral pretibial first-degree burns were still present from a prior laser treatment. The remainder of her physical examination was

normal. Pulse oximetry revealed 84% saturation while she was breathing 100% oxygen. An arterial blood gas (ABG) obtained on 100% oxygen was: pH, 7.45; PCO2 , 36 mm Hg; PO2 , 385 mm Hg. Her methemoglobin level was 20% by cooximetry. The patient received methylene blue 70 mg IV over 5 minutes, and all symptoms and signs improved within 1 hour. A repeat methemoglobin level was 2.7%. Her lidocaine concentration, drawn several hours after initial placement of the EMLA cream, was 0.68 µg/mL, confirming systemic absorption from the EMLA cream. The patient remained stable and was discharged home.41 Local anesthetics are drugs that block excitation of, and transmission along, a nerve axon in a predictable and reversible manner. The anesthesia produced is selective to the chosen body part in contrast to the nonselective effects of a general anesthetic. Local anesthetics do not require the circulation as an intermediate carrier, and they usually are not transported to distant organs. Therefore, the actions of local anesthetics are largely confined to the structures with which they come into direct contact. Local anesthetics may provide analgesia in various parts of the body by topical application, injection in the vicinity of peripheral nerve endings and major nerve trunks, or via instillation within the epidural or subarachnoid spaces. The various local anesthetic agents differ with regard to potency, duration of action, and degree of effects on sensory and motor fibers. Toxicity may be local or systemic. With systemic toxicity, the central nervous system (CNS) and cardiovascular systems typically are affected.

History Until the 1880s, the only drugs available for pain relief were centrally acting depressants such as alcohol and opioids, which blunted the perception of pain rather than attacking the root cause. The coca shrub (Erythroxylon coca ) was brought back to Europe from Peru by Karl Von Scherzer, an Austrian explorer, in

the mid-1800s. Some of the coca leaves were analyzed by the chemist Albert Niemann, who in 1860 successfully extracted and named the active principle, the alkaloid cocaine (Chap. 74 ). Although Niemann noted that cocaine crystals numbed his tongue, it was not until 1868 that the Peruvian army surgeon Moreno y Mayz initially suggested that cocaine might have medical applications as a local anesthetic. Sigmund Freud was interested in the analeptic actions of cocaine, which he hoped would help cure morphine addiction. Freud obtained a supply of cocaine from the manufacturing firm Merck and shared the supply with his good friend Carl Koller, who was a junior intern in the Ophthalmological Clinic at the University of Vienna. After dissolving coca powder in distilled water, Koller instilled the solution in the conjunctival sacs of a frog, a rabbit, and a dog. He then was able to touch their cornea without any evidence of a reflex blink. He then experimented on his own eye and that of his laboratory assistant, and he demonstrated that the eye became insensitive to touch and injury within 1 minute. In 1884, Koller performed an operation for glaucoma with topical cocaine anesthesia. Four days later, his findings were presented at the Congress of Ophthalmology in Heidelberg. Dr. Henry Noyes, an American who attended the Heidelberg meeting, reported the discovery in a letter to the New York Medical Record , and the news P.1005 spread rapidly. Within 1 year, cocaine was in worldwide use as a pain-relieving drug for surgery of the eye and was being tested on other mucous membranes, such as the upper airway. After the 1884 publication of Noyes' letter, several surgeons investigated the direct injection of cocaine into tissues. One year after Koller's discovery, Halsted reported on more than 1000 cases in which cocaine infiltration anesthesia was used at the Johns Hopkins Hospital.42 Bier reported human spinal anesthesia and the associated spinal headache in 1899. Although the clinical benefits of cocaine anesthesia were great, so

were its toxic and addictive potential. At least 13 deaths were reported in the first 7 years following the introduction of cocaine. Within 10 years following the introduction of cocaine as a regional anesthetic, reviews of “cocaine poisoning― appeared in the literature. 65 , 83 The toxicity of cocaine, coupled with its tremendous advantages for surgery, led to a search for less toxic substitutes. After the elucidation of cocaine's chemical structure (the benzoic acid methyl ester of the alkaloid ecgonine) in 1895, other benzoic acid esters were examined. Synthetic compounds with local anesthetic activity were introduced, but they either were highly toxic or irritating or had an impractical brief clinical effectiveness. In 1904, Einhorn synthesized procaine, but its short duration of action limited its clinical utility. Research then focused on synthesis of drugs with more prolonged duration of action. The potent, long-acting local anesthetics dibucaine and tetracaine were synthesized in 1925 and 1928, respectively, and were introduced into clinical practice. However, these anesthetics could not be used safely for regional anesthetic techniques because of systemic toxicity. From the large volumes of drug that were required. These drugs were very useful, however, for spinal anesthesia. Lofgren synthesized the prototypical local anesthetic lidocaine from a series of aniline derivatives in 1943. This amino amide combined high tissue penetrance and moderate duration of action with acceptably low systemic toxicity. Additionally, the metabolites of lidocaine did not include para -aminobenzoic acid, which was the reported cause of allergic reactions to the amino ester anesthetics. Subsequent to lidocaine's release in 1944, several other amino amide compounds were synthesized and introduced into clinical practice. These include mepivacaine in 1956, prilocaine in 1959, bupivacaine in 1963, etidocaine in 1971, and ropivacaine in 1996.

Epidemiology Considering the frequency with which local anesthetics are administered, both within and outside healthcare facilities, clinically significant toxic reactions are few and usually iatrogenic. In a report of 1106 fatalities resulting from toxic exposures reported to US Poison Control Centers in 2003, 3 were secondary to local anesthetics.(See Chap. 130 ) Most poisonings result from inadvertent injection of a therapeutic dose into a blood vessel, repeated use of a therapeutic dose, or unintentional administration of a toxic dose. The amide local anesthetics have largely replaced the esters because of increased stability and relative absence of hypersensitivity reactions. Differences in metabolism of these agents, however, result in a much higher likelihood of systemic toxicity. Bupivacaine, a potent and long-acting amide anesthetic, has the highest potential for cardiovascular toxicity, which can be refractory to conventional therapy. Its pure S-enantiomer levobupivacaine and the structurally similar amide ropivacaine are alternatives having similar anesthetic properties and less potential for cardiovascular toxicity. Poisoning from topical benzocaine is relatively common because of the large number of nonprescription products available for treatment of teething and hemorrhoids and because of the widespread use of benzocaine, mostly as a spray, for topical mucosal anesthesia prior to intubation, upper endoscopy, and esophageal echocardiography. Methemoglobinemia accounts for the majority of adverse events. With nonprescription use, toxic effects following exposure typically are mild, and death rarely occurs. Toxicity usually occurs as a therapeutic misadventure, but child abuse or neglect should be considered if the patient is younger than 2 years, and suicide should be considered in older children and adults. On the other hand, benzocaine spray may be the most important cause of severe acquired methemoglobinemia in the hospital setting.3 Between November 1997 and March 2002,

the US FDA received 198 reported adverse events secondary to benzocaine products. One hundred thirty-two cases (66.7%) involved definite or probable methemoglobinemia; most were serious adverse events, and 2 deaths occurred.74 In these cases, a single spray of unspecified duration of 20% benzocaine was the dose most commonly reported. Because of the difficulty in limiting the dose to the manufacturer's recommendation given the current formulations available, these authors recommend a metered dosing preparation and prominent package warnings.

Pharmacology Chemical

Structure

Local anesthetics fall into 1 of 2 chemically distinct groups: amino esters and amino amides (Figure 64-1 ). The basic structure of all local anesthetics has three major components. A lipophilic, aromatic ring is connected by an ester or amide linkage to a short alkyl, intermediate chain that is bound to a hydrophilic tertiary (or, less commonly, secondary) amine. The amine is a base (proton acceptor) that is partially charged in the physiologic pH range.

Mode of Action All local anesthetics function by reversibly binding to specific receptor proteins within the membrane-bound sodium channels of conducting tissues. These receptors can be reached only via the cytoplasmic side of the cell membrane, that is, by intracellular drug. Blockade of ion conductance through the sodium channel eventually leads to failure to form and propagate action potentials. The analgesic effect results from inhibiting axonal transmission of the nerve impulse in small-diameter myelinated and unmyelinated nerve fibers carrying pain and temperature sensation. Conduction block of these fibers occurs at lower concentrations than in the

larger fibers responsible for touch, motor function, and proprioception.22 This likely occurs in myelinated nerves because smaller fibers have closer spacing of the nodes of Ranvier. Given that a fixed number of nodes must be blocked in order for conduction failure to occur, the shorter critical length of nerve is reached sooner by the locally placed anesthetic in small fibers.36 For unmyelinated fibers, the smaller diameter limits the distance that such fibers can passively propagate the electrical impulse. In addition, differential nerve block may relate to voltage and time dependence of the affinity of local anesthetics to the sodium channels. The sodium channel can exist in three states. (See Chap. 23 .) At resting membrane potential or in the hyperpolarized membrane, the channel is closed to sodium conductance. With an appropriate P.1006 activating stimulus, the channel opens, allowing rapid sodium influx and membrane depolarization. Milliseconds later, the channel is inactivated, terminating the fast sodium current. Blockade is much stronger for channels that are activated (open) or inactivated than for channels that are resting. Pain fibers have a higher firing rate and longer action potential (ie, more time with the sodium channel open or inactivated) than other fiber types and therefore are more susceptible to local anesthetic action.48

Figure use.

64-1. Representative local anesthetics in common clinical

These effects also occur in other conductive tissues in the heart and brain that rely on sodium current. As such, sodium channel blockade initially was believed to be the sole cause of systemic toxic reactions. However, the mechanisms of toxic effects are more complex, especially in the heart, and can occur at systemic concentrations lower than previously thought.67 Local anesthetics may interact with other cellular systems at clinically relevant concentrations. For example, lidocaine inhibited muscarinic signaling in Xenopus oocytes at Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > F - Anesthetics and Related Medications > Chapter 66 - Neuromuscular Blockers

Chapter

66

Neuromuscular

Blockers

Kenneth M. Sutin Brian

Kaufman

Sanford M. Miller A 28-year-old otherwise healthy man presented to the emergency department (ED) complaining of palpitations and dry mouth that developed shortly after he intentionally consumed a marijuana-laced cookie. Although he was having troubling illusions, he had no true hallucinations. He had no chest pain, dyspnea, dizziness, abdominal pain, or extremity pain. His initial vital signs were: blood pressure, 154/80 mm Hg; pulse, 126 beats/min; respiratory rate, 18 breaths/min; and he was afebrile. On physical examination the patient was in no distress, his lungs were clear to auscultation bilaterally, and his heart sounds were rapid but regular and otherwise normal. His extremities were normal. He was neurologically intact except for occasional drifts in attention during mental status testing. An electrocardiogram demonstrated sinus tachycardia. Serum chemistry analysis and blood count were normal. Approximately 1 hour after arrival, the patient had persistent complaints of anxiety and troubling illusions. The treating physician ordered lorazepam 2

mg IV, which was administered promptly by the patient's nurse. Approximately 5 minutes later, the same nurse noted the patient was unresponsive to painful external stimulation. His repeat vital signs were: blood pressure, 210/102 mm Hg; pulse, 145 beats/min; respiratory rate, 0. The patient had normally reactive pupils, but his protective reflexes, including gag reflex, and his muscle tone were absent. Naloxone 1 mg and flumazenil 0.2 mg were administered intravenously with no response while the patient was ventilated by bag-valve-mask. Because of apnea, the patient was intubated and placed on mechanical ventilation. Approximately 2 hours later, the patient was awake and extubated by the physician in the ED. Following extubation, the patient reported that he had been fully aware of his surroundings and all activity and conversations during the entire previous period of “unresponsiveness― although he was unable to move. He stated that he felt himself being intubated and was extremely

frightened.

A count of the contents of the narcotics cabinet at the nurses station revealed that an excess of lorazepam was available compared to the amount that had been signed out. Further investigation noted that a vial of pancuronium that was located nearby in the locked portion of the medication refrigerator was missing. The vials of pancuronium and lorazepam were of identical size and shape, both had similar labels (a green outline with black lettering), and both contained 2 mg/mL of drug. The cap colors were different. The event was reported to the hospital leadership.

History Curare is the generic term for the resinous arrowhead poisons used to paralyze hunted animals.102 The curare alkaloids are derived from the bark of the ligneous Strychnos vine, and the most potent alkaloids, the toxiferines, are derived from Strychnos toxifera . Fortunately for the hunters who used curare, ingestion of their prey did not cause paralysis. Sir Walter Raleigh discovered the use of curare in Guyana in 1595, and he was the first person to bring curare to Europe. In 1898, King's American Dispensatory stated, “Curare is a frightfully poisonous extract, prepared by the

savages of South America.― Today, curare is available in a purified form as tubocurarine. Curare played a pivotal role in the discovery of the mechanism of neuromuscular transmission. In 1844, Claude Bernard placed a small piece of dry curare under the skin of a live frog and observed that the frog became limp and died.7 He performed an immediate autopsy and discovered the heart was beating. Because direct muscle stimulation produced contraction whereas nerve stimulation did not, Bernard concluded that curare paralyzed the motor nerves. He later observed that bathing the isolated nerve did not affect neuromuscular transmission, leading Bernard to conclude “curare must act on the terminal plates of motor nerves.―13 Curare was also used by Nobel Laureate physiologists Charles Sherrington, John Eccles, and Bernard Katz to further elucidate neuromuscular physiology. Its first clinical use was described in 1878 when Hunter used curare to treat tetanus and seizures.102 In 1932, Raynard West used curare to reduce the muscular rigidity of hemiplegia. More recent uses of succinylcholine have been less benign.2 The anesthesiologist Dr. Carl Coppolino was accused of murdering his wife in 1965 by succinylcholine injection. Her autopsy revealed an abnormally high concentration of succinylcholine metabolites (succinic acid and choline) in the brain and liver.69 Although this assay was not in general use in the medical community, the evidence was deemed admissible. In 1983, Dr. Michael Swango began his internship at Ohio State University Hospital. Shortly after he started his neurosurgery rotation, patients began dying inexplicably, and he was relieved of his duties.94 The elusive trail of Dr. Swango followed almost 14 years, through multiple residencies and jobs, and extended as far as Mnene Hospital in Zimbabwe. At one point, the Federal Bureau of Investigation (FBI) estimated Dr. Swango might have murdered 35–60 people. The authorities disinterred several victims whom they believed most likely were murdered. Toxicologic analysis of the 7-yearold remains of Thomas Sammarco revealed succinylcholine in the liver and gallbladder and its metabolite succinylmonocholine in multiple organs. These findings helped the prosecution to secure Swango's guilty plea for the

murder of three victims. P.1025 With the advent of new modalities of drug delivery, the toxicologist must be attuned to possible malicious intent. Emergency personnel responding to a 911 call observed the widow removing an insulin pump reservoir from her dead husband's body with the stated intent to donate the costly equipment.4 A natural cause of death was presumed, yet surprisingly, subsequent forensic analysis revealed etomidate and laudanosine (a metabolite of atracurium) in the victim's liver.

Mechanism and Block

of

Neuromuscular

Transmission

The purpose of a neuromuscular blocker (NMB) is to reversibly inhibit transmission at the skeletal neuromuscular junction (NMJ). All NMBs possess at least 1 positively charged quaternary ammonium moiety that binds to the postsynaptic nicotinic acetylcholine (nACh) receptor at the NMJ, inhibiting its normal activation by acetylcholine (ACh). The nACh receptor is a ligandgated ion channel that consists of 4 different protein subunits in a pentameric structure surrounding a central channel. The nACh receptor found in human skeletal muscle is present in 2 primary forms: a mature type found at the NMJ (ααβeδ) or as a fetal (immature) type found on muscle at extrajunctional regions of the muscle fiber (ααβγδ). Before discussing the mechanism of neuromuscular block, it is helpful first to describe normal neuromuscular transmission and excitation–contraction coupling (Figure 66-1 ). Therapeutic and toxicologic skeletal muscle paralysis can occur by several mechanisms. For example, tetrodotoxin blocks voltage-sensitive sodium channels, preventing action potential conduction by the motor neuron. On the other hand, botulinum toxin blocks ACh release from the presynaptic neuron by inhibiting the binding of ACh-containing vesicles to the neuronal membrane in the region of the synaptic cleft. Modulation of postsynaptic ACh receptor activity at the NMJ can produce paralysis by 1 of 2 mechanisms:

depolarizing (phase I block) and nondepolarizing (phase II block). Succinylcholine is the only depolarizing neuromuscular blocker (DNMB) in current clinical use. Nicotine at high doses can also cause a depolarizing block. The other agents discussed are all nondepolarizing neuromuscular blockers (NDNMBs). The process of DNMB requires several steps. First, 2 molecules of succinylcholine must bind to each α site of the nACh receptor. This action causes a prolonged open state of the nACh receptor ion channel. The initial depolarization causes a muscle action potential and usually causes brief contractions (fasciculations). In contrast to ACh, succinylcholine is not hydrolyzed efficiently by junctional (true) acetylcholinesterase (AChE); thus the effect of succinylcholine lasts much longer than ACh. The persistent presence of succinylcholine at the ACh receptor causes a sustained local muscle endplate depolarization that, in turn, causes the voltage-gated sodium channel in the perijunctional region to remain in a prolonged inactive state, inducing a desensitization block. The muscle is temporarily refractory to presynaptic release of ACh (phase I block). The NDNMBs cause skeletal muscle paralysis by competitively inhibiting the effects of ACh and thus preventing muscle depolarization. One molecule of an NDNMB bound to a single nACh receptor (on the α site) competitively inhibits normal channel activation. The NDNMBs do not block voltage-gated sodium channels on the muscle membrane, and direct electrical stimulation of muscle contraction is still possible. The NDNMBs are classified by duration of action as ultrashort, short, intermediate, and long. They also are classified by chemical structure as either synthetic benzylisoquinolinium drugs or aminosteroids (Table 66-1 ), which are derived from plant alkaloids. NDNMBs also block nACh receptors on the prejunctional nerve terminal and inhibit ACh-stimulated ACh production and release.85 This effect reduces the available pool of ACh and augments the extent of neuromuscular block.9

Pharmacokinetics The NMBs are highly water soluble and relatively insoluble in lipids. Thus,

they are rapidly distributed in the extracellular space and very slowly permeate lipid membranes such as the placenta and the normal blood–brain barrier. For this reason, they are devoid of central nervous system (CNS) effects. Because these drugs distribute in the extracellular space, their dosage is based on ideal body mass. Dosing according to the total body mass in obese patients can result in an exaggerated or prolonged drug effect. The speed of onset of an NMB is inversely related to its molar potency (ie, E D95 expressed as µmol NMB drug per kilogram body weight).56 , 57 Stated differently, the greater the affinity of the NDNMB for the ACh receptor, the fewer molecules per kilogram of tissue are required to produce a given degree of ACh receptor occupancy. Atracurium is the only drug that does not follow this generalization because it is a mixture of isomers each having a different receptor affinity. In general, small, fast contracting muscles such as the extraocular muscles are more susceptible to neuromuscular block than are larger, slower muscles such as the diaphragm. This is the so-called respiratory sparing effect. Following an IV bolus of NDNMB, paralysis of the diaphragm is coincident with paralysis of laryngeal muscles because their high perfusion results in rapid drug diffusion into the NMJ.20 Recovery from NMB is fastest for the diaphragm and intercostal muscles, intermediate for the large muscles of the trunk and extremities, and slowest for the adductor pollicis, larynx, pharynx, and extraocular muscles.20

Complications

of

Neuromuscular

Blockers

Complications associated with the use of NMBs include (1) problems associated with the care of a patient who is therapeutically or otherwise paralyzed (eg, undetected hypoventilation resulting from ventilator or airway problems, impaired ability to monitor neurologic function, unintentional patient awareness, peripheral nerve injury, deep vein thrombosis, and skin breakdown); (2) immediate side effects; and (3) effects occurring following prolonged drug exposure.75 , 76

Patient

Awareness

The NMB drugs do not affect consciousness, yet misconceptions about these drugs persist.66 The pupillary light reflex, an important P.1026 indicator of midbrain function, is preserved in healthy subjects who receive NDNMBs41 because pupillary function is mediated by muscarinic cholinergic receptors, for which the NMBs have no affinity. Atropine paralyzes the papillary constrictors and produce fixed mydriasis. Many drugs used in combination with NMBs, such as sedatives, opioids, and inhalational anesthetics, increase the amplitude of pupillary constriction in response to light, but do not produce paralysis.

Figure

66-1. Excitation–contraction coupling in skeletal muscle. At the

neuromuscular junction (NMJ), acetylcholine (ACh) released from the presynaptic nerve terminal ①crosses the 50-nm synaptic cleft to reach the nicotinic ACh receptor ②. The basal lamina, a thin layer of connective tissue, extends into the synaptic cleft and is associated with acetylcholinesterase (AChE). There are two types of receptors, a mature receptor (ααβεδ) found in normal adult NMJ and a fetal or immature receptor (ααβγδ) found on the muscle at extrajunctional sites. Proliferation of immature receptor occurs during normal embryonic development and during certain pathologic states, such as denervation injury. On the nicotinic ACh receptor, there are two negatively charged sites

that can bind ACh; one at the α–γ interface and one at the α–δ interface. All neuromuscular blockers (NMBs) possess at least 1 positively charged quaternary ammonium group that can competitively bind with the ACh binding site. Only when agonist simultaneously occupies both receptor sites does the ion channel open, becoming nonselectively permeable to monovalent cations and resulting in an influx of Na+ and an efflux of K+ . This produces local membrane depolarization (endplate potential) that, in turn, opens voltage-activated Na+ channels ③. A depolarization of sufficient amplitude generates a propagated muscle action potential (MAP ④), which is conducted along the muscle membrane and down the transverse (T) tubules. In the T tubule, the MAP triggers a voltage-activated calcium channel (dihydropyridine receptor [DHPR], ⑤), which then activates the skeletal muscle ryanodine receptor/channel (RYR-1, ). To allow the fastest activation of mammalian skeletal muscle, calcium diffusion is not necessary for activation of RYR-1; instead there is a direct electrical (protein) linkage between the DHPR and RYR-1.29 This intimate association of DHPR, RYR-1, and junctional sarcoplasmic reticulum (SR) is called the calcium release unit. In contrast, in cardiac muscle, calcium entry through the DHPR is required for activation of the cardiac ryanodine receptor RYR-2. In the skeletal muscle calcium leaves the SR through the RYR-1 channel to enter the myoplasm where it binds to troponin C, activating the contractile actin–myosin protein complex to produce muscular contraction. Active ATPase-driven reuptake of calcium into the longitudinal SR terminates muscle contraction. Many factors influence the activity of the RYR-1 channel, such as Ca2 + , Mg2 + , and anesthetic drugs such as inhalation agents that accelerate Ca2 + release in persons susceptible to malignant hyperthermia.29

Histamine

Release

The benzylisoquinolinium muscle relaxants (Table 66-1 ) produce direct, nonimmunologic dose- and rate-related histamine release P.1027 from tissue mast cells. The approximate rank order for histamine release is tubocurarine > atracurium and mivacurium > succinylcholine.27

TABLE 66-1. Pharmacology of Selected NMB Drugs

Anaphylaxis Of the anaphylactic reactions occurring during general anesthesia, approximately 60% are the result of NMBs, whereas only 17% are the result of latex.72 Rocuronium is responsible for 43% and succinylcholine for 23% of all NMB-associated anaphylaxis. Pancuronium is the agent least associated with serious allergic reactions. 101

Control

of

Respiration

At subparalyzing doses, NDNMBs blunt the hypoxic ventilatory response (HVR) but not the ventilatory response to hypercapnia.25 , 26 HVR returns to normal when the chemical paralysis is completely reversed. Hypoventilation resulting from blunting of the HVR, especially when combined with the residual effects of other drugs used during anesthesia (eg, opioids or inhalational anesthetics), can cause delayed respiratory failure.

Autonomic

Side

Effects

Neuronal nACh receptors found in autonomic ganglia, such those at the NMJ, are pentamers composed of α and β subunits. In general they are less susceptible to block by NMBs.67 There is one notable exception. At the same dose that produces neuromuscular block, tubocurarine also blocks nACh receptors at the parasympathetic ganglia, causing tachycardia, and at the sympathetic ganglia, blunting the sympathetic response. 88 In combination with tubocurarine-related histamine release, the sympathetic block can cause significant hypotension, especially in patients with heart failure or hypovolemia.10 Aminoglycosides

(eg,

amikacin,

gentamicin)

Potentiates Potentiates Dose-related decrease in presynaptic ACh release. May decrease postjunctional response to ACh. Partially reversible with calcium supplementation. Effect of neostigmine unpredictable. Anticholinesterase, peripheral acting: neostigmine, edrophonium Prolongs succinylcholine (except edrophonium) Inhibits, prolongs mivacurium (except edrophonium) Neostigmine, pyridostigmine, and physostigmine inhibit plasma AChE and prolong mivacurium and succinylcholine block. Edrophonium does not inhibit plasma cholinestarase. Anticholinesterase, centrally acting: donepezil Potentiates

Potentiates mivacurium Inhibits AChE (junctional >> plasma), long half-life (70 h) β-Adrenergic antagonist: propranolol Potentiates in cats, effects in humans uncertain Potentiates Given alone may unmask myasthenic syndrome. Blocks ACh binding at postsynaptic membrane. Reversal of block with neostigmine can cause severe bradycardia. β-Adrenergic antagonist: esmolol ? Mild prolongation Slows onset of rocuronium and mivacurium Competes for plasma AChE, slows degradation of mivacurium. Botulinum toxin Early

potentiation,

delayed

resistance

Single case report: Acutely, subclinical systemic denervation leads to vecuronium hypersensitivity. Subsequent NMJ remodeling and ACh receptor upregulation leads to vecuronium resistance. Calcium channel blockers: nifedipine, verapamil Potentiates Potentiates Causes calcium channel block pre- and postjunctionally. Verapamil has local C-l effect on nerve. May inhibit block reversal by cholinesterase inhibitor. Carbamazepine ? Inhibits, shortened duration Chronic therapy causes resistance to NDNMB, except for mivacurium and atracurium. Dantrolene ? Potentiates Blocks excitation–contraction coupling by blocking ryanodine calcium channel in sarcoplasmic reticulum of skeletal muscle. Digitalis

More prone to cardiac dysrhythmias Pancuranium increases catecholamines and may cause dysrhythmias Furosemide Biphasic dose response in cats; protein kinase inhibition at low doses and phosphodiesterase inhibition at high doses. Diuretic-related hypokalemia potentiates pancuronium in cats. vecuronium > tubocuraine > atracurium. Heterozygote for atypical plasma AChE may develop phase II block when given succinylcholine and pancuronium. Organic phosphorus compounds echothiophate Potentiates Irreversible plasma AChE inhibitor. May totally block enzyme activity. Phenelzine (MAO inhibitor) Prolongs Decreases plasma AChE activity. Phenytoin ? Resistant, shortened duration Acutely, potentiates NDNMB paralysis. With chronic use (except for mivacurium and atracurium) phenytoin induces resistance to NDNMB and increases drug metabolism. This increases the initial dose and decreases the

repeat dosing interval. Polypeptide antibiotics: polymyxin Potentiates Potentiates Can cause severe weakness. May induce postsynaptic neuromuscular block. Neostigmine increases block. Succinylcholine Self-taming dose of succinylcholine may be used to limit muscular fasciculations. Tubocurarine, pancuronium, and vecuronium slightly prolonged by prior succinylcholine Theophylline Inhibits Pancuronium and theophylline can increase cardiac dysrhythmias. Tricyclic antidepressants (TCA)

Pancuronium and TCA may cause cardiac dysrhythmias due to sympathetic effects.

Drug

Response to Succinylcholine

Response to Nondepolarizer

Comments

TABLE 66-2. Effect of Prior Administration of Many Drugs on Subsequent Response to Succinylcholine or Nondepolarizing Neuromuscular Blockers (NDNMBs) P.1028 P.1029 The muscarinic receptors (M1 –M5 ) are members of the seventransmembrane G-protein–coupled receptor family. As such they are structurally unique and mostly unaffected by NMBs. At clinical doses,

pancuronium elicits dose- and injection rate-related increases in heart rate, blood pressure, cardiac output, and sympathetic tone.89 , 91 , 95 This is attributed to a selective block of parasympathetic transmission at the cardiac muscarinic receptors (atropinelike effect),89 block of presynaptic muscarinic receptors at sympathetic nerve terminals, and perhaps an indirect norepinephrine-releasing effect at postganglionic fibers.91 Sympathetic stimulation from pancuronium may increase cardiac dysrhythmias, especially when combined with halothane and a tricyclic antidepressant.24 Dysrhythmias including bradycardia, junctional rhythms, ventricular dysrhythmias, and cardiac arrest occur rarely after succinylcholine. This situation most likely results from stimulation of the cardiac muscarinic receptors and can be prevented by pretreatment with atropine 15–20 µg/kg IV. Bradycardia is uncommon, but it may be especially severe in children during anesthetic induction when large or repeated doses of succinylcholine are given. For this reason, atropine is generally given beforehand.

Interactions Drugs

and

of

Muscle

Pathologic

Relaxants

with

Other

States

NMB has significant interactions with many medications (Table 66-2 ) and coexisting medical conditions. These interactions can affect the neuromuscular system at any level from the CNS to the muscle itself.81 , 100 For example, potent inhalation anesthetics depress CNS activity, local anesthetics inhibit propagation of nerve action potentials, chronic lithium therapy inhibits presynaptic synthesis of ACh, magnesium and aminoglycoside antibiotics inhibit presynaptic release of ACh, donepezil inhibits AChE, polypeptide antibiotics (eg, polymyxin) inhibit the postjunctional muscle membrane, and dantrolene inhibits calcium release from muscle sarcoplasmic reticulum. All of these drugs potentiate the effects of NMBs. In most neuromuscular diseases, such as muscular dystrophy, GuillainBarré syndrome, myasthenia gravis, and postpolio syndrome, sensitivity to

NDNMB is increased, so a small dose of NMB produces a profound degree of block.1 , 11 , 45 Persons with myasthenia gravis typically demonstrate resistance to the effects of succinylcholine.1 , 11 In individuals with myopathy of unknown etiology, a prudent course is to avoid succinylcholine because of the potential for malignant hyperthermia (MH), hyperkalemia, or rhabdomyolysis and to use a short-acting NDNMB to help decrease the possibility of prolonged weakness. Many systemic pathologic states potentiate the duration or intensity of NDNMB, such as respiratory acidosis, hypokalemia, hypocalcemia, hypermagnesemia, hypophosphatemia, hypothermia, shock, and liver or kidney failure. 84 Alternatively, acute sepsis and inflammatory states are associated with mild resistance to the effect of NDNMB.77

Pharmacology

of

Depolarizing

Neuromuscular Blocking (Succinylcholine)

Drugs

Succinylcholine is a bis-quaternary ammonium ion composed of 2 ACh molecules attached by their acetate groups.22 Following a conventional IV induction dose (1 mg/kg), typical serum concentrations are approximately 62 µg/mL.79 P.1030 Succinylcholine is hydrolyzed mostly by plasma (pseudo) cholinesterase (ChE) and to a slight extent by alkaline hydrolysis. Hydrolysis is a 2-step reaction; first succinylmonocholine and choline and then succinic acid and choline are formed (both are normal products of intermediary metabolism). The first reaction is approximately 6 times faster than the second reaction. Less than 3% of the administered dose is excreted unchanged in the urine.39 Following an IV bolus, the serum succinylcholine concentration rises abruptly and there is a rapid onset of NMJ block. Later the serum succinylcholine concentration undergoes a rapid decline as a result of drug redistribution to extravascular tissues and hydrolysis in the serum. Finally succinylcholine leaves the NMJ to reenter the serum as a result of reversal of the

concentration

gradient.38 , 52

Succinylcholine 1 mg/kg IV usually increases cerebral blood flow, cortical electrical activity, intracranial pressure, 58 and intraocular pressure, especially in lightly anesthetized patients. These effects, when they occur, usually are modest.

Toxicity of Blockers

Depolarizing

Neuromuscular

The important adverse drug reactions associated with succinylcholine include (1) anaphylaxis, (2) prolonged drug effect, (3) hyperkalemia, (4) acute rhabdomyolysis in patients with muscular dystrophy, (5) MH in susceptible patients, (6) muscle spasms or trismus in myotonia congenita, and (7) cardiac dysrhythmias.

Prolonged

Effect

The effects of succinylcholine may last for several hours if metabolism is slowed because of decreased plasma ChE, abnormal plasma ChE activity (genetic variant or drug inhibition), or a phase II block.15 Plasma ChE deficiency may be caused by hepatic disease, malnutrition, plasmapheresis, and pregnancy.15 Inactivation of plasma ChE can be caused by fluoride intoxication, organic phosphorus compounds, and carbamates. On the other hand, even with only 20–30% of normal plasma ChE activity, the effective duration of succinylcholine is less than doubled.31 Many genetic variants of plasma ChE are known. The most common atypical plasma ChE (atypical type, homozygous incidence 1:3000) can be assayed by its resistance to inhibition by the local anesthetic dibucaine.82 A history of uneventful exposure to succinylcholine excludes the possibility of atypical plasma ChE, except in case of hepatic transplantation. Dibucaine inhibits the ability of normal plasma ChE to hydrolyze benzoylcholine by >70% (ie, dibucaine number >70), heterozygous atypical enzyme by 40–60%, and homozygous atypical enzyme by ≤30%. Fresh-frozen plasma or plasma ChE concentrates can be infused to hasten recovery in the case of a genetic

enzyme defect or an acquired ChE deficiency. However, to avoid the risks of transfusion, it is best to simply keep the patient sedated, intubated, and ventilated until the drug is metabolized. In this setting, spontaneous reversal usually requires 3–4 hours, although in rare cases full recovery requires up to 12 hours.15 When the duration of succinylcholine is very prolonged, blood samples should be drawn for measurement of plasma ChE concentration and activity. Prolonged nondepolarizing block can occur when large doses of succinylcholine (2–8 mg/kg IV) are given over a short period. This is called phase II block. It can be partially reversed by neostigmine.

Hyperkalemia Succinylcholine 1 mg/kg IV typically causes serum [K+ ] to increase by approximately 0.5 mEq/L in normal individuals and in persons with renal failure. The acute hyperkalemic response to succinylcholine is exaggerated with coexisting myopathy or proliferation of extrajunctional muscle ACh receptors. However, the mortality is highest (30%) when rhabdomyolysis occurs. 42 Severe, precipitous, potentially life-threatening hyperkalemia occurs following succinylcholine administration in several conditions associated with proliferation of ACh receptors. These conditions include denervation (head or spinal cord injury, stroke, neuropathy, prolonged use of NDNMBs), muscle pathology (direct trauma, crush or compartment syndrome, muscular dystrophy), critical illness (hemorrhagic shock, neuropathy, myopathy, prolonged immobility), thermal burn or cold injury, and sepsis lasting several days (eg, intraabdominal infections). Following a neurologic injury, susceptibility to hyperkalemia begins within 4–7 days and may persist indefinitely. In patients who have been in the ICU for more than 1 week, a prudent course is to avoid succinylcholine altogether because of the risk of hyperkalemic cardiac arrest, which is associated with a mortality rate of at least 19%.6 , 8 , 42 , 43 Severe hyperkalemia is modified, but not prevented, by a dose of an NDNMB sufficient to prevent succinylcholine-induced muscle fasciculations. Severe or even fatal hyperkalemia has been reported in a few patients who

received succinylcholine immediately following exsanguinating hemorrhage or massive trauma. The mechanism for this condition is not the same as that following neurologic injury because of inadequate time for proliferation of extrajunctional ACh receptors. Succinic acid, a tricarboxylic acid cycle intermediate (which is also a metabolite of succinylcholine), facilitates activation of voltage-gated sodium channels in a dose-dependent fashion, increasing skeletal muscle excitability.46 In hemorrhagic shock, accumulation of succinic acid as a result of cell breakdown and anaerobic metabolism possibly augments the potassium-releasing effect of succinylcholine.

Rhabdomyolysis Severe hyperkalemia rarely occurs in the absence of a clinical history that readily discloses an obvious risk factor, with one important exception. Acute or delayed onset of rhabdomyolysis, hyperkalemia, ventricular dysrhythmias, cardiac arrest, and death have been reported in apparently healthy children who subsequently were found to have a myopathy.59 Since March 1995, a black box warning on the package insert has stated that succinylcholine should be avoided in elective surgery in children, particularly those younger than 8 years, because of the small risk of a previously undiagnosed skeletal myopathy, especially Duchenne muscular dystrophy. Sudden cardiac arrest occurring immediately following succinylcholine should always be assumed to be caused by hyperkalemia. If fever, muscle rigidity, hyperlactatemia, or metabolic and respiratory acidosis also is present, the presumptive diagnosis of MH should prompt immediate therapy with dantrolene.

Malignant

Hyperthermia

Malignant hyperthermia is a heterogeneous syndrome that typically affects individuals who are otherwise healthy, although it may be associated with certain myopathies, including Duchenne muscular dystrophy, central core disease, King-Denborough syndrome, osteogenesis imperfecta, and myotonia. The disorder is associated with a P.1031 defect of a skeletal muscle regulatory/receptor protein. Inheritance is

autosomal dominant with variable penetrance.68 In humans, multiple protein defects are causally associated with MH, which may account for the heterogeneity of its inheritance and clinical presentation. In human MH, 1 of at least 42 different mutations in the skeletal muscle ryanodine receptor type 1 (RYR-1, chromosome 19q13.1) is present in 50–80% of patients (Figure 66-1 ). 96 RYR-1 is present in both fast-twitch and slow-twitch skeletal muscle, whereas only RYR-2 is found in cardiac muscle. This situation may explain why the myocardium is hyperdynamic and relatively spared in the early phase of MH.86 Of practical importance, the existence of multiple mutations across multiple alleles means that genetic testing likely will not prove useful in detecting all susceptible individuals. The incidence of MH is approximately 1/20,000 in children and 1/50,000 in adults. MH most often occurs in the operating room shortly after initial exposure to anesthetic agents, but it may commence several hours after a general anesthetic is given74 or as long as 12 hours after surgery. In addition, recurrence can occur 24–36 hours after an initial episode. Malignant hyperthermia is caused inconsistently by exposure to certain anesthetic agents that trigger abnormal calcium release from the skeletal muscle sarcoplasmic reticulum. In patients who are MH susceptible, clinical manifestations develop less than half the time following exposure to triggering agents. For this reason, a previous uneventful anesthetic exposure does not preclude development of MH on subsequent exposure.3 Drugs associated with precipitating an attack of MH include succinylcholine and volatile inhalational anesthetics (the prototypical agent is halothane). Drugs that can be administered safely to individuals considered susceptible to MH include NDNMBs, nitrous oxide, propofol, ketamine, etomidate, benzodiazepines, barbiturates, opioids, and local anesthetics. The immediate systemic manifestations of MH result from skeletal muscle hypermetabolism. Uncontrolled release of calcium from the terminal cisternae of the sarcoplasmic reticulum causes skeletal muscle contraction. Muscular rigidity is a specific sign of MH, but it is not consistently observed. Futile cycling of calcium in the skeletal myocyte by sarcoplasmic Ca2 + ATPase causes depletion of cellular ATP, hypermetabolism, excess heat

production, core hyperthermia, increased O2 consumption and CO2 production, venous O2 desaturation and hypercarbia, anaerobic metabolism, and lactic acid generation. 47 The extreme elevation of metabolic rate causes severe mixed venous oxygen desaturation (far below the normal of 75%). Cardiac dysrhythmias, hyperkalemia, rhabdomyolysis, and disseminated intravascular coagulopathy may occur. The earliest signs of MH include an early and rapid production and arterial, venous, and end-tidal CO2 hypertension or labile blood pressure; and skeletal Despite the name of the syndrome, hyperthermia is

increase in CO2 ; tachycardia; tachypnea; and jaw muscle rigidity. not a universal finding in

MH. Moreover, when it occurs, it is often a late sign.99 Acute potassium release from muscle cells may result in life-threatening hyperkalemia. Subsequent rhabdomyolysis can exacerbate the problem by causing renal failure. In late-stage MH, cardiac decompensation results from hyperkalemia, heart failure, vascular collapse, and/or myocardial ischemia (especially with coexisting coronary artery disease). The differential diagnosis of MH includes neuroleptic malignant syndrome, propofol infusion syndrome, serotonin syndrome, thyroid storm, pheochromocytoma, baclofen withdrawal, malignant syndrome in Parkinson disease, tetanus, meningitis, poisoning by salicylates, amphetamines, cocaine or antimuscarinics, unintentional intraoperative hyperthermia, heat stroke, and transfusion reactions. Of note, early septic shock is also associated with hypermetabolism, increased cardiac output, and fever, but typically the mixed venous O2 saturation is >75%. Rarely, MH is triggered by severe exercise in a hot climate, IV potassium (which depolarizes the muscle membrane), antipsychotic drugs, and infection.18 , 51 Patients with hypermetabolism or rhabdomyolysis have responded to dantrolene, but this finding does not necessarily confirm these patients have MH. Such confirmation requires a muscle biopsy. One theory of the pathogenesis interact with an abnormal RYR-1 open state and leading to rapid sarcoplasmic reticulum into the

of MH states that MH-triggering agents channel, causing it to stay in a prolonged efflux of calcium from the skeletal muscle myoplasm. Succinylcholine triggers a

prolonged muscle depolarization leading to elevated myoplasmic calcium. This action initiates accelerated calcium-activated calcium release from the myoplasmic reticulum.44 However, not all cases of MH can be explained by an RYR-1 mutation.35 For example, the association of defects in skeletal muscle sodium channels in certain myotonic disorders has generated interest in the role of the sodium channel in MH. 35 Also, certain MH-susceptible persons manifest increased skeletal muscle fatty acid production, and fatty acids augment halothane-induced sarcoplasmic calcium release.32 , 33 a n d 34 Although definition of one pathogenic mechanism is not yet possible, any unitary hypothesis must account for these observations. By partially blocking calcium release from skeletal muscle sarcoplasmic reticulum, dantrolene rapidly reverses the signs and symptoms of hypermetabolism: fever, mottled skin, dysrhythmias, muscle rigidity, tachycardia, metabolic acidosis, and hypercapnia. Before the discovery of dantrolene, the mortality rate from MH was 70%. When acute MH is treated immediately with dantrolene, volume resuscitation, active cooling, control of hyperkalemia, and supportive care, the mortality is 17 µg/mL).12 , 37 In humans, the toxic plasma laudanosine concentration is unknown, and seizures directly attributable to atracurium have not been

observed even following prolonged drug infusion in the ICU.37 , 103 In ICU patients who received a 72-hour infusion of atracurium 1 mg/kg/h), the highest plasma laudanosine concentrations (10–20 µg/mL) were observed in patients with renal insufficiency.62

Persistent

Weakness

Nondepolarizing

Associated

Neuromuscular

with Blockers

Short-term use of an NDNMB usually results in prompt termination of the block. When an NDNMB is administered for more than 48 hours, there is a risk that weakness will persist longer than anticipated based on the kinetics of drug elimination. In addition, critical illness is associated with dysfunction of the peripheral nerve, NMJ, and muscle (Table 66-4 ). For instance, in the ICU, persistent weakness is observed in 68–100% of patients with sepsis or multiple organ failure17 , 36 , 98 and in 20–30% of patients who receive NDNMB for only 48–72 hours.64 Persistent weakness is multifactorial and associated with illness severity (Acute Physiology and Chronic Health Evaluation [APACHE] III score), sepsis, acute respiratory distress syndrome, multiorgan failure, hyperglycemia, NDNMB, systemic glucocorticoids, muscle injury, thermal injury, and electrolyte, endocrine, and nutritional disorders.16 , 21 , 48 , 63 Many drugs given to patients in the ICU can cause weakness by themselves or potentiate the effects of NDNMB.49 , 81 Progressive weakness and acute respiratory failure have been described following discharge from the ICU and can present a life-threatening situation if not immediately recognized.60 Patients who develop persistent weakness have a 2.5- to 3.5-fold increase in ICU mortality64 and ICU stay. Sensory Moderate to severe, distal > proximal Normal Normal Normal Motor Symmetric weakness, lower > upper extremity, proximal > distal or diffuse,

respiratory failure Diffuse symmetric weakness, respiratory failure Diffuse weakness, proximal > distal Symmetric weakness, proximal > distal or diffuse, respiratory failure Creatine phosphokinase Normal Normal Normal Elevated in ≤50% Electrodiagnostic studies (electromyogram [EMG], nerve conduction studies [NCS] including nerve conduction velocity [NCV]) Axonal degeneration of motor > sensory, reduced sensory and motor compound action potentials, normal NCV Fatigue at NMJ assessed by fade on repetitive nerve stimulation Normal EMG and NCV Myopathic changes, muscle membrane inexcitability, normal NCV Muscle biopsy Denervation atrophy Normal Atrophy of type 2 fibers, no myosin loss, no necrosis Atrophy of type 2 (fast-twitch) fibers, myosin loss, mild myonecrosis, no inflammatory infiltration Adapted from Bolton CF: Critical illness polyneuropathy and myopathy. Crit Care Med 2001;29:2388–2390; Lacomis D: Critical illness myopathy. Curr Rheumatol Rep 2002;4:403–408; Lacomis D, Campellone JV: Critical illness neuromyopathies. Adv Neurol 2002;88:325–335; Leijten FSS, de Weerd AW: Critical illness polyneuropathy: A review the literature, definition and pathophysiology. Clin Neurol Neurosurg 1994;96:10–19.

Critical Illness Polyneuropathy (CIP)

Residual Neuromuscular Block

Disuse (Cachectic) Myopathy

Critical Illness Myopathy (CIM)

TABLE 66-4. Acute Neuromuscular Pathology Associated with Critical Illness and/or NDNMB

Pharmacology

of

Reversal

Agents

Termination of NMB effect initially results from drug redistribution and later from drug elimination, metabolism, and/or chemical antagonism. Pharmacologic antagonism of a partial NDNMB is achieved by giving a reversal agent that inhibits junctional AChE and increases ACh at the NMJ. This increase in ACh can overcome the competitive inhibition caused by residual NDNMB. The commonly used anti-ChEs are polar molecules that possess a quaternary ammonium (Table 66-5 ). Neostigmine and pyridostigmine are hydrolyzed by ChE and form carbamyl complexes (t1 / 2 15–20 minutes) with the esteratic site of the enzyme.5 The half-life of the carbamyl–ester complex is much less than the plasma half-life of neostigmine or pyridostigmine, which explains why the latter determines the duration of clinical effect. In contrast, edrophonium is not hydrolyzed by ChE. Rather, it forms an electrostatic interaction and a hydrogen bond with the cationic site of ChE that is both competitive and reversible. In addition, neostigmine and pyridostigmine, but not edrophonium, inhibit plasma ChE and thus prolong the effects of drugs metabolized by this enzyme, such as succinylcholine and mivacurium.19 , 31

Toxicology

of

Reversal

Agents

The most common and troublesome clinical side effect of ChE inhibition is bradycardia, which usually is prevented by coadministration of an antimuscarinic drug.14 Bradydysrhythmias may be severe and lead to nodal or idioventricular rhythm, complete heart block, or even asystole.65 These side effects occur more frequently in patients with preexisting bradycardia or those receiving chronic P.1034 β-adrenergic antagonist therapy. They are not necessarily prevented by

prior administration of atropine.93 Other problems that may result from excess ChE inhibition are hypersalivation, bronchospasm, increased bronchial secretions, abdominal cramping from intestinal hyperperistalsis, cell division, tearing, and increased bladder tone. Side effects of excess antimuscarinic administration include tachycardia, bronchodilation, pupillary dilatation, and increased intraocular pressure. Following general anesthesia, use of anticholinesterases may increase the incidence of nausea, vomiting, and abdominal cramps.54 Because atropine crosses the blood–brain barrier, it can produce central anticholinergic syndrome. Initial dose (mg/kg) 0.04–0.08 0.2–0.4 0.5–1.0 Onset (min) 7–11 10–16 1–2 Duration (min) 60–120 60–120 60–120 Recommended antimuscarinic Glycopyrrolate Glycopyrrolate Atropine Structure Quaternary ammonium Tertiary amine Initial dose (mg/kg) 0.01–0.02 0.02–0.03 Onset (min) 2–3 1

Duration (min) 30–60 30–60 Elimination Renal Renal Crosses blood-brain No Yes

barrier

Antimuscarinics Glycopyrrolate

Atropine

Adapted from Bevan DR, Donati F, Kopman AF: Reversal of neuromuscular blockade. Anesthesiology 1972;77:785–805; Cronnelly R: Muscle relaxant antagonists. In: Katz R, eds: Muscle Relaxants: Basic and Clinical Aspects. New York, Grune and Stratton, 1985, pp. 197–212. Anticholinesterases Neostigmine

Pyridostigmine

Edrophonium

TABLE 66-5. Pharmacology of Intravenous Neuromuscular Blocking Reversal

Diagnostic

Drugs

Testing

Quantitative methods for analysis of blood and tissue NDNMB and metabolite concentrations using high-performance liquid chromatography and mass spectrometry are described. 53 , 90 Succinylcholine and succinylmonocholine can be assayed by gas chromatography and mass spectrometry in blood, urine, or the site of intramuscular injection.79 , 92 Less than 3% of administered succinylcholine and 10% of its metabolite succinylmonocholine are excreted in the urine.

However, both parent drug and metabolite undergo spontaneous hydrolysis, especially in alkaline conditions.97 Historically, detection of succinylcholine has proved difficult because of its rapid hydrolysis. However, techniques for detecting this parent compound in tissues even after embalming are described.40 Because succinic acid is a product of intermediary metabolism, assay of this metabolite is not useful for positive identification of prior succinylcholine exposure.73 Surprisingly, the presence of succinylmonocholine in forensic samples also cannot prove prior exposure to succinylcholine. Succinylmonocholine in concentrations of 0.01–0.20 µg/g has been detected in tissues of 6 autopsy cases with no history of succinylcholine exposure.61

Summary The two types of NMBs are depolarizing (DNMB) and nondepolarizing (NDNMB). Succinylcholine is the only DNMB in current clinical use. The primary action of an NMB is to reversibly inhibit transmission at the skeletal NMJ. Immediate side effects include dose- and rate-related histamine release and modulation of autonomic tone. Acute and potentially fatal hyperkalemia can occur after succinylcholine administration. Succinylcholine is contraindicated in certain myopathies (eg, Duchenne muscular dystrophy) because of the risk for MH, rhabdomyolysis, and hyperkalemia. In MH, acute onset of severe hypermetabolism causing acidosis, rhabdomyolysis, hyperkalemia, and death occurs if treatment with dantrolene and aggressive cooling is not given. The effect of succinylcholine is prolonged when there is an atypical genetic variant of plasma cholinesterase, when it is inhibited (eg, by pancuronium, organic phosphorus compounds, or donepezil), or when it is deficient (eg, from liver disease or plasmapheresis). The most important complications associated with use of NDNMBs arise from problems with patient care: undetected hypoventilation and prolonged drug effect. At subparalyzing doses, NDNMBs blunt the hypoxic ventilatory response without affecting the response to hypercapnia. NMBs have clinically important interactions with many xenobiotics and coexisting medical

conditions. In most neuromuscular diseases, sensitivity to NDNMB is increased. In renal failure, active metabolites of pancuronium and vecuronium can accumulate and cause prolonged block. Quantitative methods for analysis of blood and tissue NMB and metabolite concentrations have been described. Postmortem detection of succinylmonocholine or succinic acid cannot confirm the presence of premortem succinylcholine.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > F - Anesthetics and Related Medications > Antidotes in Depth - Dantrolene Sodium

Antidotes in Depth Dantrolene

Sodium

Kenneth M. Sutin Brian

Kaufman

Sanford M. Miller Dantrolene is an intracellular muscle relaxant. As such, it is the only drug proven to be effective for treatment and prophylaxis of malignant hyperthermia (MH). Although dantrolene is a hydantoin derivative that is structurally similar to local anesthetics and anticonvulsants, it possesses none of their properties.16,29

History

and

Dantrolene was first drug was first used Dramatic reversal of 1975,11 and shortly humans.15

Epidemiology synthesized in 1967.25 Four years later, the clinically to treat muscular spasticity.6 the course of porcine MH was described in thereafter dantrolene was studied in

Pharmacokinetics

Dantrolene is lipophilic and relatively insoluble in water. In plasma, dantrolene is reversibly bound to plasma proteins, especially albumin. The drug is metabolized in the liver by hydroxylation of the hydantoin ring or by reduction of the nitro group.29 Up to 25% of administered dantrolene is excreted in the urine as the 5-hydroxydantrolene metabolite, which is about half as potent as the parent drug.29 The elimination half-life is 4–8 hours for dantrolene and 15 hours for its primary metabolite. Dantrolene exhibits variable absorption by the small intestine, and peak blood concentrations are achieved 3–6 hours after ingestion. Oral bioavailability can be as high as 70%.16 Quantitative analysis of dantrolene and its metabolites has been performed using high-performance liquid chromatography.17 After a 2.4 mg/kg dose, the mean whole blood dantrolene concentration was 4.2 µg/mL.9

Mechanism Dantrolene acts at the skeletal muscle ryanodine receptor type 1 (RYR-1), causing dose-dependent inhibition of both steady and peak components of sarcoplasmic calcium release,26 reducing free myoplasmic calcium and thereby directly inhibiting excitation–contraction coupling.18 Dantrolene causes weakness but not total paralysis, and this plateau effect may be related to its poor solubility in water. In normal adults, a plateau in the twitch depression of the adductor pollicis muscle is reached at a dantrolene dose of 2.4 mg/kg IV, at which point the twitch suppression is 75% of baseline.9 Dantrolene does not change the electrical properties or excitation of nerve, neuromuscular junction (NMJ), or muscle, and it does not alter sarcoplasmic calcium reuptake. Because dantrolene does not bind to the cardiac ryanodine receptor RYR-2, it has minimal effects on the myocardium.10,28,32 It does not affect smooth muscle. Data indicate that the dantrolene binding site is at the N-terminus

of the RYR-1 receptor, specifically at the epitope composed of amino acids 590–609.20 [3 H]Dantrolene and [3 H]ryanodine appear to bind to the same sites on sarcoplasmic reticulum membrane fractions. At therapeutic concentrations, dantrolene inhibits binding of [3 H]ryanodine to the RYR-1 receptor.10

Indications Dantrolene is indicated for treatment of fulminant skeletal muscle hypermetabolism characteristic of MH and following an acute episode of MH to prevent recrudescence. Long-term oral dantrolene therapy is used rarely to treat chronic spasticity.14 Historically, dantrolene was used prophylactically in MHsusceptible individuals; however, current practice is simply to avoid exposure to MH-triggering drugs during anesthesia. Dantrolene should be considered for patients with severe hyperthermia when the diagnosis of MH cannot be excluded with certainty, especially with coexisting metabolic acidosis, coagulopathy, or rhabdomyolysis.8 Atypical presentations of MH in the presence or absence of triggering anesthetics are reported, especially in susceptible persons. In typical fulminant MH, the diagnosis is not subtle, and the course of treatment is obvious once the diagnosis is considered. This is not true when the clinical presentation is atypical. MH should be considered when hyperthermia is associated with severe hypermetabolism, increased CO2 production, lactic acidemia, hyperkalemia, and/or rhabdomyolysis, especially when the course is fulminating and refractory to supportive therapy. One important caveat: dantrolene given for hyperthermic disorders is not a substitute for aggressive cooling. For example, in heat stroke, the lowering of body temperature by active cooling alone is not accelerated when dantrolene is added.2,4 There are reports of dantrolene use for treatment of acute hyperthermia of other etiologies, including neuroleptic malignant

syndrome,1,24 heat stroke, monoamine oxidase inhibitor overdose,12 methylenedioxymethamphetamine (“ecstasy―) 22 13 overdose, intrathecal baclofen withdrawal, and thyroid storm.5 There is only anecdotal support for these indications, and scientifically rigorous proof that patients with any of these syndromes benefit from dantrolene therapy is lacking. However, it is worth emphasizing that the diagnosis of heat stroke7 or hyperthyroidism19 does not necessarily exclude the diagnosis of MH.

Dos i n g Dantrolene is supplied as a sterile lyophilized solution in a 70-mL vial that contains 20 mg dantrolene sodium and 3 g mannitol. Following reconstitution with 60 mL sterile water for injection, the pH is approximately 9.5. The initial dose of dantrolene for treatment of acute MH is an IV bolus of 2–3 mg/kg IV. It is repeated every 15 minutes until the signs of hypermetabolism are reversed or until a total dose of approximately 10 mg/kg has been administered. Occasionally higher doses are required. Following initial treatment, at least 1–2 mg/kg IV or PO should be given every 6 hours for 1–3 days to prevent recrudescence of the syndrome. Initial dosing probably should be determined by total body weight P.1038 given that dantrolene is lipophilic; however, its pharmacokinetics in obesity are not determined.9 The key point is that the total dose of dantrolene is determined by titration to a metabolic endpoint—resolution of skeletal muscle hypermetabolism. When an effective dose of dantrolene is given, signs of muscle hypermetabolism start to normalize within 30 minutes.15

Side

Effects

and

Toxicity

Following dilution, dantrolene has an alkaline pH and can cause

venous irritation and thrombophlebitis. No evidence indicates allergic cross-reactivity with dantrolene in patients with prior phenytoin allergy. Dantrolene and verapamil used in combination can cause hyperkalemia and decreased cardiac output; therefore, these drugs should not be combined.16,21 The mechanism of their interaction is unclear.23 Dantrolene given to healthy persons or for MH prophylaxis caused subjective skeletal muscle and diaphragm weakness (experienced as dyspnea) but not muscle paralysis.30,31 In healthy volunteers, dantrolene 2.5 mg/kg does not depress peak expiratory flow rate or vital capacity or alter end-tidal CO2 or respiratory rate.9 However, dantrolene may precipitate respiratory failure in patients with impaired respiratory reserve.16 Oral dantrolene may cause gastrointestinal upset, nausea, and vomiting. Other reported side effects include dizziness, lightheadedness, ptosis, difficulty focusing, and difficulty swallowing.9,31 When dantrolene is given orally for more than 2 months for treatment of muscular spasticity, there is a 1.8% risk of dose- and duration-related chronic hepatic inflammation, including elevated aminotransferase concentrations, hyperbilirubinemia, or jaundice27 that may not be reversible after dantrolene is discontinued.3

References 1. Bismuth C, Rohan-Chabot PD, Goulon M, Raphael J: Dantrolene—A new therapeutic approach to the neuroleptic malignant syndrome. Acta Neurol Scand 1984;70(Suppl 100):193–198. 2. Bouchama A, Knochel JP: Heat stroke. N Engl J Med

2002;346:1978–1988. 3. Chan C: Dantrolene sodium and hepatic injury. Neurology 1990;40:1427–1432. 4. Channa A, Seraj M, Saddique A, et al: Is dantrolene effective in heat stroke patients? Crit Care Med 1990;18:290–292. 5. Christensen PA, Nissen LR: Treatment of thyroid storm in a child with dantrolene. Br J Anaesth 1987;59:523. 6. Chyatte SB, Birdsong JH, Bergman BA: The effects of dantrolene sodium on spasticity and motor performance in hemiplegia. South Med J 1971;64:180–185. 7. Davis M, Brown R, Dickson A, et al: Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian

pedigrees.

Br

J

8. Denborough M: Malignant 1998;352:1131–1136.

Anaesth

2002;88:508–515.

hyperthermia.

Lancet

9. Flewellen E, Nelson T, Jones W, et al: Dantrolene dose response in awake man: Implications for management of malignant hyperthermia. Anesthesiology 1983;59:275–280. 10. Fruen BR, Mickelson JR, Louis CF: Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem 1997;272:26965–26971.

11. Harrison GG: Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth 1975;47:62–65. 12. Kaplan RF, Feinglass NG, Webster W, Mudra S: Phenelzine overdose treated with dantrolene sodium. JAMA 1986;255:642–644. 13. Khorasani A, Peruzzi WT: Dantrolene treatment for abrupt intrathecal baclofen withdrawal. Anesth Analg 1995;80:1054–1056. 14. Kita M, Goodkin DE: Drugs used to treat spasticity. Drugs 2000;59:487–495. 15. Kolb ME, Horne ML, Martz R: Dantrolene in human malignant

hyperthermia.

Anesthesiology

1982;56:254–262.

16. Krause T, Gerbershagen MU, Fiege M, et al: Dantrolene—A review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004;59:364–373. 17. Lalande M, Mills P, Peterson RG: Determination of dantrolene and its reduced and oxidized metabolites in plasma by high-performance liquid chromatography. J Chromatogr 1988;430:187–191. 18. Lopez JR, Gerardi A, Lopez MJ, Allen PD: Effects of dantrolene on myoplasmic free [Ca2+] measured in vivo in patients susceptible to malignant hyperthermia. Anesthesiology 1992;76:711–719.

19. Nishiyama K, Kitahara A, Natsume H, et al: Malignant hyperthermia in a patient with Graves' disease during subtotal thyroidectomy. Endocr J 2001;48:227–232. 20. Paul-Pletzer K, Yamamoto T, Bhat MB, et al: Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem 2002;277:34918–34923. 21. Rubin AS, Zablocki AD: Hyperkalemia, verapamil, and dantrolene. Anesthesiology 1987;66:246–249. 22. Rusyniak DE, Banks ML, Mills EM, Sprague JE: Dantrolene use in 3,4-methylenedioxymethamphetamine (ecstasy)mediated hyperthermia. Anesthesiology 2004;101:263. 23. Saltzman L, Kates R, Corke B, et al: Hyperkalemia and cardiovascular administration

collapse after verapamil and dantrolene in swine. Anesth Analg 1984;63:473–478.

24. Sing RF, Branas CC, Marino PL: Neuroleptic malignant syndrome in the intensive care unit. J Am Osteopath Assoc 1993;93:615–618. 25. Snyder HR, Jr, Davis CS, Bickerton RK, Halliday RP: 1-[(5arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants. J Med Chem 1967;10:807–810. 26. Szentesi P, Collet C, Sarkozi S, et al: Effects of dantrolene on steps of excitation-contraction coupling in mammalian skeletal muscle fibers. J Gen Physiol 2001;118:355–375. 27. Utili R, Boitnott J, Zimmerman H: Dantrolene-associated

hepatic injury: Incidence 1977;72:610–616.

and

character.

Gastroenterology

28. Van Winkle W: Calcium release from skeletal muscle sarcoplasmic reticulum: Site of action of dantrolene sodium? Science 1976;193:1130–1131. 29. Ward A, Chaffman M, Sorkin E: Dantrolene: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, and neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986;32:130–168. 30. Watson CB, Reierson N, Norfleet EA: Clinically significant muscle weakness induced by oral dantrolene sodium prophylaxis for malignant hyperthermia. Anesthesiology 1986;65:312–314. 31. Wedel D, Quilan J, Iaizzo P: Clinical effects of intravenously administered dantrolene. Mayo Clin Proc 1995;70:241–246. 32. Zhao F, Li P, Chen SR, et al: Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity. J Biol Chem 2001;276:13810–13816.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > G - Psychotropic Medications > Chapter 67 - Antipsychotics

Chapter

67

Antipsychotics David

Juurlink

A lethargic 41-year-old woman was brought to the emergency department by paramedics. Her husband found her unresponsive in the bedroom with an empty bottle at her side. He stated that she had a history of delusions and was under of a psychiatrist.

The patient was moderately obese, somnolent, and difficult to rouse. Her vital s were: blood pressure 95/50 mm Hg; pulse 128 beats/min and regular; respirato 10 breaths/min; and rectal temperature 100.6°F (38.1°C). The patient's skin

flushed, and her mucous membranes and axillae were dry. Gag reflex was absen there was no evidence of tongue biting or trauma. Both pupils were 3 mm in di and minimally responsive to light. The fundi could not be visualized. Examination cardiovascular and respiratory systems was unremarkable. Her abdominal exam revealed diminished bowel sounds but no tenderness or masses. The patient did respond to verbal commands, but she moaned and moved all extremities in resp vigorous sternal rub. Deep tendon reflexes were normal, the plantar responses flexion, and no clonus was present.

Two successive 2-mg boluses of naloxone were given intravenously (IV) with no response. Thiamine 100 mg IV also was given. When 2 L of 0.9% sodium chlorid

solution was administered IV, the blood pressure rose to 110/70 mm Hg. Initial blood gases determined on 40% oxygen were: pH, 7.38; PCO2 , 43 mm Hg; PO2 mm Hg; and HCO3 - , 24 mEq/L. Blood samples were sent for determination of electrolytes, glucose, creatinine, creatine kinase (CK), complete blood count, an acetaminophen.

A nasogastric tube was inserted. An abdominal radiograph showed a nonspecific gas pattern. The tip of the nasogastric tube was seen in the distal stomach, and activated charcoal was instilled. An electrocardiogram revealed sinus tachycardia normal QRS duration but a slightly prolonged QTc interval (QTc 450 msec). As t treating physician was preparing to intubate the patient, she roused somewhat

became agitated. Her speech was unintelligible, and she began thrashing on her stretcher.

The patient was placed in loose restraints to prevent her from injuring herself o medical staff. Review of the patient's medication history revealed she was being with olanzapine 10 mg daily, in addition to omeprazole, a transdermal nicotine and multivitamins. The olanzapine bottle was empty, and approximately 30 tabl

mg) were unaccounted for. Suspecting olanzapine overdose with prominent anticholinergic features, the physician administered 0.5 mg physostigmine after reviewing the electrocardiogram for widening of the QRS complex.

The patient received 2 more doses of physostigmine 0.5 mg over the next 10 m Her agitation lessened dramatically, and her heart rate fell to 92 beats/min. Alt she remained somnolent, she became much more communicative and began cry admitted to deliberately ingesting all of her olanzapine tablets following a dome dispute regarding financial difficulties.

The restraints were removed, and the patient was transferred to an observation where she was observed closely overnight. She received 3 additional 0.5-mg do physostigmine over the next 12 hours, during which time her vital signs remain and her mental status improved considerably. The following day she was transfe the inpatient psychiatry ward for further evaluation and treatment.

History

and

Epidemiology

Prior to the introduction of chlorpromazine in 1950, patients with schizophrenia

treated with nonspecific sedative agents such as barbiturates. Highly agitated p were housed in large mental institutions and often placed in physical restraints. approximately 500,000 patients with psychotic disorders were hospitalized in th States. The advent of the antipsychotics in the 1950s revolutionized the care of patients. These drugs, originally termed major tranquilizers and subsequently neuroleptics , dramatically reduced the characteristic hallucinations, delusions, paranoia that were characteristic of schizophrenia.

Shortly following the introduction of these drugs, however, it became apparent were potentially dangerous in overdose (a common occurrence in mentally ill p and that they caused P.1040

a host of adverse drugs effects, principally involving the endocrine and nervous The latter included the extrapyramidal syndromes (EPS), a constellation of diso were relatively common, sometimes irreversible, and occasionally life-threateni

The search for new drugs led to the development of several antipsychotics of v potencies and differing adverse effect profiles. The novel antipsychotic clozapine first synthesized in 1959, but it did not enter widespread clinical use until the e 1970s. Clozapine was not only relatively free of EPS, it was an extremely effect antipsychotic even in patients who had not responded well to other drugs. More unlike its predecessors, it often improved the negative symptoms of schizophren as avolition, alogia, and social withdrawal. Reports of agranulocytosis, sometim

led to the withdrawal of clozapine from the market in 1974, although it was rei in 1990.9 , 43 However, clozapine's unique therapeutic and pharmacologic prop rendered it an atypical antipsychotic, the forerunner and prototype of more than compounds that have collectively become the most widely used antipsychotics o past decade.

Most antipsychotic drug toxicity occurs by 1 of 2 mechanisms. Following overdo (intentional or unintentional), toxicity is dose related and reflects an extension drug's effects on neurotransmitter systems and other biologic processes. Howev idiosyncratic adverse reactions also can occur in the context of routine therapeu This toxicity results from individual susceptibility, usually is pharmacogenetic in and generally is unrelated to the antipsychotic dose. In both instances, the seve illness can range from minor to life threatening, depending on a host of other f

including concomitant drug exposures, comorbidity, and access to medical care.

The true incidence of antipsychotic drug reactions is not known with certainty. patients may not seek medical attention, whereas others may be misdiagnosed. among those who seek medical attention and are correctly diagnosed, notificatio poison centers or other adverse event reporting systems is discretionary and in (Chap. 130 ). With these limitations in mind, a few observations can be made.

In 2003, poison information centers in the United States were contacted about antipsychotic drug exposures. Of these reports, 32,422 were related to atypical antipsychotic agents and 4704 to phenothiazines.99 Other antipsychotics are no reported. By comparison, in 1993 phenothiazines were the sole category of antipsychotics and were the subject of 10,975 calls, despite 27% fewer total ca poison centers. 60 The changing pattern of antipsychotic overdose reflects the e of antipsychotic drug prescribing trends over the past decade.25 , 31 , 67

The vast majority of poison center calls pertain to intentional overdoses in patie years or older. Most of these patients have a good outcome. However, 94 fatali

reported in 2003, and only a minority of them occurred in patients with single-a antipsychotic overdose. A substantial body of clinical experience and some obs data suggest that the low-potency, typical antipsychotics, such as thioridazine, chlorpromazine and mesoridazine, are associated with greater toxicity than othe

antipsychotics.16 , 18 , 37 Inferences based upon aggregated population data re fatal toxicity should be extrapolated to individual patients with caution,16 , 37 bu least one well-done retrospective cohort study supports the notion that thiorida associated with greater adverse cardiovascular toxicity than other antipsychotic

Pharmacology Classification

Antipsychotics can be classified in a variety of ways, according to their chemica structure, their receptor binding profiles, or as “typical― or “atypical†antipsychotics. Table 67-1 outlines the taxonomy of some commonly used anti Classification by chemical structure was most useful prior to the 1970s, when phenothiazines and butyrophenones constituted most of the antipsychotic agents

clinical use. Currently, the surfeit of different compounds and their structural heterogeneity renders this scheme cumbersome and of limited use to clinicians. worth noting, however, that the phenothiazine antipsychotics bear a high degree structural similarity to the tricyclic antidepressants (TCAs) (Figure 67-1 ) and t share many of their manifestations in overdose. The phenothiazines can be furt subclassified according to the nature of the substituent on the nitrogen atom at 10 of the center ring as aliphatic, piperazine, or piperidine compounds.

Of greater clinical use is the classification of antipsychotics according to their b affinities for various receptors (Table 67-2 ). However, the most widely used classification system categorizes antipsychotics as either typical or atypical. Typ

called traditional or conventional ) antipsychotics dominated the first 40 years o antipsychotic therapy. They were categorized according to their affinity for the receptor as either low potency, as exemplified by thioridazine and chlorpromazin high potency, exemplified by haloperidol. These agents ameliorated the “po

symptoms― of schizophrenia, hallucinations, delusions, paranoia, and disorg of thought, but they were of little benefit for the sometimes disabling “nega symptoms― of schizophrenia: avolition, alogia, flattening of affect, and socia withdrawal. Moreover, they were associated with acute, subacute, and long-term disturbances collectively referred to as extrapyramidal syndromes (EPS).

The notion of antipsychotic atypicality has evolved over time with the introductio

compounds78 , 90 and connotes different properties to pharmacologists and clin From a clinical perspective, an atypical antipsychotic treats both the positive an negative symptoms of schizophrenia, is less likely than traditional drugs to prod at clinically effective doses, and causes little or no elevation of the serum prola concentration.49 From a pharmacologic perspective, most atypical antipsychotics inhibit the action of serotonin at the 5-HT2 A receptor. More than a dozen atypic antipsychotics are now in clinical use or under development. Despite their cons higher cost, these drugs have largely supplanted traditional antipsychotics becau their effectiveness in treating the negative symptoms of schizophrenia and their somewhat more favorable adverse effect profile.

Mechanisms

of

Antipsychotic

Drug

Action

Of the many contemporary theories of schizophrenia, the most enduring has bee

dopamine hypothesis . 87 First advanced in 1967 and supported by in vivo data,1 theory holds that the “positive symptoms― of schizophrenia (hallucination delusions, paranoia, and disorganization of thought) occur because of excessive dopaminergic signaling in the mesolimbic and mesocortical pathways.63 This hy was borne in part from the observation that hallucinations and delusions could b produced in otherwise normal individuals by drugs that increase dopaminergic transmission, such

P.1041 as cocaine and amphetamine, and that these effects could be blunted by dopam antagonists. Typical Antipsychotics Butyrophenones Droperidol 1.25–30 2–3 2–10 85–90 N Haloperidol 1–20 18–30 14–41 90 Y Diphenylbutylpiperidines Pimozide 1–20 11–62 28–214 99 Y Phenothiazines Aliphatic Chlorpromazine

100–800 10–35 18–30 98 Y Methotrimeprazine 2–50 23–42 17–78 NR Y Promazine 50–1000 30–40 8–12 98 N Promethazine 25–150 9–25 9–16 93 Y Piperazine Fluphenazine 0.5–20 220 13–58b 99 NR Perphenazine 8–64 10–35 8–12

>90 NR Prochlorperazine 10–150 13–32 17–27 >90 NR Trifluoperazine 4–50 NR 7–18 >90 Y Piperidine Mesoridazine 100–400 3–6 2–9 98 Y Thioridazine 200–800 18 26–36 96 Y Pipotiazine 25–250 (monthly IM depot) 7.5 3–11 NR N Thioxanthenes

Chlorprothixene 30–300 11–23 8–12 NR NR Flupentixol 3–6 7–8 7–36 NR NR Thiothixene 5–30 NR 12–36 >90 NR Zuclopenthixol 20–100 10 20 NR NR Atypical Antipsychotics Benzamides Amisulpride 50–1200 5.8 12 16 N Raclopride 3–6

1.5 12–24 NR N Remoxipride 150–600 0.7 3–7 80 Y Sulpride 200–1200 0.6–2.7 4–11 14–40 N Benzepines Dibenzodiazepine Clozapine 50–900 5.4 ± 3.5 6–17 95 Y Dibenzooxazepine Loxapinea 20–250 NR 2–8 90–99 Y Thienobenzodiazepine Olanzapine 5–20

10–20 21–54 93 N Dibenzothiazepine Quetiapine 150–750 10 3–9 83 N Indoles Benzisoxazole Risperidone 2–16 0.7–2.1 3–20 90 Y Imidazolidinone Sertindole 12–24 20–40 24–200 99 Y Benzisothiazole Ziprasidone 40–160 2 4–10 99 N Quinolinones

Aripiprazole 10–30 5 47–68 99 Y NR = not reported. a Loxapine's atypical profile is lost at doses >50 mg/d; hence it is sometimes c as a typical antipsychotic. b For hydrochloride salt; enanthate and decanoate have ranges of 3–4 days a 5–12 days, respectively. Adapted from references 10 ,12 ,14 ,35 ,47 ,51 . Usual Daily

Classification

Compound

Adult Dose (mg)

HalfVolume of Distribution (L/kg)

Life (Range, h)

Protein Binding (%)

A Me

TABLE 67-1. Classification of Commonly Used Antipsychotics

There are five subtypes of dopamine receptors (D1 –D5 ), but schizophrenia involves excess signaling at the D2 subtype.87 Antagonism of D2 neurotransmissi sine qua non of antipsychotic activity. Antipsychotics have different potencies at

receptor, reflected by the dissociation constant (Kd ), which in turn reflects rele the drug from the D2 receptor. For example, the receptor releases clozapine and quetiapine more rapidly than it does any other drugs.86 , 87

Dopamine receptors are present in many other areas of the central nervous sys (CNS), including the nigrostriatal pathway (substantia nigra, caudate, and puta which collectively govern the coordination of voluntary movement), tuberoinfun pathway, hypothalamus and pituitary, and area postrema of the brainstem, whi contains the chemoreceptor trigger zone (CTZ). Antipsychotic-related blockade o neurotransmission in these areas is associated with many of the other beneficia adverse effects of these drugs. For example, D2 antagonism in the CTZ alleviate

and vomiting, whereas blockade of hypothalamic D2 receptors increases prolacti by the pituitary, resulting in breast tenderness and galactorrhea. Blockade of nigrostriatal D2 receptors underlies many of the movement disorders associated antipsychotic therapy.93 , 103

Antipsychotics interfere with signaling at other receptors, including acetylcholine M 2 muscarinic receptors, H1 histamine receptors, and α-adrenergic receptors. extent to which these other receptors are blocked at doses that effectively block transmission is antipsychotic specific and can be used to predict a drug's advers profile.20 For example, drugs that antagonize muscarinic receptors at clinically doses (primarily the aliphatic and piperidine phenothiazines, clozapine, P.1042

loxapine, and olanzapine) often cause anticholinergic adverse effects during rou and can cause anticholinergic delirium following overdose (Table 67-2 ). Similar blockade of peripheral α1 -adrenergic receptors by the aliphatic and piperidine phenothiazines, clozapine, risperidone, and several other drugs more likely cau

postural hypotension during therapy and supine hypotension following overdose

Figure

67-1.

Structural

similarity

between

phenothiazines

and

tricyclic

antide

Several antipsychotics also block voltage-gated fast sodium channels (I N a ). Alt

this effect is of little consequence during therapy, in the setting of overdose the slow cardiac conduction (phase 0 depolarization) and impair myocardial contrac This effect, most notable with the phenothiazines, is both rate and voltage dep and therefore is more pronounced at faster heart rates and less negative trans potentials.17 Blockade of the delayed rectifier potassium current (IKr ) can prod prolongation of the QTc interval, creating a substrate for development of torsad pointes.68 QTc prolongation is sometimes evident during maintenance therapy, particularly in patients with previously unrecognized congenital QTc prolongation additional risk factors. This effect may partly explain the apparent increase in s cardiac death among patients treated with antipsychotic drugs.77 Clinical effect Hypotension

Central and peripheral anticholinergic effects QRS widening; rightward T40msec; myocardial QTc prolongation; torsades de pointes Typical agents Chlorpromazine +++ ++ ++ ++ Fluphenazine + + Haloperidol + ++ Loxapine +++ ++ ++ + Mesoridazine +++ +++ +++ ++ Perphenazine + + ++

depression

Pimozide + + ++ Thioridazine +++ +++ +++ +++ Trifluoperazine + + ++ Atypical agents Aripiprazole ++ Clozapine +++ +++ + Olanzapine ++ +++ Quetiapine +++ +++

+ - to + Remoxipride Risperidone ++ Sertindole + ++ Ziprasidone ++ +++ Adapted

from

references 17 ,20 ,41 ,79 ,81 .

Î ±1 -Adrenergic Antagonism

Muscarinic Antagonism

Fast Sodium Channel (IN a ) Blockade

Delayed R ( IK r ) Cu Blocka

TABLE 67-2. Toxic Manifestations of Selected Antipsychotics

Several antipsychotics exhibit a relatively high degree of antagonism at the 5-H receptor, which conveys two important therapeutic properties: (1) greater effica treatment of the negative symptoms of schizophrenia and (2) a significantly low incidence of extrapyramidal side effects. Several antipsychotics are distinguished

unique effects at other receptors. For example, loxapine and clozapine interfere reuptake of catecholamines and antagonize γ-aminobutyric acid (GABA)A recep which may explain the apparent increase in seizure activity with these agents.74 detailed description of the pharmacology of the commonly used atypical antipsy warranted given their increasing role in therapy.

Clozapine, a dibenzodiazepine compound, binds to dopamine receptors (D1 –D serotonin receptors (5-HT1A/1C , 5-HT2A/2C , 5-HT3 , and 5-HT6 ) with moderate affinity.9 , 75 , 81 It also antagonizes α1 -adrenergic, α2 -adrenergic, and H1 receptors. It has the highest binding affinity of any atypical antipsychotic at M1 muscarinic receptors.80 Despite this feature, clozapine paradoxically activates th genetic subtype of the muscarinic receptor and frequently produces sialorrhea therapy.79

Olanzapine, a thienobenzodiazepine, binds avidly to serotonin (5-HT2A/2C , 5-HT 5-HT6 ) and dopamine receptors (D1 , D2 , and D4 ), although its potency at D2 is lower than that of

P.1043 most traditional It is an exceptionally potent H1 antagonis more avidly than pyrilamine, which is a widely used antihistamine. It is also has affinity for M1 receptors and is a relatively weak α1 antagonist. antipsychotics.51 , 81

Risperidone, a benzisoxazole derivative, has high affinity for several receptors,

serotonin receptors (5-HT2A/2C ), D2 dopamine receptors, and α1 and H1 recep 79 , 81 It has no appreciable activity at M 1 receptors. Its primary metabolite (9hydroxyrisperidone) is nearly equipotent as the parent compound at D2 and 5-H receptors.51 Quetiapine, a dibenzothiazepine, is a weak antagonist at D2 , M1 , and 5-HT1 A but it is a relatively potent antagonist of α1 and H1 receptors.51 , 81 Of its 11 metabolites, at least 2 are pharmacologically active. However, they circulate at levels and likely contribute little to the drug's clinical effect. Ziprasidone, a benzothiazole derivative, is a several serotonin (5-HT 2A/2C , 5-HT1 D , and agonist activity at 5-HT1 A receptors.51 , 52 , strong, with a binding affinity approximately

potent antagonist at dopaminergic 5-HT7 ) receptors, but it also displa 81 Its α 1 antagonist activity is pa one tenth that of prazosin.

Aripiprazole, a quinolinone derivative, is a novel compound that binds avidly to D 2 and D3 receptors and serotonin 5-HT1 A , 5-HT2 A , and 5-HT2 B receptors.66 , evidence suggests that its efficacy in the treatment of schizophrenia and its low propensity for EPS may relate to partial agonist activity at dopamine D 2 recepto Aripiprazole acts as a partial agonist at serotonin 5-HT1 A receptors but is an an at serotonin 5-HT2 A receptors. Its principal active metabolite, dehydroaripiprazo affinity for dopamine D2 receptors and thus has some pharmacologic activity sim that of the parent compound.66

Pharmacokinetics

and

Toxicokinetics

With a few exceptions, the antipsychotics have similar pharmacokinetic charact regardless of their chemical classification. Most are lipophilic, have a large volum distribution, and are generally well absorbed, although anticholinergic effects m

absorption of some agents. Plasma concentration generally peak within 2 to 3 h a therapeutic dose, but this can be prolonged following overdose.

Most antipsychotics are substrates for the various isozymes of the hepatic cyto

P450 (CYP) enzyme system. For example, haloperidol, perphenazine, thioridazin sertindole, and risperidone are extensively metabolized by the CYP2D6 system, functionally absent in approximately 7% of white patients and overexpressed in of patients, depending on ethnicity.53 These polymorphisms appear to influence

tolerability and efficacy of treatment with these antipsychotics during therapeut 28 , 29 , 48 , 72 , 98 but likely do not alter the severity of antipsychotic overdose.

Drugs that inhibit CYP2D6, such as paroxetine, quinidine, and metoclopramide, increase the levels of these antipsychotic drugs and increase the risk of adverse In contrast, metabolism of clozapine is primarily mediated by CYP1A2, and incr clozapine levels can result following exposure to fluvoxamine, macrolide, and q antibiotics and after smoking cessation, which normally induces CYP1A2.33 The plays a relatively small role in the elimination of antipsychotics, and dose adjus generally is not necessary for patients with renal disease.

Pathophysiology

and

Clinical

Manifestations

Table 67-3 lists the adverse effects of antipsychotics. Some of these effects dev

following overdose, but many can occur during the course of therapeutic use.

Adverse

Effects

Extrapyramidal

During

Therapeutic

Use

Syndromes

The EPSs (Table 67-4 ) are a heterogeneous group of disorders that share the f abnormal muscular activity. Among the typical antipsychotics, the incidence of E appears to be highest with the more potent agents such as haloperidol and flup and lower with the less potent agents chlorpromazine and thioridazine. Atypical antipsychotics are associated with an even lower incidence of EPS. Although the physiologic mechanisms for this observation are not fully understood, several h have been put forth. In addition to the aforementioned antagonism of 5-HT2 A r some atypical agents dissociate more rapidly from the D2 receptor and incite a

degree of nigrostriatal dopaminergic hypersensitivity during chronic use.49 , 50 However, EPS can occur during treatment with any antipsychotic drug, regardles typicality or potency.

Acute

Dystonia

Acute dystonia is a movement disorder characterized by sustained involuntary m contractions, often involving the muscles of the head and neck, including the e muscles and the tongue, but occasionally involving the extremities. These cont are sometimes referred to as limited reactions , reflecting their transient nature

than their severity. All of the currently available antipsychotics are associated w dystonic reactions.93 Spasmodic torticollis, facial grimacing,

P.1044 protrusion of the tongue, and oculogyric crisis are among the more common manifestations. Laryngeal dystonia is a rare but potentially life-threatening vari is easily misdiagnosed because it can present with throat pain, dyspnea, stridor dysphonia rather than the usual features of dystonia.36 CNS Somnolence, coma Respiratory depression or loss of airway reflexes

Hyperthermia Seizures Extrapyramidal syndromes Central anticholinergic syndrome Cardiovascular Clinical Tachycardia Hypotension (orthostatic or resting) Myocardial depression Electrocardiographic QRS complex widening Right deviation of terminal 40 msec of frontal plane axis QTc interval prolongation Torsades de pointes Nonspecific repolarization changes Endocrine Amenorrhea, oligomenorrhea, or metrorrhagia Breast tenderness and galactorrhea Gastrointestinal Impaired peristalsis Dry mouth Genitourinary Urinary retention Ejaculatory dysfunction Priapism Ophthalmic Mydriasis or miosis Visual blurring Dermatologic Impaired sweat production Cutaneous vasodilation TABLE 67-3. Adverse Effects of Antipsychotics

Acute dystonia Hours to a few days Sustained, involuntary muscle contraction, torticollis, including blepharospasm, oculogyric crisis Imbalance of dopaminergic/cholinergic transmission Anticholinergics, benzodiazepines Akathisia Hours to days Restlessness and unease, inability to sit still Mesocortical D2 antagonism (?) Dose reduction, trial of alternate drug, propranolol, benzodiazepines, anticholin Parkinsonism Weeks Bradykinesia, rigidity, shuffling gait, masklike facies, resting tremor Postsynaptic striatal D2 antagonism

Dose reduction, anticholinergics, dopamine agonists Neuroleptic malignant syndrome 2–10 days Many (see Table 67-5 ): altered mental status, motor symptoms, hyperthermia, autonomic instability D 2 antagonism in striatum, hypothalamus, and mesocortex Cooling, benzodiazepines, supportive care, consider dantrolene, amantadine

bromocriptine,

Tardive dyskinesia 3 months to years Late-onset involuntary choreiform movements, buccolinguomasticatory moveme Excess dopaminergic activity Recognize early and stop offending drug; addition of other antipsychotic; cholin Adapted from references 73 , 93 .

Disorder

Time of Maximal Risk

Features

TABLE 67-4. The Extrapyramidal Syndromes

Postulated Mechanism

Possi Treatm

Acute dystonia often occurs within a few hours of starting of treatment but may delayed for up to a few days. Left untreated, dystonia resolves slowly over seve Risk factors include male gender, young age (children are particularly susceptib previous episode of acute dystonia, and recent cocaine use.94 , 103 Although the may appear dramatic and sometimes is mistaken for seizure activity, it rarely is threatening. Of note, drugs other than antipsychotics can sometimes cause acut dystonia, particularly metoclopramide, the antidepressants, some antimalarials, histamine H2 receptor antagonists, anticonvulsants, and cocaine.94

Treatment

of

Acute

Dystonia

Acute dystonia is generally more distressing than serious, but rare cases comp respiration, necessitating supplemental oxygen and, occasionally, assisted ven , 94 The response to parenteral anticholinergic agents often is rapid and dramat every effort should be made to administer benztropine as the first-line agent (2

intramuscularly in adults, or 0.05 mg/kg in children). Diphenhydramine often is readily available and can be used instead (50 mg IV or intramuscularly in adults mg/kg in children). Parenteral benzodiazepines such as lorazepam (0.05–0.10 IV or intramuscularly) or diazepam (0.1 mg/kg IV) should be used if patients do respond to anticholinergics, but they also important to recognize that because the shorter than that of most antipsychotics, additional doses of anticholinergic agents

can be effective as initial therapy. It elimination half-life of most anticholine dystonia can recur, and administering may be necessary over the next 48â€

hours.27 Patients in whom acute dystonia jeopardizes respiration should be obs at least 12–24 hours after initial resolution.

Akathisia

Akathisia (from the Greek, “not to sit―) is characterized by a feeling of in restlessness, anxiety, or sense of unease, often in conjunction with the objectiv of an inability to sit still. Patients with akathisia frequently appear uncomfortabl fidgety. They may rock back and forth while they are standing, or they may rep cross and uncross their legs while they are seated. Akathisia can be difficult to and may be misinterpreted as a manifestation of the underlying psychiatric illne especially anxiety.

Akathisia is common and may be an important determinant of adherence to the acute dystonia, akathisia tends to occur relatively early in the course of treatme coincides with peak antipsychotic concentrations in plasma.103 The incidence ap highest with typical, high-potency antipsychotics and lowest with atypical agent Although most cases develop within days to weeks after initiation of treatment o increase in dose, a delayed-onset or tardive variant is recognized.

The pathophysiology of akathisia is incompletely understood but appears to inv antagonism of postsynaptic D2 receptors in the mesocortical pathways.62 , 93 Interestingly, a similar phenomenon may occur in patients after commencing tr with antidepressants, particularly the selective serotonin reuptake inhibitors.8 ,

Treatment

of

Akathisia

Akathisia can be difficult to treat. A reduction in the antipsychotic dose is some helpful, as is substitution of another (generally atypical) antipsychotic drug. Tr with lipophilic β-adrenergic antagonists such as propranolol may reduce the sy of akathisia, but little evidence supports their use.56 , 73 Benzodiazepines term relief.57 Anticholinergics such as benztropine or procyclidine may

produ

P.1045 reduce symptoms of akathisia, although they more likely will be effective for ak induced by antipsychotics with little or no intrinsic anticholinergic activity.19 , 5

Parkinsonism

Antipsychotic drugs can produce a parkinsonian syndrome characterized by rigi akinesia or bradykinesia, and postural instability. It is similar to the idiopathic disease, although the classic “pill-rolling― tremor is often less pronounce syndrome typically develops during the first few months of therapy, particularly high-potency agents. It is more common among older women. Parkinsonism is t result from antagonism of postsynaptic D2 receptors in the striatum.93

Treatment

of

Drug-Induced

Parkinsonism

The incidence of drug-induced parkinsonism can be minimized by using the lowe effective dose of antipsychotic. The addition of an anticholinergic attenuates sy

This strategy often is effective in younger patients, although the routine use of prophylactic anticholinergics is not recommended. Addition of a dopamine agoni as amantadine is sometimes used, particularly in older patients who may be les of anticholinergic drugs, but it occasionally aggravates the underlying psychiatr disturbance.61

Tardive

Dyskinesias

The term tardive dyskinesia was coined in 1952 to describe the delayed onset o persistent orobuccal masticatory movements occurring in 3 women after severa of antipsychotic therapy.93 The adjective tardive , or late, was used to distingu movement disorders from those the parkinsonian movements described above. incidence of tardive dyskinesia in younger patients is approximately 3–5% per rises considerably with age. A prospective study of older patients treated with h

potency typical antipsychotics identified a 60% cumulative incidence of tardive dyskinesia after 3 years of treatment.46 Potential risk factors for tardive dyskin include alcohol use, affective disorder, prior electroconvulsive therapy, diabetes and various genetic factors.93

Several distinct tardive syndromes are recognized, including the classic orobucc masticatory stereotypy, chorea, dystonia, myoclonus, blepharospasm, and tics.9

generally accepted that the atypical antipsychotics are associated with a lower of tardive dyskinesia and other drug-related movement disorders. However, wh is true of all atypical antipsychotics is unclear. Among the atypical antipsychotic clozapine is associated with the lowest incidence of tardive dyskinesia and rispe with the highest incidence (when higher doses are used), although the reasons observation are uncertain.73 , 91 , 93

Treatment

of

Tardive

Dyskinesia

Tardive dyskinesia is highly resistant to the usual pharmacologic treatments for movement disorders. Anticholinergics do not alleviate tardive dyskinesia and ma it. Calcium channel blockers, β-adrenergic antagonists, benzodiazepines, and vi have been of limited success.34 Clozapine appears to suppress tardive dyskines temporarily. Although discontinuation of the causative agent may not produce t of symptoms, when possible the antipsychotic should be discontinued as soon as

symptoms

begin.

Neuroleptic

Malignant

Syndrome

Neuroleptic malignant syndrome (NMS) is a potentially life-threatening neurolog emergency. First described in 1960 in patients treated with haloperidol, this sy has been associated with virtually every antipsychotic.30 The reported incidence ranges from 0.2–1.4% of patients receiving antipsychotics,2 , 22 but less seve episodes may go undiagnosed or unreported. As a result, much of what is know the epidemiology and treatment of NMS is speculative and based upon case rep case series.

The pathophysiology of NMS is incompletely understood but appears to involve reductions in central dopaminergic neurotransmission in the hypothalamus, alte

core temperature “set point―39 and leading to altered thermoregulation a manifestations of autonomic dysfunction. Blockade of striatal D2 receptors contr muscle rigidity and tremor. 13 , 24 , 95 In some cases, a direct effect on skeletal

may play a role in the pathogenesis of hyperthermia.39 Altered mental status is multifactorial and may reflect hypothalamic and spinal dopamine receptor antag genetic predisposition, or the direct effects of hyperthermia and other drugs.40 also appears to play a role in the pathogenesis of NMS, because antipsychotics antagonize

5-HT2 A receptors seem to be associated with a lower incidence of N

Although NMS most often occurs during treatment with a D2 receptor antagonis withdrawal of dopamine agonists can produce an indistinguishable syndrome. Th

typically occurs in patients with long-standing Parkinson disease who abruptly c discontinue treatment with dopamine agonists such as levodopa/carbidopa, am or bromocriptine.13 Hospitalization for aspiration pneumonia, a common occurre older patients with Parkinson disease, is a particularly high-risk setting for NMS particularly dangerous because the cardinal manifestations of NMS are easily misattributed to the combined effects of infection and the underlying movemen

The vast majority of NMS cases occur in the context of therapeutic use of antip rather than following overdose. Postulated risk factors for the development of N include young age, male gender, extracellular fluid volume contraction, use of h potency antipsychotics, depot preparations, cotreatment with lithium, multiple d combination, and rapid dose escalation.2 , 23 , 54

The manifestations of NMS include the tetrad of altered mental status, muscula (classically “lead pipe―), hyperthermia, and autonomic dysfunction. These symptoms can appear in any sequence, although a review of 340 NMS cases fou mental status changes and rigidity usually preceded the development hyperther autonomic instability.96 Signs typically evolve over a period of several days, wit majority occurring within 2 weeks of starting treatment. However, it is importan recognize that NMS can occur even after prolonged use of an antipsychotic, pa following a dose increase or the addition of another drug.

There is no gold standard for the diagnosis of NMS, and at least 4 different sets criteria are proposed.32 , 3 , 22 , 54 The operating characteristics of these criteria not been formally evaluated. The criteria set forth by the Diagnostic and Statis Manual of Mental Disorders , 4th edition (DSM-IV) are perhaps the most widely

their principal limitation is that they make no provision for a causal relationship drugs other than antipsychotics.32 Because NMS is an uncommon and potentiall threatening disorder with highly variable clinical manifestations and no diagnost standard, an algorithmic approach to diagnosis in inadvisable. Rather, clinicians be aware of its many

P.1046 possible clinical and laboratory features (Table 67-5 ) and entertain the possibil NMS in any unwell patient receiving an antipsychotic, particularly when altered mentation, unexplained fever, or muscle rigidity is present.

Altered mental status Delirium, lethargy, confusion, stupor, catatonia, coma Motor symptoms “Lead pipe― rigidity, cogwheeling, dysarthria or mutism, parkinsonian sy akinesia, tremor, mutism, dystonic posture, dysphagia, dysphonia, choreiformm Hyperthermia Temperature >100.4°F (38°C) Autonomic instability Tachycardia, diaphoresis, sialorrhea, incontinence, respiratory irregularities, ca dysrhythmias, hypertension or hypotension Laboratory findings Increased muscle enzymes (creatine kinase, lactate dehydrogenase, aldolase),

leukocytosis, renal insufficiency (reflecting volume contraction and pigmentnephropathy), acidemia, myoglobinuria, modest aminotransferase eleva hypoxia, hyponatremia, increased prothrombin time/partial thromboplastin time These manifestations can occur in any combination, although hyperthermia and degree of increased muscular activity usually are present. Some manifestations fleeting. A supportive medication history (see text) is essential to the diagnosis, every effort should be made to exclude other potential causes, such as other m illnesses and other drugs and toxins. Adapted from references 2 ,23 ,54 ,95 . Feature

Potential

Manifestations

TABLE 67-5. Clinical and Laboratory Features of the Neuroleptic Mali Syndrome

Treatment Measures

of

Neuroleptic

Malignant

Syndrome:

Ge

Treatment recommendations are largely based on general physiologic principles, reports, and case series. Therapy should be individualized according to the seve duration of illness and the modifying influences of comorbidity.13 , 97

The provision of good supportive care is the cornerstone for treatment of NMS. essential to recognize the condition as an emergency and to withdraw the offen

agent immediately. When NMS ensues after abrupt discontinuation of a dopamin such as levodopa, the drug should be reinstituted promptly. Most patients with should be admitted to an intensive care unit. Supplemental oxygen should be administered, and assisted ventilation may be necessary in cases of respiratory which can result from central hypoventilation, loss of protective airway reflexes, rigidity of the chest wall muscles.

The hyperthermia associated with NMS is multifactorial in origin and, when pres should be treated aggressively. For those with life-threatening hyperthermia, s in an ice-water bath is the most rapidly efficient technique (Chap. 16 ). In patie less severe illness, evaporative cooling can be accomplished by removing the p

clothing, spraying the patient with lukewarm water, and maintaining constant a circulation with the use of fans.100

Hypotension should be treated initially with large volumes of 0.9% sodium chlo solution, followed by vasopressors if necessary. Alkalinization of the urine with bicarbonate may reduce the incidence of myoglobinuric renal failure in patients creatine kinase concentrations, but maintenance of euvolemia and adequate ren perfusion are of greater importance. Tachycardia does not require specific treat bradycardia may necessitate the use of transcutaneous or transvenous electrica Venous thromboembolism is a major cause of morbidity and mortality in patient NMS, and prophylactic doses of low-molecular-weight heparin should be conside patients who likely will be immobilized for more than 12–24 hours.

Pharmacologic Syndrome

Treatment

of

Neuroleptic

Malignant

Benzodiazepines are the most widely used pharmacologic adjuncts for treatment and are considered first line-therapy. Dantrolene and bromocriptine are not wel and their incremental benefit over good supportive care is debated.83 However, drugs are associated with relatively little toxicity, and the absence of definitive should not preclude their use, particularly in patients with moderate or severe

Benzodiazepines are frequently used in the management of NMS because of the onset of action, which is particularly important when patients are agitated or re Benzodiazepine actions are nonspecific in nature, but they presumably attenuate sympathetic hyperactivity that characterizes NMS40 by facilitating GABA-mediat chloride transport and producing neuronal hyperpolarization, in a fashion analog their beneficial effects in cocaine toxicity. The primary disadvantage of benzod is that they may cloud the assessment of mental status.

Dantrolene reduces skeletal muscle activity by inhibiting ryanodine receptor cal release channels, thereby interfering with calcium release from the sarcoplasmi reticulum. In theory, this process should reduce body temperature and total ox consumption. It also should lessen the risk of myoglobinuric renal failure. Dantr been suggested to be more useful when muscular rigidity is a prominent feature NMS.13 Dantrolene can be given by mouth (50–100 mg/d) or by IV infusion (

mg/kg/d, or up to 10 mg/kg/d in severe cases), although the latter requires lab reconstitution.13

Bromocriptine is a centrally acting dopamine agonist that is given orally or by nasogastric tube at doses of 2.5–10 mg, 3–4 daily. The rationale for its use the belief that reversal of antipsychotic-related striatal D2 antagonism will ame manifestations of NMS. Other dopamine agonists anecdotally associated with su include levodopa70 , 88 and amantadine.38 , 45 When these drugs are used, they be tapered slowly after the patient improves to minimize the likelihood of recru NMS. In severe cases, combined therapy with dantrolene and a dopamine agonis considered given their relative safety.

Electroconvulsive

Therapy

Electroconvulsive therapy (ECT) has been reported to dramatically improve the manifestations of NMS, presumably by enhancing central dopaminergic transmiss report, 5 patients received an average of 10 ECT treatments, and resolution wa

generally seen after the third or fourth session.69 Whether this result represents effect of ECT or

P.1047 simply the natural course of NMS with good supportive care alone is not clear. A drug therapies for NMS, the efficacy of ECT remains unclear and its indications speculative, but its use seems reasonable in patients with severe, persistent, or

treatment-resistant NMS and for those with residual catatonia or psychosis follo resolution of other manifestations.13 , 69

Adverse

Effects

on

Other

Organ

Systems

Sedation, dry mouth, and urinary retention occur commonly with antipsychotics particularly during the initial period of therapy. These symptoms occur most co with drugs having potent antihistaminic and antimuscarinic activity. All drugs ca the seizure threshold, but seizure activity rarely complicates therapeutic use in without additional risk factors. Because hypothalamic dopamine normally inhibit prolactin release by the pituitary gland, all antipsychotics with dopamine antago properties can cause hyperprolactinemia and galactorrhea.

The atypical antipsychotic agents are associated with weight gain, dyslipidemia, steatohepatitis, and rare but dramatic instances of glucose intolerance, includin cases of diabetic ketoacidosis.6 , 42 , 76 , 92 Other idiosyncratic reactions reporte use of antipsychotics include photosensitivity, skin pigmentation and cholestatic (which occur with the phenothiazines), myocarditis, and agranulocytosis (which with several drugs but most notably clozapine, ie, between 0.38% and 2% of p Most of these conditions result from an immunologically based hypersensitivity and develop during the first month of therapy.

Acute

Overdose

Antipsychotic overdose can produce a spectrum of toxic manifestations affecting organ systems, but most serious toxicity involves the CNS and cardiovascular s Some of these manifestations are present to a minor degree during therapeutic

They tend to be most pronounced during the early period of therapy but dissipa continued use.

Impaired consciousness is a common and dose-dependent feature of antipsycho

overdose, ranging from somnolence to frank coma. It may be associated with im airway reflexes, but significant respiratory depression is uncommon. Many antipsychotics, including several of the atypical drugs, are potent muscarinic a and can produce dramatic anticholinergic manifestations in overdose.11 , 20 , 26

Peripheral manifestations include tachycardia, decreased production of sweat an flushed skin, urinary retention, diminished bowel sounds, and mydriasis, althou also occurs. These findings may be present in isolation or coexist with central manifestations, which can be highly variable and may be mistakenly attributed t underlying psychiatric illness. These manifestations include agitation, delirium, psychosis, hallucinations, and coma.

Mild elevations in body temperature are common and reflect impaired heat diss because of impaired sweating and increased heat production in agitated patient Elevations in body temperature should always prompt a search for other manif of NMS. Tachycardia is a common finding in patients with antipsychotic overdose reflects peripheral anticholinergic effects as well as a compensatory response to hypotension. Bradycardia is distinctly uncommon. Although it may be a preterm event, its presence should prompt a search for alternate causes, including other

(particularly β-adrenergic antagonists, calcium channel blockers, cardioactive and opioids) and myocardial ischemia. Hypotension is a common feature of ant overdose. Peripheral α1 -adrenergic blockade reduces vasomotor tone. Central maintenance of vasomotor tone may be impaired, albeit by an unknown mechan

The electrocardiographic (ECG) manifestations of antipsychotic overdose are sim those of TCA toxicity (Chaps. 5 and 7 1 ) and include widening of the QRS compl rightward deflection of the terminal 40 msec of the QRS complex (T40msec, a t terminal component of the QRS complex in lead aVR). These changes reflect blo the inward sodium current (IN a ). Prolongation of the QTc interval results from of the delayed rectifier potassium current (IKr ), creating a substrate for develo

torsade de pointes.68 This situation is sometimes evident during maintenance t and may underlie the apparent increase in sudden cardiac death among users o antipsychotic drugs.77 A published meta-analysis of the operating characteristics ECG in patients with TCA toxicity found the ECG was a relatively poor predictor

seizures, dysrhythmia, and death.7 However, the ECG is a dynamic instrument, particularly in the initial hours following overdose, and few studies have evalua longitudinal changes in the ECG.55

Diagnostic

Tests

The diagnosis of antipsychotic poisoning is supported by the clinical history, the

examination, and a limited number of adjunctive tests. Both the clinical and electrocardiographic findings are nonspecific and can occur following overdose o different drug classes, including TCAs, skeletal muscle relaxants, carbamazepine first-generation antihistamines. Moreover, the absence of typical ECG changes d exclude a significant antipsychotic ingestion, particularly early following overdose least 1 additional ECG should be performed in the following 2–3 hours. Historically, positive urine colorimetric test strips indicated the presence of densities in the gastrointestinal tract, radiopaque. However, these tests are routinely recommended.

testing using ferric chloride or Phenistix phenothiazines. Abdominal radiography ma as some solid dosage forms of phenothiaz neither sensitive nor specific, and they ar

Plasma concentrations of antipsychotics are not widely available, do not correlat

with clinical signs and symptoms, and do not help guide therapy. Comprehensiv drug screens using high-performance liquid chromatography or gas chromatogr mass spectrometry may indicate the presence of antipsychotics, but these tests available at only a few hospitals and provide only a qualitative result. Blood and immunoassays for TCAs may yield a false-positive result in the presence of phenothiazines. 5 , 82

Management

The care of a patient with an antipsychotic overdose should proceed with the r that other drugs, particularly other psychotropics, may have been coingested an confound both the clinical presentation and management. Regularly encountered coingestants include antidepressants, sedative-hypnotics, anticholinergic agents acid, and lithium, as well as ethanol and nonprescription analgesics such as acetaminophen

and

aspirin.

P.1048 Supportive care is the cornerstone for treatment of patients with antipsychotic Supplemental oxygen should be administered if hypoxia is present. Patients wit

mental status should receive thiamine, naloxone, and parenteral dextrose as ne Intubation and ventilation are rarely required but may be necessary for patients very large overdoses of antipsychotic agents or ingestion of other CNS depressa symptomatic patients should undergo continuous cardiac monitoring. In addition electrocardiogram should be recorded and reliable venous access obtained. Asymptomatic patients with a normal electrocardiogram 6 hours after exposure exceedingly low risk of complications and no longer require cardiac monitoring. Symptomatic patients and those with an abnormal ECG should have continuous monitoring for a minimum of 24 hours.

Gastrointestinal

Decontamination

Gastrointestinal decontamination with activated charcoal (1 g/kg by mouth or nasogastric tube) should be considered for patients who present within a few ho large or polydrug overdose. Although this intervention is unproven and time se many antipsychotics exhibit significant antimuscarinic activity and slow gastric

which increase the likelihood that activated charcoal will be beneficial. Orogastr and whole-bowel irrigation likely will not improve clinical outcomes, and induced is absolutely contraindicated because of the high potential for pulmonary aspira

Treatment

of

Cardiovascular

Complications

Vital signs should be monitored closely. Hypotension may result from peripheral blockade and most likely occurs with older, low-potency antipsychotics such as thioridazine. The hypotension should be treated initially with appropriate titratio 0.9% sodium chloride solution (30–40 mL/kg). If vasopressors are required, acting α agonists such as norepinephrine or phenylephrine are preferred over dopamine, which is an indirect agonist and likely will be ineffective. Vasopressin analogs also can be used. Continuous, intraarterial blood pressure monitoring m warranted in these cases. Central venous pressure monitoring and pulmonary a

catheterization rarely influence treatment decisions and should be used only if t patient's clinical status is obfuscated by significant coingestion or comorbidity.

Progressive widening of the QRS complex (usually with thioridazine and mesori

reflects sodium channel blockade and slowing of phase 0 depolarization in the H Purkinje system. This condition may be associated with reduced cardiac output malignant ventricular dysrhythmias. Sodium bicarbonate (1–2 mEq/kg) is the therapy for ventricular dysrhythmias and should be considered for patients with

dysrhythmias or QRS widening >0.12 seconds. The rationale for this strategy is upon the treatment of cyclic antidepressant overdose (Antidotes in Depth: Sodiu Bicarbonate and Chap. 71 ) At least 2 mechanisms underlie the beneficial effect sodium bicarbonate. First, the degree of sodium channel blockade is lessened by increase in extracellular sodium. In fact, hypertonic saline alone may be benefi Second, the binding of these drugs to the sodium channel is pH dependent, with extensive binding at higher pH.

Repeated doses of bicarbonate can be given to achieve a target blood pH of 7.5. patient is intubated, hyperventilation also can be used but is not comparably e If ventricular dysrhythmias persist despite sodium bicarbonate, lidocaine (1–2 followed by continuous infusion) is a reasonable second-line antidysrhythmic ag Class IA antidysrhythmics (procainamide, disopyramide, and quinidine), class IC antidysrhythmics (propafenone, encainide, and flecainide), and class III antidy

(amiodarone, sotalol, and bretylium) can aggravate cardiotoxicity and should no used. When administering sodium bicarbonate to patients with antipsychotic ov caution must be taken to avoid hypokalemia, as many of these antipsychotics b cardiac potassium channels thereby prolonging the QTc . Hypokalemia can exac this blockade and potentially produce torsades de pointes.

Sinus tachycardia should not be treated unless it is associated with active ische which, although uncommon, may complicate antipsychotic overdose in patients existing coronary disease. Should sinus tachycardia occur, a short-acting β-ad antagonist such as esmolol may be preferable. Prolongation of the QTc interval no specific treatment other than correction of potential contributing causes such

hypokalemia and hypomagnesemia. Torsades de pointes should be treated with magnesium sulfate, taking care to prevent hypotension, which is dose and rate dependent. Overdrive pacing with isoproterenol or transcutaneous or transvenou should be considered if the patient does not respond to magnesium sulfate, alth theory this therapy may worsen the rate-dependent sodium channel blockade.

Treatment

of

Seizures

Seizures associated with antipsychotic overdose are generally short-lived and o require no pharmacologic treatment. Multiple or refractory seizures should prom search for other causes, including hypoglycemia and ingestion of other proconv

medications. When treatment is necessary, benzodiazepines such as lorazepam diazepam generally suffice, although phenobarbital may be necessary. Although phenytoin is part of the standard algorithm for status epilepticus, it is ineffectiv xenobiotic-induced seizures; barbiturates are preferred. Refractory seizures sho respond to propofol infusion or general anesthesia. Seizures complicated by hyperthermia are considerably more ominous and warrant aggressive lowering o temperature with aggressive rapid cooling measures. Finally, seizures can abrup serum pH and abruptly increase the cardiotoxicity of these drugs; therefore, an should be recorded following resolution of seizure activity.

Treatment

of

the

Central

Antimuscarinic

Syndr

Many of the older-generation and newer-generation antipsychotics have pronou

anticholinergic properties. Case reports and observational studies suggest that cholinesterase inhibitor physostigmine (Antidotes in Depth: Physostigmine Salic can safely and effectively ameliorate the agitated delirium associated with the anticholinergic syndrome by indirectly increasing synaptic acetylcholine levels.2 , 101 Although benzodiazepines will control agitation, they will further impair m status, obfuscating the assessment of mental status and increasing the risk of complications.21

Physostigmine should be used with caution. It should not be used in patients wi dysrhythmias, any degree of heart block, or widening of the QRS complex. If physostigmine is used, it should be given in 0.5-mg increments every 3–5 mi

with close observation of the patient. If bradycardia, bronchospasm, or broncho develop, they can be treated with glycopyrrolate 0.2 to 0.4 mg IV. Atropine also

P.1049 be used, although it crosses the blood–brain barrier and may further worsen underlying delirium. Physostigmine's effects are transient, typically ranging from

30–90 minutes, and additional doses are often necessary. Of note, physostigm not prevent other complications of antipsychotic overdose, particularly those in the cardiovascular system.

Other commonly used cholinesterase inhibitors, such as edrophonium, neostigm pyridostigmine, should not be used to treat anticholinergic delirium because they cross the blood–brain barrier. Case reports involving other anticholinergics su

that cholinesterase inhibitors used for treatment of dementia (eg, tacrine, done galantamine) may be alternatives to physostigmine for patients who can take medications orally.44 , 64 , 71

Enhanced

Elimination

No pharmacologic rationale supports the use of multiple-dose charcoal or manip urinary pH to increase the clearance of antipsychotics. One volunteer study foun urinary acidification may increase remoxipride elimination,102 but this practice impractical and possibly dangerous. Because most antipsychotics have large vol distribution and extensive protein binding (Table 67-1 ), neither hemodialysis n hemoperfusion is expected to significantly increase clearance. These modalities be considered only if the patient has concomitantly ingested other xenobiotics

to extracorporeal removal, such as lithium.

Summary

Over the past decade, the atypical antipsychotics have largely supplanted tradi drugs, which were associated with greater toxicity in overdose and a higher inc extrapyramidal reactions. Consequently, atypical antipsychotics are now implicat majority of overdoses.

With both typical and atypical antipsychotics, toxicity can occur either during th of therapy or following overdose. Of the various toxicities that arise during the use, NMS is the most dangerous. Its manifestations are protean, and it may be to recognize. Altered mental status, muscle rigidity, fever, and autonomic insta its hallmarks, but the diagnosis should be considered in any unwell patient trea

antipsychotics, particularly in the 2 weeks following a change in the antipsychot regimen. Treatment of NMS is largely supportive and often dependent on use of benzodiazepines. Dantrolene, dopamine agonists such as bromocriptine, and electroconvulsive therapy are anecdotally associated with dramatic clinical imp

The principal manifestations of antipsychotic overdose involve the CNS and cardiovascular system. Depressed mental status, hypotension, and anticholinerg are nonspecific features that support particularly in conjunction with typical prolongation. Most fatalities following coingestion of other CNS depressants

the diagnosis of antipsychotic overdose, ECG findings of sodium channel blockade antipsychotic overdose occur in cases inv or cardiotoxic medications. Supportive care

mainstay of therapy for patients with antipsychotic overdose, although selective nonspecific antidotes, such as activated charcoal, sodium bicarbonate, and physostigmine, may improve outcomes in some patients.

Acknowledgments

Frank LoVecchio and Neal Lewin contributed to this chapter in a previous edition

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > G - Psychotropic Medications > Chapter 68 - Lithium

Chapter

68

Lithium Howard A. Greller Lithium MW Lithium

levels

=

6.94

daltons

=

0.6–1.2 (mmol/L)

(serum):

Therapeutic level for bipolar depression

mEq/L

A 55-year-old man was brought to the emergency department (ED) with a 3-day history of progressively worsening confusion and tremor. The patient was an accountant and normally was a highly functioning, intelligent person. Eight days prior to presentation, he saw his primary care physician for complaints of fever, chills, cough, myalgias, arthralgias, and malaise. Symptomatic therapy with an oral decongestant, acetaminophen, and oral hydration was prescribed. His symptoms improved, but he became progressively more confused and tremulous.

Upon questioning the family, the patient was found to have a medical history significant for bipolar disorder, for which he was receiving a stable dose of lithium carbonate for more than 10 years. He had no psychiatric hospitalizations, no history of suicide attempts, and took no other psychiatric medications. No other medications were available in the household. On physical examination, the patient was a well-appearing, slightly disheveled man in no apparent respiratory distress. His vital signs were: blood pressure, 135/86 mm Hg; pulse, 105 beats/min and regular; respiratory rate, 14 breaths/min; temperature, 99.5°F (37.5°C); oxygen saturation, 97% on room air; and a rapid bedside glucose concentration, 106 mg/dL. Examination revealed prominent horizontal nystagmus. Pupils were equal, round, and reactive to light and accommodation. The oral mucosa were dry, but the remainder of the head and neck examination was unremarkable. The chest was clear to auscultation regular rate or gallops. examination

and percussion. Cardiac examination revealed a and rhythm, without the presence of murmurs, rubs, Abdominal examination was unremarkable, and rectal revealed good rectal tone, a normal prostate, and no

occult blood. The skin was warm, dry, and free of rashes or other findings. The patient had difficulty complying fully with the neurologic examination because of his altered level of consciousness. He was alert and oriented to person but disoriented to time and place. Throughout the examination, he continuously attempted to get off the bed so that he could “attend an important meeting.― He was mildly agitated and had a noticeable tremor in his upper extremities. His cranial nerves were normal with the exception of his horizontal nystagmus. His motor strength was normal and symmetric. All deep tendon reflexes were hyperactive and symmetric with clonus in both ankles. The patient was unable to comply with formal cerebellar function testing.

The patient was attached to a cardiac monitor, and 2 L oxygen was administered by nasal cannula. A large-bore intravenous catheter was inserted, and blood samples were obtained for determination of serum electrolytes, complete blood count (CBC), acetaminophen, salicylate, ethanol and lithium concentrations. An infusion of 0.9% sodium chloride solution was started. An electrocardiogram showing sinus tachycardia at a rate of 105, with normal axis, intervals, and T waves and no evidence of acute STsegment changes. A chest radiograph showed no evidence of active or acute pulmonary disease. The patient was sedated with 1 mg intravenous lorazepam for persistent agitation. The serum lithium concentration was reported as 2.74 mEq/L, and a repeat specimen was drawn and sent for analysis. The acetaminophen, salicylate and ethanol concentrations were negative. The blood urea nitrogen (BUN)/Cr ratio of 21/1.3 mg/dL was elevated compared to a ratio of 9/0.8 mg/dL determined 3 weeks earlier. All other laboratory values were unremarkable. Infusion of 0.9% sodium chloride solution was increased to 2 times the maintenance rate, and a nephrology consultation was requested. The repeat lithium concentration was 2.38 mEq/L. Based on the combination of clinical and laboratory findings, hemodialysis was initiated. After 4 hours of hemodialysis the patient's mental status improved by all measures. The immediate postdialysis lithium concentration was 0.74 mEq/L, and the concentration 6 hours postdialysis was 1.41 mEq/L, after which the patient underwent a second P.1053 4-hour dialysis. The lithium concentration after the second dialysis was 0.97 mEq/L and did not rebound higher during the remainder of the hospitalization. When the patient was discharged on hospital day 3, he has a normal neurologic examination and had returned to his baseline mental status.

History Lithium has a long history of use beginning in the mid-19th century, when lithium salts were used to treat gout. The therapy also improved symptoms of mania and depression. 91,161 Lithium was the original “active― ingredient in the soft drink 7-Up.3 During the 1930s and 1940s, it was used as a salt substitute (“Westsal―) for patients with heart failure but was discontinued after several cases of acute lithium poisoning were described.40,47,64,42 The beneficial effects of lithium on bipolar disorder were “rediscovered― by Cade in 1949, when he noticed the calming effect of lithium carbonate on guinea pigs. 31,32 The same year, however, the FDA banned the use of lithium in response to reported poisonings.31,127,142 The FDA lifted the ban in 1970 and approved the use of lithium for treatment of mania. Lithium is the most efficient long-term therapy for treatment and prevention of bipolar affective disorders,161 with a demonstrated antisuicidal effect and an ability to improve both the manic and depressive symptoms of the illness.12,13,60,144,161 Investigations on the use of lithium for compulsive gambling have also demonstrated beneficial results.71 In most industrialized nations, approximately 1 in 1000 persons is using 1 or more of the various lithium formulations.6,141

Pharmacology The simplicity of the lithium molecule belies the complexity of its mechanism of action. Although lithium has been used therapeutically for almost 50 years, the precise pharmacology of its therapeutic effects has not yet been elucidated.56 Part of the difficulty in defining the precise mechanism of action of lithium is the difficulty in defining the precise pathophysiology of bipolar disorder. Early efforts focused on dysfunctional neurotransmitter systems, particularly the role of biogenic amines. Lithium

increases basal and stimulation-induced serotonin release and receptor sensitivity to serotonin.29,162 Lithium modulates the effect of norepinephrine through its interactions with the Gprotein–mediated effects on the β-adrenergic receptor, thereby stabilizing fluctuations in the intracellular pool of cyclic adenosine monophosphate (cAMP). It performs this function by inhibiting not only the inhibitory subunit Gi, which raises basal concentrations of cAMP, but also the stimulatory subunit Gs , preventing fluctuations from adrenergic stimulation.29 Clinically, the therapeutic effects of lithium (and other moodstabilizing pharmaceuticals) become evident only after chronic administration, so their mechanism of action likely is not solely the result of acute biochemical interactions. Postulated mechanisms go beyond simple neurotransmitter function or dysfunction and focus on altered cellular signaling, neuronal plasticity, and neurogenesis. Rather than trying to identify any single neurotransmitter system as responsible for the complexity of depressive illness, efforts now are directed at elucidating the functional balance between interacting systems. Along with these advances, a clearer understanding of the action of lithium is developing.18,29,56,67,90,91,144 The prevailing theory for the mechanism of action of lithium is the inositol-depletion hypothesis. Inositol is a 6-carbon sugar that forms the backbone of a number of cellular signaling mechanisms. Therapeutic lithium treatment results in decreased myoinositol (the most biologically active stereoisomer of inositol) concentration in the cerebral cortex. 4,67,84 Abnormalities in regional brain myoinositol concentrations are thought to occur in bipolar patients. This theory is partially supported by experimental magnetic resonance spectroscopy data.146,175 Myoinositol is phosphorylated to form phosphatidyl inositol (PIP), which is further phosphorylated and combined with diacylglycerol (DAG) to form phosphatidyl 4,5-bisphosphate (PIP2 ). Upon stimulation of a cell, G-protein–coupled receptors activate phospholipase C

(PLC), which hydrolyzes PIP2 to release the secondary messengers DAG and inositol 1,4,5-triphosphate (IP3 ) .67,143,146,175 Each of these secondary messengers in turn initiates a cascade of events, including activation of protein kinase C (PKC), which is important for calcium homeostasis and neurotransmitter release,106,107,118,146 as well as independent mobilization and regulation of intracellular calcium.14,36,114,129,146 Many extracellular signals, including some serotonin receptor subtypes, activate PLC to exert their actions.61,105,121 Serial dephosphorylation of IP3 leads to regeneration of myoinositol and recycling of the inositol pool. Two enzymes involved in this pathway are inhibited by lithium. The first enzyme, inositol 1,4-bisphosphate 1-phosphatase (IPPase), dephosphorylates the bisphosphate to inositol monophosphate (IMP). The second enzyme, inositol 1-monophosphatase (IMPase), dephosphorylates IMP to myoinositol. The inhibition of IMPase is interesting and important. First, the mechanism of inhibition is uncommon. Lithium uncompetitively inhibits IMPase by binding to the enzyme–substrate complex and preventing the release of a phosphate. It performs this function by displacing a magnesium ion from the active site after hydrolysis. Essentially, uncompetition means the higher the concentration of the substrate, the more the enzyme is inhibited.7 This supports a theory about the pathophysiology of bipolar disorder involving an excess of myoinositol and is 1 reason why the mood-stabilizing effects of lithium are thought to be found only in bipolar patients.67 That is, the uncompetitive nature of the action of lithium serves as a regulator to preferentially block pathologic signaling caused by excessive myoinositol while leaving the normal signaling intact. As described, IMPase is an important step in the cellular recycling of the inositol pool. Lithium inhibits the last step in this cycle. Myoinositol is also generated de novo from glucose-6-phosphate

by inositol synthase, which forms IMP. The inhibition of IMPase by lithium subsequently leads to myoinositol depletion by preventing the conversion of the newly synthesized IMP to inositol. Interestingly, valproic acid (VPA) also inhibits inositol synthase, illustrating a potential mechanism for the synergy of these complementary mood stabilizers.119 A third mechanism of intracellular diminution of inositol by lithium (as well as VPA and carbamazepine) is the effect of lithium on reducing activity and transcription of the sodium myoinositol transporter (SMIT), thereby preventing the uptake of exogenous myoinositol by the cell. This mechanism of inhibition can be overcome by increased extracellular concentration of myoinositol.67,173 The result of these effects is depletion of the inositol pool available to the cell, causing a series of events at different points in the signal transduction cascade that leads to differential gene transcription and expression. This sequence ultimately is responsible for the P.1054 observed clinical effects of lithium on the

CNS.29,143

Experimental

data, using dextroamphetamine as a model for clinical mania, have shown that dextroamphetamine increases regional inositol signaling in the human brain, and that pretreatment with lithium attenuates this increase, lending support to the hypothesis.21 Another proposed theory for the mechanism of action of lithium is inhibition of the family of glycogen synthase kinase-3 (GSK-3) kinases. GSK-3β overactivity is associated with neuronal degeneration and sensitivity to apoptotic stimulation. GSK-3β is a key regulator of neuronal cell fate, with a proapoptotic effect in many settings.42,50,70,78,79 a n d 80,133 GSK-3β is involved in regulating the activity of β-catenin, Jun, and cAMP response element-binding protein (CREB), transcription factors important in embryonic patterning, cell proliferation, neuronal modeling and plasticity, neuronal signal transduction, and cytoskeletal remodeling. Lithium inhibits GSK-3β indirectly through

phosphorylation (by activation of PKC) and directly through inhibition of enzymatic activity through magnesium mimicry. Inhibition of GSK-3β by lithium is thought to be neuroprotective.29,63,68,126,134,176 A link between GSK-3β activity and bipolar disorder and depression is supported by the finding that serotonergic activity inhibits GSK-3β in vivo.92 Additionally, hypoxia contributes to increased GSK-3β activity, which can be counteracted or inhibited through mood-stabilizing drugs. Vascular depression, or depression following stroke, is an organic model of major depression.111 The finding that this depressive state responds similarly to intervention with mood stabilizers lends additional support to the GSK-3β hypothesis.81 Thus, the depressed serotonergic activity associated with depression, or the hypoxicinduced activation of GSK-3β, may lead to impaired inhibition of GSK-3β. Mood stabilizers counteract this dysregulation and may explain their effectiveness in depression. This theory is under active investigation.29,61,67,68,126,171 Lithium is implicated in the neuroprotective modulation of the bcl2 gene, which is known for its role in preventing apoptosis and in downregulation of the proapoptotic protein p53. In rats treated with either Li+ or VPA, concentrations of Bcl-2 protein doubled.34 These findings, although not necessarily replicated in human beings, are supported by the findings that patients undergoing long-term therapy with either drug had prefrontal cortex volumes significantly greater than in patients not treated with either agent, suggesting a protective effect in human patients.29,37,45 In summary, although the precise mechanism of action of lithium is unknown, some common features of investigation have emerged. The potential targets, widely found and disparate in function, all seem to be inhibited by lithium in an uncompetitive fashion, most commonly through displacement of a divalent cation, usually Mg2 +. The systems affected by this inhibition vary widely.

Downstream targets seem to modulate secondary cell messengers and intracellular signal transduction, transcription factors and gene expression, and neuronal plasticity and cellular differentiation. Further study is needed to elucidate the complex interaction of these pathways with the action of lithium in order to form an integrated hypothesis.

Pharmacokinetics

and

Toxicokinetics

The volume of distribution of lithium is between 0.6 and 0.9 L/kg. It displays no discernible protein binding and distributes freely in total body water, except for the cerebrospinal fluid (CSF), from which it is actively extruded.48,122,148 The extrusion is believed to occur through an active transport process involving sodium/lithium exchange at the arachnoid processes.49 The immediate-release preparations of lithium are rapidly absorbed from the gastrointestinal (GI) tract. Peak plasma concentrations are achieved within 1–2 hours.76 Sustained-release products demonstrate variable absorption, with a delay to peak of 6-12 hours. In overdose, a longer delay to reach peak concentrations or multiple peaks may occur.46 Chronic therapy prolongs the elimination of lithium, as does advancing age.122 Although lithium is rapidly absorbed, tissue distribution is a complex phenomenon, with a significant delay in reaching a steady state. Lithium exhibits preferential uptake into certain tissues (eg, kidney, thyroid, and bone) over others (eg, liver, muscle). Lithium distribution into the brain can take up to 24 hours to reach equilibrium. Lithium is concentrated in red blood cells (RBCs) by both passive diffusion and active transport. RBC concentration may correlate closely with brain concentrations, although further study to confirm this possibility is warranted.33,128 The pharmacokinetic profile of lithium is described as an open, two-compartment model.53,77 Each 300-mg lithium carbonate tablet contains 8.12 mEq lithium.161 Ingestion of a single 300-mg tablet is expected to

acutely raise the serum lithium concentration by approximately 0.1–0.3 mEq/L (assuming a volume of distribution of approximately 0.6–0.9 L/kg and a patient weight 50–100 kg). Lithium is eliminated almost entirely (95%) by the kidneys, with a small amount eliminated in the feces.76 Lithium is also found in sweat, saliva, and breast milk.43,73,115 In an adult with normal renal function, lithium clearance ranges from 25–35 mL/min.20,158,159 At steady-state equilibrium, as in patients undergoing chronic therapy, total body clearance equals renal clearance. Lithium is handled by the kidneys much in the same way as sodium. Lithium is freely filtered, and more than 60% is reabsorbed by the proximal tubule. Evidence also indicates a small amount of reabsorption by the loop of Henle and distal tubule.8,24,25,44,54,89,122,161 Lithium excretion is dependent on factors that affect the glomerular filtration rate (GFR) or decrease sodium concentration. Any condition that makes the kidney sodium-avid (eg, volume depletion or salt restriction) increases lithium reabsorption in the proximal tubule.8 Risk factors for development of lithium toxicity therefore include advanced age with its associated decrease in GFR, thiazide diuretics, nonsteroidal antiinflammatory drugs, angiotensin-converting enzyme (ACE) inhibitors, decreased sodium intake, and low-output heart failure.76,89 The therapeutic index for lithium is narrow. The generally accepted steady-state therapeutic range of serum lithium concentrations is 0.6–1.2 mmol/L, although much disagreement exists about whether this serum concentration truly reflects therapeutic efficacy.58,59,135 Both in therapeutic and overdose situations, clinical signs and symptoms seem to be a more valuable indicator of brain lithium concentrations.135

Clinical

Manifestations

Similar to other substances having prolonged redistributive phases and tissue burdens, lithium exposure can be divided into 3 main categories of toxicity: acute, acute-on-chronic, and chronic. In acute lithium toxicity, the patient has no body burden of lithium present at the time of ingestion. The toxicity that develops depends on the rate of absorption and distribution. In chronic toxicity, the P.1055 patient has a stable body burden of lithium as serum concentration is maintained in the therapeutic range, and then some factor disturbs this balance, either by enhancing absorption, or more commonly, decreasing elimination. For the chronic user of lithium small perturbations in the equilibrium between intake and elimination can patient ingests unintentionally) saturation, any

lead to toxicity. In acute-on-chronic toxicity, the an increased amount of lithium (intentionally or in the setting of a stable body burden. With tissue additional lithium leads to signs and symptoms of

toxicity.

Acute

Toxicity

Lithium is a metal salt. Acute ingestions of lithium-containing preparations produce a clinical picture similar to that of ingestions of other metal salts, with predominant early GI symptoms. Nausea, vomiting, and diarrhea are prevalent. A large volume loss can result from these symptoms. Patients may complain of lightheadedness and dizziness, and they can be orthostatic on evaluation. Neurologic manifestations are a late finding in acute toxicity, as the lithium redistributes slowly into the CNS. Lithium is associated with a number of electrocardiographic abnormalities, although the evidence for significant effects is tenuous. The most commonly reported manifestation is T-wave flattening or inversion, primarily in the precordial leads.28,124,160 Lithium is associated with prolongation of the QTc interval.174 A

study has associated elevated serum lithium concentrations with QTc prolongation >440 msec, although the number of patients studied was small.72 Associations exist between lithium and sinoatrial nodal dysfunction, with bradycardia. Theoretically, this condition may result from lithium's effect on G-protein–mediated cAMP generation, and subsequent modification of calcium channel opening and calcium influx in the pacemaker cells.28,72,124,160 For the most part, lithium has few consequential effects on cardiac function, even in overdose, and malignant dysrhythmias or significant dysfunction is rare.99,117,122

Chronic

Toxicity

Lithium is primarily a neurotoxin.2 The earliest case reports of lithium toxicity described predominantly neurologic symptoms.41,169 Of note, neurotoxicity does not correlate with serum concentrations. The initial clinical condition of the patient and the duration of exposure to an elevated concentration seem to be more closely predictive of outcome than the initial serum lithium concentration.2,6,16,65,87,116,140,166 Tremor, a common finding in patients undergoing chronic therapy, can increase with toxicity. Other findings of chronic toxicity include fasciculations, hyperreflexia, choreoathetoid movements, clonus, dysarthria, nystagmus and ataxia.122,161 Mental status often is altered and can progress from confusion to stupor, coma, and seizures.30 Electroencephalographic changes are most frequently reported as “slowing.― The progression of these symptoms follows no order, and any patient undergoing chronic therapy can have 1 or any combination of these features. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) is a descriptive syndrome of the irreversible neurologic and neuropsychiatric sequelae of lithium toxicity.2 SILENT is defined as neurologic dysfunction caused by lithium in the absence of prior neurologic illness that persists for at least 2 months after

cessation of the drug. Case reports in the literature support these findings and this definition. However, as is true in most case reports, confounders make wide applicability of the findings difficult. Because of the polypharmacy prevalent in psychiatric treatment, long-term neurologic sequelae attributed to lithium are described in patients using lithium in combination with other medications, such as haloperidol, chlorpromazine, carbamazepine, phenytoin, aspirin, valproic acid, amitriptyline, β-adrenergic antagonists, calcium channel blockers, ACE inhibitors, diuretics and nonsteroidal antiinflammatory drugs.2,10,38,52,53,66,104,113,166 However, patients who used lithium without coingestants and had no comorbid illness but sustained lasting dysfunction as a result of lithium toxicity are reported.6,85,116,123,140,166 Cerebellar findings seem to predominate in SILENT.2,62,82,85,108 One predictor of persistent neurologic dysfunction seems to be the concomitant finding of hyperpyrexia, an ominous finding in lithium toxicity.62,108 The mechanism of persistent dysfunction is unclear, but demyelination and cellular loss are proposed.2,108,116,138

Acute-on-Chronic

Toxicity

Patients undergoing chronic therapy who acutely ingest an additional amount of lithium (either intentionally or unintentionally) are at risk for signs and symptoms of both acute and chronic toxicity. Such patients display prominent GI and neurologic symptoms and can be difficult to diagnose and manage. Serum lithium concentrations in cases of acute or chronic toxicity can be difficult to interpret, and therapy should be guided by the patient's clinical status.

Other Systemic Manifestations Chronic Lithium Therapy

of

The most common adverse effect of chronic lithium therapy is the

development of nephrogenic diabetes insipidus. The process thought to be involved is the interference of lithium on magnesium-dependent G proteins that activate vasopressinsensitive adenylate cyclase, leading to decreased generation of cAMP in the cell membranes of distal tubular cells.35,109,149,167 Decreased cAMP leads to reduced expression and translocation of the vasopressin-regulated water channel aquaporin-2 (AQP-2), making the distal tubules resistant to the action of vasopressin.5,39,83,109,110,137,170 Lithium also inhibits the transport of sodium through the amiloride-sensitive Na+ channel.157 Another theory proposed for the mechanism of lithium-induced nephrogenic diabetes insipidus suggests that lithium inhibits GSK3β, directly and through a phosphorylation pathway. GSK-3β exhibits tonic inhibition of cyclooxygenase-2 (COX-2). When this inhibition is removed by lithium, COX-2 activity leads to increased prostaglandin expression in the renal medulla. Increased prostaglandin expression is thought to play an important role in nephrogenic diabetes insipidus through regulation of glomerular blood flow.102,130 Chronic lithium therapy is associated with chronic tubulointerstitial nephropathy, as manifested by the development of renal insufficiency with little or no proteinuria and biopsy findings of tubular cysts. This association was demonstrated in 1 biopsybased study of 24 chronically treated patients, although the overall prevalence of this condition is low.109 Lithium is associated with a number of endocrine disorders. The most prevalent endocrine manifestation of chronic lithium therapy is hypothyroidism. The causative etiology is multifactorial. Lithium is selectively concentrated in the thyroid gland and impairs iodine uptake, synthesis of triiodothyronine (T3 ), responsiveness of the gland to thyroid-stimulating hormone (TSH), release of T3 and P.1056

tetraiodothyronine (T4 ), and peripheral conversion of T4 to T3 . Additionally, lithium decreases responsiveness of peripheral tissues to T3 and leads to the development of antithyroglobulin antibodies.120,172 Although hypothyroidism is most common, hyperthyroidism and frank thyrotoxicosis also are reported.15 However, hyperthyroidism, by altering proximal tubule function, leads to decreased lithium excretion.19 Thus, hyperthyroidism may lead to chronic lithium toxicity through impaired elimination, and the elevated lithium concentrations may mask the manifestations of hyperthyroidism.120 Further investigation of this condition is warranted. The combination of hyperparathyroidism and hypercalcemia is frequently reported with chronic lithium therapy, most commonly in women. The mechanism is thought to be modification of calcium feedback on parathyroid hormone release, although stimulation of parathyroid hyperplasia and adenomas is suggested.1,9,23,88,147,161 Developmentally, in utero exposure to lithium increases the incidence of congenital heart defects, specifically Ebstein anomaly.73,126,147 Additionally, many effects similar to those that occur in patients undergoing chronic therapy are found in infants exposed in utero, including thyroid disease and neurotoxicity.73 Lithium causes a leukocytosis and an increase in neutrophils. It has been proposed as an adjunct to chemotherapy-induced neutropenia, other marrow suppressive therapies, and acquired immunodeficiency syndrome (AIDS). Although lithium increases the total neutrophil count, no improved clinical outcomes are documented, and its use has been superseded by recombinant colony-stimulating factors.26,126,132,147,151

Diagnostic

Testing

Because of the prevalence of lithium use, therapeutic drug

monitoring is readily available in most settings, and concentrations should be readily obtainable. A lithium concentration should be requested upon patient presentation and serial measurements requested or considered in most instances, especially in cases of sustained-release ingestions. Emphasis should be placed upon the lithium concentration as a marker of exposure and response to therapy, not necessarily as a determinant of toxicity. The choice of therapy should be guided by the patient's clinical signs and symptoms (and history) rather than an absolute lithium concentration. The sample must be sent in an appropriate lithiumfree tube, because certain lithiated-heparin tubes can lead to false-positive results. Serum electrolyte concentrations including renal function should be monitored, because renal function is important in determining the need for more aggressive therapy, including enhanced elimination technique (ie, hemodialysis). If the patient is hypernatremic, nephrogenic diabetes insipidus should be suspected, and determinations of serum and urine osmolarity help confirm the diagnosis. If clinical thyroid disease is suspected, thyroid function tests can be obtained. As with all deliberate ingestions, a serum acetaminophen concentration should be obtained. An electrocardiogram is also indicated for this type of ingestion. The complete blood count may indicate a leukocytosis, which may merely be a stress response or caused by the effects of lithium.

Management Initial management and stabilization begins with assessment of the basics of resuscitation: airway, breathing, and circulation. Lithium rarely, if ever, affects the airway or breathing of the patient, although coingestants may. Emesis, which occurs at a significant incidence and is associated with acute lithium exposure, may lead to aspiration and respiratory compromise. Once the patient is stable, the nature of the exposure should be determined while physical examination and laboratory assessment commence. The

formulation and nature of the product should be ascertained as immediate-release or sustained-release. Information should be obtained regarding whether or not lithium is part of the patient's medication regimen, which will help determine whether the ingestion is acute, acute-on-chronic, or chronic.

Gastrointestinal

Decontamination

For patients who present after an acute (or acute-on-chronic) overdose, a risk-to-benefit analysis of GI decontamination must be undertaken. Two factors should be considered. With an acute overdose and predominance of early GI symptoms, including emesis, self-decontamination may have already started. Second, immediate-release preparations are often rapidly absorbed and may not lend themselves to GI evacuation. Few GI decontamination options are available to the treating physician. Although syrup of ipecac is no longer generally recommended as a standard decontamination choice, emesis still may be useful in certain instances of sustained-release preparation ingestions when care may be delayed or is distant, as in remote or rural areas. Immediate-release preparations of lithium are rapidly absorbed and produce emesis, whereas sustained-release formulations of lithium (ie, controlled-release tablets) and a slowly dissolving film-coated formulation often are too large to fit through even the largest lavage tube. Thus, orogastric lavage has essentially no role in the acute management of a lithium overdose, unless indicated for a coingestant. Lithium is a monovalent cation that does not bind readily to activated charcoal. 97 Because no beneficial effect from activated charcoal is expected, the danger of a depressed level of consciousness, potential loss of protective airway reflexes, and prominent emesis contraindicate activated charcoal use, except for treatment of a potential coingestant.

Sodium polystyrene sulfonate (SPS) is a cationic exchange resin often used for treatment of severe hyperkalemia. It binds potassium in exchange for sodium, allowing elimination of excess potassium in the feces. Because of the similarity between potassium and lithium, use of SPS has been proposed for decontamination of patients being treated for lithium toxicity. A number of animal models have been used to examine the effectiveness of this technique.93,94,95,96,97 a n d 98,100,101 Use of SPS has many theoretical benefits, including demonstrated effectiveness of lithium binding compared to activated charcoal and the ability of orally administered SPS to reduce serum concentrations of intravenously administered lithium in mice.95,97,98 Unfortunately, the finding that doses used to increase lithium elimination also lead to significant hypokalemia in human subjects limits the application of this technique.94,136 In a murine model, potassium supplementation with SPS was found to mitigate process, but only at the expense of elevated lithium concentrations.100 Two reports in the literature demonstrate increased lithium elimination with SPS, one in a healthy volunteer and another in a patient with an acute overdose. However, the serum potassium concentration was not reported in either case.57,131 At present, use of SPS in the management of the lithium-poisoned patient cannot be recommended. P.1057 Whole-bowel irrigation (WBI) is the only GI decontamination modality that has shown any efficacy in eliminating lithium from human subjects. In one of the few clinical trials of WBI, the lithium serum concentrations of 10 normal volunteers who had ingested sustained-release lithium carbonate were plotted against time over a 72-hour period. In the second phase of the trial, the volunteers received 2 L/hour polyethylene glycol solution 1 hour after the ingestion. This study showed a significant reduction (67%) in the serum concentration, even as early as 1 hour after the ingestion.150 Thus, use of WBI is recommended for sustained-

release

Fluid

preparations.

and

Electrolytes

The critical initial management of the lithium-poisoned patient should focus on restoration of intravascular volume, both in acute poisonings, with GI losses, and in chronic poisonings, with toxic effects that are often the result of disturbances of renal function and lithium elimination. Many patients with lithium toxicity have volume-responsive decreases in renal function,122 which can be managed by infusion of 0.9% sodium chloride solution at 1.5–2 times the maintenance rate. This therapy increases renal perfusion, increases the GFR, and increases lithium elimination. Urine output must be closely monitored. Electrolyte abnormalities should be corrected. Caution should be used in patients with renal insufficiency or failure or congestive heart failure. Monitoring for the development of hypernatremia in patients suspected of having nephrogenic diabetes insipidus is critical.161 Lithium-induced nephrogenic diabetes insipidus can be reversed by discontinuation of the drug and through repletion of electrolytes and free water. However, cases of permanence are reported.103,109,156 Clinical application of amiloride to mitigate lithium-induced polyuria is reported, although the potential for volume contraction and stimulation of lithium reabsorption limits recommendation of this drug as a routine adjunct to acute care.17,51,55,86 Attempts to enhance lithium elimination through forced diuresis with loop diuretics (furosemide), osmotic agents (mannitol), carbonic anhydrase inhibitors (acetazolamide), or phosphodiesterase inhibitors (aminophylline) should be avoided. An initial small increase in elimination may be achieved but typically salt and water depletion develop and are followed by increased lithium retention. Use of sodium bicarbonate for urinary alkalinization does not significantly increase elimination over

volume expansion with sodium chloride and can lead to hypokalemia, alkalemia, and fluid overload; therefore, sodium bicarbonate also should be avoided.

Extracorporeal

Drug

Removal

Debate surrounds the efficacy and practicality of using enhanced elimination techniques in cases of lithium poisoning. Lithium has physicochemical properties that make it amenable to extracorporeal removal.69,75,76,89 With these characteristics, lithium seems to be an ideal candidate for hemodialysis. In fact, hemodialysis is often recommended for treatment of acute, acuteon-chronic, and chronic lithium toxicity.11,74,75 a n d 76,108,125,155,161,168 However, some characteristics of lithium make extracorporeal elimination difficult. Lithium is predominantly localized intracellularly and diffuses slowly across cell membranes.122 When traditional intermittent hemodialysis is used for chronic exposures, clearance of the plasma compartment is often followed by a rebound phenomenon of redistribution from tissue stores leading to increased plasma concentrations, in some cases approaching predialysis concentrations.27 An additional complicating factor is that the brain, the “target organ― of toxicity, is not amenable to rapid artificial elimination processes. Attempts have been made to correlate the serum concentration with the lithium concentration in the CSF and brain. In the few studies where CSF concentrations were obtained, serum and CSF lithium concentrations seemed to correlate, but brain concentrations and toxicity did not.76,139 Magnetic resonance spectroscopic studies of bipolar patients with steady-state lithium concentrations demonstrated a significant variability between brain and serum concentrations, especially within the therapeutic range.76,135,139 No consensus recommendation on the appropriate time to initiate therapy is available.11,76,136 In addition, because of the toxicokinetic profile of lithium, serum concentrations do not correlate well with toxicity.47,76,152,161

Hemodialysis or an alternative extracorporeal technique is clearly indicated for 3 groups of patients. The first group consists of patients who are manifesting severe signs and symptoms of neurotoxicity, such as alterations in mental status. The second group consists of patients who have renal failure and show signs or symptoms of lithium toxicity. These patients are unable to eliminate their lithium burden and should be dialyzed. The third group consists of patients who show little or no sign of toxicity but who cannot tolerate sodium repletion therapy; these patients should be considered for early hemodialysis. This group includes patients with congestive heart failure or redistributive diseases such as liver failure, pancreatitis, or sepsis. If the patient belongs to one of these groups, the next step is to determine the probability that the patient will develop toxicity if elimination is not enhanced. Serum concentrations do not necessarily correlate with toxicity. However, they can be a useful aid in making the decision for hemodialysis. As an adjunct to the clinical presentation, an absolute lithium concentration >4.0 mEq/L (mmol/L) with any type of overdose or a concentration >2.5 mEq/L with chronic toxicity should prompt dialysis. These criteria originate from a case series of 23 patients and review of 100 other patients published in 1978, prior to the introduction of sustained-release products.65 Although this recommendation has never been prospectively evaluated, it still can serve as a useful guide in the management of the lithium-poisoned patient. 11,20 The dialysate bath should contain bicarbonate rather than acetate. This composition should help lessen the intracellular sequestration of lithium that occurs because of activation of the sodium/potassium antiporter, with preferential intracellular transport of lithium.125,155 Whether hemodialysis diminishes or enhances the risk of permanent neurologic sequelae is a subject of debate.153,154 Although no controlled studies have analyzed this important

management question, the preponderance of evidence suggests a reduced risk.2,6,11,76,108,112,122,125,140,161 Continuous venovenous hemodialysis and continuous venovenous hemodiafiltration are two continuous renal replacement therapies (CRRTs) commonly used for treatment of acute renal failure and volume overload and for elimination of exogenous substances. 20,89,163,164 a n d 165 Both techniques are effective in patients who are hemodynamically unstable, because blood flow through the filter is pump driven and is not dependent on the patient's arterial blood pressure.69 Other continuous techniques that use patient blood pressure as the basis for flow through the system also may have application here.164 Traditional intermittent hemodialysis offers clearance P.1058 rates that vary between 50 and 170

mL/min.20,22,89,122,125,164

Although CRRT techniques offer lower clearance per hour than does intermittent hemodialysis, their overall daily clearances are similar.20,89 With continued improvements in techniques, use of high volumes, and high dialysate flow rates, clearances are improving, approaching more than half the clearance per hour achieved by intermittent hemodialysis in some studies.20,69,89,164 Although one case of a rebound phenomenon in a patient treated with continuous arteriovenous hemodiafiltration is reported,22 no cases with use of venovenous techniques are reported, offering a clear advantage over intermittent hemodialysis. Unfortunately, CRRT requires prolonged anticoagulation with its inherent risks. Nevertheless, these techniques may be beneficial in patients who are hemodynamically unstable, or they can be used in series with traditional dialysis in other patients to prevent redistribution of lithium and rebound of serum concentrations. Peritoneal dialysis (PD) has been recommended in the past but offers no increased efficacy in clearance of lithium ion over the natural clearance of normal kidneys.11,69,76,136 Given the infrequent use of this technique and its potential for serious

complications (eg, bowel perforation), PD should not be used in the management of the lithium-poisoned patient.

Summary Lithium is a simple ion with extremely varied and complex clinical and pathophysiologic effects. It is available in multiple formulations, both immediate-release and sustained-release. Lithium remains an essential part of the pharmacologic arsenal of clinical psychiatry. Because of the complexity of lithium's pharmacokinetic profile, toxicity can develop in a wide range of conditions and can be precipitated by both intentional overdose and therapeutic misadventure. The care of the lithium-poisoned patient should be predicated on rapid identification of the poisoning, followed by management that includes use of volume resuscitation and, when indicated, WBI and hemodialysis or other extracorporal techniques to prevent or treat severe neurologic morbidity and to prevent mortality.

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hemodialysis in acute intoxications. Clin Toxicol 1987;25:81–94. 75. Jaeger A, Sauder P, Kopferschmitt J, Jaegle ML: Toxicokinetics of lithium intoxication treated by hemodialysis. J Toxicol Clin Toxicol 1985;23:501–517. 76. Jaeger A, Sauder P, Kopferschmitt J, et al: When should dialysis be performed in lithium poisoning? A kinetic study in 14 cases of lithium poisoning. J Toxicol Clin Toxicol 1993;31:429–447. 77. Jermain DM, Crismon ML, Martin ES 3rd: Population pharmacokinetics of lithium. Clin Pharm 1991;10:376–381. 78. Jin N, Kovacs AD, Sui Z, et al: Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3, activation, c-jun expression and neuronal cell death. Neuropharmacology 2005;48:576–583. 79. Jope R: Lithium and GSK3: One inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 2003;24:441–443. 80. Jope RS, Johnson GV: The glamour gloom of glycogen synthase kinase-3. Trends Biochem Sci 2004;29:95–102. 81. Jorge RE, Robinson RG, Arndt S, Starkstein S: Mortality and poststroke depression: A placebo-controlled trial of antidepressants. Am J Psychiatry 2003;160:1823–1829. 82. Juul-Jensen P, Schou M: Letter: Permanent brain damage

after lithium intoxication. Br Med J 1973;4:673. P.1060 83. King LS, Agre P: Pathophysiology of the aquaporin water channels. Annu Rev Physiol 1996;58:619–648. 84. Kofman O, Belmaker RH: Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression. Biol Psychiatry 1993;34:839–852. 85. Kores B, Lader MH: Irreversible lithium neurotoxicity: An overview.

Clin

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86. Kosten TR, Forrest JN: Treatment of severe lithium-induced polyuria with amiloride. Am J Psychiatry 1986;143:1563–1568. 87. Lang EJ, Davis SM: Lithium neurotoxicity: The development of irreversible neurological impairment despite standard monitoring of serum lithium levels. J Clin Neurosci 2002;9:308–309. 88. Laroche M, Lamboley V, Amigues JM, et al: Hyperparathyroidism during lithium therapy. Two new cases. Rev Rhum Engl Ed 1997;64:132–134. 89. Leblanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kid Dis 1996;27:365–372. 90. Lenox RH, Hahn CG: Overview of the mechanism of action

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model.

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94. Linakis JG, Hull KM, Lacouture PG, et al: Sodium polystyrene sulfonate treatment for lithium toxicity: Effects on serum potassium concentrations. Acad Emerg Med 1996;3:333–337. 95. Linakis JG, Hull KM, Lacouture PG, et al: Enhancement of lithium elimination by multiple-dose sodium polystyrene sulfonate. Acad Emerg Med 1997;4:175–178. 96. Linakis JG, Hull KM, Lee CM, et al: Effect of delayed treatment with sodium polystyrene sulfonate on serum lithium concentrations in mice. Acad Emerg Med 1995;2:681–685. 97. Linakis JG, Lacouture PG, Eisenberg MS, et al: Administration of activated charcoal or sodium polystyrene sulfonate (kayexalate) as gastric decontamination for lithium

intoxication: An animal model. Pharmacol Toxicol 1989;65:387–389. 98. Linakis JG, Savitt DL, Lockhart GR, et al: In vitro binding of lithium using the cation exchange resin sodium polystyrene sulfonate. Am J Emerg Med 1995;13:669–670. 99. Linakis JG, Savitt DL, Schuyler JE, et al: Lithium has no direct effect on cardiac function in the isolated, perfused rat heart. Pharmacol Toxicol 2000;87:39–45. 100. Linakis JG, Savitt DL, Trainor BJ, et al: Potassium repletion fails to interfere with reduction of serum lithium by sodium polystyrene sulfonate in mice. Acad Emerg Med 2001;8:956–960. 101. Linakis JG, Savitt DL, Wu TY, et al: Use of sodium polystyrene sulfonate for reduction of plasma lithium concentrations after chronic lithium dosing in mice. J Toxicol Clin Toxicol 1998;36:309–313. 102. MacGregor DA, Baker AM, Appel RG, et al: Hyperosmolar coma due to lithium-induced diabetes insipidus. Lancet 1995;346:413–417. 103. MacGregor DA, Dolinski SY: Hyperosmolar coma. Lancet 1999;353:1189. 104. Mani J, Tandel SV, Shah PU, Karnad DR: Prolonged neurological sequelae after combination treatment with lithium and antipsychotic drugs. J Neurol Neurosurg Psychiatry 1996;60:350–351.

105. Manji HK, Hsiao JK, Risby ED, et al: The mechanisms of action of lithium: I Effects on serotonergic and noradrenergic systems in normal subjects. Arch Gen Psychiatry 1991;48:505–512. 106. Manji HK, Lenox RH: Long-term action of lithium: A role for transcriptional and posttranscriptional factors regulated by protein kinase C. Synapse 1994;16:11–28. 107. Manji HK, Potter WZ, Lenox RH: Signal transduction pathways: Molecular targets for lithium's actions. Arch Gen Psychiatry 1995;52:531–543. 108. Manto M, Godaux E, Jacquy J, Hildebrand JG: Analysis of cerebellar dysmetria associated with Neurol Res 1996;18:416–424.

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109. Markowitz GS, Radhakrishnan J, Kambham N, et al: Lithium nephrotoxicity: A progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 2000;11:1439–1448. 110. Marples D: Water channels: Who needs them anyway? Lancet 2000;355:1571–1572. 111. Mast BT, Neufeld S, MacNeill SE, Lichtenberg PA: Longitudinal support for the relationship between vascular risk factors and late-life depressive symptoms. Am J Geriatr Psychiatry 2004;12:93–101. 112. Meyer RJ, Flynn JT, Brophy PD, et al: Hemodialysis followed by continuous hemofiltration for treatment of lithium

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115. Moretti ME, Koren G, Verjee Z, Ito S: Monitoring lithium in breast milk: An individualized approach for breast-feeding mothers. Ther Drug Monit 2003;25:364–366. 116. Nagaraja D, Taly AB, Sahu RN, et al: Permanent neurological sequelae due to lithium toxicity. Clin Neurol Neurosurg 1987;89:31–34. 117. Newland KD, Mycyk MB: Hemodialysis reversal of lithium overdose cardiotoxicity. Am J Emerg Med 2002;20:67–68. 118. Nishizuka Y: Membrane phospholipid degradation and protein kinase c for cell signaling. Neurosci Res 1992;15:3–5. 119. O'Donnell T, Rotzinger S, Nakashima TT, et al: Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain. Brain Res 2000;880:84–91. 120. Oakley PW, Dawson AH, Whyte IM: Lithium: Thyroid effects and altered renal handling. J Toxicol Clin Toxicol 2000;38:333–337.

121. Odagaki Y, Koyama T, Matsubara S, et al: Effects of chronic lithium treatment on serotonin binding sites in rat brain. J Psychiatr Res 1990;24:271–277. 122. Okusa MD, Crystal LJ: Clinical manifestations and management of acute lithium intoxication. Am J Med 1994;97:383–389. 123. Omata N, Murata T, Omori M, Wada Y: A patient with lithium intoxication developing at therapeutic serum lithium levels and persistent delirium after discontinuation of its administration. Gen Hosp Psychiatry 2003;25:53–55. 124. Paclt I, Slavicek J, Dohnalova A, et al: Electrocardiographic dose-dependent changes in prophylactic doses of dosulepine, lithium and citalopram. Physiol Res 2003;52:311–317. 125. Peces R, Pobes A: Effectiveness of haemodialysis with high-flux membranes in the extracorporeal therapy of lifethreatening acute lithium intoxication. Nephrol Dial Transplant 2001;16:1301–1303. 126. Phiel CJ, Klein PS: Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 2001;41:789–813. 127. Price LH, Heninger GR: Lithium in the treatment of mood disorders. N Engl J Med 1994;331:591–598. 128. Pringuey D, Yzombard G, Charbit J, et al: Lithium kinetics during hemodialysis in a patient with lithium poisoning. Am J Psychiatry 1981;138:249–251.

129. Rana RS, Hoken LE: Role of phosphoinositides in transmembrane signaling. Physiol Rev 1990;70:115–164. 130. Rao R, Zhang MZ, Zhao M, et al: Lithium treatment inhibits renal GSK-3, activity and promotes cyclooxygenase 2dependent polyuria. Am J Physiol Renal Physiol 2005;288: F642–F649. 131. Roberge RJ, Martin TG, Schneider SM: Use of sodium polystyrene sulfonate in a lithium overdose. Ann Emerg Med 1993;22:1911–1915. 132. Roberts DE, Berman SM, Nakasato S, et al: Effect of lithium carbonate on zidovudine-associated neutropenia in the acquired immunodeficiency syndrome. Am J Med 1988;85:428–431. P.1061 133. Roh MS, Eom TY, Zmijewska AA, et al: Hypoxia activates glycogen synthase kinase-3, in mouse brain in vivo: Protection by mood stabilizers and imipramine. Biol Psychiatry 2005;57:278–286. 134. Ryves WJ, Harwood AJ: Lithium inhibits glycogen synthase kinase-3, by competition for magnesium. Biochem Biophys Res Commun 2001;280:720–725. 135. Sachs GS, Renshaw PF, Lafer B, et al: Variability of brain lithium levels during maintenance treatment: A magnetic resonance spectroscopy study. Biol Psychiatry 1995;38:422–428.

136. Scharman EJ: Methods used to decrease lithium absorption or enhance elimination. J Toxicol Clin Toxicol 1997;35:601–608. 137. Schieppati A, Remuzzi G: Nephrology. The year of the pores. Lancet 1996;348(Suppl 2):SII13. 138. Schneider JA, Mirra SS: Neuropathologic correlates of persistent neurologic deficit in lithium intoxication. Ann Neurol 1994;36:928–931. 139. Schou M: Pharmacology and toxicology of lithium. Annu Rev Pharmacol Toxicol 1976;16:231–243. 140. Schou M: Long-lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 1984;70:594–602. 141. Schou M: Clinical aspects of lithium in psychiatry. In: Birch NJ, ed: Lithium and the Cell: Pharmacology and Biochemistry. London, Academic Press 1991, pp. 1–6. 142. Schou M: Forty years of lithium treatment. Arch Gen Psychiatry 1997;54:9–13. 143. Shaldubina A, Agam G, Belmaker RH: The mechanism of lithium action: State of the art, ten years later. Prog Neuropsychopharmacol Biol Psychiatry 2001;5:855–866. 144. Shastry BS: Bipolar disorder: An update. Neurochem Int 2005;46:273–279. 145. Sheean GL: Lithium neurotoxicity. Clin Exp Neurol

1991;28:112–127. 146. Silverstone PH, McGrath BM, Kim H: Bipolar disorder and myo-inositol: A review of the magnetic resonance spectroscopy findings. Bipolar Disord 2005;7:1–10. 147. Simard M, Gumbiner B, Lee A, et al: Lithium carbonate intoxication. A case report and review of the literature. Arch Intern Med 1989;149:36–46. 148. Singer I, Rotenberg D: Mechanisms of lithium action. N Engl J Med 1973;289:254–260. 149. Singer I, Rotenberg D, Puschett JB: Lithium-induced nephrogenic diabetes insipidus: In vivo and in vitro studies. J Clin Invest 1972;51:1081–1091. 150. Smith SW, Ling LJ, Halstenson CE: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991;20:536–539. 151. Stein R, Beaman C, Ali, MY, et al: Lithium carbonate attenuation of chemotherapy-induced neutropenia. N Engl J Med 1977;297:430–431. 152. Strayhorn JM Jr, Nash JL: Severe neurotoxicity despite “therapeutic― serum lithium levels. Dis Nerv Syst 1977;38:107–111. 153. Swartz CM, Dolinar LJ: Encephalopathy associated with rapid decrease of high levels of lithium. Ann Clin Psychiatry 1995;7:207–209.

154. Swartz CM, Jones P: Hyperlithemia correction and persistent delirium. J Clin Pharmacol 1994;34:865–870. 155. Szerlip HM, Heeger P, Feldman GM: Comparison between acetate and bicarbonate dialysis for the treatment of lithium intoxication. Am J Nephrol 1992;12:116–120. 156. Thompson CJ, France AJ, Baylis PH: Persistent nephrogenic diabetes insipidus following lithium therapy. Scott Med J 1997;42:16–17. 157. Thomsen K, Bak M, Shirley DG: Chronic lithium treatment inhibits amiloride-sensitive sodium transport in the rat distal nephron. J Pharmacol Exp Ther 1999;289:443–447. 158. Thomsen K, Schou M: Renal lithium excretion in man. Am J Physiol 1968;215:823–827. 159. Thomsen K, Schou M: Avoidance of lithium intoxication: Advice based on knowledge about the renal lithium clearance under various circumstances. 1999;32:83–86.

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160. Tilkian AG, Schroeder JS, Kao JJ, Hultgren HN: The cardiovascular effects of lithium in man. A review of the literature. Am J Med 1976;61:665–670. 161. Timmer RT, Sands JM: Lithium intoxication. J Am Soc Nephrol 1999;10:666–674. 162. Treiser SL, Cascio CS, O'Donohue TL, et al: Lithium

increases serotonin release and decreases serotonin receptors in the hippocampus. Science 1981;213:1529–1531. 163. van Bommel EF: Should continuous renal replacement therapy be used for “non-renal― indications in critically ill patients with shock? Resuscitation 1997;33:257–270. 164. van Bommel EF, Kalmeijer MD, Ponssen HH: Treatment of life-threatening lithium toxicity with high-volume continuous venovenous hemofiltration. Am J Nephrol 2000;20:408–411. 165. van Bommel EF, Leunissen KM, Weimar W: Continuous renal replacement therapy for critically ill patients: An update. J Intensive Care Med 1994;9:265–280. 166. Von Hartitzsch B, Hoenich NA, Leigh RJ, et al: Permanent neurological sequelae despite haemodialysis intoxication. Br Med J 1972;4:757–759.

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171. Williams R, Ryves WJ, Dalton EC, et al: A molecular cell biology of lithium. Biochem Soc Trans 2004;32:799–802. 172. Wilson R, McKillop JH, Crocket GT, et al: The effect of lithium therapy on parameters thought to be involved in the development of autoimmune thyroid disease. Clin Endocrinol (Oxf) 1991;34:357–361. 173. Wolfson M, Bersudsky Y, Zinger E, et al: Chronic treatment of human astrocytoma cells with lithium, carbamazepine or valproic acid decreases inositol uptake at high inositol concentrations but increases it at low inositol concentrations. Brain Res 2000;855:158–161. 174. Woosley RL: Lithium. Centers for Education & Research on Therapeutics. http://www.qtdrugs.org, Accessed October 4, 2005. Tuscon, AZ, The University of Arizona Health Sciences Center, 2005. 175. Yildiz A, Moore CM, Sachs GS, et al: Lithium-induced alterations in nucleoside triphosphate levels in human brain: A proton-decoupled 31P magnetic resonance spectroscopy study. Psychiatry

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176. Zhang F, Phiel CJ, Spece L, et al: Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J Biol Chem 2003;278:33067–33077.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > G - Psychotropic Medications > Chapter 69 - Monoamine Oxidase Inhibitors

Chapter

69

Monoamine

Oxidase

Inhibitors

Lada Kokan A 50-year-old man with a history of hypertension and depression was found face down on the floor in his home. He was last known to be well 24 hours before arrival of Emergency Medical Services (EMS). A medication list was found and listed clomipramine, tranylcypromine, olanzapine, rosuvastatin, and hydrochlorothiazide. EMS described the patient as nonverbal and diaphoretic but breathing spontaneously. He had mottled skin and involuntary movements of the right arm. In the emergency department, the patient's vital signs were: blood pressure, 160/130 mm Hg; pulse, 120 beats/min; respiratory rate, 30 breaths/min; rectal temperature, 106.8°F (41.6°C). On physical examination, the patient was noncommunicative, incontinent of urine, and had shaking movements of his entire body. His pupils were 5 mm and sluggishly reactive bilaterally. Pulmonary, cardiac, and abdominal examinations were unremarkable. His neurologic examination revealed that all four extremities were stiff with neither cogwheel nor lead pipe rigidity

and reflexes that were 2+ in the upper extremities and 1+ in the lower extremities. Rapid-sequence intubation was immediately performed, for which the patient was given benzodiazepines and neuromuscular blockers. A 500-mL intravenous bolus of 0.9% sodium chloride solution was empirically administered, and the patient was cooled in an ice bath until his temperature was 101°F (38.3°C). The initial laboratory results were notable for the following: white blood cell (WBC) count, 14,000/mm3 ; hemoglobin, 15 g/100 mL; sodium, 163 mEq/L; potassium, 4.6 mEq/L; chloride, 116 mEq/L; HCO- 3 , 24 mEq/L; blood urea nitrogen (BUN), 69 mg/dL; creatinine, 4.6 mg/dL; glucose, 56 mg/dL. Creatinine kinase concentration was 13,000 U/L, hepatic aminotransferases were normal, and blood ethanol concentration was negative. An arterial blood gas prior to intubation while the patient was being ventilated with a bag-valve-mask on 100% oxygen showed: pH, 7.25; PCO2 , 45 mm Hg; PO2 , 127 mm Hg; lactate, 2.9 mmol/L. Initial urinalysis revealed light-red color with 100 red blood cells per high-power field (RBC/HPF) but no WBCs, leukocyte esterase, or nitrates. The cerebrospinal fluid obtained by lumbar puncture was normal. A propofol infusion was started, and cyproheptadine 6 mg was administered via a nasogastric tube. After resuscitation, additional information regarding the patient's history was obtained from the psychiatrist. The patient had been taking olanzapine 20 mg daily and clomipramine 300 mg daily for an unspecified period. Tranylcypromine had successfully treated his depression in the past but it had been discontinued. However, because he continued to suffer from depression while on the olanzapine and clomipramine regimen, tranylcypromine was restarted 3 weeks prior to presentation. Approximately 1 week prior to presentation, his tranylcypromine dose was increased from 20 to 30 mg daily, and the clomipramine dose was lowered from 300 to 250 mg daily. Shortly after the dose change, he began to

experience palpitations and diaphoresis for which his psychiatrist prescribed terazosin. However, the terazosin was discontinued when the patient developed orthostatic hypotension. During his hospital stay, the patient remained intubated for 6 days. His creatinine kinase concentrations continued to rise and peaked at 200,000 U/L, whereas his creatinine concentration dropped steadily. Both values normalized by the time of his discharge 8 days later. The patient was taking no antidepressants upon discharge, but his psychiatrist planned to restart tranylcypromine as monotherapy.

History

and

Epidemiology

The monoamine oxidase inhibitors (MAOIs) were first used in the early 1950s to treat tuberculosis and hypertension. Once their mood-elevating properties were recognized, they were prescribed for the treatment of depression.34 Despite their effectiveness, the use of MAOIs was limited by their potential food and drug interactions and by their toxicity in overdose. As a result, the MAOIs were largely replaced by tricyclic antidepressants during the 1970s. In the 1980s, there was a resurgence of MAOI use for treatment of refractory depression, phobias, and anxiety disorders.10 Use of MAOIs again declined following the appearance of less toxic antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Currently, patients are carefully selected for MAOI therapy based on strict clinical needs and their ability to comply with the rigorous dietary restrictions.18 In an attempt to decrease the problems associated with the first generation of MAOIs, drugs selective for the MAOI subtypes were explored. The monoamine oxidase type B (MAO-B) selective drugs, such as selegiline, are used for treatment of Parkinson disease but do not have antidepressant effects. The monoamine oxidase type A (MAO-A) selective drug clorgyline is an effective antidepressant but is associated with the same food and drug interactions as the

first-generation MAOIs. The third-generation MAOIs are both selective and reversible inhibitors of MAO-A (RIMA). The best studied drug of the third-generation MAOIs is moclobemide, which now is being used for an expanded range of indications, including depression, the phobias, anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder.64 P.1063 In 2003, only 2 fatalities from MAOIs were reported to the American Association of Poison Control Centers (Chap. 130 ). MAOIs were involved in 0.3% of reported exposures to antidepressants and 0.7% of all reported antidepressant-related deaths. For comparison, SSRIs were involved in 55.3% of reported exposures to antidepressants and 38.7% of reported antidepressant-related deaths, whereas cyclic antidepressants were involved in 12.3% of reported exposures to antidepressants and 29.6% of reported antidepressant-related deaths. Thus, the ratio of deaths to exposures (by percent) attributed to each category of antidepressants is almost identical for MAOIs and cyclic antidepressants but approximately 3 times less for SSRIs.

Pharmacology Monoamines, also known as biogenic amines , are a group of neurotransmitters, including norepinephrine, dopamine, and serotonin, that have in common the presence of a single amine group and metabolism by MAO. MAO is a flavin-containing enzyme present on the outer mitochondrial membrane of central nervous system (CNS) neurons, hepatocytes, and platelets. In a 2-step reaction, MAO catalyzes the oxidative deamination of its various substrates. Importantly, the reaction liberates H2 O2 , a reactive oxygen species that is associated with neurodegenerative diseases, including Parkinson disease. Two isoforms of MAO are differentiated by their anatomical location and substrate specificity (Table 69-1 ). MAO-A is located

primarily in cells of the gastrointestinal tract, including the liver, and in serotonergic neurons of the locus caeruleus.52 Gastrointestinal MAO-A reduces the bioavailability of ingested serotonin, tyramine, and other biogenic amines. Circulating monoamines are inactivated in the liver. MAO-B is found primarily in the dopaminergic raphe neurons of the CNS and in platelets.52 This substrate specificity explains the use of MAO-A inhibitors as antidepressants and MAO-B inhibitors for treatment of Parkinson disease. Certain xenobiotics are substrates for both MAO subtypes, including tyramine, dopamine, octopamine, and tryptamine.63 MAO degradation of monoamines helps regulate presynaptic neurotransmitter stores in the nerve terminal. Therefore, inhibition of MAO prevents presynaptic degradation of monoamines, ultimately resulting in increased neuronal release of monoamines (Figure 69-1 ). Elevated synaptic concentration of serotonin most closely is correlated with the antidepressant effects of MAOIs. As with other antidepressants, the enzymatic inhibitions produced by MAOIs precede their clinical effects by as long as 2 weeks. The reason for this finding is not well characterized but may relate to a time requirement for downregulation of postsynaptic CNS serotonin receptors.48 The antidepressant activity of MAOIs is correlated with a greater than 85% inhibition of platelet MAO enzymatic activity, and the effect continues to rise linearly above this level of inhibition.20 , 23 MAOIs are a chemically heterogeneous group of drugs (Figure 69-2 ). Iproniazid, the original MAOI, is a derivative of hydrazine, as are the currently available agents phenelzine and isocarboxazid. As with other hydrazine derivatives, seizures are expected after overdose. Tranylcypromine is structurally an amphetamine derivative. As with other amphetamines, release of stored presynaptic neurotransmitter occurs following therapeutic dosing and with overdose, resulting in varying degrees of autonomic hyperactivity.36

The first-generation MAOIs, including phenelzine, isocarboxazid, and tranylcypromine, are nonselective inhibitors of both MAO-A and MAO-B. Therefore, patients taking these drugs must be placed on a restrictive diet to prevent adverse events resulting from the ingestion of tyramine. These first-generation MAOIs bind covalently to MAO and irreversibly inhibit the enzyme's function. Thus, patients taking these MAOIs are depleted of the enzyme until new MAO is synthesized, a process that takes up to 2 weeks. Patients taking first-generation MAOIs remain at risk for food and drug interactions during much of this period.

Figure 69-1. Sympathetic nerve terminal. Norepinephrine (NE) is synthesized in the sympathetic nerve cell and stored in vesicles. An action potential causes the vesicles to migrate to and fuse with the presynaptic membrane. NE diffuses across the synaptic cleft and binds with and activates postsynaptic α- and β-adrenergic receptors. NE then is taken back up into the neuron by the

monoamine reuptake pump and repackaged into vesicles. NE that is taken up by the neuron but escapes repackaging is inactivated by mitochondrial monoamine oxidase (MAO). NE that diffuses away from the synaptic cleft is inactivated by catechol-O -methyl transferase (COMT).

Selegiline (deprenyl) is an irreversible inhibitor of MAO-B when used at doses Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > G - Psychotropic Medications > Chapter 70 - Serotonin Reuptake Inhibitors and Atypical Antidepressants

Chapter

70

Serotonin Reuptake Antidepressants

Inhibitors

and

Atyp

Christine M. Stork

A 36-year-old woman presented to the emergency department 36 hours after a intentional ingestion of 1000 mg citalopram. She complained of palpitations and

numbness in her arms. Her medical history was significant for bulimia, anorexia abuse, and suicide attempts. In the emergency department, her vital signs were pressure, 84/44 mm Hg; pulse, 102–160 beats/min; respiratory rate, 18 bre temperature 99.3°F (37°C). ECG revealed ventricular bigeminy with a QTc of msec (Figure 70-1A ). High-flow oxygen and 2 g intravenous magnesium were administered. When she developed ventricular tachycardia, a lidocaine bolus and were instituted. Torsades de pointes developed (Figure 70-1B ). Treatment incl potassium chloride and potassium phosphate for hypokalemia and a transvenou pacemaker. Twenty-four hours later, her ECG showed normal sinus rhythm with 529 msec (Figure 70-1C ). At 48 hours, the QTc narrowed to 442 msec. The cit concentration was 477 ng/mL (therapeutic 40–110 ng/mL,) and the didesmethylcitalopram concentration was 123.2 ng/mL (therapeutic 14–40 ng

History

and

Epidemiology

Most antidepressants inhibit serotonin and/or norepinephrine reuptake as a mea achieve their therapeutic effect. The class of selective serotonin reuptake inhib

(SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fl fluvoxamine, paroxetine, and sertraline (Figure 70-2 ). Atypical antidepressants past the pharmacologic principles of SSRIs and have other pharmacologic activi thought to be beneficial for patients with depression.

SSRIs initially were marketed in the United States in the early 1980s and still a considered a first-line therapy for treatment of depressive disorders.119 SSRIs a effective as the tricyclic antidepressants for treatment of major depression and less significant side effects53 (Chap. 71 ). As such, they have become the large prescribed class of medication for treatment of depression.138 , 179 SSRIs also a to treat obsessive-compulsive disorders, panic disorder, alcoholism, obesity, and medical and psychologic disorders such as migraine headache and chronic pain

syndromes.52 , 124 The relative safety of the SSRIs when taken in overdose, co with cyclic antidepressants and monoamine oxidase inhibitors (MAOIs), also ma desirable.55 An increased risk of suicidal behavior is reported compared with nondrug therapy or no therapy.5 , related to delayed onset of drug efficacy coupled initiation. The low fatality rate of SSRI overdose

with the use of many antidep 109 The reason for this finding with increased energy related compared with cyclic antidepr

and MAOIs was demonstrated in a Swedish study of fatalities from 1994–1999 Citalopram was the cause of only 1.4% of 358 overdose fatalities, even though the most frequently prescribed drug in 2000.94

Pharmacology

Table 70-1 lists the pharmacology, therapeutic doses, and metabolism of the c available SSRIs and other atypical antidepressants. Modulation of serotonin and norepinephrine neurotransmission has a definitive role in the treatment of depression.145 The selectivity of SSRIs for serotonin reuptake is structurally rel -trifluoromethyl or p -fluoro substitution, which is seen in many of these drugs. Serotonin neurons are located almost exclusively in the median raphe nucleus o

brainstem, where they extend into and are in close proximity to norepinephrine that are located primarily in the locus caeruleus7 (Figure 70-3 ). The interplay norepinephrine and serotonin likely explains the effectiveness of other atypical antidepressants that do not directly modulate serotonin neurotransmission.

The exact etiology of depression and the mechanism by which increased seroto and norepinephrine neurotransmission modulates mood remain unclear. Some postulated causes of depression include decreased neuronal serotonin storage, decreased synaptic serotonin, increased serotonin receptor sensitivity, and sero overactivity resulting in depressed dopamine neurotransmission.145 , 164 , 183 , According to the first theory, desensitization and downregulation of serotonin of

somatodendritic and presynaptic inhibitory autoreceptors occur after extended u SSRIs.27 Ultimately this results in increased activity of raphe neurons, increase synthesis of serotonin, and increased release of serotonin. Unfortunately, no d in the concentration of serotonin binding sites is reported between depressed p who respond to SSRIs and those who do not respond.153 In the second theory, potentiate the activity of neuronally released serotonin

P.1071 at 5-HT2 A receptors and subsequently decrease the sensitivity of the serotonin receptor.27 In depressed patients, these receptors are downregulated after trea

but no overall difference in receptor activity is observed between depressed and nondepressed populations. Finally, increased serotonergic activity, particularly a receptors, is theorized to result in antidepressant activity through reduction of dopaminergic release.187

Figure 70-1. A. ECG showing bigeminy at point of transition to ventricular tac B . ECG demonstrating torsades de pointes. C . ECG following resolution of the dysrhythmia showing persistent prolongation of the QTc interval.

Unlike tricyclic antidepressants and other atypical antidepressants, SSRIs have direct interaction with cholinergic receptors, γ-aminobutyric acid (GABA) recep sodium channels, or adrenergic reuptake (Table 70-2 ).

Pharmacokinetics

and

Toxicokinetics

The SSRIs display diverse elimination patterns and have numerous active meta which substantially increase both the duration of therapeutic effectiveness and duration during which drug interactions and adverse drug effects can occur after drug is discontinued (Table 70-1 ). Important pharmacokinetic and pharmacody drug interactions are reported with therapeutic dosing (see Serotonin Syndrome SSRIs and their active metabolites are substrates for, and potent inhibitors of,

and other CYP isoenzymes.73 , 144 For example, fluoxetine, fluvoxamine, citalop venlafaxine, mirtazapine, paroxetine, and sertraline are substrates for CYP2D6, paroxetine, norfluoxetine, and fluoxetine inhibit the same isoenzyme38 (Table 7 Alternatively, mirtazapine induces CPY3A4 isoenzymes, while trazodone metabol

be decreased after this same enzyme is inhibited.160 , 165 The consequences of interactions are manifest when the metabolism of xenobiotics that rely on these isozymes for metabolic transformation is altered (Chap. 9 ).

Figure 70-2. Structures of common selective serotonin reuptake inhibitors. Ci is shown as the s-enantiomer (escitalopram).

Clinical Acute

manifestations Overdose

The majority of effects that occur following overdose are direct extensions of th pharmacologic activity of SSRIs in therapeutic doses. Excess serotonergic stimu prominent and nonselective. Acute signs and symptoms include nausea, vomitin dizziness, blurred vision, and, less commonly, central nervous system (CNS) de and sinus tachycardia.22 , 23 Seizures and QRS complex prolongation are reporte rarely occur with most SSRIs, even after large overdoses23 , 72 , 91 (Figure 70Selective serotonin Citalopram (Celexa) 20–60 12–15

reuptake

33–37 2C19, 3A4, 2D6 Monodesmethylcitalopram, 59 h None/unknown Escitalopram 10–20 19

(Lexapro)

22–32 2C19,3A4,2D6, S(+)-Desmethylcitalopram 59 h None Fluoxetine (Prozac) 10–80 14–100 24–144 2C9, 2D6 Norfluoxetine

inhibitors

(SSRI)

didesmethylcitalopram

4–16 d 2D6 (d,m), 2C19 (d,m), 2D6 (d,m), 3A4 (m) Fluvoxamine (Luvox) 100–300 25 15–23 1A2, 2D6 None N/A 1A2, 2C9, 2C19, 3A4 Paroxetine (Paxil) 10–50 8–28 2.9–44 2D6 None N/A 2D6 Sertraline

(Zoloft)

50–200 20 24 2C9, 2B6, 2C19, 2D6, 3A4 Desmethylsertraline 62–104 h 2C19 (d,m) SSRI with α1 -adrenergic antagonism Trazodone (Desyrel) 50–600 0.47–1 3–9 2D6, 3A inhibitors may increase concentration Metachlorophenylpiperazine ?

None/unknown SSRI with inhibition of reuptake of norepinephrine Venlafaxine (Effexor) 75–375 6–7 3–4 2D6 O -desmethylvenlafaxine, depends on 3A4 and 2C19 for metabolism 10 h None/unknown Duloxetine (Cymbalta) 40–60 23 8–17 2D6,1A2 4-hydroxyduloxetine, 5-hydroxy, 6-methoxy-duloxetine sulfate (unknown ? 2D6 SSRI with α2 -adrenergic antagonism: 5HT2 /5HT3 antagonism Mirtazapine 15–45 ? 20–40

(Remeron)

3A4 Desmethylmirtazapine ? 3A4 induction Inhibition of reuptake of biogenic amines or dopamine Bupropion (Wellbutrin, Zyban) 150–450 20 9.6–20.9 2D6 Hydroxybupropion, erythrohydrobupropion, threohydrobupropion

if

act

24–37 h None/unknown

Dr

Drug

Typical Daily Dose Range (mg)

Vd (L/kg)

t1 / 2 (h)

Major Metabolic Isozyme

Major Active Metabolites

Major Active Metabolite t1 / 2

Met

In

TABLE 70-1. Drug Mechanism and Drug Information for Currently Ava SSRIs and Atypical Antidepressants

Figure 70-3. Neuroanatomy and effects of several common therapeutic drugs o serotonin neurotransmission in the brain.

P.1072

P.1073 Infrequently, SSRI overdose results in life-threatening effects. In one fatality, t patient reportedly ingested 75 times the maximum daily dose of fluoxetine. The fluoxetine concentration was 6000 ng/mL and the norfluoxetine concentration w ng/mL; more than 10 times higher than therapeutic serum concentrations.97 SSRIs Citalopram (Celexa) SSRI, antimuscarinic 0 ++++ 0 0 Escitalopram SSRI

(Lexapro)

0 ++++ 0 0 Fluoxetine (Prozac) SSRI 0 ++++ 0 0 Fluvoxamine (Luvox) SSRI 0 ++++ 0 0 Paroxetine (Paxil)

SSRI, antimuscarinic + ++++ + 0 Sertraline (Zoloft) SSRI 0 ++++ + + Other Bupropion (Wellbutrin, Zyban) Inhibits reuptake of biogenic amines ++ + + +++ Duloxetine

(Cymbalta)

SRI, norepinephrine ++ ++++ 0

reuptake

inhibitor

++ Mirtazapine (Remeron) Î ±2 -adrenergic antagonism, 5HT2 /5HT3 antagonism 0 ++++ 0 + Reboxetine (Edronax, Vestra) Selective norepinephrine reuptake inhibitor ++++ 0

0 ++++ Tianeptine Unclear ? ? ? ? Trazodone (Desyrel) SRI,α-adrenergic antagonist 0 ++++ 0 0–+ Venlafaxine (Effexor) SRI, norepinephrine ++ ++++ 0

reuptake

inhibitor

++ SSRI = selective serotonin reuptake inhibitor; SRI = serotonin reuptake inhibito + weak if any agonism; ++, weak agonism; +++, strong agonism; ++++, very agonism; 0, no effect.

Drug

Mechanism

Degree of Norepinephrine Reuptake Inhibition

Degree of Serotonin Reuptake Inhibition

Degree of Dopamine Reuptake Inhibition

Degr Perip Î Adre Ago

TABLE 70-2. Receptor Activity of SSRIs and Related Antidepressants

Citalopram

Citalopram and its enantiomer escitalopram cause QTc interval widening and se a dose-related manner. These effects are reported at doses as low as 400 mg fo citalopram.33 Larger case series found that these effects typically occur after e to doses exceeding 600 mg citalopram or in patients with serum concentrations than 40 times the expected therapeutic concentrations.74 , 133 , 134 In one case seizures were an early finding, whereas the development of ECG abnormalities delayed for as long as 24 hours following ingestion.134

Although the mechanisms are unclear, experimental models suggest that the didesmethylcitalopram metabolite of citalopram prolongs the QTc interval by blo , whereas high concentrations of both the parent drug and this metabolite result

seizures21 , 30 (Chap. 23 ). The elimination half-life of the R-enantiomer of cita appears to exceed that of the S-enantomer.184 The implications of this differenc formation and effects of racemic forms of didesmethylcitalopram are unclear.

Management

Treatment of patients with acute SSRI overdose is largely supportive. Dextrose thiamine should be considered in patients who present with altered mental statu clinically warranted. Although cardiac manifestations after SSRI overdose are rar lead ECG should be obtained to identify other cardiotoxic drugs such as tricyclic

antidepressants to which the patient may have access (Chaps. 5 and 2 3 ). If ov citalopram or escitalopram is suspected, 24 hours of cardiac monitoring is reco to exclude the possibility of QTc prolongation and subsequent risk for ventricula dysrhythmias. Serum electrolytes and an acetaminophen concentration may be

for monitoring and treatment of patients with intentional overdose. After the pa stabilized, oral activated charcoal (1 g/kg) may be useful to adsorb drug remain the

P.1074 gastrointestinal tract. Because SSRI overdose is rarely life threatening, orogast lavage is not generally indicated. Patients with small unintentional overdoses of other than citalopram and escitalopram are not expected to develop significant and symptoms of poisoning. Fatalities resulting from SSRIs are rare and most c occur after multiple drug ingestions and manifestations of drug interactions res from excess serotonergic effects66 (see Serotonin Syndrome ). Forensic analysis

suggests the minimum lethal concentrations of fluoxetine, paroxetine, and sert after isolated overdose are 0.63, 0.4, and 1.5 mg/L, respectively. Patients, freq children, with well-defined small unintentional oral ingestions can be managed s home with close observation.123 Classic SSRIs Citalopram (Celexa) +++ +++ 0–+ Escitalopram (Lexapro) +++ +++ 0–+ Fluoxetine + 0 0–+ Fluvoxamine + 0

(Prozac)

(Luvox)

0–+ Paroxetine (Paxil) + 0 0–+ Sertraline (Zoloft) + 0 0–+ Atypical Antidepressants

Bupropion

(Wellbutrin,

Zyban)

++++ 0–+ 0–+ Duloxetine ++++ Unknown Unknown Mirtazapine Unknown Unknown ++ Reboxetine ++++ Unknown Unknown

(Cymbalta)

(Remeron)

(Edronax,

Vestra)

Tianeptine Unknown Unknown Unknown Trazodone 0–+ 0 0

(Desyrel)

Venlafaxine (Effexor) +++ 0–+ +++ 0 does not cause; + very rarely causes; ++ rarely causes; +++ causes; ++++ commonly causes. Drug

Seizures

QTc

Prolongation

QRS

Prolongation

TABLE 70-3. Predictive Analysis of the Relative Potential for Seizures a Abnormalities of SSRIs and Related Antidepressants

Adverse

Effects

After

Therapeutic

Doses

Adverse effects commonly attributed to therapeutic doses of SSRIs that also ma in overdose include gastrointestinal symptoms (anorexia, nausea, vomiting, dia sexual dysfunction in both males and females, headache, insomnia, jitteriness, dizziness, and fatigue. 189 Genetic polymorphism typing holds promise in identif patients at highest risk for adverse drug events with therapeutic dosing.192 Les common adverse effects include sedation, particularly following citalopram and paroxetine as a result of their weak anticholinergic activity, and anxiety followin fluoxetine treatment.111 The mechanism of serotonin-mediated inhibition of pla function is unclear; however, early human data show that the risk of bleeding, i very low.102 , 105 , 106 , 115 , 135 Other rarely reported adverse effects include

onset panic disorder, priapism, photopigmentation, bradycardia, hepatotoxicity, urinary incontinence.25 , 46 , 89 , 90 , 120 , 168 Movement disorders, most commo akathisia, parkinsonism, myoclonus, and dystonia, also occur after SSRI use.4 , These extrapyramidal side effects may be related to the complex interplay betw

serotonergic and dopaminergic activity. Predisposing factors for the developmen movement disorders include concomitant use of dopamine antagonists such as antipsychotics.103

The syndrome of inappropriate antidiuretic hormone (SIADH), in which severe hyponatremia may occur rapidly, is associated with SSRI use. In an animal mod effect appears to be serotonin mediated, with increased concentrations of serum

cortisol, adrenocorticotropin (ACTH), and vasopressin.57 Rat studies demonstrat stimulation of 5HT1 C receptors increases antidiuretic hormone secretion.132 How human case control studies have not confirmed defects in osmoregulated release vasopressin through normal water loading tests and measurement of vasopress concentrations after 3–11 months of paroxetine use.113 A review of the litera identified women older than 70 years who are concomitantly receiving diuretic to be at greatest risk for developing SIADH.93 , 98 Although reported to occur fr days to 4 months after initiation of therapy, a case-matched control study of 20 patients identified that SIADH occurs most frequently within the first 2 weeks o therapy.121 As a class, hyponatremia is demonstrated to occur when switching f SSRI to another.6 Efforts to predict risk through poor CYP2D6 genotype metabo status or high serum concentrations have not been successful.170

Serotonin

Syndrome

The most common severe adverse effect associated with SSRIs is the developme serotonin syndrome. This syndrome, also referred to as the serotonin behaviora hyperactivity syndrome , was first described in patients treated with MAOIs who given other drugs that enhance serotonergic activity.35 , 70 , 129 , 166 However, ingestion of an MAOI is not required for this syndrome to develop, and its deve is unpredictable (Table 70-4 ).

Pathophysiology

The pathophysiologic mechanism of the serotonin syndrome is not completely understood but involves excessive selective stimulation of serotonin 5-HT2 A and

5-HT1 A receptors. Animal models demonstrate that specific stimulation of 5-HT1 receptors results in signs and symptoms of serotonin syndrome even when 5-HT receptors were inactivated using a specific antagonist.41 However, a subsequent study and a human retrospective case series showed that the potency of 5-HT2 A

antagonist therapy was directly related to resolution of symptoms attributed to serotonin syndrome.65 5-HT1 D receptors are not implicated in cases of serotonin syndrome.

Clinical

Manifestations

Symptoms of serotonin syndrome include altered mental status, agitation, myo hyperreflexia, diaphoresis, tremor, diarrhea, incoordination, muscle rigidity, and hyperthermia (Table 70-5 ). The clinical manifestations of serotonin

P.1075 syndrome are diverse, and minor manifestations are common after initiation of atypical antidepressant therapy. In fact, a prospective study of depressed inpat given clomipramine demonstrated that 16 of 38 patients experienced symptoms consistent with the serotonin syndrome.108 Fourteen of 16 cases demonstrated spontaneous resolution within 1 week without discontinuation of therapy. Drugs That Inhibit Serotonin Breakdown Monoamine oxidase inhibitors (nonselective)

Phenelzine,

moclobemide,

clorgyline,

isocarboxazid 24 ,31 ,35 ,54 ,64 ,69 ,82 ,96

,159 ,163 ,166 ,173 ,175

Harmine and harmaline from Ayahuasca preparations, psychoactive beverag for religious purposes in the Amazon and Orinoco River basins31 Drug That Block Serotonin Reuptake Clomipramine99 ,137 ,148 ,166 Cocaine175 Dextromethorphan146 Meperidine64 Pentazocine79 SSRIs Fluoxetine, citalopram, paroxetine, fluvoxamine, sertraline10 ,13 ,15 ,24 ,36 ,4 ,60 ,63 ,69 ,71 ,79 ,110 ,122 ,130 ,137 ,142 ,150 ,159 ,162

Trazodone60 ,67 ,126 ,141 ,142 Venlafaxine39 ,82 ,100 Serotonin Precursors or Agonists L–Tryptophan167 Lysergic acid diethylamide (LSD)158 Drugs That Enhance Serotonin Release Amphetamines, especially Buspirone10 ,67 Cocaine175 Lithium99 ,122 ,127

MDMA

(ecstasy)96 ,163

Mirtazapine14 ,44 TABLE 70-4. Potential Causes of Serotonin Syndrome

Life-threatening effects invariably result from hyperthermia caused by excessive activity. Sustained severe hyperthermia can lead to death through denaturation essential protein and enzymatic function that ultimately results in lactic acidosis rhabdomyolysis, myoglobinuria, renal and hepatic dysfunction, disseminated intravascular coagulation, or adult respiratory distress syndrome116 , 171 (Chap.

Diagnosis

The serotonin syndrome occurs most frequently following use of combinations o serotonergic agents (Table 70-4 ). Drug interactions resulting in serotonin synd occur while switching serotonergic pharmacologic agents when an insufficient tim occurs before initiating the alternative therapy.150 , 151 Residual pharmacologic receptor downregulation or upregulation, and the presence of active metabolites causative in these circumstances. For example, fluoxetine metabolism results in active metabolite norfluoxetine, which has comparable pharmacologic effects and life substantially longer than that of the parent drug. The metabolite persists an result in serotonin syndrome when another serotonergic agent, usually another antidepressant, is given prior to complete clearance of norfluoxetine, which tak approximately 2 weeks.36

This syndrome is reported in patients following a single dose, high therapeutic or overdoses of certain serotonergic agents in adults and children.39 , 63 , 95 , 1 130 , 141 , 148 Although sporadic reports occur, selective MAO subtype B (MAO-B inhibitor drug combinations are rarely reported to result in serotonin syndrome therapeutic doses.48 , 118 Mental Status Consciousness altered Restlessness Elevated mood Insomnia Coma Other Neurologic Signs and Symptoms Coma Incoordination Myoclonus Mydriasis Tremor Akathisia Shivering Rigidity

Hyperreflexia Vital Signs and Autonomic Manifestations Fever (Hyperthermia) Tachycardia Sweating Tachypnea or Dyspnea Diarrhea Hypertension or hypotension

Serotonin syndrome is diagnosed by the presence of at least 4 major sympto major plus 2 minor symptoms following the addition or an increase in a kno serotonergic agent. Underlying psychiatric disorder should be excluded. Other etiologies must be excluded, including initiation of a neuroleptic or ot dopamine antagonist or withdrawal from a dopamine agonist.

Adapted from Radomski et al.140 Major

Minor

TABLE 70-5. Diagnostic Criteria for Serotonin Syndrome

Currently no diagnostic test capable of determining whether a patient is experie serotonin syndrome is available. Although fulminant life-threatening cases are e recognize, mild cases are more difficult to distinguish from other causes. In an determine diagnostic criteria, a study that included 38 cases of presumed serot syndrome was performed. This trial led to suggested diagnostic criteria for sero syndrome to include three of the following signs and symptoms—altered ment agitation, myoclonus, hyperreflexia, diaphoresis, tremor, diarrhea, and incoordination—when other etiologies are excluded.171 A modification, the Hun Serotonin Toxicity Criteria,49 which included the variables myoclonus, agitation, diaphoresis, hyperreflexia, hypertonicity, and fever, was validated in 473 patien

found to correlate best with a clinical toxicologic diagnosis of the serotonin syndrome.171 The most comprehensive review of signs and symptoms in a litera review found altered mental status, other neurologic signs and symptoms, vital and autonomic manifestations most commonly associated with the development serotonin syndrome. Diagnostic criteria based on these clinical findings are give Table 70-5 .140

Management

Treatment of patients with serotonin syndrome begins with supportive care and on decreasing muscle rigidity. Because muscular rigidity is thought to be partly responsible for hyperthermia and death, rapid external cooling in conjunction w aggressive use of benzodiazepines should limit complications and mortality. In cases, neuromuscular blockade should be considered to achieve rapid muscle r

The time course of the serotonin syndrome is variable and related to the time r to decrease drug concentrations of the offending agents. In most patients, the syndrome resolves within 24 hours after the offending drug is removed. Howeve serotonin syndrome can be prolonged when it is caused by drugs with long half protracted duration of effects, or active metabolites.

P.1076 Animal models indicate that pretreatment with serotonin antagonists can preven development of the serotonin syndrome.62 , 84 , 169 Several case reports indicat

successful use of 4 mg oral or intravenous cyproheptadine, an antihistamine wit nonspecific antagonist effects at 5-HT1 A and 5-HT2 A receptors.71 , 104 Patients w responded typically had mild to moderate symptoms of serotonin syndrome and not hyperthermic. Cyproheptadine use in this patient group is supported. Furthe research is warranted to determine the success of higher doses given to gain s 5-HT2 A antagonistic effects in more severely affected patients.65 Other drugs th anecdotally reported to be successful for treatment of symptoms caused by the serotonin syndrome include methysergide, chlorpromazine, atypical antipsychoti propranolol.64 , 65 , 67 , 75 , 152 Because all of these drugs are of unproven utilit can be dangerous, aggressive cooling and sedation with a benzodiazepine remai basis of therapy.

Differential Diagnosis of the Serotonin the Neuroleptic Malignant Syndrome

Syndrome

Many features overlap between the serotonin syndrome and the neuroleptic ma syndrome (NMS) (Chap. 67 ). Some authors call these “spectrum disorders†can be caused by drugs with both antidopaminergic and/or proserotonergic effe 190 This position is supported by the finding that 5-HT 2 A agonism results in an decrease in neuronal dopamine release. Some authors report NMS with use of enhancing drugs. However, low concentrations of measured dopamine and norm concentrations of serotonin metabolites in the NMS patients reported support th hypothesis of central dopaminergic hypoactivity.8 , 126 It now is clear that the implicated drugs, time course, pathophysiologic mechanism, and manifestations distinct65 (Table 70-6 ). Altered mental status, autonomic instability, and chang neuromuscular tone that may result in hyperthermia are common to both syndr

The development of NMS involves rapid blockade of dopaminergic neurons in the whereas the serotonin syndrome appears to result from acute overstimulation o serotonin receptors (5-HT2 A ).

In addition to the associated medications, the time courses of the two syndrome substantially different. Signs and symptoms of the serotonin syndrome develop minutes to hours after exposure to the offending agents, whereas NMS typically

develops days to weeks after daily exposure to the drug in question.69 In additi symptoms develop and offending drugs are discontinued, NMS can last for as lon weeks, whereas the serotonin syndrome usually resolves quickly, coinciding with offending drug's pharmacokinetic metabolism. A review of the literature indicate

patients presenting with serotonin syndrome were more likely to exhibit agitatio hyperactivity, clonus and myoclonus, ocular oscillations, shivering, tremors, and hyperreflexia, whereas patients presenting with NMS were more likely to exhibit bradykinesia and lead pipe rigidity.65 Historical Diagnostic Clue Inciting drug pharmacology Dopamine antagonist Serotonin agonist Time course of initiation of symptoms after exposure

Days to weeks Hours Duration of symptoms Days to 2 weeks Usually 24 hours Symptoms Autonomic instability +++ +++ Fever +++ +++ Altered mental status +++ +++ Altered mental status +++ + Lead pipe rigidity +++ + Tremor, +

hyperreflexia,

(depressed/confusion)

(agitation/hyperactivity)

myoclonus

+++ Shivering +++ Bradykinesia +++ - not found; + rare finding; +++ common finding. NMS

SS

TABLE 70-6. Comparison of Neuroleptic Malignant Syndrome (NMS) Serotonin Syndrome (SS)

Atypical

Antidepressants

Atypical antidepressants are defined as not belonging strictly to a set antidepressants. They are not SSRIs, cyclic antidepressants, or MAOIs. atypical antidepressants are the newer antidepressants, most of which SSRIs and have additional pharmacologic effects that were selected in

classificat In gener are deriv an attem

decrease the undesirable side effects of traditional antidepressants.

Serotonin/Norepinephrine

Reuptake

Inhibitors

Venlafaxine

In addition to inhibiting serotonin reuptake, venlafaxine inhibits norepinephrine reuptake. Venlafaxine produces rapid downregulation of central β-adrenergic r which may result in a faster onset of antidepressant effect.157 Patients with acu venlafaxine overdose may present with nausea, vomiting, dizziness, tachycardia depression, hypotension, hyperthermia, elevated hepatic enzyme concentrations seizures.86 , 186 , 194 Sodium channel blocking effects are rarely clinically appa however, QRS prolongation and ventricular tachycardia have resulted in death.1 149 , 194 Although no clinical data regarding efficacy are available, sodium bica may be helpful in attenuating these cardiotoxic effects (Antidotes in Depth: Sod Bicarbonate ).

Overdose information on duloxetine, a similar drug, is limited, but duloxetine is expected to have similar effects.177 Milnacipran is an investigational drug that a expected to have similar effects.28 , 34

Norepinephrine

Reuptake

Inhibitors

Reboxetine

P.1077 Reboxetine is a selective norepinephrine reuptake Lack of experien precludes an analysis of overdose data. However, toxicity can be extrapolated f adverse effects reported in clinical trials and from experience with other drugs inhibitor.182

possessing similar pharmacologic characteristics. In particular, overdosed patie should be carefully monitored for tachycardia, hypertension or hypotension, and development of seizures. Cases of acute mania and hepatotoxicity are reported therapeutic use.17

Other Atypical Agents with Part of Their Mechanism

Reuptake

Inhibition

Bupropion

The pharmacologic mechanism of action of bupropion, a unicyclic antidepressant unclear, but both the parent drug and an active metabolite inhibit the reuptake dopamine and, to a lesser extent, serotonin and norepinephrine.145 Extended-re formulations of bupropion are frequently used as adjuncts in smoking cessation therapy.88 Chronic doses greater than 450–500 mg/d place the patient at risk seizures.42 , 93

Frequent effects after overdose include tachycardia, hypertension, gastrointesti symptoms, and agitation.11 , 16 Large acute overdoses may result in seizures w without QRS complex prolongation.29 , 81 , 131 , 161 , 172 In some cases, these were delayed for up 10 hours, particularly after ingestion of sustained-release preparations.80 Symptoms are reported to continue for up to 48 hours.

Several studies suggest that seizures following either bupropion overdose or hig therapeutic doses are caused by its metabolite hydroxybupropion.56 , 136 Elevat

hydroxybupropion concentrations are documented after seizures when bupropio concentrations were no longer detectable. The exact mechanism for seizures cau hydroxybupropion is unclear at this time.42 , 56 , 147

Treatment, when required for seizures, should be supportive and includes judici of benzodiazepines, followed by barbiturates. If QRS prolongation occurs, the p should be treated with sodium bicarbonate (Antidotes in Depth: Sodium Bicarbo

Early after sustained-release bupropion overdose, activated charcoal should be considered, with use of multiple doses of activated charcoal or whole-bowel irri after large, potentially life-threatening ingestions.

Other serious adverse effects reported after bupropion use include cholestatic a hepatocellular hepatic dysfunction, and rhabdomyolysis, with isolated reports of pain, dystonia, trigeminal nerve dysfunction, mania, generalized erythrodermic psoriasis, erythema multiforme, dyskinesia, altered vestibular and sensory funct serum sickness.2 , 3 , 37 , 40 , 45 , 47 , 59 , 68 , 112 , 176 , 191

Trazodone

Trazodone is a serotonin agonist that acts through inhibition of serotonin reupta addition, trazodone may have some peripheral α-adrenergic antagonist activity depression and orthostatic hypotension are the most common complications afte overdose of trazodone.58 Trazodone is rarely reported to cause SIADH. This effe be responsible for seizures, which rarely occur after acute overdose.9 , 180 Priap reported with therapeutic use of trazodone, may occur occasionally after overdo 58 Management of hypotension includes supportive care and administration of fl vasopressors, if necessary.

Mirtazapine

The mechanism of mirtazapine action is unique. In addition to serotonin reuptak inhibition, mirtazapine increases neuronal norepinephrine and serotonin through adrenergic antagonism.43 Mirtazapine also blocks some subtypes of 5-HT recep including 5-HT2 and 5-HT3 , which appear to have antidepressive effects.128 The effects that occur after acute mirtazapine overdoses include altered mental stat tachycardia.26 , 181 Large overdoses may cause respiratory depression and pro of the QTc interval.26 , 61 , 85 , 143 Because more overdose data are required be precise constellation of symptoms can be attributed to this drug, careful clinical

monitoring is advised. Therapeutic use of mirtazapine causing serotonin syndro hepatitis, hypertension, and reversible agranulocytosis is reported.1 , 83 , 87 , 12

Tianeptine

Tianeptine is an investigational drug for treatment of anxiety and depression.18 mechanism of tianeptine is unclear but may include serotonin reuptake enhance that ultimately reduces expression of serotonin transporter mRNA and serotonin transporter binding sites.101 No information about this drug in the overdose set available. Careful observation is warranted until more information becomes ava

Drug

Discontinuation

Syndrome

A drug discontinuation syndrome is defined as withdrawal manifestations that a pharmacologically based and occur after therapeutic use of a drug. Drug discon syndromes are commonly reported after withdrawal of conventional antidepress including tricyclic antidepressants and MAOIs107 (Chaps. 69 and 7 1 ). SSRIs are

reported to cause a discontinuation syndrome that typically begins within 5 day drug discontinuation and may last up to 3 weeks.76 The most frequently reporte symptoms include dizziness, lethargy, paresthesias, nausea, vivid dreams, irrit and depressed mood. 77 , 78 , 155 , 193 The risk factors associated with developm

discontinuation syndrome are not fully clarified, although the syndrome is more with SSRIs having a shorter elimination half-life (paroxetine > fluvoxamine > s > fluoxetine). In addition, SSRIs with high-potency serotonin

P.1078 reuptake inhibition are more frequently implicated (paroxetine > sertraline > clomipramine > fluoxetine > venlafaxine > trazodone). Of the SSRIs, paroxetine often results in discontinuation syndrome, which is estimated to occur at a rate cases per million prescriptions. A meta-analysis of published cases from 1986â found that 65% of cases were attributed to paroxetine, 17% to sertraline, 11% fluoxetine, and 7% to fluvoxamine.18 Fluoxetine discontinuation syndrome occur frequently, at only two cases per million prescriptions.139 The long elimination of fluoxetine and its active metabolite norfluoxetine probably decrease the incid discontinuation syndrome by providing a tapered effect after cessation. Although compared to the other SSRIs, citalopram appears to have a low incidence of

discontinuation

symptoms.114

Because of difficulty in distinguishing symptoms of discontinuation syndrome fro underlying disease, many authors have proposed diagnostic criteria for the SSR discontinuation syndrome.19 All proposed criteria include discontinuation of the concordance with CNS effects, gastrointestinal distress, or anxiety.174

The biochemical basis of the discontinuation syndrome is hypothesized to result serotonin receptor downregulation leading to alterations in serotonergic activity including interactions with other neurotransmitters (GABA, norepinephrine, and dopamine).154 Although postulated, antimuscarinic withdrawal seems an unlikely because the antimuscarinic effects of desipramine failed to protect against paro withdrawal in a human model.51

Treatment of patients exhibiting discontinuation symptoms should include supp care and reinitiation of the discontinued drug or administration of another SSRI reinitiation of the drug is contraindicated. The drug then should be tapered at a that allows for improved patient tolerance. Many of the other antidepressants discussed in this chapter also result in discontinuation reactions. Symptoms appear similar to those reported after discontinuation of SSRIs and are treated in a similar manner.14 , 92

Summary

In acute overdose SSRIs or atypical antidepressants usually are not life threate although a few drugs produce seizures or cardiac toxicity. Treatment is general supportive for all of these drugs. However, significant drug interactions and adv drug effects are associated with serotonin reuptake inhibitors and may lead to a life-threatening events. In addition, the management of these patients frequentl complicated because they likely have concomitant access to more life-threatenin antidepressants such as tricycle antidepressants and MAOIs.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > G - Psychotropic Medications > Chapter 71 - Cyclic Antidepressants

Chapter

71

Cyclic

Antidepressants

Erica L. Liebelt A 2.5-year-old girl was brought to the emergency department (ED) for evaluation of a seizure. The child previously was well and had no other medical problems. The young girl and her sibling ate dinner at a neighbor's house 2 hours prior to this incident. After the girl returned home, the mother noticed that the child looked tired. The girl subsequently had a generalized tonic-clonic seizure that lasted approximately 1 minute. The paramedics described the young girl as postictal, with vital signs of blood pressure, 90/50 mm Hg; pulse 160 beats/ min; respiratory rate 26 breaths/min. At the request of the paramedics and the ED physician on medical control, the mother called the neighbor to determine whether the girl could have accessed any prescription medications or other pills while she was in the house. The neighbor revealed that her son's amitriptyline bottle had been spilled. According to the neighbor's count, one or two 75-mg amitriptyline tablets were missing. In the ED 15 minutes later, the girl was still sleepy, but she responded to the physician's questions and cried when the IV line

was placed. Vital signs were: blood pressure, 90/50 mm Hg; pulse, 200 beats/min; respiratory rate, 26 breaths/min; temperature 99.7°F (37.6°C); and pulse oximeter revealed 97% oxygen saturation on room air. Physical examination demonstrated large (6mm) pupils that were sluggishly reactive to light, slightly dry mucous membranes, no meningismus, and altered mental status. Initial bedside rapid glucose concentration was 110 mg/dL. Arterial blood gas showed: pH 7.28; PCO2 , 38 mm Hg; PO2 , 94 mm Hg; [HCO3 - ] , 13 mEq/L. Blood was obtained for determination of electrolytes, liver enzymes, complete blood count, and amitriptyline concentration. The 12-lead electrocardiogram (ECG) revealed a wide-complex tachycardia with a rate of approximately 200 beats/min and a variable QRS interval with a minimum duration of 220 msec (Figure 71-1A). The girl then had another generalized tonic-clonic seizure, which lasted approximately 60 seconds. Her blood pressure dropped to 60/30 mm Hg. Lorazepam 0.1 mg/kg IV was given, followed by an IV bolus of sodium bicarbonate 1 mEq/kg over 3 minutes and a 1 mg/kg bolus of lidocaine. A 20-mL/kg bolus of 0.9% sodium chloride solution was administered through a second intravenous line, and the blood pressure increased to 88/47 mm Hg. The patient was intubated, orogastric lavage was performed with a 24-French tube, and activated charcoal 1 g/kg was administered via the orogastric tube. A second ECG obtained 30 minutes after initial interventions showed a heart rate of 150 beats/min and narrowing of the QRS complex to 140 msec with a terminal R wave in lead aVR (RaVR) of 6 mm (Figure 71-1B). A continuous infusion of sodium bicarbonate and 0.9% sodium chloride solution was administered at 60 mL/h by adding 100 mEq hypertonic sodium bicarbonate (1 mEq/mL) to 5% dextrose/0.25% saline to give a cumulative sodium concentration of 138 mEq/L. A venous blood gas showed a pH of 7.43. Prior laboratory studies did not reveal any abnormalities except for a measured [HCO3 - ] of 14 mEq/L. The patient was transferred to the pediatric intensive care unit (PICU) of a tertiary care children's

hospital for further management. On arrival to the PICU, the patient was sedated. Her blood pressure was 99/53 mm Hg and heart rate was 136 beats/min. A third ECG obtained 10 hours after the initial ECG showed heart rate of 120 beats/min, QRS interval of 80 msec, and RaVR of 4.5 mm (Figure 711 C). The patient was extubated within 6 hours and remained in the intensive care unit overnight for continuous ECG monitoring. The ECG abnormalities resolved, and the last ECG showed QRS duration of 80 msec and RavR of 1 mm. The patient was awake, alert, and normotensive. The quantitative serum amitriptyline concentration from the sample obtained at the initial hospital was 1003 ng/mL. The patient was discharged home the next day after social service consultation and a total of 24 hours of observation following extubation, termination of sodium bicarbonate infusion, and resolution

of

ECG

abnormalities.

Cyclic antidepressants (CAs) consist of a group of pharmacologically related drugs used for treatment of depression, as well as neuralgic pain, migraines, enuresis, and attention deficit hyperactivity disorder. Most CAs have at least 3 rings inherent in their chemical structure. They include the traditional tricyclic antidepressants (TCAs) imipramine, desipramine, amitriptyline, nortriptyline, doxepin, trimipramine, protriptyline, and clomipramine, as well as cyclic compounds such as maprotiline and amoxapine (Table 71-1) . These drugs share unique toxicologic characteristics that have led to an array of basic science and clinical research primarily aimed at innovative and optimal treatment modalities.

History

and

Epidemiology

Imipramine was the first TCA used for treatment of depression in the late 1950s. However, the synthesis of iminodibenzyl, the “tricyclic― core of imipramine, and the description of its chemical characteristics date back to 1889. Structurally related to the phenothiazines, imipramine originally was developed as a

hypnotic agent for the sedation of agitated or psychotic patients and was serendipitously found to alleviate depression. From the 1960s until the late 1980s, the TCAs were the major pharmacologic treatment P.1084 for depression in the United States. However, by the early 1960s, cardiovascular and central nervous system (CNS) toxicity were recognized as major complications of TCA overdoses. The newer CAs were developed in the 1980s and 1990s to decrease some of the adverse effects that occurred with older TCAs, improve the therapeutic index, and reduce the incidence of serious toxicity. The newer CAs included the tetracyclic drug maprotiline and the dibenzoxapine drug amoxapine (Table 71-1) .

Figure

71-1.

Case

electrocardiograms. A . Initial ECG shows a

wide-complex tachycardia with a variable QRS duration (minimum 220 msec). B . ECG 30 minutes after presentation following sodium bicarbonate shows narrowing of the QRS interval to a duration of 140 msec and an amplitude of RaVR of 6.0 mm. C . ECG 9 hours after presentation shows further narrowing of the QRS interval to 80 msec and decrease in the amplitude of RaVR to 4.5 mm. (Reproduced with permission from Liebelt EL: Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: The pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998;14:293–298.74)

The epidemiology of CA poisoning has evolved significantly in the last 10 years, resulting in great part from the introduction of the newer selective serotonin reuptake inhibitors (SSRIs). The antidepressants are a leading cause of drug-related self-poisonings in the world, primarily because of their ready availability to people with depression who by virtue of the disease are at high risk for overdose. Between 1993 and 1997, 95% of poisoning deaths in England and Wales were associated with TCAs, particularly dothiepin and amitriptyline. TCAs were associated with 5.3 deaths per 100,000 prescriptions.128 Numerous epidemiologic studies in both the United States and Europe demonstrate that the comparative risk of death is significantly greater with the TCAs as a group compared with the newer antidepressants, including the SSRIs.60 However, over the last 10 years, more medical indications for TCA use, including chronic pain, obsessive-compulsive disorder, and, particularly in children, enuresis and attention deficit hyperactivity disorder, have emerged, thus increasing their availability even more. Based on data from the American Association of Poison Control Centers' (AAPCC) Toxic Exposure Surveillance System (TESS), CAs (primarily TCAs) were the leading cause of poisoning fatalities in the United States until 1993, when they were overtaken by the analgesics (Chap. 130). In the last 10 years, the number of deaths caused by CAs reported to poison centers has remained relatively constant, although the total number of CA exposures has decreased slightly. There is a significant underreporting of deaths attributable to antidepressants through the AAPCC TESS data.54 What cannot be determined from these particular poison center data is whether prehospital deaths have changed and whether the total number of prescriptions for CAs has declined or remained constant, factors that would contribute more meaning to the actual number of deaths. Children younger than 6 years have consistently accounted for approximately 12–13% of all CA exposures during the last 10 years. Antidepressants (specifically TCAs) are the second most

commonly with a

prescribed

psychotropic

medication

in

preschool

children,

P.1085 >200% increase from 1991–1995.159 Despite the emergence of the SSRIs in the early 1990s, TCAs were still among the top 5 psychotropic drugs most frequently prescribed by pediatric officebased practices in 1995.59 CA poisoning likely will continue to be among the most lethal unintentional drug ingestions in younger children because only 1 or 2 adult-strength pills can cause serious poisoning in children of this age.

Pharmacology In general, the TCAs can be classified into tertiary and secondary amines based on the presence of a methyl group on the propylamine side chain (Table 71-1). The tertiary amines amitriptyline and imipramine are metabolized to the secondary amines nortriptyline and desipramine, respectively, which themselves are marketed as antidepressants. In therapeutic doses, the CAs exhibit numerous pharmacologic effects on the autonomic system, CNS, and cardiovascular system. However, the drugs can be distinguished from each other by their relative potencies with which they produce the diverse clinical effects. These pharmacologic differences appear to be pronounced even with therapeutic dosing.

TABLE

71-1.

Cyclic Antidepressants—Classification Chemical Structure

by

Therapeutically, CAs inhibit presynaptic reuptake of norepinephrine and/or serotonin, thus functionally increasing the amount of these neurotransmitters at CNS receptors. The tertiary amines, especially clomipramine, are more potent inhibitors of serotonin reuptake, whereas the secondary amines are more potent inhibitors of norepinephrine reuptake. Although these pharmacologic actions formed the basis of the monoamine hypothesis of depression in the 1960s, antidepressant actions of these drugs appear to be much more complex. Extensive research has led to the “receptor sensitivity hypothesis of antidepressant drug action,― which postulates that following chronic CA administration, alterations in the sensitivity of various receptors are responsible for antidepressant effects. Chronic TCA administration alters the number and/or function of central βadrenergic and serotonin receptors.114 In addition, TCAs modulate glucocorticoid receptor gene expression and cause alterations at the genomic level of other receptors.8,72 All of these actions play a role in the antidepressant effects of TCAs. Additional pharmacologic mechanisms of CAs are responsible for their side effects and overdose presentations.27 All of the CAs are competitive antagonists of the muscarinic acetylcholine receptors, although they have different affinities. Acetylcholine blockade is responsible for central and peripheral anticholinergic adverse effects, such as dry mouth, urinary retention, blurred vision, and sedation. The CAs also antagonize peripheral α1 -adrenergic receptors, producing vasodilation and orthostatic hypotension. The membranestabilizing effect of CAs is responsible for cardiac conduction abnormalities that occur even at therapeutic doses and, following overdose, is the mechanism of life-threatening cardiac toxicity.42 Finally, animal research demonstrates interactions of CAs on the γaminobutyric acid (GABA) receptor–chloride–ionophore complex in the brain. The effects of chronic CA administration on chloride influx, chloride uptake, GABA transport, and specific GABA receptors may offer a novel mechanism of antidepressant drug action and a

mechanism for seizure occurrence after CA overdoses.80,81,94,138 Amoxapine is a dibenzoxapine CA derived from the active antipsychotic loxapine. Although it has a 3-ringed structure, this drug has little similarity to the other tricyclics. It is a potent norepinephrine reuptake inhibitor, has no effect on serotonin reuptake, and blocks dopamine receptors. Maprotiline is a tetracyclic antidepressant that predominantly blocks norepinephrine reuptake. Both of these CAs have a slightly different toxic profile than the traditional TCAs.

Pharmacokinetics

and

Toxicokinetics

CAs are rapidly and almost completely absorbed from the gastrointestinal (GI) tract, with peak concentrations 2–8 hours after administration of a therapeutic dose. CAs are weak bases (high p Ka ); thus, changes in acid–base status alter the proportion of ionized to nonionized drug. In CA overdose, the decreased GI motility caused by CA anticholinergic effects and the ionization in gastric media delay CA absorption. Because of extensive metabolism by the liver, the oral bioavailability of CAs is variable, although metabolism may become saturated in

the acidic first-pass low and overdose,

increasing bioavailability. These properties contribute to the recommendations and rationale for delayed GI decontamination and the need for aggressive decontamination. P.1086 CAs are highly lipophilic and possess large and variable volumes of distribution (15–40 L/kg). They are rapidly distributed to the heart, brain, liver, and kidney, where the tissue-to-plasma ratio generally exceeds 10:1. In the canine myocardium, CA concentrations exceed plasma concentrations by >200-fold.57 Less than 2% of the ingested dose is present in blood several hours after overdose, and serum TCA concentrations decline biexponentially.106,123 The CAs are extensively bound to α1 -acid glycoprotein (AAG) in the plasma, although differential binding among the specific drugs is observed.2

Changes in AAG concentration or pH can alter binding and the percentage of free or unbound drug.107,124 Specifically, a low blood pH (which often occurs in a severely poisoned patient) may increase the amount of free drug, making it more available to exert its effects. Animal studies demonstrate that although administration of AAG increases the concentration of total desipramine and proteinbound desipramine in the serum, the concentration of active free desipramine does not significantly decline.107 Redistribution of CAs from tissues may account for this small change in the free fraction of the drug. All of these pharmacokinetic properties limit the value of serum antidepressant concentrations in assessing toxicity. The TCAs undergo demethylation, aromatic hydroxylation, and glucuronide conjugation of the hydroxy metabolites. The tertiary amines imipramine and amitriptyline are demethylated to desipramine and nortriptyline, respectively. The hydroxy metabolites of both tertiary and secondary amines are pharmacologically active and may contribute to toxicity after the first 12–24 hours. The glucuronide metabolites are inactive. Genetically based differences in the activity of the CYP2D6 enzymes account for wide interindividual variability in metabolism and steadystate plasma concentrations. Genetic polymorphisms of the CYP2D6 gene, which is responsible for hydroxylation of imipramine and desipramine, are responsible for the slow metabolism in certain patients.17,28 These “poor metabolizers― may recover more slowly from an overdose or demonstrate toxicity with therapeutic dosing.13,136,142 The metabolism of CAs also may be influenced by concomitant ingestion of ethanol and other medications such as barbiturates, which may enhance their metabolism, or by drugs that inhibit the CYP2D6 isoenzyme (eg, SSRIs including fluoxetine, paroxetine, sertraline), which may increase the concentration of the parent CAs.16,97,132 Patient variables such as age and ethnicity also affect CA metabolism. Elimination half-lives for therapeutic doses of CAs vary from 7–58

hours (54–92 hours for protriptyline), with even longer half-lives in the elderly.114,123 The half-lives may be more prolonged in overdose as a result of saturable metabolism. A small fraction (15–30%) of CA elimination occurs through biliary and gastric secretion.39,82 The metabolites are then reabsorbed in the systemic circulation, resulting in enterohepatic and enterogastric recirculation and reducing their fecal excretion. Finally, 1000 ng/mL usually are observed in patients with significant clinical toxicity (coma, seizures, and dysrhythmias), although life-threatening toxicity has also been observed in patients with serum concentrations 100 msec Ra vr ≥3 mm T40-ms axis >130

Sodium bicarbonate: 1–2 mEq/kg IV boluses at 3- to 5-min intervals to reverse

the abnormality or to a target serum pH no greater than 7.55 Controlled ventilation (if clinically indicated for hypoventilation)

Dysrhythmias

Sinus

tachycardia

Wide-complex tachycardia/ventricular tachycardia

No

treatment

Sodium bicarbonate: 1–2 mEq/kg IV boluses to reverse the dysrhythmia or to a target serum pH no greater than 7.55 Correct hypoxia, acidosis, hypotension Consider lidocaine: 1 mg/kg slow IV bolus, followed by infusion of 20–50 µg/kg/min Consider hypertonic saline (3% NaCl) Consider magnesium sulfate 25–50 mg/kg (maximum 2.0 g) IV over 2 min Controlled ventilation (if clinically indicated)

Torsades

de

pointes

Magnesium sulfate Overdrive pacing

Hypotension

Isotonic saline (0.9% NaCl) boluses (up to 30 mL/kg) Correct hypoxia, acidosis Sodium bicarbonate: 1–2 mEq/kg IV boluses to a target serum pH of no greater than 7.50–7.55 Norepinephrine Consider extracorporeal mechanical circulation (extracorporeal membrane oxygenation, cardiopulmonary bypass)

Seizures

Benzodiazepines,

propofol

Secure airway with intubation if necessary Correct hypoxia, acidosis Barbiturates Continuous infusion of midazolam or propofol if barbiturates fail Consider neuromuscular paralysis/general anesthesia if all other measures fail

Wide-Complex Conduction

Dysrhythmias,

Delays,

and/or

Hypotension

The mainstay therapy for treating wide-complex dysrhythmias and for reversing conduction delays and hypotension is the combination P.1091

of serum alkalinization and sodium loading. Controlled in vitro and in vivo studies in various animal models demonstrate that hypertonic sodium bicarbonate effectively reduces QRS complex prolongation, increases blood pressure, and reverses or suppresses ventricular dysrhythmias caused by CAs.95,96,104,120,121,122 These studies also showed either equivalent or fewer beneficial effects of hyperventilation, hypertonic sodium chloride, and other nonsodium buffer solutions compared to sodium bicarbonate, suggesting multiple reasons for its effectiveness. A systematic review of all animal and human studies published until 2001 revealed that alkalinization therapy was the most beneficial therapy for consequential dysrhythmias and shock.12 Increasing the extracellular concentration of sodium, or sodium loading, may overcome the effective blockade of sodium channels through gradient effects (Figure 71-2). This mechanism explains why in some animal studies sodium bicarbonate was more effective in decreasing cardiotoxicity than were other sodium-free buffer solutions. Hypertonic sodium chloride loading reverses cardiotoxicity in several animal studies,51,87,104 including doses as high as 15 mEq Na/kg.86 However, the does of hypertonic saline for TCA poisoning has never been evaluated in humans, and the suggested dose in animals exceeds the amount that most clinicians would consider safe (1–2 mEq/kg). Unfortunately, no controlled human studies investigate which of the proposed mechanisms is most important, although the mechanism most likely is a combination. Furthermore, no controlled human studies demonstrate that sodium bicarbonate is effective; however, numerous reports and extensive clinical experience support its efficacy in treating serious CA cardiotoxicity.12,18,19,52,53 The optimal dosing and mode of administration of hypertonic sodium bicarbonate and the indications for initiating and terminating this treatment are unsupported by controlled clinical studies. Instead, the information is extrapolated from animal studies, clinical experience, and an understanding of the pathophysiologic mechanisms of CA

toxicity. A bolus, or rapid infusion over several minutes, of hypertonic sodium bicarbonate (1–2 mEq/kg) should be administered initially.19,86,104 Higher doses have successfully treated patients, but experience is limited. Continuous ECG monitoring should be in place to follow the progression of ECG abnormalities. Additional boluses every 3–5 minutes can be administered until the QRS interval narrows and the hypotension improves. Blood pH should be monitored after several bicarbonate boluses, aiming for a target pH of no greater than 7.50–7.55. Because CA may redistribute from the tissues into the blood over several hours, it may be reasonable to begin a continuous sodium bicarbonate infusion to maintain the pH in this range. Differences in outcomes between repetitive boluses alone and boluses with further bicarbonate infusions are not well studied. Although diluting sodium bicarbonate in 5% dextrose in water and infusing it slowly renders it less able to raise the sodium gradient at the cell, the beneficial effects of pH elevation still may be warranted. No evidence supports prophylactic alkalinization in the absence of severe cardiovascular toxicity. Use of hypertonic saline solutions (3% NaCl) or combined sodium bicarbonate and 0.9% sodium chloride solutions for rapid infusion theoretically should be efficacious, although these modalities are not adequately studied in humans. A case report describes the successful use of 7.5% NaCl to treat hypotension and QRS widening with ventricular ectopy in a patient with a nortriptyline overdose who was unresponsive to boluses of sodium bicarbonate and 0.9% sodium chloride solution.90 The role of hypertonic saline remains undefined. However, it could be considered in situations of refractory hypotension, wide-complex tachycardia, and/or dysrhythmias. Potential risks of this treatment include fluid overload, sodium overload, and hyperchloremic metabolic acidosis. Hyperventilation is a more rapid and easily titratable method of serum alkalinization but is not as effective as a single modality in reversing cardiotoxicity.63,86 Simultaneous hyperventilation and sodium bicarbonate administration may result in profound alkalemia

and should be performed only with extreme caution and careful monitoring of pH.157 Hyperventilation without bicarbonate administration may be indicated in patients with acute lung injury or congestive heart failure in whom administration of large quantities of sodium are contraindicated. Alkalinization and sodium loading with hypertonic sodium bicarbonate and/or hypertonic saline along with controlled ventilation (if clinically indicated) should be administered to all overdose patients presenting with major cardiovascular toxicity. Indications include any conduction delays (QRS > 100 msec, R aVR ≥3 mm, and/or an unexplained or new right bundle-branch block), wide-complex tachycardia, and hypotension. It is imperative to initiate treatment until CA toxicity can be excluded because of the risk for rapid and precipitous deterioration. Although commonly assumed, it is unclear whether the failure of the QRS complex to narrow with sodium bicarbonate treatment excludes CA toxicity. Alkalinization may be continued for at least 12–24 hours after the ECG has normalized because of the drug's redistribution from the tissue. However, the time observed for resolution or normalization of conduction abnormalities is extremely variable, ranging from several hours to several days despite continuous bicarbonate infusion.76 In some patients, clinical improvement occurred both before and during ECG changes. We recommend stopping alkalinization when the patient improves clinically and shows improvement, not necessarily normalization, of abnormal ECG findings.

Antidysrhythmic

Therapy

Lidocaine is the antidysrhythmic most commonly advocated for treatment of CA-induced dysrhythmias, although no controlled human studies demonstrate its efficacy.18,19,105 Because lidocaine has sodium channel-blocking properties, some investigators argue against its use in CA poisoning.1 These theoretical concerns are not well supported in the literature or in theory. The use of class IA

(quinidine, procainamide, disopyramide, and moricizine) and class IC (flecainide, propafenone) antidysrhythmics is absolutely contraindicated because they have similar pharmacologic actions to CAs and thus may worsen the sodium channel inhibition caused by CAs and exacerbate cardiotoxicity. Class III antidysrhythmics (amiodarone, bretylium, and sotalol) prolong the QTc interval and, although unstudied, may be contraindicated as well. Because magnesium sulfate has antidysrhythmic properties, it may be beneficial in the treatment of ventricular dysrhythmias. Animal studies of the effects of magnesium on CA-induced dysrhythmias yield conflicting results.64,65 However, successful use of magnesium sulfate in the treatment of refractory ventricular fibrillation after TCA overdose is reported.67 The routine use of magnesium requires further evaluation and currently is not recommended. Based on electrophysiologic studies in animal models, the widecomplex tachycardia/ventricular tachycardia caused by CAs is rate dependent.3,121 Slowing the heart rate in the presence of CAs may allow more time during diastole for drug unbinding from sodium channels and might result in an improvement in ventricular conduction, which then could abolish the reentry mechanism for P.1092 dysrhythmias. This mechanism was the rationale for the past use of physostigmine and propranolol. Thus, it is hypothesized that decreasing the sinus rate may itself be effective in abolishing ventricular dysrhythmias by eliminating rate-dependent conduction slowing. Propranolol terminated ventricular tachycardia in an animal model but unfortunately also caused significant hypotension.122 In 1 case series, patients developed severe hypotension or had a cardiac arrest shortly after receiving a β-adrenergic antagonist.37 Other animal studies suggest that preventing or abolishing tachycardia by sinus node destruction or by using bradycardic agents that impede sinus node automaticity without affecting myocardial repolarization or contractility may successfully prevent CA-induced ventricular dysrhythmias.3,4 The combined negative inotropic effects of β-

adrenergic antagonists and CAs along with the significant cardiac and CNS effects reported with physostigmine use do not support their routine use in the management of CA-induced tachydysrhythmias. Use of phenytoin as an antidysrhythmic agent in CA toxicity has been extensively studied. Several animal and human studies indicate phenytoin is successful in preventing or reversing some conduction abnormalities.27,47,85 However, these studies were not well controlled for other confounding factors, such as blood pH and sodium bicarbonate administration, they had very small numbers, and, in some, the cardiotoxicity was not severe. Phenytoin may have a prodysrhythmogenic effect in the presence of CAs, thus inducing or worsening ventricular dysrhythmias.23 Based on available evidence, phenytoin is not recommended for wide-complex tachydysrhythmias associated with CAs.

Hypotension Hypotension is the most common cause of death secondary to CA toxicity.130 Standard initial treatment for hypotension should include volume expansion with isotonic saline and alkalinization/sodium loading with hypertonic sodium bicarbonate (if conduction abnormalities also are present). Hypotension unresponsive to these therapeutic interventions necessitates the use of inotropic and/or vasopressor drug support and possibly extracorporeal cardiovascular support. The choice of specific direct-acting or indirect-acting drug(s) for treatment of CA-associated hypotension is controversial. Available data are limited and contradictory. Norepinephrine, epinephrine, dopamine, and dobutamine are proposed to be effective drugs for hypotension, but no controlled human studies are available. Furthermore, the pharmacologic properties of CAs complicate the choice of a specific agent. Specifically, CA blockade of neurotransmitter reuptake theoretically could result in depletion of intracellular catecholamines. This blockade of norepinephrine and

dopamine reuptake then could blunt the effect of dopamine, which is dependent on the release of endogenous norepinephrine for its inotropic activity.20 This α-adrenergic blockade and downregulation of receptors induced by CAs suggest that a direct-acting vasopressor such as norepinephrine is more efficacious than an indirect-acting catecholamine such as dopamine. Norepinephrine at high doses may be dysrhythmogenic and might exacerbate cardiovascular toxicity. Pure β-adrenergic agonists, such as isoproterenol and dobutamine, and even combination α- and β-adrenergic agonists, such as dopamine, theoretically could worsen the hypotension. Animal data comparing various drugs are conflicting, and their direct applicability to clinical human poisoning is limited.33,56,150 Both norepinephrine and epinephrine increased the survival rate in TCApoisoned rats.66 In addition, epinephrine was superior to norepinephrine when used both with and without sodium bicarbonate, and the most effective treatment regimen in their study was epinephrine plus sodium bicarbonate; neither drug precipitated dysrhythmias. The authors propose that epinephrine is more efficacious because it augments myocardial perfusion more than norepinephrine and improves the recovery of CA sodium channel blockade by hyperpolarization of the membrane potential through its stimulation

of

increased

potassium

intracellular

transport.

Limited clinical data suggest that norepinephrine is more efficacious than dopamine. 145 In a retrospective study of 26 adult hypotensive patients, response rates to norepinephrine (5–53 µg/min) were significantly better than response rates to dopamine (5–10 µg/kg/min).147 Patients who did not respond to dopamine at vasopressor doses (10–50 µg/kg/min) responded to norepinephrine (5–74 µg/min). However, the retrospective nature of this study, the subsequent lack of standard management therapies (which are indications for instituting vasoactive agents), and the heterogeneity of the population limit its generalizability. In another case report of CA toxicity, glucagon is reported to cause sustained increases in blood pressure.126

Based on the available data, pharmacologic effects, theoretical concerns, and experience, norepinephrine (0.1–0.2 µg/kg/min) is recommended for hypotension that is unresponsive to volume expansion and hypertonic sodium bicarbonate therapy. Central venous pressure and/or pulmonary artery catheterization may be necessary to guide the choice of additional vasopressor or inotropic agents, especially in the presence of other cardiodepressant drugs. If pharmacologic measures fail to correct hypotension, extracorporeal life support measures should be considered. Extracorporeal membrane oxygenation, extracorporeal circulation, and cardiopulmonary bypass are successful adjuncts for refractory hypotension and life support when maximum therapeutic interventions fail.46,70,155 These modalities can provide critical perfusion to the heart and brain and maintain metabolic function while giving the body time to metabolize and eliminate toxic concentrations of the drug by maintaining hepatorenal blood flow. Extracorporeal measures then may allow the impaired myocardium to recover.

Central

Nervous

System

Toxicity

Endotracheal intubation should be performed in any comatose patient or in a patient with a significantly depressed mental status with acute CA toxicity. Use of flumazenil in the patient with known or suspected CA ingestion is contraindicated. Several case reports of patients with CA overdoses describe seizures following administration of flumazenil.48,73,88 Physostigmine was used in the past to reverse the CNS toxicity of CAs21,98 (Antidotes in Depth: Physostigmine) . However, physostigmine is not recommended because it may increase the risk of cardiac toxicity, cause bradycardia and asystole, and precipitate seizures in CA-poisoned patients.109 Seizures caused by CAs usually are brief and may stop before treatment can be initiated. Recurrent seizures, prolonged seizures

(>2 minutes), and status epilepticus require prompt treatment to prevent worsening acidosis, hypoxia, and development of hyperthermia and rhabdomyolysis. Benzodiazepines are effective as first-line therapy for seizures.9 If this therapy fails, barbiturates or propofol should be administered. Propofol also acts at the GABA–chloride–ionophore complex. Propofol controlled refractory P.1093 seizures resulting from amoxapine toxicity.92 Failure to respond to barbiturates should lead to consideration of neuromuscular paralysis and general anesthesia with continuous EEG monitoring. Phenytoin is not recommended for seizures because data do not demonstrate clear beneficial effects and administration could cause cardiovascular toxicity.9,23

Enhanced

Elimination

No specific treatment modalities have demonstrated clinical significant efficacy in enhancing the elimination of CAs. Some investigators propose multiple doses of activated charcoal to enhance CA elimination because of their small enterohepatic and enterogastric circulation.82 Human volunteer studies and case series of patients with CA overdoses suggest that the half-life of CAs may be decreased by multiple-dose activated charcoal (MDAC).26,61,101,143 MDAC reduced the apparent half-life of amitriptyline to 4–40 hours in overdose patients, compared to previously published values of 30 to >60 hours.143 Changes in the severity or duration of clinical toxicity, however, were not reported. Other investigators showed in human volunteers that MDAC reduced the half-life of therapeutic doses of amitriptyline approximately 20% compared with no activated charcoal administration.61 However, the methodologic flaws and equivocal findings of these studies and the lack of any positive outcome data for this intervention from additional studies do not provide overwhelming evidence supporting its use in this setting.25,44 The pharmacokinetic properties of CAs (large volumes of distribution, high plasma-protein binding) weighed against the small increases in

clearance and the potential complications of MDAC, such as impaction, intestinal infarction, and perforation, do not warrant its routine use.25 However, MDAC conceivably might shorten the duration of clinical toxicity in patients who are “slow metabolizers.― One additional dose of activated charcoal may be given to patients with evidence of significant CNS and cardiovascular toxicity if bowel sounds are present. Measures to enhance urinary CA excretion have a minimal effect on total clearance.61 Hemodialysis is ineffective in enhancing the elimination of CAs because of their large volumes of distribution, high lipid solubility, and extensive overcomes some of the limitations that effective because of the large Several uncontrolled case reports

protein binding.50 Hemoperfusion of hemodialysis but should not be volumes of distributions of CAs.106 anecdotally described improvement

in cardiotoxicity during hemoperfusion, although the finding may have been coincidental.36 Currently, little substantial evidence supports the use of hemoperfusion in the management of CA overdose.

Investigational

Therapies

The development and investigation of an affinity-purified ovine polyclonal Fab fragment to TCAs spanned more than 10 years.29,55,62,110 Initial clinical trials showed favorable results with TCA-specific Fab fragment treatment in improving both cardiovascular and CNS toxicity.49 The emergence of the SSRIs with the resultant significant decrease in TCA prescriptions and the significant cost of producing the TCA-specific Fab have limited the interest in clinical trials and production of this new therapy. Experimental studies demonstrate that induction of ventricular tachydysrhythmias during TCA toxicity is dependent upon heart rate.3 The bradycardic agent UL-FS 49 effectively impedes the marked sinus tachycardia and frequency-dependent ventricular conduction delay associated with amitriptyline toxicity in a canine

model.4 Pretreatment with this drug effectively prevented the onset of sustained ventricular tachydysrhythmias. In addition, unlike other β-adrenergic antagonists that have negative inotropic affects, UL-FS 40 did not appear to adversely influence hemodynamics, thereby potentially decreasing the risk of significant hypotension associated with its use. This investigational drug warrants further clinical studies in patients presenting with marked sinus tachycardia and conduction delays to determine its effectiveness in preventing widecomplex dysrhythmias and/or ventricular tachydysrhythmias.

Hospital

Admission

Criteria

All patients who present with known or suspected CA ingestion should undergo continuous cardiac monitoring and serial electrocardiography for a minimum of 6 hours. Fears of delayed complications and inability to predict toxicity led clinicians in the past to adopt all-inclusive admission guidelines for suspected CA ingestion. The once-standard practice of admitting all patients with CA ingestion for medical monitoring because of the risk of late complications or sudden death is not supported by the current literature. Most patients develop major clinical toxicity within several hours of presentation.26 Several retrospective studies support a disposition algorithm that takes into account presenting clinical signs and symptoms.7,26,39,144 If the patient is asymptomatic at presentation, undergoes GI decontamination, has normal ECGs, or has sinus tachycardia (with normal QRS complex) that resolves, and the patient remains asymptomatic in the healthcare facility for a minimum of 6 hours without any treatment interventions, the patient may be medically cleared for psychiatric evaluation (if appropriate) or discharged home as appropriate. A prospective study of 67 patients used the Antidepressant Overdose Risk Assessment (ADORA) criteria to identify patients who were at high risk for developing serious toxicity and thus proposed the following criteria for hospitalization. 34 In this study, the presence of

QRS interval >100 msec, cardiac dysrhythmias, altered mental status, seizures, respiratory depression, or hypotension on presentation to the ED (or within 6 hours of ingestion if the time was known) was 100% sensitive in identifying patients with significant toxicity and subsequent complications. Furthermore, none of the lowrisk patients (defined as absence of all these criteria) developed any further toxicity or complications, supporting the decision for medical clearance and/or discharge. Criteria specifically for ICU admission (other than patients requiring ventilatory and/or blood pressure support) versus an inpatient bed with continuous cardiac monitoring are less clear and probably more institution dependent.139 The disposition of patients with persistent isolated sinus tachycardia or prolonged QTc with no concomitant altered mental status or blood pressure changes is not clearly defined. Previous studies demonstrate that these 2 parameters alone are not predictive of subsequent clinical toxicity or complications.34,35,45 In addition, the sinus tachycardia may persist for up to 1 week following ingestion.99,127 However, another study of pure TCA overdose patients reported that a heart rate >120 beats/min and QTc interval >480 msec were associated with an increased likelihood of major toxicity.24 These patients might be good candidates for observation units with continuous ECG monitoring and serial ECGs for 24 hours.

Inpatient

Cardiac

Monitoring

The duration of cardiac monitoring in any patient initially exhibiting signs of major clinical toxicity depends on many factors. P.1094 Certainly the duration of CA cardiotoxicity and neurotoxicity may be prolonged, as might be expected from the long serum half-life of CAs, in patients who are slow hydroxylators, or in the presence of a coingestant that alters the metabolism of CAs or causes cardiac or neurologic toxicity. Recommendations in the older literature for

48–72 hours of ICU monitoring even in mild CA ingestions stem from isolated case reports of late-onset dysrhythmias, CNS effects, and sudden deaths.38,40,108,125 However, review of these cases shows inadequate gastric decontamination, inadequate therapeutic interventions, and significant ongoing complications of overdose. Several retrospective studies demonstrate that late, unexpected complications in CA overdoses (eg, seizures, dysrhythmias, and death) do not occur in patients who had few or no major signs of toxicity at presentation or a normal level of consciousness and normal ECG for 24 hours.22,31,45,111,139 All fatalities resulting directly from CA toxicity occur in the first 12–24 hours. Using normalization of ECG abnormalities as an end point for therapy and discharge is problematic. Some studies document the variable resolution and normalization of QRS prolongation and T40-ms axis rotation.103,131 Based on the available literature, it is reasonable to recommend that after the mental status and blood pressure normalize, patients should be monitored for another 24 hours off all therapy, including alkalinization, antidysrhythmics, and inotropics/vasopressors. If the patient shows improvement of ECG abnormalities with these criteria, the patient can be discharged to a monitored bed on the ward with a low risk of further complications.

Summary CA poisoning continues to be a cause of serious morbidity and mortality worldwide. The distinctive characteristics of these drugs can cause significant CNS and cardiovascular toxicity, the latter being responsible for mortality as a result of overdose of these drugs. Cardiovascular toxicity ranges from mild conduction abnormalities and sinus tachycardia to wide-complex tachycardia, hypotension, and asystole. CNS toxicity includes delirium, lethargy, seizures, and coma. The ECG is a simple, readily available diagnostic test that can predict the development of significant toxicity, particularly seizures and/or dysrhythmias. Management strategies

are based primarily on the pathophysiology of these drugs, namely, sodium channel blockade in the myocardium. Alkalinization and sodium loading with hypertonic sodium bicarbonate and isotonic saline are the principal modes of specific therapy for cardiovascular toxicity. Guidelines for observing or admitting patients to the hospital may be based on initial clinical presentation and/or development of clinical symptomatology and ECG changes.

Acknowledgment Paul D. Francis contributed to this chapter in a previous edition.

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1988;6:121–124. 147. Tran TP, Panacek EA, Rhee KJ, et al: Response to dopamine vs norepinephrine in tricyclic antidepressant-induced hypotension. Acad Emerg Med 1997;4:864–868. 148. Varley CK, McClellan J: Case study: Two additional sudden deaths with tricyclic antidepressants. Am Acad Child Adolesc Psychiatry 1997;36:390–394. 149. Veith RC, Raskid MA, Caldwell JH, et al: Cardiovascular effects of tricyclic antidepressants in depressed patients with chronic heart disease. N Engl J Med 1982;306:954–959. 150. Vernon DD, Banner W, Garrett JS, et al: Efficacy of dopamine and norepinephrine for treatment of hemodynamic compromise in amitriptyline intoxication. Crit Care Med 1991;19:544–549. 151. Vohra J, Burrows G, Hunt D, et al: The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. Eur J Cardiol 1975;3:219–227. 152. Wallace DE: Bowel ischemia in two patients following tricyclic antidepressant drugs [abstract]. Vet Hum Toxicol 1989;31:377. 153. Wedin GP, Oderda GM, Klein-Schwartz W: Relative toxicity of cyclic antidepressants. Ann Emerg Med 1986;15:797–804. 154. Weld FM, Bigger JT Electrophysiological effects of imipramine on ovine cardiac Purkinje and ventricular muscle fibers. Circ Res

1980;46:167–174. 155. Williams JM, Hollingshed MJ, Vasilakis A, et al: Extracorporeal circulation in the management of severe tricyclic antidepressant overdose. Am J Emerg Med 1994;12:456–458. 156. Wolfe TR, Caravati EM, Rollins DE, et al: Terminal 40-ms frontal plane QRS axis as a marker for tricyclic antidepressant overdose. Ann Emerg Med 1989;18:348–351. 157. Wrenn K, Smith BA, Slovis CM: Profound alkalemia during treatment of tricyclic antidepressant overdose: A potential hazard of combined hyperventilation and intravenous bicarbonate. Am J Emerg Med 1992;10:553–555. 158. Zaccara G, Muscas GC, Messori A: Clinical features, pathogenesis and management of drug-induced seizures. Drug Saf 1990;5:109–151. 159. Zito JM, Safer DH, DosReis S, et al: Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000;283:1025–1030.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > G - Psychotropic Medications > Chapter 72 - Sedative-Hypnotics

Chapter

72

Sedative-Hypnotics David C. Lee A 73-year-old man was brought to the emergency department by ambulance after his family found him unconscious in his bedroom. On presentation, he was lethargic and intermittently followed commands. He had a medical history significant for hypertension and coronary artery disease. According prescribed a new medication as a were: blood pressure, 138/90 mm respiratory rate, 12 breaths/min;

to the family, he recently was sleeping aid. Initial vital signs Hg; heart rate, 65 beats/min; oral temperature, 98.3°F

(36.8°C); room air pulse oximetry, 94%. His pupils were 3 mm, and there were no signs of trauma. He had an appropriate gag reflex, and his physical examination was otherwise unremarkable. His bedside glucose concentration and electrocardiogram were normal. He was treated with 2 mg intravenous naloxone and 100 mg intravenous thiamine without response. He was placed on supplemental oxygen (FiO2 28%), which raised his oxygen saturation to 96%. However, he had periods of bradypnea during which his saturation fell to 90%. His family produced a recently prescribed bottle of zolpidem. After firmly establishing with the family that he

did not have a history of seizures, use of cyclic antidepressants, or dependence on benzodiazepines, the decision was made to reverse his sedation with flumazenil (1 mg intravenously), upon which he awoke. He admitted to “having a few drinks― and had taken his new medication to help him sleep. His blood alcohol concentration was 180 mg/dL, and results of routine laboratory screening was unremarkable. He was admitted to the hospital for medical observation and psychiatric evaluation. He required no further medical intervention other than supplemental oxygen, and he was discharged 24 hours later. Sedative-hypnotics are drugs that are prescribed to induce a calming effect, limit excitability (sedative), or induce drowsiness and sleep (hypnotic). Anxiolytics or tranquilizers are other medical terms that are often used to describe drugs that are sedative-hypnotics. The term tranquilizer has fallen out of favor because of the lack of precision. The term anxiolytic is the preferred term because this medication diminishes feelings of anxiety. Other drugs that are not classically considered sedative-hypnotics, such as serotonin reuptake inhibitors, are used successfully to treat anxiety conditions. Because many different types of drugs and dietary supplements are used for their sedative or hypnotic effect, this group of xenobiotics actually encompasses a wide range of various compounds. This chapter focuses primarily on pharmaceutical drugs used solely for their sedative-hypnotics effects, specifically drugs that primarily interact with the γ-aminobutyric acid (GABA) receptor (Table 72-1 ).

History

and

Epidemiology

Throughout history, sedative-hypnotic use and abuse have been commonplace. Mythology of ancient cultures is replete with stories of poisons or compounds that cause sleep or a state of unconsciousness (Chap. 1 ). Overdoses were reported soon after the commercial introduction of bromide preparations, the first commonly available class of sedative-hypnotic agent, in 1853. Other commercial

xenobiotics that subsequently were developed include chloral hydrate, paraldehyde, sulfonyl, and urethane. The barbiturates were introduced in 1903 and quickly supplanted the older xenobiotics. This class of drugs dominated the sedativehypnotic market for the first half of the 20th century. Unfortunately, because barbiturates have a relatively low therapeutic-to-toxic ratio and substantial potential for abuse, they quickly became a major health problem. By the 1950s and 1960s, barbiturates were frequently implicated in overdoses and were responsible for the majority of drug-related suicides. As fatalities from barbiturates increased, attention shifted to preventing their abuse and finding less toxic alternatives.22 , 141 These “safer― drugs included methyprylon, glutethimide, ethchlorvynol, and methaqualone. Unfortunately, many of these drugs also had significant undesirable effects. With the introduction of benzodiazepines in the early 1960s, barbiturates and the alternative drugs were quickly supplanted. Intentional and unintentional overdoses with sedative-hypnotic agents are common. According to the American Association of Poison Control Centers, the sedative-hypnotic class of agents is consistently one of the top 5 classes of drugs associated with, although not usually causative of, overdose fatalities (Chap. 130 ). With the ubiquitous worldwide use of sedative-hypnotics, they probably also are associated with substantially more deaths than are officially reported. Chlordiazepoxide, the first commercially available benzodiazepine, initially was synthesized by Hoffman-LaRoche in 1955 and marketed in 1960. Now more than 50 benzodiazepines are marketed, and more are being developed. In the 1980s, benzodiazepines captured >80% of the sedative market and >50% of the hypnotic market.70 , 159 Compared with an overdose of barbiturates, an overdose of a benzodiazepine alone accounts for relatively few deaths.49 Most deaths associated with benzodiazepines result from mixed overdoses of benzodiazepines and other respiratory depressants, especially

alcohol.61 Because of the popularity of benzodiazepines and the perception of widespread abuse, changes in local regulations and restrictions in P.1099 prescribing practices for benzodiazepines led to a resurgence in the use of older sedative-hypnotic agents in specific areas. In New York State, where restrictions were implemented in 1989 for prescribing benzodiazepines by the use of designated prescriptions issued by the state to physicians, a 60% decrease in benzodiazepine prescriptions was noted, as well as a 125% increase in meprobamate, 136% increase in chloral hydrate, and 30% increase in butabarbital prescriptions in the following year67 , 189 and a proportional increase in overdoses of some of these drugs. Although benzodiazepines represent most of the market for prescribed sedatives, the recently introduced hypnotic agents zolpidem, zaleplon and eszopiclone have replaced benzodiazepines as the most prescribed pharmaceutical sleeping aids. Benzodiazepines Agents with full agonist activity at the benzodiazepine site Alprazolam Xanax 1.0 10–14 80 0.8 No Chlordiazepoxide Librium 50 5–15 96 0.3 Yes

Clorazepate Tranxene 15 97 0.9 Yes Unclear Clonazepam Klonopin 0.5 18–50 85.4 Unclear Yes Diazepam Valium 10 20–70 98.7 1.1 Yes Estazolam ProSom 2.0 8–31 93 0.5 No Flunitrazepama Rohypnol 1.0 16–35 80 1.0–1.4

Yes Flurazepam Dalmane 30 2.3 97.2 3.4 Yes Lorazepam Ativan 2.0 9–19 90 1–1.3 None Midazolam Versed — 3–8 95 0.8–2 Yes Oxazepam Serax 30 5–15 Unclear Unclear No Temazepam Restoril 30 10–16 97

0.75–1.37 No Triazolam Halcion 0.25 1.5–5.5 90 0.7–1.5 Yes Nonbenzodiazepine agents active mainly at the type I (ω1 ) benzodiazepine site Eszoplicone Lunesta ? 6 55 1.3 No Zaleplon Sonata 20 1.0 92 0.54 No Zolpidem Ambien 20 1.7 92 0.5 No Barbiturates Amobarbital

Amytal — 8–42 Unclear Unclear Unclear Aprobarbitala Alurate — 14–34 Unclear Unclear Unclear Butabarbital Butisol — 34–42 Unclear Unclear Unclear Barbitala — 6–12 25 Unclear Unclear Mephobarbital Mebaral — 5–6 40–60 Unclear Yes

Methohexital Brevital — 3–6 73 2.2 Unclear Pentobarbital Nembutal 100 15–48 45–70 0.5–1.0 Unclear Phenobarbital Luminal 30 80–120 50 0.5–0.6 No Primidone Mysoline — 3.3–22.4 19 Unclear Yes Secobarbital Seconal — 15–40 52–57 Unclear

Unclear Thiopental Pentothal — 6–46 72–86 1.4–6.7 Unclear Other Chloral hydrate Aquachloral NA 4.0–9.5 35–40 0.6–1.6 Yes Ethchlorvynola Placidyl NA 10–25 30–40 4 Unclear Etomidate Amidate NA 2.9–5.3 98 2.5–4.5 Unclear Glutethimidea Doriden NA 5–22

47–59 2.7 Unclear Methprylona Nodular NA 3–6 60 0.97 Unclear Meprobamatea Miltown NA 6–17 20 0.75 Unclear Methaqualonea Quaalude NA 19 80–90 5.8–6.0 Yes Paraldehyde a Paral NA 7 Unclear 0.9 Unclear Propofol Diprivan NA

4–23 98 2–10 No NA = not applicable comparison. a Not presently available in the United States. b This table is an approximation of equipotent doses of drugs affecting the benzodiazepine receptor and several barbiturates. All of the full agonist benzodiazepines have similar amnestic, anxiolytic, sedative, and hypnotic effects. These effects are a reflection of dose and plasma concentration. There can be significant variation of these effects according to age and gender. Equipotent Dosing Trade Name

TABLE

Oral Dose (mg)b

72-1.

Protein Plasma t1 / 2

Pharmaceutical

Binding (%)

Active Vd (L/kg)

Metabolite Important

Sedative-Hypnotics

Pharmacology All of the sedative-hypnotics produce central nervous system (CNS) depression. Most clinically effective sedative-hypnotics produce their physiologic effects by enhancing the function of GABA-mediated chloride channels. The presence of sedative-hypnotics alters the receptor and affects the function of the chloride channel. These alterations include increasing the frequency of opening or the duration of opening.4 The varying effects of the sedative-hypnotics can be explained further by their action on the various GABA receptor subtypes. Different sedative-hypnotics have variable affinities for certain GABA receptors with specific subunits (Chap. 14 ). P.1100

GABAA receptors are the primary mediators of inhibitory neurotransmission in the brain. The GABAA receptor is a pentameric structure composed of various polypeptide subunits associated with a chloride channel on the postsynaptic membrane. These subunits are classified into 3 families (α, β, γ). Variations in the 5 subunits of the GABA receptor confer the potency of its sedative, anxiolytic, hypnotic, amnestic, and muscle-relaxing properties. The most common GABAA receptor in the brain is composed of α1 β2 γ2 subunits. Almost all sedative-hypnotics bind to GABAA receptors containing the α1 subunit. One possible exception is etomidate, which produces sedation at the β2 unit and anesthesia at the β3 subunit.30 , 122 , 142 , 172 Low doses of benzodiazepines are effective only at GABAA receptors with the γ2 subunit. Even within the classes of sedative-hypnotics, there are varying affinities for different subunits. 40 , 106 Many sedative-hypnotics have activity at multiple different receptor sites. Not only do sedative-hypnotics increase the effects of GABAmediated inhibitory neurotransmission, many sedative-hypnotics, such as trichloroethanol, decrease the effects of glutamate-mediated excitatory neurotransmission.35 , 132 , 149 Barbiturates, benzodiazepines, etomidate, and propofol interact with N -methyl-Daspartate (NMDA) and AMPA/kainate receptor function. Barbiturates and propofol markedly attenuate the excitatory effects of glutamate.24 , 48 , 130 , 190 Benzodiazepines inhibit adenosine metabolism and reuptake, thereby potentiating both A1 -adenosine (negative dromotropy) and A 2 -adenosine (coronary vasodilatation) receptor-mediated effects.118 , 157 Benzodiazepines interact with serotonergic pathways. Diazepam modulates morphine analgesia via serotonergic pathways, and the anxiolytic effects of clonazepam can be partially explained by upregulation of serotonergic receptors, specifically 5-HT1 and 5-HT2 .8 , 119 , 180

Pharmacokinetics/Toxicokinetics

Most sedative-hypnotics are rapidly absorbed in the gastrointestinal (GI) tract, with the rate-limiting step consisting of dissolution and dispersion of the drug. Barbiturates and benzodiazepines are primarily absorbed in the small intestine. Clinical effects are determined by the relative ability of these drugs to penetrate the blood–brain barrier. Drugs that are highly lipophilic penetrate most rapidly. The ultrashort-acting barbiturates are clinically active in the most vascular parts of the brain (gray matter first), with sleep occurring within 30 seconds of administration. After initial distribution, many of the sedative-hypnotics undergo a redistribution phase as they are dispersed to other body tissues, specifically fat. Drugs that are redistributed, such as the lipophilic (ultrashort-acting) barbiturates and some of the benzodiazepines (diazepam, midazolam), may have a brief clinical effect as the early peak concentrations in the brain rapidly decline. The clinical activity of many of these drugs is determined by their rapid distribution and redistribution (alpha phase) and not by their elimination (beta phase) (Chap. 9 ). Many of the sedative-hypnotics are metabolized to pharmacologically active intermediates. This is particularly true for chloral hydrate and some of the benzodiazepines. Benzodiazepines can be demethylated, hydroxylated, or conjugated with glucuronide in the liver. Glucuronidation proceeds rapidly with the production of inactive metabolites. Benzodiazepines, such as diazepam, undergo demethylation that yields active intermediates with a more prolonged therapeutic half-life than the parent compound. Because of the individual pharmacokinetics of sedative-hypnotics and the production of active metabolites, there often is no correlation between the therapeutic half-life and the biologic half-life. The majority of sedative-hypnotics, such as the highly lipid-soluble barbiturates and the benzodiazepines, are highly protein bound. These drugs are poorly filtered by the kidney, and elimination occurs principally by hepatic metabolism. Chloral hydrate and meprobamate

are notable exceptions. Drugs with a low lipid-to-water partition coefficient, such as meprobamate and the longer-acting barbiturates, are poorly protein bound and more subject to renal excretion. Renal elimination can be increased by manipulation of urinary pH (Chap. 1 0 ). Phenobarbital is a classic example of a drug whose elimination can be manipulated with this technique. Most other drugs are not amenable to pH manipulation.

Toxicodynamics Overdoses of combinations of sedative-hypnotics can be more toxic than overdoses of a single xenobiotic because multiple xenobiotics can produce synergistic clinical effects mediated by interactions on the GABA receptor (Chap. 14 ). For example, both barbiturates and benzodiazepines act on the GABA site, but barbiturates prolong the opening of the chloride ionophore, whereas benzodiazepines increase the frequency of ionophore opening.159 Various sedative-hypnotics may increase the affinity of another xenobiotic at their respective binding sites. For example, pentobarbital increases the affinity of γhydroxybutyrate (GHB) for its non-GABA binding site.161 Propofol potentiates pentobarbital's effect on chloride influx at the GABA receptor.168 Propofol also increases the affinity and decreases the rate of dissociation of benzodiazepines from their site on the GABA receptor.21 , 144 These actions increase the clinical effect of each xenobiotic and may lead to deeper CNS and respiratory depression. Another mechanism of synergistic toxicity is the alteration of metabolism. The combination of ethanol and chloral hydrate, historically known as a “Mickey Finn,― has additive CNS depressant effects. Chloral hydrate competes for alcohol dehydrogenase, thereby prolonging the half-life of ethanol. The metabolism of ethanol generates the reduced form of nicotinamide adenine dinucleotide NADH, which is needed as a cofactor for the metabolism of choral hydrate to trichloroethanol, an active metabolite. Finally, ethanol inhibits the conjugation of

trichloroethanol, which in turn inhibits the oxidation of ethanol (Figure 72-1 ). 154 , 155 Because of the great variety of drugs, multiple drug–drug interactions can occur that may prolong the half-life of many sedative-hypnotics and significantly increase their potency. For example, the half-life of midazolam, which undergoes hepatic metabolism via cytochrome CYP3A4, can increase dramatically in the presence of certain drugs that compete for metabolism.124 Specifically, the half-life of midazolam rises 400-fold when coadministered with itraconazole.7

Tolerance Ingestions of relatively large doses effects in patients who chronically patients often develop tolerance , diminution of effect of a particular

may not have the predicted use sedative-hypnotics. These defined as the progressive drug with repeated

administrations that results in a need for greater doses to achieve the same effect. Tolerance can be secondary to pharmacodynamic or pharmacokinetic P.1101 factors. However, in the majority of cases, tolerance to sedativehypnotics is caused by pharmacodynamic changes160 (Chap. 15 ).

Figure 72-1. Metabolism of chloral hydrate and ethanol, demonstrating the interactions between chloral hydrate and ethanol metabolism. Note the inhibitory effects (dotted lines) of ethanol on trichloroethanol metabolism and the converse. (Adapted from Sellers EM, Lang M, Koch-Weser J, et al: Interaction of chloral hydrate and ethanol in man. I. Metabolism. Clin Pharmacol Ther 1972;13:40.)

Pharmacodynamic tolerance occurs when adaptive neural and

receptor changes (“plasticity―) occur after repeated exposures. These changes include a decrease in the number of receptors (“downregulation―), reduction of firing of receptors (“receptor desensitization―), structural changes in receptors (“receptor shift―), and reduction of coupling of sedativehypnotics and their respective GABAA -related receptor site. In this setting, a drug has a decreased effect even though drug concentrations do not change significantly. For example, benzodiazepine-dependent patients have decreased GABAA receptor density and sensitivity.52 , 136 Chronic benzodiazepine administration in rats causes uncoupling of the benzodiazepine receptor and the chloride channel in the GABA receptor–chloride channel complex.3 , 137 Pharmacodynamic tolerance secondary to receptor changes can occur quickly, even during short-term use.69 With certain xenobiotics, tolerance develops within minutes.31 , 71 I n one study using IV infusions of thiopental at variable rates and a specific EEG pattern, rapidly increasing thiopental concentrations were needed to produce a constant state of anesthesia.17 The “Mellanby effect― describes the development of acute tolerance such that, at a given serum concentration, a greater clinical effect occurs when serum concentrations are rising than when they are declining. This effect, initially described for alcohol, may also apply to all sedative-hypnotics drugs.31 , 72 , 90 , 104 Acute tolerance may not follow a linear pattern, and increasing tolerance may occur at certain thresholds. In a study in which rats were infused with propofol at variable rates and monitored by EEG, acute tolerance occurred only at certain times.72 Thus, pharmacodynamic tolerance can occur rapidly and have a nonlinear relationship to dose. Pharmacokinetic tolerance occurs when metabolic changes cause decreasing concentrations of a chronically administered drug. For example, repeated use of phenobarbital induces hepatic microsomal enzyme expression, thereby decreasing its own half-life. Increasing doses of phenobarbital may be required to achieve the same steady-

state

concentration.

Cross-tolerance readily exists among the sedative-hypnotics. For example, chronic use of benzodiazepines not only decreases the activity of the benzodiazepine site on the GABA receptor but also decreases the binding affinity of the barbiturate sites.4 , 68 Diazepam-tolerant mice are tolerant to the sedative-hypnotic properties of isoflurane.50 After therapy is terminated, tolerance can be lost as the desensitized target receptors return to their original level of function. The rate at which this process occurs is governed by the biologic half-life of the particular sedative-hypnotic and any biologically active intermediates produced. Tolerance persists for a period of time after the active xenobiotics

are

eliminated.147

Dependence

and

Withdrawal

Physical drug dependence refers to a condition of physiologic withdrawal induced by sudden termination of a drug. All sedativehypnotics produce dependence and withdrawal. Approximately one third of chronic benzodiazepine users experience withdrawal when benzodiazepine use is suddenly decreased or discontinued.85 Factors that contribute to the severity of withdrawal include shorter half-life of the agent, higher daily dosage, and underlying medical and psychological

illness

(Chap. 15 ).

Other areas of concern are unrecognized development of dependence and iatrogenic precipitation of withdrawal. Potent, fast-acting, shortlived sedatives are commonly used in the critical care setting. However, these same characteristics increase the potential for dependence. Rapid weaning from these medications or use of flumazenil may precipitate withdrawal. Delayed presentation of withdrawal after extubation and cessation of sedation occurs often with rapid weaning.19 , 164 Approximately one third of intensive care unit patients who were mechanically ventilated for >1 week suffered

from acute withdrawal when opioids or sedative-hypnotic agents were discontinued.25

Clinical

Manifestations

Patients with significant sedative-hypnotic overdoses manifest slurred speech, ataxia, and incoordination, a syndrome similar to ethanol intoxication. Patients with moderate to severe toxicity are stuporous or comatose. In the most severe cases, all neurologic responses may be lost. In most instances, respiratory depression parallels CNS P.1102 depression. contributes

Hypoventilation produces respiratory to cardiovascular depression.

Hypothermia Barbiturates, bromides, Unique odors

ethchlorvynol

Chloral hydrate, ethchlorvynol Cardiac dysrhythmias Meprobamate Bradycardia GHB Tachydysrhythmias Chloral hydrate Muscular twitching GHB, methaqualone, propofol, etomidate Acneiform rash Bromides Fluctuating coma Glutethimide, meprobamate GI bleeding Chloral hydrate, methaqualone Discolored urine Propofol (green/pink)

acidosis

and

Anticholinergic Glutethimide Clinical

signs

Signs

Sedative-Hypnotics

TABLE 72-2. Clinical Findings of Sedative-Hypnotic Overdose Although the physical examination rarely identifies particular sedative-hypnotics, it can give clues to the class of sedativehypnotics (Table 72-2 ). Hypothermia has been described with most of the sedative-hypnotics but may be more pronounced with barbiturates.74 , 148 , 183 Barbiturates may cause fixed drug eruptions that often are bullous and appear over pressure-point areas. However, this phenomenon is not specific to barbiturates and has been documented with other xenobiotics, including carbon monoxide, methadone, imipramine, glutethimide, and benzodiazepines. Methaqualone can cause muscular rigidity and clonus.1 Glutethimide can present with anticholinergic signs and symptoms.59 Chloral hydrate may present with vomiting, gastritis, and

cardiac

dysrhythmias.58 , 93 , 123 , 171

Large intravenous doses of sedative-hypnotics are associated with toxicities that are independent of the characteristics of the sedativehypnotic but rather are associated with their diluents. Propylene glycol inducing hypotension, hyperosmolar states, and metabolic acidosis occur in patients with prolonged use of lorazepam and etomidate.87 , 96 , 105 , 143 , 170 In one study, two thirds of critical care patients given high doses of lorazepam (0.16 mg/kg/h) for more than 48 hours had significant accumulations of propylene glycol as manifested by hyperosmolar anion gap metabolic acidosis.6 Fatal reactions are associated with the carrier base of intravenous propofol.139

Diagnostic

Testing

In the undifferentiated comatose patient without a clear history and when overdose is a primary concern, laboratory testing, including electrolytes, liver enzymes, thyroid function tests, blood urea nitrogen (BUN), creatinine, glucose, venous or arterial blood gas analysis, and cerebrospinal fluid analysis, may be useful to exclude metabolic abnormalities. Diagnostic imaging studies, such as head CT scans, may be warranted on a case-by-case basis. Routine laboratory screening for “drugs of abuse― generally are not helpful in the management of undifferentiated comatose adult patients, although they may be useful for epidemiologic purposes in a particular community. These tests vary in type, sensitivity, and specificity. The majority of sedative-hypnotics, including the most common class, benzodiazepines, typically are not included or detected on drug-abuse screens (Chap. 7 ). The typical benzodiazepine screen identifies metabolites of 1,4benzodiazepines, such as oxazepam or desmethyldiazepam. Many benzodiazepines that are metabolized to alternative compounds remain undetected. Benzodiazepines that are 7-amino analogs, such as clonazepam and flunitrazepam, may not be detected because they do not have a metabolite with a 1,4-benzodiazepine structure. Alprazolam and triazolam are not detected because they undergo minimal metabolism.44 Specific laboratory concentrations (eg, alcohol or phenobarbital) may be helpful to confirm or disprove overdoses of a xenobiotic. However, specific concentrations of sedative-hypnotics other than phenobarbital are not routinely performed in most hospitals. Abdominal radiographs may detect GI chloral hydrate because of its radiopacity (Chap. 6 ). Although immediate identification of a particular sedative-hypnotics agent may be helpful in predicting the length of toxicity, it rarely affects the acute management of the patient. Phenobarbital may be the exception, for which urinary alkalinization may alter management.

Management Historically, analeptics and other nonspecific arousal agents (Antiquated Antidotes in Depth) were used, but their use is to be condemned. Deaths secondary to sedative-hypnotic overdose result from cardiorespiratory collapse. Therefore, careful attention should focus on monitoring and maintaining adequate airway, oxygenation, and hemodynamic support. Supplemental oxygen, respiratory support, and prevention of aspiration are the cornerstones of treatment. Hemodynamic instability, although often a secondary or a delayed manifestation of sedative-hypnotic poisoning typically following respiratory collapse, should be approached with volume expansion. Vasopressors should be used only when patients do not respond to intravenous fluids or when evidence of volume overload is present. Patients with chloral hydrate overdoses classically present with both respiratory depression and cardiac toxicity, including lethal ventricular dysrhythmias, resulting from its active halogenated metabolite trichloroethanol. In the setting of cardiac dysrhythmias, judicious use of β-adrenergic antagonists is proposed.16 , 58 , 181

Decontamination All clinically stable patients with significant ingestions should receive activated charcoal. Multiple-dose activated charcoal (MDAC) increases phenobarbital elimination by 50–80%.10 , 11 , 15 , 181 However, in the only controlled study, no difference could be demonstrated in outcome measures (time to extubation and length of hospitalization) in intubated, phenobarbital-poisoned patients who were randomized to single-dose activated charcoal versus MDAC.135 Although inconclusive, after ensuring an adequately protected airway, activated charcoal has potential benefits that outweigh any risk (Antidotes in Depth: Activated Charcoal ).

Although the efficacy of delayed orogastric lavage is controversial, orogastric lavage should be considered in patients who overdose with xenobiotics that may slow GI motility or may develop concretions, specifically phenobarbital and meprobamate.78 , 152 No antidotes counteract all sedative-hypnotic overdoses. Flumazenil, a competitive benzodiazepine antagonist, rapidly reverses the sedative effects of benzodiazepines. However, use of flumazenil has a poor risk-to-benefit ratio in patients who present with a depressed mental status and have an undifferentiated overdose (Antidotes in Depth: see Flumazenil ). P.1103 Patients with sedative-hypnotic overdose require invasive therapy for few situations other than respiratory support. Hemodialysis should be considered in patients with chloral hydrate overdose who develop life-threatening cardiac manifestations and patients who ingest extremely large quantities of phenobarbital and meprobamate and require prolonged intubation times. Because the lethality of sedative-hypnotics is associated with their ability to cause respiratory depression, asymptomatic patients can be downgraded to a lower level of care after a period of observation. Patients who have been monitored for a period of time (8–12 hours) without signs or respiratory depression can be transferred to a general medical floor. Patients with symptomatic overdoses of long-acting drugs, such as meprobamate and clonazepam, or drugs that can have significant enterohepatic circulation, such as glutethimide, will require 24 hours of observation (Chap. 11 ).

Specific

drugs

Barbiturates

Figure. No Caption Available.

Barbital became the first commercially available barbiturate in 1903. Although many other barbiturates subsequently were developed, their popularity has greatly waned since the introduction of benzodiazepines. Barbiturates are derivatives of barbituric acid (2,4,6-trioxo-hexa-hydropyrimidine), which itself has no CNS depressant properties. Various side chains at the X, Y, and Z sites (see barbiturate chemical structure) influence lipophilicity, potency, and rate of elimination. Barbiturates with long side chains tend to have increased properties in all three areas. However, the observed clinical effects also depend on absorption, redistribution, and the presence or absence of active metabolites. For this reason, the duration of action of barbiturates (like those of benzodiazepines) do not correlate well with their biologic half-lives. After ingestion, barbiturates are preferentially absorbed in the small intestine and are eliminated by hepatic and renal mechanisms. Longer-acting barbiturates tend to be more lipid soluble and more protein bound, have a high pKa , a more rapid onset and shorter duration of action, and are metabolized almost completely in the liver. Renal excretion of unchanged drug is significant for phenobarbital. Elimination of phenobarbital, a long-acting barbiturate with a relatively low pKa (7.24), can be influenced by manipulation of urinary pH. Alkalinization of the urine with sodium bicarbonate to maintain a urinary pH of 7.5–8.0 can increase the amount of phenobarbital excreted by 5- to 10-fold. This procedure is not effective for the short-acting barbiturates because they have higher pKa values, are more protein bound, and are primarily

metabolized by the liver with very little excretion by the kidneys (Chap. 10 ). Barbiturates (especially the shorter-acting barbiturates) can accelerate their own hepatic metabolism by enzyme autoinduction. Barbiturate use results in a marked increase in the enzyme content of the hepatic smooth endoplasmic reticulum and an increased rate of metabolism of a number of xenobiotics. Phenobarbital is a nonselective inducer of hepatic cytochromes, with the greatest effect on CYP2B1, CYP2B2, and CYP2B10.80 Not surprisingly, a variety of drug interactions are reported following the use of barbiturates. Clinically significant interactions as a result of enzyme induction lead to increased metabolism of β-adrenergic antagonists, corticosteroids, doxycycline, estrogens, phenothiazines, quinidine, and theophylline. Similar to other sedative-hypnotics, patients with significant barbiturate overdoses present with CNS and respiratory depression. Hypothermia and cutaneous bullae are often present.12 , 43 These two signs are also described for other patients with sedativehypnotic overdoses, but they may be more pronounced with barbiturates.74 , 148 Early deaths caused by barbiturate ingestions result from respiratory arrest and cardiovascular collapse, whereas delayed deaths result from acute renal failure, pneumonia, acute lung injury, cerebral edema, and multiorgan system failure.2 , 60

Benzodiazepines

Figure. No Caption Available.

The commercial use of benzodiazepines began with the introduction of chlordiazepoxide for anxiety in 1961 and shortly thereafter of diazepam for seizures in 1963.50 Benzodiazepines are used principally as sedatives. Temazepam and triazolam are exceptions; they are used as hypnotics to produce sleep. Clonazepam is the only benzodiazepine approved for use as a chronic anticonvulsant agent. Benzodiazepines rarely causes paradoxical psychological effects, including nightmares, delirium, psychosis, and transient global amnesia.2 , 13 , 14 , 46 , 115 The incidence and intensity of CNS adverse events increases with age.112 The benzodiazepines are organic bases with a benzene structure and a 7-member diazepine moiety. Similar to barbiturates, various side chains at R1, R2, R2′, R3, R4, R5, and R7 influence potency, duration of action, metabolites, and rate of elimination. Benzodiazepines tend to be highly protein bound and lipophilic. They passively diffuse into the CNS, their main site of action. Because of their lipophilic nature, benzodiazepines are extensively metabolized via oxidation and conjugation in the liver prior to their renal elimination. Benzodiazepines have a unique distribution and subtypes of receptor sites. Benzodiazepines associated with GABA receptors tend to bind at specific areas in the CNS. Two structurally different “central― benzodiazepine receptors are found in the brain: type I (ω1 ) and type II (ω2 ). Type I receptors tends to be located throughout the brain and contain the GABAA α subunit.40 They are hypothesized to affect anxiety, sleep, and amnesia. Type II receptors are concentrated predominantly in the hippocampus, striatum, and the spinal cord. They are hypothesized to affect muscle relaxation and dependence. Benzodiazepines are also active at certain types of benzodiazepine receptors that are not associated with the GABA receptor.

P.1104 These receptors differ structurally, pharmacologically, and physiologically from GABA-associated benzodiazepine receptors. The function and structure of these receptors are not well defined, so attempts to classify them are not satisfactory. These receptors are located predominantly on the outer membrane of the mitochondria, but they also are present in erythrocytes that lack mitochondria.125 , 126 , 131 Although presently termed peripheral , they also are located in the brain. Peripheral benzodiazepine receptors are found throughout the body, with the greatest concentrations in steroidproducing cells in the adrenal gland, anterior pituitary gland, and reproductive organs. The exact endogenous ligands that bind to these receptors are not clearly elucidated. Several types of endogenous benzodiazepinelike substances, endozepines, anthralin, porphyrins, and diazepam-binding inhibitor are proposed to bind to these

receptors.54

The exact role of these receptors is unclear, but benzodiazepines are postulated to influence basic cellular functions such as mitochondrial respiratory control, cell growth, and cell differentiation. Peripheral benzodiazepine receptors appear to affect several biologic systems designed to cope with stress, such as the hypothalamic-pituitary system, sympathetic nervous system, renin-angiotensin system, and neuroendocrine-immune system.54 , 188 They may have a “neurosteroid― effect by modulating steroidogenesis.39 , 101 , 121

Peripheral benzodiazepine receptors may be significant in modulating pathologic conditions such as hepatic encephalopathy, anxiety disorders, and abnormal immune function. Peripheral benzodiazepine receptors are markedly decreased after neurotoxic insults caused by the excitatory amino acid domoic acid and the neurotoxins soman and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).82 , 83 , 88 These peripheral receptors are increased in encephalopathies caused by hepatic failure and thiamine deficiency.23 , 91 , 94 , 95 Cardiac benzodiazepine receptor sites are linked to calcium channels

(specifically to dihydropyridine 109 , 110 , 111 This mechanism benzodiazepines for treatment such as chloroquine, cocaine,

sites) in animal tissues.92 , 107 , 108 , may theoretically support the use of of the cardiac toxicity of xenobiotics and other sympathomimetics.9 , 75 , 99

, 116

Another unique property of the benzodiazepines is their relative safety even after substantial ingestion, which probably results from their GABA receptor properties. 40 , 127 Unlike many other sedativehypnotics, benzodiazepines do not open GABA channels independently at high concentrations. Benzodiazepines are not known to cause any specific systemic injury, and their long-term use is not associated with specific organ toxicity. Deaths resulting from benzodiazepine ingestions alone are extremely rare. Most often deaths are secondary to a combination of alcohol or other sedativehypnotics.61 , 156 Supportive care is the mainstay of treatment. Tolerance to the sedative effects of the benzodiazepines occurs more rapidly than does tolerance to the antianxiety effects. 100 , 146 Abrupt discontinuation following long-term use of benzodiazepines may precipitate benzodiazepine withdrawal, which is characterized by autonomic instability, changes in perception, paresthesias, headaches, tremors, and seizures. Withdrawal from benzodiazepines is common, manifested by almost one third of long-term users.85 Alprazolam and lorazepam are associated with more severe withdrawal symptoms and more frequent recurrent symptoms compared with chlordiazepoxide and diazepam,85 , 86 drugs that may protect the user because of the effects of their active metabolites. Withdrawal can occur when a chronic user of a particular benzodiazepine is switched to another benzodiazepine that has different receptor activity.102

Chloral

Hydrate

Figure. No Caption Available.

Chloral hydrate belongs to one of the oldest classes of pharmaceutical hypnotics, the chloral derivatives. Chloral hydrate was introduced in 1832. It still is used most commonly in children, although its use has substantially decreased. Chloral hydrate is well absorbed but is irritating to the GI tract. It has a wide tissue distribution, rapid onset of action, and rapid hepatic metabolism by alcohol dehydrogenase. Trichloroethanol, the first active metabolite, is lipid soluble and is responsible for chloral hydrate's hypnotic effects. Chloral hydrate is metabolized by hepatic alcohol dehydrogenase (Figure 72-1 ). Trichloroethanol has a plasma half-life of 4–12 hours and is metabolized to inactive trichloroacetic acid by alcohol and aldehyde dehydrogenases. It is also conjugated with glucuronide and excreted by the kidney as urochloralic acid. Less than 10% is excreted unchanged. Metabolic rates in children vary widely because of variable development and function of hepatic enzymes.41 The elimination half-life of chloral hydrate and trichloroethanol is markedly increased in children younger than 2 years. The half-life of trichloroethanol ranges between 27.8 ± 21.3 hours in newborns and between 9.7 ± 1.7 hours in toddlers. Several comprehensive studies of clinical and pharmacologic characteristics of chloral hydrate use in neonates and infants suggest that even single-dose administration results in prolonged chloral hydrate, trichloroethanol, and trichloroacetic acid half-lives. 103 , 140 This latter metabolite still could be detected 6 days after administration in infants. These factors may be of concern in neonates and in infants exposed to repetitive doses. Acute chloral hydrate poisoning is atypical of the other sedative-

hypnotics. Cardiac dysrhythmias appear to be the main cause of death.58 Chloral hydrate and its metabolites reduce myocardial contractility, shorten the refractory period, and increase myocardial sensitivity to catecholamines.18 , 26 , 166 , 181 Persistent cardiac dysrhythmias (ventricular fibrillation, ventricular tachycardia, torsades de pointes) are common terminal events.58 Standard antidysrhythmics often are ineffective. A β-adrenergic antagonist currently is considered the drug of choice for treatment of most dysrhythmias secondary to chloral hydrate toxicity.16 , 18 , 186 Chloral hydrate can also cause GI toxicity. Overdoses can produce vomiting, hemorrhagic gastritis, and rarely gastric and intestinal necrosis, leading to perforation and esophagitis with stricture formation.93 , 123 , 171 Chloral hydrate is radiopaque and occasionally is detected on radiographs. Few hospital-based laboratories have the ability to rapidly detect chloral hydrate or its metabolites.

Ethchlorvynol

Figure. No Caption Available.

Ethchlorvynol was introduced in 1955 as a substitute for barbiturates. It is no longer legally available in the United States. It is rapidly absorbed and primarily metabolized by the liver, with a half-life of approximately 25 hours after a single use. However, it is readily P.1105 stored in adipose tissue because of its high lipophilicity, and its halflife can exceed 100 hours following overdoses. Whether its major metabolite ethynyl 3,4-diol is active is unclear. Because of the

drug's formulation, stomach contents often reveal a pink-tinged (500-mg capsules) or green-tinged (750-mg capsules) content. Extraction of the compound and intravenous injection is an alternative route of abuse. Acute lung injury often occurred rapidly afterward.34 Symptoms and signs of ethchlorvynol overdoses can resemble barbiturate overdoses, including prolonged coma, hypothermia, and bullous lesions. Prolonged coma and a pungent plastic or vinyl odor on the breath are characteristics of ethchlorvynol poisoning.163

Glutethimide

Figure. No Caption Available.

Glutethimide was introduced in 1954 as a substitute for barbiturates. It is no longer legally available in the United States. It is poorly water soluble and is slowly and erratically absorbed from the GI tract. Absorption may be significantly enhanced by coingestion of ethanol. It concentrates in fat-containing tissues because of its lipophilic nature. It is metabolized in the liver. More than 14 metabolites are identified, some of which are biologically active and may contribute to its toxicity.36 High lipid solubility and delayed absorption may explain the cyclic variation in CNS depression that occurs in patients with acute overdoses. The enterohepatic circulation of metabolites may explain the fluctuating clinical course that occurs in severely intoxicated patients. Active metabolites include 2-phenylglutarimide and γ-butyrolactone (a precursor of GHB). Unlike many of the other sedative-hypnotic agents, glutethimide can cause anticholinergic symptoms.59 It reportedly

produces thick and tenacious bronchial secretions with impairment of ventilation.28 Psychosis, seizures, cerebellar ataxia, and peripheral neuropathy are associated with prolonged use of glutethimide.28

Methaqualone

Figure. No Caption Available.

Methaqualone was introduced in 1956 as another substitute for barbiturates. It has anticonvulsant, anesthetic, antihistaminic, and antispasmodic characteristics. Its effects as a mood “elevator― led to extensive abuse and its subsequent withdrawal from the US market. The drug is rapidly and completely absorbed from the GI tract within 2–3 hours. It is highly protein bound (70–90%) and almost exclusively metabolized in the liver to 4hydroxymethaqualone and numerous other hydroxy metabolites.20 , 73 Unlike many of the other sedative-hypnotics, hyperreflexia, clonus, and significant muscular hyperactivity can occur. Paresthesias and polyneuropathies can be residual effects after overdoses.1

Methyprylon

Figure. No Caption Available.

Methyprylon was introduced in the 1950s and is used only as a hypnotic. It is no longer legally available in the United States. It is rapidly absorbed in the GI tract and is metabolized almost entirely in the liver by oxidation and dehydrogenation. Because methyprylon is water soluble, hemodialysis was used in severe cases but was rarely indicated.32 , 134

Meprobamate/Carisoprodol

Figure. No Caption Available.

Meprobamate was introduced in 1950 and was used for its musclerelaxant characteristics. Carisoprodol, which was introduced in 1955, is metabolized to meprobamate. These propanediol carbamates have pharmacologic effects on the GABAA receptor similar to those of the barbiturates. Like barbiturates, meprobamate can directly open the GABA-mediated chloride channel and may inhibit N -methyl-Daspartate (NMDA) receptor currents.145 They both are rapidly absorbed from the GI tract. The drug is metabolized in the liver to inactive hydroxylated and glucuronidated metabolites that are excreted almost exclusively by the kidney. Of all the nonbarbiturate tranquilizers, meprobamate most likely will produce euphoria.76 , 77 Large masses or bezoars of pills have been noted in the stomach at autopsy.152 Thus, orogastric lavage with a large-bore tube and MDAC may be indicated for significant meprobamate ingestion. Whole-bowel irrigation may be helpful if multiple pills or small concretions are noted. Because patients can experience recurrent toxic manifestations as a result of concretion formation and delayed absorption, careful monitoring of the clinical course is essential even

after the patient shows initial improvement.

Bromides Bromides were previously used as “nerve tonics,― headache remedies, and anticonvulsants. Although pharmaceutical bromides have largely disappeared from the US pharmaceutical market, bromide toxicity still occurs because of the availability of bromide salts of common drugs, such as dextromethorphan.120 Cases occur in immigrants and travelers from other countries where bromides are still therapeutically used.51 The drug is irritating to the GI tract and is difficult to ingest. A sufficient amount is retained to achieve a toxic concentration without vomiting. Bromide has a long plasma half-life (12 days), and toxicity typically occurs over time as concentrations accumulate in tissue. Bromide and chloride ions have a similar distribution pattern in the extracellular fluid. It is postulated P.1106 that because the bromide ion moves across membranes slightly more rapidly than the chloride ion, it is more quickly reabsorbed in the tubules from the glomerular filtrate than the chloride ion. Although osmolar equilibrium persists, CNS function is progressively impaired by a poorly understood mechanism, with resulting inappropriateness of behavior, headache, apathy, irritability, confusion, muscle weakness, anorexia, weight loss, thickened speech, psychotic behavior, tremulousness, ataxia, and eventually coma.27 , 187 Delusions and hallucinations can occur. Bromide can lead to hypertension, increased intracranial pressure, and papilledema. Chronic use of bromides can lead to dermatologic changes, with the hallmark characteristic of a facial acneiform rash.65 , 167 Toxicity with bromides during pregnancy may lead to accumulation of bromide in the fetus.133 A spurious hyperchloridemia may result from bromide's interference with the chloride assay on older analyzers184 (Chap. 17 ).

Zolpidem/Zaleplon

Figure. No Caption Available.

Zolpidem is an imidazopyridine hypnotic. Zaleplon is a pyrazolopyrimidine hypnotic. These xenobiotics have supplanted benzodiazepines as the most commonly prescribed hypnotics.47 Although zolpidem and zaleplon are structurally unrelated to the benzodiazepines, they bind preferentially to the type I (ω1 ) benzodiazepine receptor subtype in the brain, specifically the GABAA Î ±1 subunit.40 Zolpidem and zaleplon have a lower affinity for type II (ω2 )receptors than benzodiazepine hypnotics, so they have potent hypnotic effects and benzodiazepines that prolong stages 3 and 4 of rapid eye zaleplon have little effect on

less addiction potential.40 , 64 Unlike the first 2 stages of sleep and shorten movement (REM) sleep, zolpidem and the stages of sleep. Because of their

selectivity, they appear to have minimal effect at other sites on the GABA receptor that mediate anxiolytic, anticonvulsant, or musclerelaxant effects.89 , 173 Both drugs are hepatically metabolized. In isolated overdoses, drowsiness and CNS depression are common, but coma and respiratory depression are exceptionally rare. Even at 40 times the therapeutic dose, no biologic or electrocardiographic abnormalities have been reported.53 Flumazenil can reverse the effects of both agents.97 , 179 Withdrawal is documented with abrupt discontinuation but typically is mild.62 , 177 Deaths have resulted when zolpidem was taken in large amounts with other CNS

depressants.53

Propofol

Figure. No Caption Available.

Propofol is a rapid-acting intravenous sedative-hypnotic that is a postsynaptic GABAA agonist. It induces presynaptic release of GABA.117 Propofol also interacts with dopamine release at various sites. It promotes nigral dopamine release possibly via GABAB receptors128 , 153 and has partial agonist properties at dopamine (D2 ) and NMDA receptors.151 It is used for either induction or maintenance of general anesthesia. Propofol is highly lipid soluble, so it crosses the blood–brain barrier rapidly. Onset of anesthesia usually occurs in less than 1 minute, with duration of action after short term dosing of 3–8 min because of its rapid redistribution from the CNS. Propofol use is associated with various adverse outcomes. Acutely, propofol causes dose-related respiratory depression. Transient apnea may occur. The drug may decrease systemic arterial pressure and cause myocardial depression. Although propofol does not typically cause dysrhythmias or myocardial ischemia, atropine-sensitive bradydysrhythmias have been noted, specifically sinus bradycardia and Mobitz type I atrioventricular block.165 , 176 , 185 Prolonged infusions for more than 48 hours at rates of 5 mg/kg/h are associated with acidosis, cardiac, and skeletal muscle injury.79 Propofol is suggested to induce disruption of mitochondrial free fatty acid metabolism, causing a syndrome similar to other mitochondrial myopathies. 29 , 158 Case reports associate propofol with lactic

acidosis and fatal myocardial failure in children and young adults.129 Cases of metabolic acidosis may be associated with an inborn disorder of acylcarnitine metabolism.182 However, a direct causeand-effect relationship remains unproven. The unique nature of the carrier base, a milky soybean emulsion formulation, is associated with multiple adverse events. It is a fertile medium for many organisms, such as enterococcal, pseudomonal, staphylococcal, streptococcal, and candidal strains. In 1990, the Centers for Disease Control and Prevention (CDC) reported an outbreak of Staphylococcus aureus associated with contaminated propofol. This carrier base also impairs macrophage function and causes29 hypertriglyceridemia,45 , 84 , 98 abnormalities in blood coagulability, platelet function,5 , 38 , 66 and histamine-mediated anaphylactoid reactions.42 , 81

Etomidate

Figure. No Caption Available.

Etomidate is a nonbarbiturate, hypnotic agent primarily used as an anesthesia induction agent. It is active at the GABAA receptor, specifically the β2 and β3 subunits.122 , 142 Only the intravenous formulation is available in the United States. The onset of action is less than 1 minute and its duration is less than 5 minutes. Etomidate is commercially available as a 2 mg/mL solution in a 35% propylene glycol solution (Amidate).169 The propylene glycol is

implicated in the development of a hyperosmolar metabolic acidosis.105 , 169 , 170 Etomidate has minimal effect on cardiac function, but rare cases of hypotension are reported.55 , 56 , 57 , 63 , 162 It has proconvulsant and anticonvulsant properties.33 , 138 Involuntary muscle movements are common during induction. They may be caused by etomidate interaction with glycine receptors at the spinal cord level.37 , 113 , 114 P.1107 Etomidate depresses adrenal production of cortisol and aldosterone even after a single dose.150 , 174 , 175 This effect is suggested to increase mortality with long-term etomidate use.178

Summary Sedative-hypnotics in combination with alcohol and other respiratory depressants are among the most common drugs implicated in deaths resulting from poisoning. Patients with sedative-hypnotic overdoses often present with the primary manifestation of CNS depression; however, death typically results from respiratory depression. Careful monitoring and supportive care are the cornerstones of treatment. Specific antidotes such as flumazenil and treatments such as hemodialysis are rarely indicated.

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with

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antagonist Bay voltage Sci

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > G - Psychotropic Medications > Antidotes in Depth - Flumazenil

Antidotes in Depth Flumazenil Mary Ann Howland

Figure. No Caption Available.

Flumazenil is a competitive benzodiazepine receptor antagonist. It has no role in cases of unknown overdose because seizures and dysrhythmias may occur when the effects of a benzodiazepine are

reversed in a mixed overdose. Flumazenil also has the potential to induce benzodiazepine withdrawal symptoms, including seizures in patients who are benzodiazepine dependent. Flumazenil does not reliably reverse the respiratory depression induced by intravenous benzodiazepines but does reverse central nervous system (CNS) depression.50 Flumazenil is ideal for the few patients who are naive to benzodiazepines and who overdose solely on a benzodiazepine. Because the duration of effect of flumazenil is shorter than that of most benzodiazepines, repeat doses may be necessary and vigilance is warranted. Flumazenil has no role in the management of ethanol intoxication but may be considered for patients with hepatic encephalopathy. However, further study is needed before its routine use can be recommended.3 Case reports raise the possibility of a role for flumazenil in patients with paradoxical reactions to therapeutic doses of midazolam. Flumazenil is not expected to be effective in overdoses such as baclofen in which a benzodiazepine receptor is not involved.13 Flumazenil is effective for overdoses of zolpidem and zaleplon, nonbenzodiazepines that interact with ω1 receptors, a subclass of

central

benzodiazepine

receptors.36,46,47

History Haefely and Hunkeler's initial work on chlordiazepoxide synthesis62 led to an attempt to develop benzodiazepine derivatives that would act as antagonists.27 This endeavor initially was unsuccessful, so they investigated the promising γ-aminobutyric acid (GABA) hypothesis of benzodiazepine mechanism of action. In 1977, the then-new technique of radioligand binding identified specific high-affinity benzodiazepine binding sites. Other investigators simultaneously isolated a product produced by a Streptomyces species that had the basic 1,4-benzodiazepine structure. Synthetic compounds subsequently were derived from this molecule to act as potential tranquilizers. Hunkeler attempted to produce benzodiazepines with potent anxiolytic and

anticonvulsant activity and diminished sedative and musclerelaxing properties. Testing revealed these derivatives had high in vitro binding affinities but lacked in vivo activity. An inability to enter the CNS was considered an explanation for the discordance. During an experiment that attempted to demonstrate CNS penetration of these derivatives, diazepam given to incapacitate the animals had a surprisingly weak effect. This lack of potency led to the discovery of a benzodiazepine antagonist. Further modifications led to the synthesis of flumazenil (Ro 15-1788).18,48

Pharmacology Flumazenil is a water-soluble benzodiazepine analog with a molecular weight of 303 daltons. It is a competitive antagonist at the benzodiazepine receptor, with very weak agonist properties in animal models and in humans.45 The benzodiazepine receptor modulates the effect of GABA on the GABAA receptor by increasing the frequency of Cl- channel opening, leading to hyperpolarization. Agonists such as diazepam stimulate the benzodiazepine receptor to produce anxiolytic, anticonvulsant, sedative, amnestic, and muscle-relaxant effects at low doses and hypnosis at high doses.28 Inverse agonists bind the benzodiazepine receptor and result in the opposite effects of anxiety, agitation, and seizures. Antagonists, such as flumazenil, competitively occupy the benzodiazepine receptor without causing any functional change and without allowing an agonist or inverse agonist access to the receptor. The zero set point of intrinsic activity may be influenced by the activity of the GABA system or by chronic treatment with benzodiazepines.20 Positron emission tomography investigations reveal that 1.5 mg flumazenil leads to an initial receptor occupancy of 55%, whereas 15 mg causes almost total blockade of benzodiazepine receptor sites.53 The structures of flumazenil, diazepam, and midazolam are shown in the figure. Table A21-1 summarizes the physiochemical and

pharmacokinetic

TABLE

properties

flumazenil.32

of

A21-1. Physicochemical and Pharmacologic Properties of Flumazenil

p KA

Weak base

Partition coefficient pH 7.4

14

(octanol/aqueous

PO4 buffer)

at

Volume of

1.06 L/kg

distribution

Distribution

≤5

minutes

half-life (t1 / 2α) Metabolism

Hepatic:

High

three

clearance

Elimination

First order

Protein

54–64%

binding

Elimination half-life (t1 / 2β)

53 minutes

inactive

metabolites

Onset of action

1–2

Duration action

Dependent on dose and elimination ofbenzodiazepine, time interval, dose offlumazenil, and hepatic function

of

minutes

P.1113

Volunteer

Studies

Volunteer studies demonstrate the ability of flumazenil to reverse the effect of benzodiazepines.16 Reversal is dose dependent and begins within minutes. Peak effects occur within 6–10 minutes.50 Most individuals achieve complete reversal of benzodiazepine effect with a total IV dose of 1 mg.4,12 A 3-mg IV dose produces similar effects that last approximately twice as long as the 1-mg dose.

Conscious

Sedation

A number of studies evaluated patients undergoing conscious sedation for endoscopy or cardioversion who received diazepam or midazolam.5,11,12,34,35 When a benzodiazepine is given for conscious sedation during a procedure, flumazenil appears safe and effective for reversal of sedation and partial reversal of amnesia and cognitive impairment.22 Most patients respond to total doses of 0.6–1 mg. Administering flumazenil slowly at a rate of 0.1 mg/min minimizes the disconcerting symptoms associated with rapid arousal, such as confusion, agitation, and emotional lability. Resedation occurs within 20–120 minutes, depending on the dose and pharmacokinetics of the benzodiazepine and the dose of flumazenil. For this reason, patients must be carefully monitored and subsequent doses of

flumazenil given as needed. Because the amnestic effect of benzodiazepines and the cognitive and psychomotor effects are not fully reversed, posttreatment instructions should be reinforced in writing and given to a responsible caretaker accompanying the patient.16,22 Because of the risk of resedation, many practitioners elect not to use flumazenil routinely. Two cases of patients undergoing endoscopy who developed seizures following benzodiazepine reversal are reported.57 One patient had a history of seizures, and the other had no obvious etiology. Both patients recovered uneventfully.

Use for Paradoxical Reaction to Midazolam Paradoxical reactions to benzodiazepines are uncommon.24,41 The mechanism is unclear and has been attributed to a disinhibition reaction.19 Management strategies include administering higher doses of the benzodiazepines, adding other drugs such as opioids or droperidol, stopping the procedure, and using flumazenil.31,49,58,59 Three patients undergoing endoscopy were premedicated with meperidine, droperidol, and midazolam in doses up to 10 mg.17 Each patient exhibited paradoxical agitation and restlessness. Following flumazenil 0.5 mg IV, the patients became calm and sedated, allowing successful completion of endoscopy. A satisfactory explanation has not been established.

Effects on Respiratory

Benzodiazepine-Induced Depression

Flumazenil has not consistently reversed benzodiazepine-induced respiratory depression and is not approved for this use.50,55 If respiratory depression is mediated through the benzodiazepine receptor, then flumazenil should be effective as a reversal agent,

but this effect does not occur consistently.14,25,39,43,55 The effect of IV midazolam on respiratory depression was examined using oxygen saturation measurements and plethysmography to determine minute ventilation volumes in patients undergoing endoscopy.14 Flumazenil awakened patients rapidly but failed to affect minute ventilation and had little effect on oxygen saturation. When a benzodiazepine was used concomitantly with an opioid, the effects on ventilation were even more confusing.63,65 Rebound respiratory depression and prolonged hypoxic episodes were documented. Flumazenil may even have a slight respiratory depressant effect when combined with an opioid. 63 Clinical assessment of respiratory rate is inadequate for detecting hypoxia. Benzodiazepine-induced apnea should be managed with standard procedures such as supplemental oxygen, airway stabilization, bag-valve-mask ventilation, and endotracheal intubation, if indicated.

Use in the Overdose Setting Use of flumazenil in the overdose setting is controversial. The first argument against flumazenil use is the rare morbidity and mortality associated with benzodiazepine use. An analysis of 702 patients who had taken benzodiazepines alone or in combination with ethanol or other drugs and were admitted to a medical intensive care unit (ICU) over a 14-year period revealed a 0.7% fatality rate (5 deaths) and 9.8% complication rate (69 patients).30 In comparison, the fatality rate for patients with nonbenzodiazepine-related overdoses was 1.6% (55/3430 patients). In the pure benzodiazepine group, 2 patients died and 18 (12.5%) of 144 patients had complications, mostly aspiration pneumonitis and decubitus ulcers. Proponents of flumazenil therapy suggest that some of the 29 diagnostic procedures used in the patients were unnecessary, and some of the complications could have been prevented. Opponents of flumazenil therapy suggest that many of the cases of aspiration pneumonitis occurred

prior to hospital admission and that the patients also suffered from trauma and infectious disease, making most diagnostic procedures necessary. In an effort to develop indications for safe and effective use of flumazenil, overdosed comatose patients were retrospectively assigned to either a low-risk or non–low-risk group.26 Low-risk patients had CNS depression with normal vital signs, no other neurologic findings, no evidence of ingestion of a tricyclic antidepressant by history or electrocardiogram (ECG), no seizure history, and absence of an available history of chronic benzodiazepine ingestion. All other patients fell into the non–low-risk category. Of 35 consecutive comatose patients, 4 patients were assigned to the low-risk group. Flumazenil caused complete awakening in 3 patients and partial awakening in the fourth patient in the low-risk group, with no adverse effects. In the non–low-risk group of 31 patients, flumazenil caused complete awakening in 4 patients and partial awakening in 5 patients. Seizures occurred in 5 patients, of whom 1 had a history of seizures, 5 were long-term benzodiazepine P.1114 users, 4 had abnormal vital signs, and 3 had evidence of hyperreflexia or myoclonus. Therefore, although flumazenil use probably was safe and effective in the low-risk group, few patients met the criteria for inclusion in that risk group. The risk of seizures is substantial in the non–low-risk group.

TABLE A21-2. Indications for Flumazenil Use in the Overdose Setting

Pure benzodiazepine overdose in a nontolerant individual who has CNS depression Normal vital signs, including SaO2 Normal ECG Otherwise normal neurologic examination

In conclusion, the risks of flumazenil usually outweigh the benefits in overdose patients.54 When non–benzodiazepine-dependent patients ingest benzodiazepines alone in overdose, as rarely occurs in adults but might be expected in children, the risks associated with flumazenil use may be limited. 68 Table A21-2 summarizes the indications for flumazenil use in the overdose setting.

Adverse

Effects

and

Safety

Issues

Flumazenil has been studied in more than 3500 patients worldwide, including healthy volunteers and overdosed or consciously sedated patients. The safety of flumazenil in healthy volunteers is well established, with no discernible objective or subjective effects. However, precipitation of seizures in benzodiazepine-dependent patients, unmasking of dysrhythmias in patients who coingest benzodiazepine with a prodysrhythmic drug, and resedation within 20–120 minutes in patients receiving benzodiazepine for conscious sedation are recognized adverse effects associated with flumazenil administration.

The ability of flumazenil to precipitate acute benzodiazepine withdrawal seizures in a more controlled environment than the overdose setting was demonstrated by reversal of long-term benzodiazepine sedation in the ICU. A study of 1700 patients revealed that 14 patients developed adverse drug reactions, probably half related to abrupt arousal.5 Two patients with a history of epilepsy developed tonic-clonic seizures, and 1 patient developed myoclonic seizures.5 Dose-dependent induction of withdrawal reactions is suggested. Small doses of flumazenil (1 mg flumazenil. In category 2, 20 patients received flumazenil for reversal of a benzodiazepine in a mixed-drug overdose. Many of these patients had coingested tricyclic antidepressants. Thirteen of these patients received >1 mg flumazenil. Two of the patients in this group developed status epilepticus and died, possibly secondary to a severe tricyclic antidepressant overdose. Category 3 included 5 patients who received benzodiazepines for

suppression of non–drug-induced seizures. Two of these 5 patients received >1 mg flumazenil. Category 4 included 3 patients with acute benzodiazepine overdoses in the presence of chronic benzodiazepine dependence. Category 5 included 2 patients who received a benzodiazepine for conscious sedation. Therefore, flumazenil use may place the patient at risk for seizures by unmasking a toxic effect in mixed overdose, by removing the protective anticonvulsant effect in a patient with non–druginduced seizures, or by precipitating acute benzodiazepine withdrawal. The risks of flumazenil appear to greatly outweigh the potential benefits of reversal when benzodiazepines are used chronically or acutely to treat a seizure disorder. Flumazenil is best avoided in the overdose setting when evidence indicates ingestion of a drug capable of causing seizures or dysrhythmias. For example, any indication that theophylline, carbamazepine, chloral hydrate, chloroquine, and/or chlorinated hydrocarbons was ingested is a contraindication to flumazenil use.66 Flumazenil should not be used when involvement of a cyclic antidepressant is strongly suggested based on history, clinical findings, or ECG findings (prolonged QRS complex).29,38,44,66 In the event of flumazenilinduced seizures, a therapeutic dose of a benzodiazepine such as diazepam should be effective. Flumazenil is a competitive antagonist; higher doses of benzodiazepines will reverse higher doses of flumazenil. Table A21-3 summarizes the contraindications to flumazenil use.

TABLE A21-3. Contraindications to Flumazenil Use

Prior seizure history or current treatment of seizures History of ingestion of a xenobiotic capable of provoking seizures or cardiac dysrhythmias Long-term use of benzodiazepines ECG evidence of cyclic antidepressants (terminal rightward 40 msec axis, QRS or QTc prolongation) Abnormal vital signs; hypoxia

P.1115

Do si ng Slow IV titration (0.1 mg/min) to a total dose ≤1 mg seems most reasonable. Extravasation should be avoided because of the risk of local irritation. Resedation may occur at 20–120 minutes, and readministration of flumazenil may be necessary. Although not approved by the FDA, continuous IV infusion of flumazenil 0.1–1.0 mg/h in 0.9% sodium chloride solution or 5% dextrose in water has been used following the loading dose.36,67,69

Availability Flumazenil is available as Romazicon in a concentration of 0.1 mg/mL with parabens in 5-mL and 10-mL vials.

Role

in

Hepatic

Nonbenzodiazepine

Toxicity

Encephalopathy

Hepatic encephalopathy is considered a reversible metabolic

encephalopathy characterized by a spectrum of CNS effects. Symptoms may progress from confusion and somnolence to coma. The current hypothesis implicates an increase in GABAergic tone in the development of encephalopathy.6,56 Animal studies of hepatic encephalopathy secondary to galactosamine or thioacetamide (hepatotoxins) demonstrate an increase in GABA effect, which is antagonized by flumazenil, bicuculline (a GABA-receptor antagonist), and isopropylbiclophosphate chloride (a calcium channel blocker).6 Cerebrospinal fluid (CSF) from these animals contained a benzodiazepine receptor ligand with agonist activity. Rat studies involving hepatic encephalopathy resulting from acute liver ischemia showed only a slight response to flumazenil but significant improvement after administration of a partial inverse agonist.10,64 Human studies have detected benzodiazepine-binding activity in the CSF, but not in serum, of patients with hepatic encephalopathy. One group identified 4–19 peaks representing benzodiazepine-binding ligands from the frontal cortex of 11 patients who died of hepatic encephalopathy.9 Two of the peaks were identified as diazepam and N-desmethyldiazepam. Brain concentrations of these substances were 2–10 times higher than normal in 6 of the patients and were normal in 5 patients. Patients with idiopathic recurring stupor who have measurable “endozepines― (endogenous benzodiazepine ligands) in serum and CSF are reported.51,61 Flumazenil improves the clinical and electrophysiologic responses of patients with hepatic encephalopathy and idiopathic recurring stupor.7,17,51,61 Some patients with encephalopathy have improved from stage IV to stage II encephalopathy after IV flumazenil. Maximal improvement after flumazenil lasts approximately 1–2 hours and gradually dissipates within 6 hours. The response rate in a meta-analysis averaged

approximately 30%.23 The proposed explanations for the unresponsiveness include cerebral edema, hypoxia, other diseases or complications, and irreversible CNS damage.

systemic

Animal and human data convincingly support the concept that increased GABAergic tone is responsible for hepatic encephalopathy. Evidence for endogenous benzodiazepine ligands that enhance GABA action also are demonstrated but controversial.1,2 The source of these benzodiazepine receptor agonists is unclear, but diet and/or production by gut bacteria is postulated.6 Most authorities believe endogenous de novo synthesis is unlikely and propose prior benzodiazepine exposure and persistence as an explanation. Neurosteroids and hemoglobin metabolites are also implicated in the pathophysiology of hepatic encephalopathy.2,52 Flumazenil can lead to improvement of the clinical condition of a subgroup of patients with hepatic encephalopathy and may prove useful as an addition to conventional therapy.8 Additional research is necessary to identify prospective responders, dosing considerations, and adverse effects.

Ethanol

Intoxication

Animal studies indicate that many of the actions of ethanol are mediated through GABA neurotransmission.60 Acute ethanol administration appears to enhance GABA transmission and inhibit N-methyl-D-aspartate (NMDA) excitation. Chronic ethanol administration leads to downregulation of the GABA system. Ethanol enhances GABAA -induced chloride influx in a dosedependent fashion without a direct effect on chloride. Flumazenil does not influence this action of GABA. Chronic ethanol use selectively increases the sensitivity to inverse benzodiazepine agonists, invoking a change in coupling or conformation of the receptor. These changes may explain the development of tolerance and the kindling and production of seizures that occur on

withdrawal. Two double-blind studies in patients with benzodiazepine or ethanol overdose evaluated the response to flumazenil. In one study of 13 patients with suspected ethanol intoxication, 6 had no response to placebo when it was given first, whereas all 13 patients responded to 5 mg flumazenil.42 Improved consciousness occurred after 15 minutes, and respiratory rates increased from 14 to 16 breaths/min. Heart rate and blood pressure were not affected. The 5-mg dose of flumazenil was selected because no improvement in mental status or vital signs was observed when 1 mg flumazenil was administered to 4 patients. Another

comparable

study

demonstrated

similar

results.37

Flumazenil (1 mg) administered to 9 ethanol-intoxicated patients produced the same effects as placebo. Subsequent administration of 2–5 mg flumazenil in the open part of the study produced a clear improvement in the modified Glasgow coma scale in 5 of 11 patients. However, a closer inspection of phase 1 of the study reveals that an arousal reaction occurred in 7 of 9 patients after the flumazenil dose and in 5 of 9 patients following placebo administration. It is conceivable that the improvement in phase 2 was a continuation of the arousal reaction. One case report indicates that ethanol-induced respiratory depression was reversed by flumazenil,40 but whether the actual data support the authors' conclusions is unclear. A randomized, double-blind, crossover study of 8 male volunteers given IV ethanol to achieve a constant serum ethanol concentration P.1116 of 160 mg/dL was conducted.15 Once stabilized, the volunteers were given either placebo or 5 mg flumazenil. Subjective and objective psychomotor tests were conducted, with no differences noted between volunteers given flumazenil and volunteers given placebo. The probability of ethanol reversal at the suggested doses

appears

unlikely.

Based on this information, flumazenil likely does not have a significant effect on ethanol intoxication. Low doses of flumazenil ( Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 73 - Amphetamines

Chapter

73

Amphetamines William K. Chiang

Figure. No Caption Available.

A 25-year-old woman was brought to the emergency department (ED) by ambulance from a dance club. The paramedics reported that

the patient had become agitated in the club and had a generalized seizure. They also reported that the patient had used “ecstasy― during the night. The woman was delirious, agitated, hallucinating, and paranoid. At times she was exceedingly hyperactive, jumping repeatedly on and off the stretcher. Frequently, she appeared to be involved with her hallucinations. The physical examination revealed a blood pressure of 170/100 mm Hg; pulse of 120 beats/min and regular; respiratory rate of 18 breaths/min; rectal temperature of 102.7°F (39.3°C); and a pulse oximetry reading of 97% on room air. The patient appeared to be of normal habitus, acyanotic, and anicteric, but diaphoretic. Her head was normocephalic. Her pupils were dilated to 6 mm bilaterally, and they reacted slowly to light. The conjunctivae, extraocular movements, and the fundi were normal. Her neck was supple, exhibiting no thyromegaly. Examination of her heart was unremarkable, except for tachycardia. Her lungs were clear. The abdomen was soft, nontender, and without hepatomegaly; bowel sounds were normal. The extremities were normal, without any evidence of track marks, bruises, swelling, or rash. The patient moved all her extremities spontaneously and had normal symmetric deep-tendon reflexes with plantar flexion. A rapid bedside glucose was 95 mg/dL. She was treated with a total of 20 mg of diazepam IV (given in 10-mg increments) for sedation and attached to a continuous cardiac monitor. She was given 1.5 L of 0.9% sodium chloride solution over 60 minutes. External cooling with ice packs around the axillae and groin was initiated. She became calm and less paranoid. Her rectal temperature decreased to 100°F (37.7°C) within 15 minutes. Her complete blood count was remarkable for an elevated white blood cell count of 15,000 cells/mm3 . The serum electrolytes were P.1119 remarkable for: sodium, 109 mEq/L; potassium, 3.6 mEq/L; chloride, 81 mEq/L; bicarbonate, 20 mEq/L; blood urea nitrogen (BUN), 10

mg/dL; creatinine, 1.1 mg/dL; and glucose, 105 mg/dL. The liver enzymes were normal. The urinalysis was negative for blood and protein, and the urine osmolality was 497 mOsm/kg. The chest radiograph was normal. The electrocardiogram (ECG) revealed a sinus tachycardia. A noncontrast head computed tomography (CT) scan was normal. Further therapy consisted of the administration of 3% sodium chloride solution at 50 mL/h for 6 hours with frequent serum sodium concentration monitoring. The repeat serum sodium concentration after 6 hours was 123 mEq/L. The patient's mental status improved and she had no further seizures. At this time, the patient was placed on free water restriction and her sodium slowly improved to 130 mEq/L by 24 hours. By that time, the patient's mental status had completely normalized. Her liver enzymes, renal function, and urinalysis remained normal. The patient was discharged from the hospital after 4 days without any sequelae. Amphetamine is the trivial name and acronym for racemic βphenylisopropylamine or α-methylphenylethylamine and belongs the family of phenylethylamines. Numerous substitutions of the phenylethylamine structure are possible, resulting in different

in

amphetaminelike compounds. Commonly, these compounds are referred to as amphetamines or amphetamine analogs, although phenylethylamines is more precise. For the purposes of this chapter, the term amphetamines refers to amphetamine analogs, and amphetamine specifically refers to β-phenylisopropylamine. Since the initial marketing of amphetamines, continued abuse and misuse have been substantial.17,101,184 Amphetamines have been advocated by the medical communities for the treatment of depression, obesity, enuresis, postencephalitic parkinsonism, coma, ADHD, and even alcoholism.101,138 By 1970, the legal annual production of amphetamines was more than 10 billion tablets, with the majority diverted for illicit usage.101 Currently, there are very few medical indications for amphetamines,

including narcolepsy, attention deficit hyperactivity disorder, and short-term weight reduction.122 The prescriptive amphetamines include methylphenidate, pemoline, phentermine, phendimetrazine, amphetamine, dextroamphetamine, and methamphetamine. Because of structural differences, some amphetamines are marketed as nonamphetamine products in their package inserts. Despite the controlled status of amphetamines, there has been a resurgence of amphetamine abuse, particularly with methamphetamine and methylenedioxymethamphetamine (MDMA).47,99,208,210,265,272

History

and

Epidemiology

Edeleano first synthesized amphetamine (racemic βphenylisopropylamine) in 1887. However, it was not rediscovered until the 1920s, when there was significant concern about the supply of ephedrine for asthma therapy. In the search for the synthesis for ephedrine, Alles from UCLA rediscovered dextroamphetamine and Ogata from Japan discovered methamphetamine (dphenylisopropylmethylamine hydrochloride).101 Amphetamine was marketed as Benzedrine inhaler, a nasal decongestant, by Smith, Kline, and French in 1932.17 Amphetamine tablets were available in 1935 for the treatment of narcolepsy, and were advocated as anorexiants in 1938. The stimulant and euphoric effects of amphetamines were widely recognized, resulting in diverse forms of abuse and misuse. Amphetamine abuse was reported as early as 1936.138 Benzedrine inhalers, each containing 250 mg of amphetamine, were widely abused, leading to a ban by the FDA in 1959. Propylhexedrine (Benzedrex) inhalers, a less-potent amphetaminelike substance marketed in 1949, supplanted Benzedrine inhalers.7 Propylhexedrine was also significantly misused.6 Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war in World War II.17,185 Widespread methamphetamine abuse in Japan persisted for more

than a decade after the war. From 1950 to the 1970s, there were sporadic periods of widespread amphetamine use and abuse in the United States. In the 1960s, various amphetamine derivatives such as methylenedioxyamphetamine (MDA) and paramethoxyamphetamine (PMA) were popularized as hallucinogens. Until 1971, only a small proportion of the amphetamines produced by pharmaceutical companies was used for legitimate medical problems.101,187 The Controlled Substance Act of 1970 placed amphetamines in Schedule II to regulate the diversion of pharmaceutical amphetamines for nonmedicinal uses.52 Amphetamine abuse subsequently declined in the 1970s.38,148,187 In the 1980s, the so-called designer amphetamines (Table 73-1) , mostly methylenedioxy derivatives of amphetamine and methamphetamine, came into vogue, as a mechanism of circumventing existing regulations. The most well known substances were MDMA and 3,4-methylenedioxyethamphetamine (MDEA), but more than 200 different derivatives are known.62,248 Before 1986, the Controlled Substances Act classified drugs as illegal only after they were synthesized and formally recognized by their structure, effects, or illegal usage. During this period, any analogs (such as these “designer drugs―) not yet formally classified could be sold legally. In 1986, the standard became prospective for any agent that was used as a stimulant, hallucinogen, or depressant, and for any agent designed as such.26 In effect, this amendment eliminated the legal loophole that allowed the designer drug industry to flourish. Although the meaning of the term “designer drugs― has changed and is no longer legally relevant, many of these analogs are still widely illicitly available.117,130,177 From the late 1980s to the 1990s, a dramatic resurgence of methamphetamine abuse spread throughout much of the United States. A high purity preparation of methamphetamine hydrochloride was marketed in a large crystalline form termed “ice― by abusers.9,42,65,184 In fact, methamphetamine surpassed cocaine and became the primary substance of abuse among those seeking care in

the drug treatment programs of San Diego and San Francisco counties in the 1990s.99,114 From 1991 to 1994, the number of methamphetamine-related deaths in the United States reported by medical examiners tripled from 151 to 433, with a disproportional distribution from the Los Angeles, San Diego, San Francisco, and Phoenix metropolitan areas. The number of methamphetaminerelated emergency department visits also increased from 4900 in 1991 to 17,400 in 1994.99 The number of methamphetamine-related emergency department visits has remained stable since the mid1990s despite significant local geographical changes.71 Recently, methamphetamine use has become particularly prevalent among men having sex with men in New York City.106 Although the initial source of methamphetamine was from Pacific Rim countries such as Korea and Taiwan, currently the majority is produced in the United States.43,78,265 Methamphetamine is the most common illicit drug produced by clandestine laboratories in the United States at this time. Because of the ease and low cost of methamphetamine synthesis, the end user cost of methamphetamine is less than onethird P.1120 that of

cocaine.78

P.1121 Methamphetamine production in United States was

primarily located in California and Oregon in the late 1990s, but it has spread through every state, although it remains particularly prevalent in the midwest and western United States.265 The number of clandestine methamphetamine laboratory seizures nationally increased from 327 in 1995 to 15,994 in 2004.125 Both the cost and the prolonged duration of effect may contribute to the increased popularity of methamphetamine.99,150,265

TABLE

73-1.

Designer

Amphetamines

Beginning in the mid-1990s, MDMA became and remains the amphetamine most widely used by college students and teenagers. MDMA is used by this population in large gatherings, known as “rave― or “techno― parties in England, Australia, and the United States.215,216,272 MDMA use is prevalent in parties and clubs worldwide. Other MDMA-like analogs are often used or sold as MDMA in these gatherings.10,272 Despite the popularity of MDMA, recent data in the United States demonstrates a decline in its past year use from 3.2 million in 2002 to 2.1 million in 2003.259 Reports of methcathinone (a Khat-derived substance) use in the midwestern United States,94,282 and a resurgence of 4-bromo-2,5methoxyphenylethylamine (2CB) in dance clubs occurred in the 1990s.75,88 Fortunately, the fear for the widespread use of these agents never materialized. Although the trend of a particular amphetamine analog waxes and wanes, use and abuse of amphetamines in general is likely to continue to be consequential.

Pharmacology The pharmacologic effects of amphetamines are complex but the primary mechanism of action is the release of catecholamines, particularly dopamine and norepinephrine, from the presynaptic terminals. Although there are conflicting mechanistic models of amphetamine induction of catecholamine release, the variable results may be directly correlated with the different concentrations of amphetamines used in experimental models. The best models to study the mechanism of action of amphetamines are based on dopaminergic neurons; similar mechanisms are invoked for norepinephrine and serotonin. Two storage pools exist for dopamine in the presynaptic terminals: the vesicular pool and the cytoplasmic pool. The vesicular storage of dopamine and other biogenic amines is maintained by the acidic environment inside the vesicles and the persistence of a stabilizing electrical gradient with respect to the cytoplasm. This environment is maintained by an adenosine

triphosphate (ATP)-dependent active proton transport system.243 At low doses, amphetamines release dopamine from the cytoplasmic pool by exchange diffusion at the dopamine uptake transporter site in the membrane. At moderate doses, amphetamines diffuse through the presynaptic terminal membrane and interact with the neurotransmitter transporter on the vesicular membrane to cause exchange release of dopamine into the cytoplasm. Dopamine is subsequently released into the synapse by reverse transport at the dopamine uptake site.243,261 At high doses, an additional mechanism is invoked as amphetamine diffuses through the cellular and vesicular membranes, alkalinizing the vesicles, permitting dopamine release from the vesicles and delivery into the synapse by reverse transport.261,262 Binding selectivity to the neurotransmitter transporters largely determine the range of pharmacologic effects for the particular amphetamine. The MDMA affinity for serotonin transporters is 10 times greater than that for dopamine and norepinephrine transporters, hence producing primarily serotonergic effects.97 Amphetamines may also block the reuptake of catecholamines by competitive inhibition.102,122 However, the effects of this mechanism are considered to be minor. At higher doses, amphetamines can cause the release of serotonin (5-hydroxytryptamine [5-HT]) and affect central serotonin receptors. Certain amphetamines, such as MDMA and 4-bromo-2,5-dimethoxyamphetamine (DOB), have more significant serotonergic effects.85,122 Amphetamines are structurally similar to nonhydrazine amine-derivative monoamine oxidase inhibitors such as phenelzine and tranylcypromine, and most also have weak monoamine oxidase-inhibiting activities, the clinical significance of which is unclear.212 The most identifiable effects of amphetamines are those caused by catecholamine release and the resultant stimulation of peripheral αand β-adrenergic receptors. In the central nervous system, increased norepinephrine at the locus caeruleus mediates the anorectic and alerting effects, and also some locomotor

stimulation.101 The increase in central dopamine (particularly at the neostriatum) mediates stereotypical behavior and some of the other locomotor activities.51,92,102,140 The activity of dopamine in the neostriatum appears to be linked to glutamate release and inhibition of GABAergic efferent neurons.92,139,140 Stimulation of the glutamatergic system contributes significantly to the stereotypical behavior, locomotor activities, and neurotoxicity of amphetamines. 18,24,139,140,256,257 The effects of serotonin and dopamine on the mesolimbic system alter perception and cause psychotic behavior.92,121 Because amphetamines directly interact with neurotransmitter transporters, minor modifications of the molecule may significantly alter its pharmacologic profile. 128 The αmethyl group in the amphetamine structure introduces chirality to the molecule. Except for MDMA and certain MDMA analogs, the denantiomers are much more potent (typically 4–10 times) than the l forms of amphetamines. Substitution at different positions of the phenylethylamine molecule alters general clinical effects of amphetamines, as demonstrated by animal discrimination studies and human observations. Compounds with methyl substitution at the α carbon, such as amphetamine and methamphetamine, possess strong stimulant, cardiovascular, and anorectic properties.91,196 Large group substitution at the α carbon reduces the stimulant and cardiovascular effects, but retains the anorectic properties (such as in phentermine).12 Substitution at the para position of the phenyl ring enhances the hallucinogenic or serotonergic effects of amphetamines (such as in para-chloroamphetamine and 12,82,181 MDMA). Although some of these generalizations enable scientists to understand the effects of amphetamines, there are many exceptions, and such generalizations may not apply when large doses of a particular molecule are ingested.72 In terms of the spectrum of activities, methamphetamine has the most potent cardiovascular effects, and DOB has the most potent hallucinogenic or serotonergic effects.91,196

Pharmacokinetics

and

Toxicokinetics

In general, amphetamines are relatively lipophilic and hence they can readily cross the blood–brain barrier. They have large volumes of distribution, varying from 3–5 L/kg for amphetamine and 3–4 L/kg for methamphetamine and phentermine, to 11–33 L/kg for methylphenidate. Pemoline is the exception as it has a small volume of distribution (0.2–0.6 L/kg).11 Amphetamines differ from catecholamines in that they lack the catechol structure (hydroxyl groups at the 3 and 4 positions of the phenyl ring) and are resistant P.1122 to metabolism by catechol-O-methyltransferase (COMT).122 The addition of an α-methyl group in amphetamines confers resistance to metabolism by monoamine oxidase. These characteristics permit better oral bioavailability and longer duration of effects.196 Amphetamines are eliminated via multiple pathways, including diverse routes of hepatic transformations, and by renal elimination. For MDMA and its analogs, N-dealkylation, hydroxylation, and demethylation are the dominant hepatic pathways.43,44,172 Depending on the particular substance, active metabolites of secondary amphetamines and ephedrine derivatives may be formed.11,43 N-demethylation of methamphetamine and MDMA result in the formation of amphetamine and MDA, respectively.43 Dealkylation and demethylation are mainly performed by cytochrome P450 (CYP) isozymes, including CYP1A2, CYP2D6, and CYP3A4, but they are also performed by flavin monooxygenase (FMO).172 Polymorphism of CYP2D6 in humans was discovered as a result of decreased p-hydroxylation of amphetamine in certain individuals. Since its discovery, CYP2D6 polymorphism has been implicated in drug toxicity, substance use and abuse, and lack of drug efficacy in selected individuals.246 Increased amphetamine toxicity is a potential concern in patients with decreased CYP2D6 activity. Although animals with CYP2D6 deficiency are more susceptible to MDMA toxicity,49 limited studies in humans do not demonstrate an association of

mortality and CYP2D6 deficiency.86,199 In general, because multiple enzymes and pathways (including renal) are involved in amphetamine eliminations, it is less likely that CYP2D6 polymorphism or drug interactions with CYP3A4 alone will significantly increase toxicity. However, it is unclear if toxicity is enhanced when multiple mechanisms for altering drug metabolism and renal dysfunction are present simultaneously. Renal elimination is substantial for amphetamine (30%), methamphetamine (40–50%), MDMA (65%), and phentermine (80%). Amphetamines are relatively strong bases with a typical pKa range from 9–10, and renal elimination varies depending on the urine pH.11 The half-life of amphetamines varies significantly: amphetamine, 8–30 hours; methamphetamine, 12–34 hours; MDMA, 5–10 hours; methylphenidate, 2.5–4 hours; and phentermine, 19–24 hours.11,43 Repetitive administration, which occurs typically during binge use, may lead to drug accumulation and prolongation of the apparent half-life and duration of effect.132

Clinical

Manifestations

The clinical effects of amphetamines are largely related to the stimulation of central and peripheral adrenergic receptors. These clinical manifestations and complications are similar to those from cocaine use and may be indistinguishable except for the duration of effect of amphetamines, which tends to be longer (up to 24 hours).65 Compared to cocaine, amphetamines are less likely to cause seizures, dysrhythmias, and myocardial ischemia. This may be related to the sodium channel-blocking effects and to the thrombogenic effect of cocaine.93 Psychosis appears to be more likely with amphetamines than cocaine, which may be related to the more prominent dopaminergic effects of amphetamines.8,92 Tachycardia and hypertension are the most common manifestations of cardiovascular toxicity. Most patients present to the emergency department, however, because of the CNS manifestations.65,129,276

These patients are anxious, volatile, aggressive, and may have lifethreatening agitation. Visual and tactile hallucinations, as well as psychoses, are common.21,66,67,112,164,226,239 Other sympathetic findings include mydriasis, diaphoresis, and hyperthermia (Table 732) .66,70 Death from amphetamine toxicity most commonly results from hyperthermia, dysrhythmias, and intracerebral hemorrhage.39,61,79,135,142,163,206,227 Direct CNS effects may result in seizures. Tachycardia, hypertension, and vasospasm may lead to cerebral infarction,95,153,231 intraparenchymal and subarachnoid hemorrhage,57,110,126,141,258,281 myocardial ischemia or infarction,81,207,269 aortic dissection,57,69 acute lung injury,29,193,194 obstetrical complications, fetal death,162 and ischemic colitis.16,119,133 Dysrhythmias vary from premature ventricular complexes to ventricular tachycardia and ventricular fibrillation.135,165 Agitation, increased muscular activity, and hyperthermia can result in metabolic acidosis, rhabdomyolysis,54 acute tubular necrosis (acute renal failure), and P.1123 coagulopathy.70,87,134,143 Unless these systemic signs and symptoms are rapidly reversed, multiorgan failure and death ensue.

TABLE

73-2.

Acute Toxicity Cardiovascular system Hypertension Tachycardia Dysrhythmias Myocardial ischemia Aortic dissection Vasospasm

Amphetamine

Toxicity

Central nervous system Hyperthermia Agitation Seizures Intracerebral hemorrhage Headache Euphoria Anorexia Bruxism Choreoathetoid movements Hyperreflexia Paranoid psychosis Other sympathetic symptoms Diaphoresis Tachypnea Mydriasis Tremor Nausea Other organ

systems

Rhabdomyolysis Muscle rigidity Acute lung injury Ischemic colitis Chronic toxicity Vasculitis Cardiomyopathy Pulmonary hypertension Aortic and mitral regurgitation Permanent damage to dopaminergic neurons Laboratory abnormalities Leukocytosis Hyperglycemia Hyponatremia

and

serotonergic

Elevated CPK Elevated liver enzymes Myoglobinuria

Amphetamine users seeking intense “highs― may go on “speed runs― for days to weeks. Because of the development of acute tolerance, they use increasing amounts of amphetamines during these periods, usually without much sustenance or sleep, attempting to achieve their desired euphoria.17,52,155,252,263 Acute psychosis resembling paranoid schizophrenia may occur during these binges and has contributed to both amphetamine-related suicides and homicides.73,151 Return to a normal sensorium occurs within a few days after discontinuation of the drug. Once an amphetamine user experiences psychosis, it is likely to be recurrent, even after prolonged abstinence, which may be related to a kindling phenomenon.17,204,263 Amphetamine-induced psychosis has contributed to the understanding of dopamine's function in schizophrenia. Typically after such binges, patients may sleep for prolonged periods, feeling hungry and depressed when awake. During this period of depression or withdrawal, the patient continues craving

amphetamines.112,152,158

There are some direct neurologic effects of amphetamines. Compulsive repetitive behavior patterns are reported in humans and animals. Individuals may constantly pick at their skin, grind their teeth (bruxism), or perform repetitive tasks, such as constantly cleaning their house or car.17 MDMA users often carry pacifiers to relieve bruxism. Choreoathetoid movements, although uncommon, are reported with acute and chronic amphetamine usage.149,167,171,219,238,251 The etiology of the choreoathetoid movements may be related to increased dopaminergic activity at the striatal area. Necrotizing vasculitis is associated with amphetamine abuse.19,46 Angiography typically demonstrates beading and narrowing of the

small and medium-size arteries (see Fig. 6-25) .233,258 Progressive necrotizing arteritis57 can involve multiple organ systems, including the central nervous, cardiovascular, gastrointestinal, and renal systems. Complications include cerebral infarction and hemorrhage, coronary artery disease, pancreatitis, and renal failure.46,109,166,233,258,258,281 The etiology of the arteritis remains unclear. Although various contaminants associated with parenteral drug use were postulated as potential etiologies, oral and IV amphetamine use in animal models are also associated with vasculitis, suggesting that this is a direct amphetamine effect.234,235,266 Cardiomyopathy is also reported with acute and chronic amphetamine abuse.19,123,200,254 Excessive catecholamine exposure in patients with pheochromocytomas and chronic cocaine use may be responsible for their associated cardiomyopathies; amphetamine-induced cardiomyopathy may be produced by similar mechanisms.101,137,275 Primary pulmonary hypertension, a rare and potentially fatal disease, is reported with chronic methamphetamine and propylhexedrine use.6,68,156,241 However, substantial epidemiologic risk for primary pulmonary hypertension is demonstrated only with fenfluramine and aminorex (2-amino-5-phenyl-2-oxazoline).23,103,249 Pulmonary hypertension was associated with the use of aminorex as an anorectic agent in Europe from 1965 to 1968.104 In 1996, a casecontrolled study substantiated the increased risk of pulmonary hypertension with the use of amphetamine appetite-suppressant drugs, particularly with fenfluramine.1 The risk of pulmonary hypertension was increased 23-fold when the cumulative use of anorectic agents totaled more than 3 months.1 Pulmonary hypertension may develop following exposure to anorectic agents that may be as brief as 3 weeks.103 The exact cause of the pulmonary hypertension is unclear. Increased serotonin or direct effects of 5-HT2 B receptors in the pulmonary vasculature is postulated to result in pulmonary vasoconstriction and endothelial proliferation.120,193,229 Interestingly, although fenfluramine is a

weak agonist for 5-HT2 B receptors, its metabolite norfenfluramine is a potent agonist for 5-HT2 B receptors and may be responsible for causing pulmonary hypertension. 124 Pulmonary hypertension that develops following the use of anorectic drugs may be partially reversible after withdrawal of the agent; however, the median survival of patients studied during the European aminorex epidemic was 3.5 years from the time of diagnosis.103 With current advances in therapy, improved survival is expected.232 Valvular heart disease is also associated with the use of the appetitesuppressants fenfluramine, dexfenfluramine, and phentermine, particularly if the duration of therapy is greater than 4 months.50,83,131,145,273 The initial reports, in 1997, implicated significant aortic and mitral regurgitation with the use of these drugs and the prevalence was as high as 32%.37 These reports resulted in the withdrawal of fenfluramine and dexfenfluramine. Subsequent studies demonstrated mostly mild aortic regurgitation and possible mitral regurgitation; the overall prevalence varies from study to study, ranging from 0.14% to 22.7%. 83,131,145,271 The highest risks appear to be in patients taking combination therapy with fenfluramine and phentermine, and those who used the drug for prolonged periods (>4 months).131 The dramatic differences in the overall prevalence rate in these studies may be related to differences in patient population, duration of therapy, and the timing of echocardiography (ie, during therapy or after the cessation of therapy). The most recent meta-analysis demonstrated a 12% prevalence rate of valvular regurgitation (mostly aortic) with more than 90-day use of the appetite-suppressants, compared to 5.9% in the unexposed group. There was no difference when the appetitesuppressants' use was less than 90 days.236 Echocardiographic findings of the valvular dysfunctions typically improve following cessation of these drugs.118 The exact etiology of the valvular disease is postulated to be related to increased serotonin or direct effects on 5-HT2 B receptors. Similar valvular disorders are recognized in patients exposed to persistently increased serotonin

levels with conditions such as malignant carcinoid syndrome; its unclear why carcinoid syndrome predominately affects right-sided valves versus primarily left-sided valves for these drugs. 228 Although the chronic administration of MDMA and its analogs are better publicized, chronic administration of various amphetamines, including amphetamine and methamphetamine, to animals, alters dopamine and serotonin transporters functions, depletes dopamine and serotonin in the neuronal synapses, and produces irreversible destruction of those neurons.15,85,222,223,225,242,278 The etiology of neuronal toxicity may be related to the generation of free oxygen radicals, resulting in the generation of toxic dopamine and serotonin metabolites and neuronal destruction. 85,157,244,278,279 Based on animal models, dose, frequency and duration of exposure, and ambient temperature can affect neurologic injuries. Intact dopamine or serotonin transporters are necessary to produce neurologic injury. Drugs that inhibit transporter functions may prevent neurologic injuries in animals.97 Significant differences are also noted across species; mice are typically resistant to MDMA-induced neurologic injury.175 Although not as well-studied as MDMA, recent studies of former methamphetamine users demonstrated impaired memory and psychomotor functions, as well as corresponding dopamine transporter dysfunction and abnormal glucose metabolism on PET scans.245,267,268 However, we still do not understand the difference in species susceptibility to neurologic injuries, the duration of effects in primates and humans, and functional P.1124 consequences of neurotoxicity in humans. The potential for permanent neurologic effects associated with chronic amphetamine use in humans requires further study. Despite the first report of neurologic injuries from methamphetamine in animals in 1976, many questions remain unanswered. Finally, multiple medical complications can result from parenteral drug use and from the associated contaminants. Contamination with infectious agents may result in HIV infection, hepatitis, and malaria.

Bacterial and foreign-body contamination may result in endocarditis, tetanus, wound botulism, osteomyelitis, and pulmonary and softtissue abscesses.41

Diagnostic

Testing

Diagnosis by history is rarely reliable as patients often do know the exact drug they have used.148 Also, there is no readily available drug-specific serum analysis. Qualitative urine immunoassay testing for amphetamines is available, but it is not valuable in the acute overdose setting. Typically, the turnaround time for the test result is at least several hours, which is far too long to be clinically useful. Both false-positive and false-negative results are common. Many cold preparations contain structurally similar substances (such as pseudoephedrine) that may cross-react with the immunoassay.48,55,80,213 Likewise, selegiline, a selective monoamine oxidase type B (MAO-B) inhibitor used for the treatment of parkinsonism, is metabolized to amphetamine and methamphetamine. Patients taking selegiline will react positively with most amphetamine-testing techniques.138 Even a true-positive result only means the patient has used an amphetamine analog within the last several days. In addition, most immunoassays do not react with all amphetamines, resulting in false-negative results. For example, MDMA frequently goes unrecognized on standard urinary drug testing.16,48 Although newer, rapid, serum qualitative drug screens are available, false-positive and false-negative results remain common and may be misleading. The gold standard for drug testing, gas chromatography–mass spectrometry analysis, can misidentify isomeric substances such as l-methamphetamine, which is present in nasal inhalers, with d-methamphetamine, if performed by inexperienced personnel. 253 In summary, the suspicion of amphetamine toxicity cannot be confirmed rapidly with a high level of reliability by the laboratory. The physical and psychological assessment is nonspecific, and

polydrug abuse is quite common. As such, the prevalence of amphetamine abuse in the local geographic region should heighten the suspicion of amphetamine toxicity in patients with an appropriate presentation. Management decisions must be determined by the clinical manifestations and impressions. Blood specimens should be sent for glucose, BUN, and electrolyte assays. Hyponatremia should be considered for any patient with an altered sensorium and suspected MDMA usage (Chap. 17). An ECG should be obtained to exclude ischemia, hyperkalemia, and drug toxicity (cyclic antidepressant), and continuous cardiac monitoring should be initiated. A complete blood count, urinalysis, coagulation profile, chest radiograph, CT of the head, and lumbar puncture may be necessary, depending on the clinical presentation.

Management Table 73-3 summarizes the therapeutic approach to a patient with amphetamine toxicity. The initial medical assessment of the agitated patient must include the vital signs and a rapid complete physical examination. An often-neglected vital sign is the rectal temperature.

TABLE 73-3. Management of Patients with Amphetamine Toxicity

Agitation Benzodiazepines (usually adequate for the cardiovascular manifestations) Diazepam 10 mg (or equivalent) IV, repeat rapidly until the patient is calm (cumulative dose may be >100 mg of diazepam) Seizures Benzodiazepines Barbiturates Propofol Hyperthermia External cooling Control agitation rapidly Gastric decontamination and elimination Activated charcoal for oral ingestions Hypertension Control agitation first α-Adrenergic receptor antagonist (phentolamine) Vasodilator (nitroprusside, nitroglycerin) Delirium or hallucinations with abnormal vital signs If agitated: benzodiazepines Delirium or hallucinations with normal vital signs Consider

haloperidol

or

droperidol

(consider

risk/benefit)

Hyperthermia, a frequent and rapidly fatal manifestation in patients with drug-induced delirium, requires immediate interventions to achieve cooling.87,134,143 Some patients will require physical restraint to gain clinical control and prevent personal harm to themselves or others. Because agitation and resistance against physical restraint may lead to rhabdomyolysis and continued heat generation, intravenous chemical sedation should be instituted immediately. Blood specimens should be sent for glucose, BUN, and electrolyte assays. Hyponatremia should be considered for patients

with altered sensorium and suspected MDMA usage (Chap. 17) . Intravenous (IV) glucose (D50W, 0.5–1 g/kg) and thiamine 100 mg should be given as indicated. Because the clinician cannot accurately distinguish the diverse etiologies of drug-induced delirium, the choice of chemical sedation should be safe and effective regardless of the etiology. The most appropriate choice of sedation is a benzodiazepine because these drugs have a high therapeutic index and good anticonvulsant activity. They are effective for the treatment of delirium induced by acute overdose of cocaine, amphetamines, and other drugs, and the delirium associated with ethanol and sedative-hypnotic withdrawal.63,66,93,205 The dose of benzodiazepine should be titrated rapidly intravenously until the patient is calm. In our clinical experience, cumulative benzodiazepine dosages required in the initial 30 minutes to achieve adequate sedation frequently exceeds 100 mg of diazepam or its equivalent. Antipsychotics, particularly potent dopamine antagonists such as haloperidol and droperidol, are frequently recommended by others for amphetamine-induced delirium. Antipsychotics may actually antagonize some of the effects of amphetamines via dopamine blockade.63,64,76 In animal models, haloperidol may be P.1125 superior to diazepam in preventing mortality from amphetamine toxicity.34,59,63,64 In clinical experience, however, the benzodiazepines appear to be as efficacious as the antipsychotics in the management of amphetamine toxicity.66 Antipsychotics may lower the seizure threshold, alter temperature regulation, may cause acute dystonia and cardiac dysrhythmias, and do not interact with the benzodiazepine–γ-aminobutyric acid (GABA)–chloride channel receptor complex. All of these effects may worsen the clinical outcomes related to occult or concomitant cocaine toxicity and ethanol withdrawal.93,98,205 Rhabdomyolysis from amphetamine toxicity usually results from agitation and hyperthermia. 82,143 Sedation prevents further muscle

contraction and heat production. External cooling should be instituted for significant hyperthermia. Adequate IV hydration and cardiovascular support should maintain urine output of 1–2 mL/kg/h. Although urinary acidification can significantly increase the elimination and decrease the half-lives of amphetamine and methamphetamine,11,13,14,58 this pH manipulation does not decrease toxicity, and, in fact, may increase the risk of renal compromise and acute tubular necrosis from rhabdomyolysis by precipitating ferrihemate in the renal tubules.54 Patients with acute renal failure, acidemia, and hyperkalemia will likely require urgent hemodialysis. Amphetamine body packers should transport cocaine (Chap. 74). Any suggesting leakage of the packets Fluids, benzodiazepines, intubation,

be treated similarly to those who sympathomimetic symptom requires surgical intervention.270 and external cooling may be

necessary to stabilize these patients.

Individual

Xenobiotics

Methamphetamine Methamphetamine abuse in the United States is not new. From the 1950s to the 1970s, there were multiple epidemics of methamphetamine abuse.17 Methamphetamine was and sometimes still is referred to as “crack,― “speed,― “yaba,― and “go.― The pharmacologic profile of methamphetamine is quite similar to amphetamine, although the effects on the central nervous system are more substantial.42 “Ice,― the common name for methamphetamine in the 1990s because of the crystal forms, does not differ pharmacologically from other forms of methamphetamine. Methamphetamine is readily absorbed by the oral, parenteral, and inhalational routes. Because of a prolonged half-life of 19–34 hours, the duration of its acute effects can be greater than 24 hours.42,65,66

Since the 1990s, the activity and purity of methamphetamine available on the street is substantially higher than previous epidemics because of the method of synthesis.160 Methamphetamine is now typically greater than 80–90% pure and almost exclusively in the dextroisomer form, which is most active on the CNS. Methamphetamine is easily synthesized with the proper chemicals and minimal equipment.84 The primary ingredient of methamphetamine synthesis is ephedrine, which can be hydrogenated into methamphetamine. The ephedrine method, using pharmaceutical grade L-ephedrine, produces a product with few contaminants that is stereochemically pure.65,214 The production of the large crystal is possible by creating a supersaturated solution of methamphetamine hydrochloride.65 Nonprescription sales of ephedrine are now restricted and monitored in many states.265 Phenyl-2-propanone (P2P), as an alternative ingredient, can be methylated into ephedrine and then into methamphetamine.28 Because of the strict control of ephedrine and P2P, illicit chemists use phenylacetic acid to synthesize P2P.28,56 Lead acetate, which is used as a substrate for the reaction, resulted in an epidemic of lead poisoning associated with methamphetamine abuse in Oregon.3,40 Lead levels reported in drug users were as high as 513 µg/dL, and some samples of illicitly manufactured methamphetamine had lead contents as high as 60% by weight.40 Mercury contamination was also documented, although clinical mercury toxicity has not been reported.26 The number of potential chemicals involved in the methamphetamine manufacturing process is significant, and without any legal monitoring, contamination of the product and the environment is inevitable.4,28,127,154 In fact, 20–30% of the illicit methamphetamine manufacturing sites discovered were discovered because of laboratory explosion.78,125 In California's San Bernardino County alone in 1995, 360 methamphetamine laboratories were identified and closed by drug enforcement agents.78 These makeshift methamphetamine laboratories pose a significant health risk to law enforcement officers and the general public, causing respiratory and

eye irritation, headaches, and burns.35 Currently, sale of other potential amphetamine synthesis ingredients, such as hydrochloric acid, hydrogen chloride gas, anhydrous ammonia, red phosphorus, and iodine, are also monitored and restricted in the United States.28,36,265

3,4-Methylenedioxymethamphetamine MDMA was first synthesized in 1912, and was rediscovered in 1965 by Shulgin.26 It is currently one of the most widely abused amphetamines by college students and teenagers. 47,208,272,276 It is commonly known as “ecstasy,― “E,― “Adam,― “XTC,― “M&M,― and “MDM.― Other structural relatives of MDMA, MDEA (“Eve―) and MDA (“love drug―), are also used or distributed as MDMA in areas of MDMA use. These xenobiotics have similar clinical effects and acute and chronic toxicity. Recently, other MDMA-related substances are also found in “rave― scenes, 2CB, 2,4-dimethoxy-4-(n)propylthiophenylethylamine (2C-T7), and N-methyl-1-(3,4methylenedioxyphenyl)-2-butanamine (MBDB).33,75,88,146 The term, “ecstasy― may be used for all of these substances. Typically, MDMA is available in colorful and branded tablets that vary from 50 mg to 200 mg. MDMA and similar analogs are so-call entactogens (meaning touching within), capable of producing euphoria, inner peace, and a desire to socialize.177,255 In addition, some psychologists used MDMA to enhance psychotherapy until the Controlled Substances Act of 1986.195 People who use MDMA report that it enhances pleasure, heightens sexuality, and expands consciousness without the loss of control.26,100,177 Negative effects reported with acute use included ataxia, restlessness, confusion, poor concentration, and memory problem.255 MDMA has about onetenth the CNS stimulant effect of amphetamine. Unlike amphetamine and methamphetamine, MDMA is a potent stimulus for the release of serotonin.30,60,102 The concentration of MDMA required to stimulate the release of serotonin is 10 times less than that required for the

release of dopamine or norepinephrine. In animal models, the stereotypic and the discriminatory effects of MDMA and its congeners can be distinguished from those of other amphetamines.31,195 The sympathetic effects of MDMA are mild in low doses. However, when a large amount of MDMA is taken, the clinical presentation is similar to that of other amphetamines and deaths can result from abuse.70,116,117,191,276 Those patients at greatest risk develop dysrhythmias, hyperthermia, rhabdomyolysis, and disseminated P.1126 intravascular coagulation.70,117,250 Significant hyponatremia has been well reported with MDMA use.2,113,173,197 MDMA and its metabolites increase the release of vasopressin (antidiuretic hormone) and may be related their serotonergic effects.77,115 Furthermore, large free-water intake combined with sodium loss from physical exertion (in dance clubs) may be crucial to the development of

hyponatremia.

A major concern with MDMA usage brain. In numerous animal models, leads to the decrease in serotonin function and numbers. Recovery in weeks. Repetitive administration of

is its long-term effects on the acute administration of MDMA reuptake transporter (SERT) SERT function may take several MDMA ultimately leads to

permanent damage to serotonergic neurons, typically causing injury to the axons and the terminals while sparing the cell bodies. 174,178,180,201,220,222 Some regeneration of synaptic terminals can occur even with neuronal damage, but functional recovery is not complete. Intact SERT function is necessary for MDMA-induced neurotoxicity. Xenobiotics that inhibit the uptake of serotonin prevent MDMA-induced neurotoxicity in animals. Animal data suggest that MDMA induces hydroxyl free-radical generation and decreases antioxidants in serotonergic neurons.224,247 MDMA does not directly cause neurotoxicity, but its metabolites 3-α-methyldopamine and Nmethyl-α-methyldopamine do produce neurotoxicity in animals.186 When sufficient antioxidants are depleted, neuronal damage may occur.

The evidence for these potential neurotoxic effects in humans is less clear. Indirect evidence of serotonergic effects in humans includes lower concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebral spinal fluid (CSF) of MDMA users than in controls.221 Case reports and studies of MDMA users demonstrate alteration in mood, sleep, anxiety, cognition, memory, and impulse control—all functions that are believed to be affected by serotonin.5,176,179,181,185 Either single-photon emission tomography (SPECT) or positron emission tomography (PET) demonstrates decreased SERT function in MDMA users, even after prolonged abstinence.27,202,218 Memory deficits appeared to persist even in abstinent MDMA users.96,190 A major deficit in human studies is finding comparable control groups; it is possible that people with psychiatric problems are more likely to be MDMA users.182 MDMA users are also associated with other drug use. Currently, there are no human histopathologic (postmortem) data for MDMA users. 147 Further studies are required to address the long-term neuropsychiatric effects of MDMA.

Propylhexedrine

Smith, Kline, and French introduced propylhexedrine in 1949 as the primary active ingredient in Benzedrex nasal inhaler, to replace amphetamine in nasal inhalers because of the widespread abuse.7,82 Propylhexedrine is an alicyclic aliphatic sympathomimetic amine that is structurally similar to amphetamine, with a local vasoconstrictive

Figure. No Caption Available.

Smith, Kline, and French introduced propylhexedrine in 1949 as the primary active ingredient in Benzedrex nasal inhaler, to replace amphetamine in nasal inhalers because of the widespread abuse.7,82 Propylhexedrine is an alicyclic aliphatic sympathomimetic amine that is structurally similar to amphetamine, with a local vasoconstrictive effect and approximately 10% of the CNS stimulatory effect of amphetamine.7 Propylhexedrine abuse became prevalent after the removal of amphetamine from nasal inhalers. The abusers disassembled the inhaler and ingested the cotton pledget vehicle of propylhexedrine itself, diluted it in beverages, or reconstituted the drug for intravenous injection. Numerous effects were reported with propylhexedrine abuse, including sudden death, myocardial infarction, cardiomyopathy, pulmonary hypertension, and acute psychosis.6,7,53,68,82,161,169,170,274 Although propylhexedrine in nasal inhalers has largely been replaced by safer sympathomimetic agents (Chap. 50), the drug is still readily available and is abused as an inexpensive, legal “high.―

Khat,

Cathinone,

and

Methcathinone

Khat (also known as quat and gat), the fresh leaves and stems from the Catha edulis shrub, is a commonly used drug in eastern and central Africa, and in parts of the Arabian peninsula. Attention to khat was highlighted in the early 1990s by the media coverage of war in Somalia and Ethiopia. Khat is sold in small bundles of leaves in the local markets of these countries. The leaves and the tender stems are chewed or occasionally concocted into tea. Khat chewing has a significant role at social gatherings in these countries.168 There is a trend of increasing khat consumption and binges among adolescents in these countries.203 When the dried leaves and stems were studied, the primary active ingredient was thought to be

cathine (norpseudoephedrine), present as 0.1–0.2% of the dried material. Cathine has about one-tenth the stimulant effects of Damphetamine. Numerous other amphetaminelike compounds are also isolated, but occur in minute quantities.136 When the fresh leaves are analyzed, however, cathinone (benzylketoamphetamine), a more potent psychoactive compound, was demonstrated to be the primary active agent.89,105,136 As the leaves age, cathinone is degraded into cathine, which also explains why dried khat is neither popular nor widely distributed. Imported fresh khat must be consumed within a week, before it loses much of its potency. The primary effects of khat are increased alertness, insomnia, euphoria, anxiety, and hyperactivity. Increased khat consumption is linked to psychosis. Significant adrenergic complications are much less frequent than those associated with amphetamine abuse. Methcathinone, the methyl derivative of cathinone, chemically synthesized from ephedrine, has been abused in Russsia and other former members of the Soviet Union for many years. The potency of methcathinone is comparable to that of methamphetamine.90,280 Methcathinone—also termed ephedrone, or sold under the street names of “cat― or “Jeff―—currently remains widely abused in Russia. Methcathinone abuse was first reported in Michigan in the early 1990s and is now reported in other states as well.74

Ephedrine

or

Ma-Huang

Herbal

Products

Figure. No Caption Available.

Ephedrine is commonly found in nonprescription cold preparations. Ephedrine is also the active substance in the Chinese plant mahuang, which has been used for centuries for the treatment of asthma. Although ephedrine is much less potent than amphetamine, when combined with other catecholamine-stimulating xenobiotics or when taken in large quantities, significant toxicity may occur.25,32,209,240 In the United States, numerous ephedrine products, such as “go,― “ultimate xphoria,― “up your gas,― and “herbal ecstasy,― are marketed primarily to teenagers. Some of these products P.1127 contain more than 500 mg of ephedrine, which may be combined with pseudoephedrine, phenylpropanolamine, and caffeine; other products contain the plant extract ma-huang.159,209,211 Many of these products are marketed as legal stimulants or safe herbal stimulants for a natural “high.― Similarly, ma-huang is also widely marketed as a “safe― herbal weight-reducing product. Sales appeared to increase when it was recognized that phenylpropanolamine was associated with brain hemorrhage in women.144 Unfortunately, these products are linked to numerous

deaths and adverse reactions.107,108,192,211,264,277,282 Because these products are sold as food supplements, they are not regulated by the FDA unless a product can be demonstrated to be unsafe (Chap. 43). In 2004, the FDA finally banned the use of ephedra products. In April 2005, a federal judge in Utah reversed the ban of ephedra sales in Utah, illustrating the difficulty of the FDA in the regulation of herbal products.111 Herbal products with Citrus aurantium (bitter orange), contain a number of adrenergic amines, including synephrine, have now supplanted ephedra products. Citrus aurantium has similar pharmacologic effects and toxicity as ephedra.20,198

Summary Amphetamine usage is increasing dramatically throughout the United States. Similarly, ED visits and morbidity and mortality related to amphetamines parallel amphetamine usage. Many of these complications are similar to those of cocaine, such as agitation, hyperthermia, rhabdomyolysis, myocardial ischemia, and cerebral infarction. Physicians, more than ever, must understand the pathophysiology of amphetamines and be ready to diagnosis and treat its toxicity. The chronic effects of amphetamines as demonstrated in animal models pose serious concerns for humans, particularly as amphetamine usage becomes more prevalent; further studies are required to achieve prevention and management.

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use. Acad Emerg Med 1998;5:839–840. 3. Allcott JV, Barnhart RA, Mooney LA: Acute lead poisoning in two users of illicit methamphetamine. JAMA 1987;258:510–511. 4. Allen A, Cantrell T: Synthetic reductions in clandestine amphetamine and methamphetamine labs. J Forensic Sci 1989;42:183–199. 5. Allen RP, McCann UD, Ricaurte GA: Persistent effects of (+)3,4-methylenedioxymethamphetamine (MDMA, “ecstasy―) on human sleep. Sleep 1993;16:560–564. 6. Anderson RJ, Garza HR, Garriott JC, et al: Intravenous propylhexedrine abuse and sudden death. Am J Med 1979;67:15–20. 7. Anderson RJ, Reed WG, Hillis LD: History, epidemiology, and medical complications of nasal inhaler abuse. Clin Toxicol 1982;19:95–107. 8. Angrist B: Amphetamine psychosis: Clinical variation of the syndrome. In: Cho AK, Segal DS, eds: Amphetamines and Its Analogs. Psychopharmacology, Toxicity, and Abuse. San Diego, CA, Academic Press, 1994, pp. 387–414. 9. Baggott M, Heifets B, Jones RT, et al: Chemical analysis of ecstasy pills. JAMA 2000;284:2190. 10. Bailey DN, Shaw RF: Cocaine and methamphetamine-related deaths in San Diego County (1987): Homicides and accidental overdoses. J Forensic Sci 1989;34:407–422.

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cerebral

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 74 - Cocaine

Chapter

74

Cocaine Robert S. Hoffman

Figure. No Caption Available.

A 54-year-old man called 911 because of chest discomfort that had begun about 4 hours earlier. The patient had a history of cigarette smoking, daily cocaine use, and a questionable history of hypertension. He stated that shortly following the use of 1 g of cocaine, he developed midsternal chest pressure that radiated to the back, was worse with exertion, and was associated with nausea and three episodes of vomiting. When emergency medical services (EMS) technicians arrived they gave him oxygen, 162 mg of aspirin, and sublingual nitroglycerin spray. The pain resolved by

the time he arrived to the hospital. On arrival at the hospital the patient was alert and in no distress and his vital signs were as follows: blood pressure, 145/95 mm Hg; pulse, 114 beats/min; respirations, 20 breaths/min; temperature, 96.8°F (37°C). His oxygen saturation while breathing room air was 97% by pulse oximetry, and a rapid reagent glucose test was normal. Physical examination was remarkable for normal pupils, the absence of diaphoresis, normal chest auscultation, and normal heart sounds. The patient was neurologically and cognitively intact. The patient was attached to a continuous cardiac monitor, given high flow oxygen, an ECG was obtained (Fig. 74-1 ), and a chest radiograph was ordered. An intravenous line was inserted and blood samples were obtained and sent for electrolytes, glucose, cardiac enzymes, and a complete blood count analysis. Additionally, about 1 hour after arrival, 10 mg of diazepam was given IV for continued tachycardia. Following that, his repeat vital signs were: blood pressure, 141/93 mm Hg; pulse, 115 beats/min. Another 5 mg of diazepam was administered IV but resulted in no change in the patient's vital signs. The chest radiograph was unremarkable. Approximately 2 hours after admission to the emergency department, the troponin I was reported as positive at 1.5 ng/mL and the patient was given 325 mg of aspirin and an intravenous loading dose of heparin, followed by a continuous heparin infusion. Two doses of metoprolol (2.5 mg each) were administered IV 10 minutes apart, for persistent tachycardia. Within 10 minutes of the second dose the patient complained of severe crushing substernal chest pain, and became diaphoretic and nauseated. Shortly thereafter his systolic blood pressure dropped to 50 mm Hg. The patient was intubated and resuscitative attempts included administration of atropine, epinephrine, vasopressin, and glucagon. A bedside ultrasonogram showed global akinesis of the

heart and the patient died about 3 hours after presentation. After review of the case an adverse drug event report was filed with the hospital's drug safety committee citing a probable interaction between cocaine and metoprolol.

History

and

Epidemiology

Cocaine is a natural alkaloid contained in the leaves of Erythroxylum coca , a shrub that grows abundantly in Columbia, Peru, Bolivia, the West Indies, and Indonesia. As early as the 6th century the inhabitants of Peru chewed or sucked on the leaves for social and religious reasons. In the 1100s, the Incas used cocainefilled saliva as local anesthesia for ritual trephinations of the skull.69 In 1859, Albert Niemann isolated cocaine as the active ingredient of the plant. By 1879 Vassili von Anrep demonstrated that cocaine could numb the tongue.114 However, Europeans knew little P.1134 about cocaine until 1884, when the Austrian ophthalmologist Karl Koller introduced cocaine as an effective local anesthetic for eye surgery and Koller's colleague, Sigmund Freud, wrote extensively on the psychoactive properties of cocaine.57 Following these revelations, Merck, Europe's main cocaine producer increased production from less than 0.75 pounds in 1883 to more than 150,000 pounds in 1886.109

Figure 74-1. The ECG from the 54-year old man with cocaineassociated chest pain described in the case. The ECG shows 1–2 mm elevations of the ST segments in the anterior leads (V2 , V3 ).

Nearly simultaneously, reports of complications resulting from the therapeutic use of cocaine began to appear. In 1886, a 25-yearold man had a “pulseless― syncopal event after cocaine was applied to his eye to remove a foreign body.220 By 1887 more than 30 cases of severe toxicity were reported,189 and by 1895 at least 8 fatalities resulting from a variety of doses and routes of administration were summarized in one article.59 Recreational cocaine use was legal in the United States until 1914, when it was restricted to medical professionals. It was not until 1982, however, that the first cocaine-associated myocardial infarction was reported in the United States.28 Today, cocaine remains an approved pharmaceutical, primarily used either for topical anesthesia of cutaneous lacerations or as both a vasoconstrictor and topical anesthetic for otolaryngology procedures. Multiple factors, including severe complications despite the use of approved doses, complicated regulatory standards for storage, record keeping requirements, and comparable available alternatives have fostered a decline in the medicinal use of cocaine.19 , 65 , 135 Unfortunately, the recreational use of cocaine remains a significant problem. Although drug use statistics are always questionable, recent estimates suggest that almost 34 million Americans have used cocaine at least once, with just over 2 million being current regular users.41

Pharmacology The alkaloidal form of cocaine (benzoylmethylecgonine) is extracted from the leaf by mechanical degradation in presence of a hydrocarbon. The resultant product is converted into a hydrochloride salt and extracted into an aqueous phase, which is

subsequently evaporated to yield a white powder (cocaine hydrochloride). Cocaine hydrochloride can be insufflated or applied to other mucous membranes, dissolved in water and injected, or ingested, but it rapidly degrades during pyrolysis. Smokeable cocaine (crack) is formed by dissolving cocaine hydrochloride in water and adding a strong base. A hydrocarbon solvent is added, the cocaine base is extracted into the organic phase, and then evaporated. The term free-base refers to the use of cocaine base in solution. Typically a tobacco or marijuana cigarette is dipped into the free-base solution and allowed to dry prior to smoking. Cocaine is rapidly absorbed following all routes of exposure; however, when applied to a mucous membrane or ingested its vasoconstrictive properties slow the rate of absorption and delay the peak effect. Whereas bioavailability exceeds 90% with intravenous and smoked cocaine, it is only approximately 80% following nasal application.105 Data for ingested cocaine and application to other mucus membranes such as the urethra, vagina, or rectum are inadequately documented. Table 74-1 lists the typical onsets and durations of action for various uses of cocaine. Following absorption cocaine is approximately 90% bound to plasma proteins. Although binding to both albumin and α1 -acid glycoprotein are reported, it appears that albumin binding is less important.174 Based on human volunteer studies, the volume of distribution is reported to be about 2.7 L/kg.105 It is unclear if the volume of distribution changes with overdose. Peak levels were determined in nonnaive human volunteers by administering intravenous, nasal, or smoked doses that were selected to produce approximately the same subjective peak effects.105 The resultant peak levels were as follows: after intravenous injection of 20.5 mg, 180 ± 56 ng/mL; after nasal administration of 95 mg, 220 ± 39 ng/mL; and after smoking of 40 mg, 203 ± 88 ng/mL. In this same study, the terminal

elimination half-life of cocaine was on the order of 1 hour. Intravenous 90%) eliminated by the liver via enzymatic oxidation, with 5–10% excreted unchanged by the kidneys, lungs, and sweat. Ethanol is metabolized via at least three different pathways: the aforementioned alcohol dehydrogenase (ADH) pathway, located in the cytosol of the hepatocytes; the MEOS (CYP2E1), located on the endoplasmic reticulum; and the peroxidase–catalase system, associated with the hepatic peroxisomes (Fig. 75-1.).137 The ADH system is both the main pathway for ethanol metabolism in the body and is the rate-limiting step. ADH is a zinc metalloenzyme that uses oxidized nicotinamide adenine dinucleotide (NAD+) as a hydrogen ion acceptor to oxidize ethanol to acetaldehyde. In this process, a hydrogen ion is transferred from ethanol to NAD+ , converting it to its reduced form, NADH. Subsequently, a hydrogen ion is transferred from acetaldehyde to NAD+ . Under normal conditions acetate is converted to acetylcoenzyme A (acetyl-CoA), which enters the Krebs cycle and is metabolized to carbon dioxide

and water. The entry of acetyl-CoA into the Krebs cycle is dependent on thiamine (Antidotes in Depth: Thiamine Hydrochloride) . The MEOS (CYP2E1) is responsible for very little ethanol metabolism in the uninitiated drinker, but becomes more important as the ethanol concentration rises or as ethanol use becomes chronic (Fig. 75-1.). CYP2E1 uses oxidized nicotinamide adenine dinucleotide phosphate (NADP+) as an electron acceptor to oxidize ethanol to acetaldehyde.95 In this process, electrons are transferred from ethanol to NADP+ , converting it to its reduced form, NADPH. Subsequently, acetaldehyde is further oxidized to acetate, as a hydrogen ion is transferred from acetaldehyde to NADP+ . Ethanol's ability to induce the MEOS forms the basis for the well-established interactions between ethanol and a host of other xenobiotics metabolized by this system. 36,52

Figure 75-1. Ethanol oxidation. The major, minor, and inducible pathways used for ethanol metabolism.

ADH is saturated at relatively low blood ethanol concentrations. As the system is saturated, ethanol elimination changes from first-order to zero-order kinetics (Chap. 9). In adults, the average rate of ethanol metabolism is 100–125 mg/kg/h in occasional drinkers and up to 175 mg/kg/h in habitual drinkers.17,63 As a result, the average-sized adult metabolizes 7–10 g/h and the blood ethanol concentration falls 15–20 mg/dL/h (3.26–4.35 mmol/L/h). Tolerant drinkers, by recruiting CYP2E1, may increase their clearance of ethanol to 30 mg/dL/h (6.52 mmol/L/h).17,63 Studies of ethanolintoxicated patients indicate that although the average ethanol clearance rate is about 20 mg/dL/h (4.35 mmol/L/h), there is considerable individual variation (standard deviation of about 6 mg/dL/h [1.30 mmol/L/h]).17,63

Xenobiotic

Interactions

Ethanol interacts with a variety of xenobiotics (Table 75-2.).186 The most frequent interactions occur as a result of an ethanol-induced increase in hepatic xenobiotic-metabolizing enzyme activity. In contrast, acute ethanol use may inhibit metabolism of other xenobiotics, which may be a result of decreased hepatic enzyme activity or blood flow. The interaction between ethanol and disulfiram (Antabuse) is well described, and it can be life-threatening (Chap. 7 7) . Acute intoxication with ethanol can transiently prolong the elimination of certain xenobiotics, such as phenytoin, because of competition for shared metabolic pathways; an increase in the MEOS (CYP2E1) with chronic ethanol ingestion leads to accelerated metabolism and shortens the half-lives of drugs such as phenytoin, methadone, isoniazid, and warfarin.83 Ethanol has additive sedative effects when ingested with antihistamines, cyclic antidepressants, phenothiazines, opioids, and other sedative-hypnotics such as benzodiazepines, barbiturates,

P.1151 glutethimide, and chloral hydrate (“Mickey Finn―). Ethanol also potentiates the pharmacologic effects of vasodilators and oral hypoglycemic agents, and may enhance the antiplatelet action of aspirin.

TABLE

75-2.

Ethanol

Xenobiotic

Xenobiotics Antihistamines

(H1 )

Interactions

Adverse Enhanced

CNS

depression

Carbamates

Disulfiramlike

effect

Cephalosporinsa

Disulfiramlike

effect

Chloral

Enhanced

hydrate

CNS

Effects

depression

Chloramphenicol

Disulfiramlike

effect

Chlorpropamide

Disulfiramlike

effect

Cocaine

Formation

cocaethylene

Coprinus mushrooms

Disulfiramlike

Disulfiram (Antabuse)

Nausea, vomiting, abdominal pain, flushing, diaphoresis, chest pain, headache, vertigo, palpitations

of

effect

Griseofulvin

Disulfiramlike

effect

Heroin

Enhanced

CNS

Isoniazid

Increased increased

incidence of hepatitis; metabolismb

Methadone

Increased

methadone

Metronidazole

Disulfiramlike

effect

Nitrofurantoin

Disulfiramlike

effect

Phenytoin

Increased

phenytoin

Ranitidine,

Increased

ethanol

Sedative–hypnotics

Enhanced

CNS

Thiram

Disulfiramlike

depression

metabolismb

metabolism

concentration

cimetidine

derivatives

Warfarin a Those b Effect

Increased

depression

effect

warfarin

metabolismb

containing a N-methylthiotetrazole side chain. possibly associated with chronic alcohol consumption.

Concomitant use of cocaine and ethanol leads to the formation of an active metabolite, cocaethylene, through transesterification of

cocaine by the liver.152 Cocaethylene has a longer half-life than cocaine itself (2 hours vs. 48 minutes), which might explain some of the delayed cardiovascular effects attributed to cocaine use.7,193 Both ethanol and cocaethylene inhibit the metabolism of cocaine, thereby prolonging the elimination of cocaine and enhancing its effect (Chap. 74) .143 Case reports and retrospective case series suggest that chronic ethanol consumption may predispose a person to acetaminophen (APAP) hepatotoxicity (Chap. 34) 42,113,119,158,202 even when APAP has been taken according to the manufacturer's recommended dosage of not more than 4 g daily.201 Because ethanol induces cytochrome P450, the enzyme involved in the metabolism of acetaminophen to its hepatotoxic intermediate, N-acetyl-pbenzoquinoneimine (NAPQI), a theoretical basis for this association exists. However, in a double-blind placebo-controlled study, where confirmed alcoholics were given acetaminophen 4 g daily or placebo for 3 consecutive days, there were no differences between the two groups with regard to liver enzymes or to coagulation profiles. 94 Recent fasting, common in alcoholics, was also associated with a predisposition to acetaminophen hepatotoxicity, likely as a consequence of depletion of glutathione (Chap. 34) .191 However, in a retrospective study, heavy drinkers did not develop more severe hepatoxicity following APAP overdose when compared to nondrinkers.114

Pathophysiology Ethanol affects practically every organ system in the body (Table 753); the relationships between ethanol use, nutrition, and liver disease are reviewed elsewhere.105 In addition to the harmful effects of ethanol itself (eg, impairment of protein synthesis), its metabolite, acetaldehyde, is inherently toxic to biologic systems.100,107,182,200 Acetaldehyde directly impairs cardiac contractile function, disrupts cardiac excitation–contractile coupling, inhibits myocardial protein

synthesis, interferes with phosphorylation, causes structural and functional alterations in mitochondria and hepatocytes, and inactivates coenzyme A. Acetaldehyde can also react with intracellular proteins to generate adducts. Acetaldehyde adducts are believed to play an important role in the early phase of alcoholic liver disease, and in advanced liver disease they contribute to the development of hepatic fibrosis. Ethanol metabolism through the hepatic CYP2E1 pathway generates highly reactive oxygen radicals, including the hydroxyethyl radical (HER) molecule. Elevated oxygen radical levels generate a state of oxidative stress, which leads to cell damage. Oxygen radicals can also initiate lipid peroxidation, resulting in reactive molecules such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE). These reactive molecules react with proteins or acetaldehyde to form adducts, which contribute to the development of alcoholic liver injury. Oxidation of ethanol generates an excess of reducing potential in the cytosol in the form of NADH, with the ratio of NADH to NAD+ being dramatically increased. This ratio, also known as the redox potential, determines the ability of the cell to carry on various oxidative processes. The unfavorable change in redox potential as a consequence of ethanol metabolism contributes to the development of metabolic disorders (eg, impaired gluconeogenesis, alterations in fatty acid metabolism, fatty liver, hyperlipidemia, hypoglycemia, lactic acidemia, hyperuricemia [gouty attacks]), increased collagen and scar tissue formation associated with alcoholism, and a clinical syndrome of alcoholic ketoacidosis. Recent studies in alcoholic liver disease have focused on Kupffer cell activation by endotoxin that is released by intestinal bacteria. When Kupffer cells are activated, they produce regulatory nuclear factorkappa B (NF-δB) and generate significant amounts of superoxide radicals (O2 - ) and cytokines (tumor necrosis factor and interleukin8), which are an essential factor in the injury to hepatocytes

associated with alcoholic liver disease.118,190

Clinical

Features

Ethanol is a selective CNS depressant at low doses and a general depressant at high doses. Initially, it depresses those areas of the brain involved with highly integrated functions. Cortical release leads to animated behavior and the loss of restraint. This paradoxical CNS stimulation is caused by disinhibition. In cases of mild intoxication, the signs of ethanol inebriation are quite variable. The patient may be energized and loquacious, expansive, emotionally labile, and increasingly gregarious, or may appear to have lost self-control, exhibit antisocial behavior, and be ill-tempered. As the degree of intoxication increases, there is successive inhibition and impairment of neuronal activity. The patient may become irritable, abusive, aggressive, violent, dysarthric, confused, disoriented, or lethargic. With severe intoxication, there is loss of airway protective reflexes, coma, and increasing risk of death from respiratory depression. An ethanol-naive adult with a blood ethanol concentration >250 mg/dL (54.35 mmol/L) is usually comatose.1 The acute effects of ethanol ingestion also depend on the habituation of the drinker. This is mainly a result of the development of P.1152 tolerance, which has both a metabolic (pharmacokinetic) and a functional (pharmacodynamic) component.169 Metabolic tolerance to ethanol is based on enhanced elimination by the ADH enzyme and CYP2E1 system. Functional tolerance (resistance to the effects of ethanol at the cellular level) is a more important determinant of habituation and may be mediated through alterations in serotonergic and adrenergic neurons.88,89,168 Acute alcohol tolerance may be demonstrated by the Mellanby effect, which involves the comparison of physiologic responses or behavioral effects at the same blood ethanol concentration on the ascending and descending limbs of the blood ethanol curve. Impairment is greater at a given blood ethanol

concentration when the blood ethanol concentration is increasing, than for the same blood ethanol concentration when the blood ethanol concentration is falling.136,185 Although individuals who are acutely intoxicated move through a progressive sequence of events, the association of a particular aspect of intoxication with a specific blood ethanol concentration is not usually possible without knowing the pattern of ethanol use of the patient. Acute ethanol intoxication occurs in habitual drinkers when they raise their ethanol concentration an equivalent amount above baseline, and specific clinical manifestations of inebriation typically occur in habitual drinkers at a significantly higher blood ethanol concentration than in nontolerant individuals. Regardless, the absolute change above baseline may be important.

TABLE 75-3. Systemic Effects Associated with Alcoholism

Cardiovascular Cardiomyopathy “Holiday heart― (dysrhythmias) “Wet― beriberi (thiamine deficiency) Endocrine and metabolic Hypoglycemia Hypophosphatemia Hypokalemia Hypomagnesemia Hypothermia Hypertriglyceridemia Hyperuricemia Metabolic acidosis Malnutrition Gastrointestinal Mouth Cancer of the mouth, pharynx, larynx

Cheilosis Nutritional stomatitis Esophagus Boerhaave syndrome Cancer of the esophagus Diffuse esophageal spasm Esophagitis Mallory-Weiss tear Stomach and duodenum Gastritis Chronic hypertrophic gastritis Diarrhea Hematemesis Malabsorption Peptic ulcer Liver Steatosis Hepatitis Cirrhosis Pancreas Pancreatitis (acute Genitourinary Hypogonadism

or

chronic)

Impotence Infertility Hematologic Coagulopathy Folate, B12, iron-deficiency anemias Hemolysis (Zieve syndrome, stomatocytosis, anemia) Leukopenia Thrombocytopenia Neurologic Alcohol amnestic syndrome

spur-cell

Alcoholic hallucinosis Alcohol withdrawl Central pontine myelinolysis Cerebral atrophy (dementia) Cerebellar degeneration CVA (SAH, infarction) Wernicke encephalopathy Korsakoff psychosis Intoxication Marchiafava-Bignami disease Myopathy Polyneuropathy Pellagra Ophthalmic Tobacco–ethanol amblyopia Psychiatric Animated behavior Loss of self-restraint Manic-depressive illness Suicide and Respiratory Atelectasis Pneumonia

depression

Respiratory Respiratory

depression acidosis

A patient may present with obvious signs and symptoms consistent with ethanol intoxication that include flushed facies, diaphoresis, tachycardia, hypotension, hypothermia, hypoventilation, mydriasis, nystagmus, vomiting, dysarthria, muscular incoordination, ataxia, altered consciousness, and coma. However, an ethanol-intoxicated patient may present to the ED with a broad range of diagnostic possibilities and should prompt the physician to carefully evaluate the patient for a variety of covert clinical and metabolic disorders. A

meticulous and systematic approach to the evaluation and management of an inebriated patient will help the clinician avoid potential pitfalls in such a situation.56 The presence or absence of an odor of ethanol on the breath is an unreliable means of ascertaining whether a person is intoxicated or whether ethanol was recently consumed.130 Diplopia, visual disturbances, and nystagmus may be evident, which may be caused by the toxic effects of ethanol or may represent Wernicke encephalopathy. Hypothermia may be exacerbated by environmental exposure, from malnutrition and loss of carbohydrate or energy substrate, and from ethanol-induced vasodilation. Ethanol intoxication can impair cardiac output in patients with preexisting cardiac disease.66 Dysrhythmias, such as atrial fibrillation and nonsustained ventricular tachycardia, as well as atrioventricular block, are documented in binge drinkers.40,67,68 The association between ethanol use and cardiac dysrhythmias, particularly supraventricular tachydysrhythmias in apparently healthy people, is called “holiday heart syndrome.―90,96,121 The syndrome was first described in people with heavy ethanol consumption, who typically presented on weekends or after holidays, and it may also occur in patients who binge, but who usually drink little ethanol. The most common dysrhythmia is atrial fibrillation, which usually reverts to normal sinus rhythm within 24 hours. Although the syndrome may recur, the clinical course is benign in patients without anatomic cardiac pathology, and specific antidysrhythmic therapy is usually not warranted.54,68 P.1153 Acute heavy ethanol drinking may precipitate silent myocardial ischemia in patients with stable angina pectoris.155 Variant angina is reported to occur in patients following ethanol ingestion at a time when the blood ethanol concentration has decreased almost to zero.49,82,116,124,141,156,172 Acute altered mental status in an alcoholic patient can be the result of a variety of causes, including acute ethanol or toxic ethanol intoxication; hypoglycemia; therapeutic or illicit drug overdose; Wernicke-Korsakoff syndrome;

head trauma; a postictal condition; infection; an intracranial hematoma (acute or chronic); hepatic encephalopathy; an electrolyte or acid–base disorder; or ethanol withdrawal. Ethanol-induced seizures are reported in adults, but are more frequent in children. Sometimes they are associated with hypoglycemia.28,76 Patients presenting with acute ethanol intoxication commonly have decreased serum ionized magnesium concentrations, although their total serum magnesium concentration is within the normal range. 197 Total body magnesium may be depleted because of poor dietary intake, decreased GI absorption secondary to ethanol, and renal wasting as a consequence of the ethanol-related diuresis.50,81,154,160,167

Diagnostic

Tests

There are numerous qualitative and quantitative assays for ethanol in biologic fluids and exhaled breath. Immunoassay or gas chromatography is commonly used for determination of ethanol in liquid specimens in most hospitals. Hospital laboratory analysis of blood samples for ethanol content is usually based on serum (liquid portion of whole blood after the cellular components and clotting factors are removed), rarely on plasma (acellular liquid portion of whole blood), and forensic ethanol concentration is defined in whole blood. Serum contains slightly more water than does plasma and whole blood, and will have a slightly higher ethanol concentration. The median ratio of serum to whole blood ethanol concentration is 1.15 (range: 0.88–1.59:1)151 and the mean ratio of plasma to whole blood ethanol concentration is 1.10 (range: 1.03–1.24:1).80 As a result, a serum ethanol concentration of 88–159 mg/dL (19.13–34.57 mmol/L) is equivalent to a whole-blood ethanol concentration of 100 mg/dL (21.74–39.75 mmol/L). The excretion of ethanol by the lungs is first order and obeys the Henry law: The ratio between the concentration of ethanol in the alveolar air and the blood is constant. Although the alveolar air-toblood constant is quite low and very little ethanol is excreted by this

route, the fixed relationship forms the basis for the sampling of a person's breath to estimate their blood ethanol concentration. The mean breath-to-blood ratio is 1:2300 during the postabsorptive phase of ethanol kinetics and a ratio of 1:2100 is used in forensic casework.137 There are individual and interindividual variations in the normal blood-to-breath ethanol ratio, and log-transformation of the values is used to calculate means and confidence intervals.69,79,97 Breath ethanol analyzers make use of electrochemical sensors for ethanol oxidation or infrared spectral analysis for ethanol determination.137 They are widely available and are routinely used by law enforcement agencies as ethanol-screening devices. In the ED, they have been shown to accurately predict serum ethanol levels.188 However, the unconscious or uncooperative patient may be unable to comply with the proper use of the breath alcohol analyzer. Breath-ethanol devices adapted with mouth cups and nasal tubes, to sample the breath of unconscious patients, produce results that correlate fairly well with serum ethanol concentrations.46,61 Breathethanol concentration may not always reflect the concentration of ethanol in blood. Potential sources of interference include recent use of ethanol-containing products, belching or vomiting of gastric ethanol contents, inadequate exhalation, obstructive pulmonary disease, mouth ethanol retained in the bridges or periodontal spaces, and poor technique.4,101,177 Multidose inhalers (eg, Tornalate [bitolterol mesylate with 38% ethanol], Bronkometer [isoetharine mesylate with 30% ethanol], Primatene Mist [adrenaline with 34% ethanol], and salbutamol) and mouthwashes (eg, Listerine [26.9% alcohol], Scope [18.9% alcohol], and Lavoris [6.0% alcohol]) may contain significant concentrations of ethanol and can cause elevations of breath ethanol above the legal criteria for intoxication.12,65,110,125 However, these effects are transient and may be prevented by a 10–15-minute interval between the use of multidose inhaler or mouthwash and breath-ethanol testing.65,110,125 Ethanol-saliva testing is a promising alternative to breath ethanol analysis in the rapid assessment of blood ethanol levels in patients,

regardless of their mental status.31,163 Fatty acid ethyl esters (FAEEs) may be a highly sensitive test for recent ethanol use.14,38,164 Because FAEEs remain in the system for at least 24 hours, they may have a role as a marker of recent ethanol use, even after ethanol is completely metabolized. However, their availability is limited and their place in patient management is undefined. Blood tests that should be considered for patients with ethanol intoxication or alcoholic ketoacidosis include CBC, electrolytes, BUN, creatinine, ketones, acetone, lipase, liver enzymes, a prothrombin time, ammonia, calcium, and magnesium. Patients with an anion gap metabolic acidosis should have urine ketones and serum lactate concentration analysis (Chaps. 17 and 103). High serum acetone concentrations may be indicative of isopropanol intoxication, whereas elevated serum or urinary ketones concentrations may be indicative of alcoholic ketoacidosis, starvation Because the laboratory nitroprusside (acetoacetate and acetone) and not for urinary ketones in patients with only mildly positive.

ketosis, or diabetic ketoacidosis. reaction detects only ketones β-hydroxybutyrate, the assay alcoholic ketoacidosis may be

A blood ethanol concentration analysis should be included in the initial laboratory studies.75 If the blood ethanol concentration is inconsistent with the patient's clinical condition, prompt reevaluation of the patient is indicated to elucidate the etiology of the altered mental status, including toxic–metabolic, trauma-related, neurologic, and infectious etiologies. Comatose patients with concentrations below 300 mg/dL (65.22 mmol/L), and those with values in excess of 300 mg/dL (65.22 mmol/L) who fail to improve clinically during a limited period of close observation, should have a head CT scan, followed by a lumbar puncture if warranted. Because chronically ethanol-tolerant patients are prone to trauma and coagulopathies, both of which can cause intracerebral bleeding, the threshold for head CT scanning should be low.

Management

of

the

Intoxicated

Patient

Ethanol is rapidly absorbed from the gastrointestinal tract. In situations where recent ingestion (within 1 hour of presentation), delayed absorption, and concomitant ingestions are under consideration, gastrointestinal decontamination may be considered. Occasionally, the extremely intoxicated or comatose patient may have severe respiratory depression, necessitating endotracheal intubation and ventilatory support. P.1154 Any patient presenting to the ED with an acute altered mental status mandates immediate investigation and treatment of reversible etiologies such as hypoxia, hypoglycemia, and opioid intoxication. In addition, Wernicke encephalopathy should be considered. Supplemental oxygen should be administered if the patient is hypoxic; intravenous dextrose (0.5–1.0 g/kg), thiamine 100 mg, and naloxone should be administered as clinically indicated. Abnormal vital signs should be addressed and stabilized. Patients who are combative and violent should be both physically and then chemically restrained with a benzodiazepine. Caution should be taken because of additive effects of ethanol and benzodiazepine on respiratory depression. Attempts by those who are clinically intoxicated to sign out against medical advice, or attempt to leave, should also be prevented (Chap. 135). The patient's fluid and electrolyte status should be assessed and abnormalities corrected. Multivitamins with folate, thiamine, and magnesium may be added to the maintenance IV solution. A variety of techniques and xenobiotics have been advocated, either to reverse the intoxicating effects of ethanol or to enhance its elimination. Neither coffee nor caffeine itself counteracts the impaired psychomotor functions that occur with acute intoxication (Antiquated Antidotes in Depth).138 Earlier anecdotal reports suggested a role for naloxone in reversing ethanol intoxication, but these reports could not be reliably reproduced.139 The specific

benzodiazepine antagonist flumazenil has no predictable effect on ethanol intoxication.51 It is unlikely that a specific ethanol antagonist will be discovered because ethanol's mechanisms of action are complex and are not apparently mediated by a single receptor. Rapid intravenous saline (1 L) loading does not accelerate ethanol clearance in intoxicated patients.104 Hemodialysis is an effective means of enhancing the systemic elimination of ethanol because of the small volume of distribution and low molecular weight of ethanol. In severe ethanol poisoning that results in respiratory failure or coma, hemodialysis may be an adjunct treatment to supportive care. However, this is rarely indicated or necessary.

Indications

for

Hospitalization

A patient with uncomplicated ethanol intoxication can be safely discharged from the ED after a careful observation and social service or psychiatric counseling. An individual should not be discharged while still clinically intoxicated. However, consideration may be given to a situation where the intoxicated patient is discharged to a protected environment under the supervision of a responsible, not intoxicated, adult. In this case, the clinical assessment of the patient is more important than the blood ethanol level. Indications for hospital admission include persistently abnormal vital signs; persistently abnormal mental status, with or without an obvious cause; a mixed overdose with other concerning xenobiotics; concomitant serious trauma; consequential ethanol withdrawal, and an associated serious disease process, such as pancreatitis or gastrointestinal hemorrhage. Chronic alcoholism leads to an organic brain syndrome that is irreversible. The patients' socioeconomic condition and their ability to comply with a treatment plan are critical in making a disposition. Alcoholics requesting ethanol detoxification can be admitted for rehabilitation. Inpatient detoxification programs differ substantially from outpatient programs, but their most consequential advantages

may be that they enforce abstinence, provide more support and structure, and separate the patient from the social surroundings associated with drinking.135 For patients who are not admitted, a referral should be offered to Alcoholics Anonymous or another suitable ethanol rehabilitation program.

Ethanol-Induced

Hypoglycemia

Mechanism of Hypoglycemia

Ethanol-Associated

Hypoglycemia associated with ethanol consumption is believed to occur when ethanol metabolism provides a high cellular reduction-tooxidation (redox) ratio. This redox state favors the conversion of pyruvate to lactate, diverting pyruvate from gluconeogenesis (Fig. 75-2.).74 Hypoglycemia typically occurs when there is a reduced caloric intake and only after the hepatic glycogen stores are depleted, as in an overnight fast. The mechanism by which hypoglycemia is associated with ethanol consumption in the well nourished individual is less well defined.

Population

at

Risk

Although the conditions that cause hypoglycemia in adults may also be present in infants and children, children with their smaller livers have less glycogen stores than adults and are more likely to develop hypoglycemia. Hypoglycemia associated with ethanol consumption usually occurs in malnourished chronic alcoholics and children (Chap. 4 8). It may also occur in binge drinkers who do not eat. A 22% incidence of hypoglycemia was reported in one retrospective study of children with documented ethanol ingestion.102 In another retrospective study of pediatric and adolescent patients, there was a 3.4% incidence of hypoglycemia (serum glucose concentration Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Antidotes in Depth - Thiamine Hydrochloride

Antidotes in Depth Thiamine

Hydrochloride

Robert S. Hoffman

Biochemistry

Vitamin B1

(Thiamine

Hydrochloride)

Thiamine (vitamin B1 ) is a water-soluble vitamin that is essential in the creation and utilization of cellular energy. As a coenzyme in

the pyruvate dehydrogenase complex, thiamine diphosphate, the active form of thiamine, accelerates the conversion of pyruvate to acetylcoenzyme A (acetyl-CoA). This reaction occurs at thiamine's C2 atom, which is located between the nitrogen and sulfur atoms on the thiazolium ring.21 In the protein-rich environment of the enzyme complex, this C2 atom is deprotonated to form a carbanion that rapidly attaches to the carbonyl group of pyruvate, thereby stabilizing it for decarboxylation.28 In a series of subsequent reactions, the hydroxyethyl group that remains bound to thiamine diphosphate is transferred to lipoamide, where an acetyl group is later broken off and attached to coenzyme A (CoA). This overall process links anaerobic glycolysis to the Krebs cycle, where subsequent aerobic metabolism produces the equivalent of 36 moles of adenosine triphosphate (ATP) from each mole of glucose (Fig. A22-1). When pyruvate cannot be converted to acetyl-CoA because of thiamine deficiency, for example, only 2 moles of ATP can be generated by anaerobic metabolism from each mole of glucose. Thiamine is also required as a cofactor for αketoglutarate dehydrogenase, a second enzyme in the Krebs cycle, and for transketolase, an enzyme in the pentose phosphate pathway, in which nicotinamide adenine dinucleotide phosphate (NADPH) is formed for subsequent use in reductive biosynthesis. In addition, thiamine is important in maintaining normal neuronal conduction.61,76 Thiamine is available from natural sources, such as organ meats, yeast, eggs, and green leafy vegetables, in a basic form composed of a substituted pyrimidine ring and a substituted thiazole ring connected by a methylene bridge. This connection between the two rings is weak, and the molecule is unstable in an alkaline milieu and in a high temperature environment. In addition, thiamine is highly water soluble, allowing it to leach out of foods that are washed or cooked in water for prolonged times. However, thiamine, which is synthesized as a hydrochloride salt is usually quite stable. Thiamine requirements are determined by total

caloric intake and energy demand, with a minimum daily requirement of 0.5 mg/1000 calories.61

Pharmacology Thiamine is well absorbed from the human gastrointestinal tract by a complex process.34,53 At low concentrations, thiamine absorption occurs through a saturable mechanism, that is most effective in the duodenum, with absorption occurring to a lesser degree in the large bowel and stomach. As thiamine concentrations increase, however, the majority of absorption occurs through simple passive diffusion. Although more recently synthesized analogs such as thiamine propyl disulfide, benfotiamine, and fursultiamine have enhanced bioavailability, their use remains largely experimental.21,69 Chronic liver disease, folate deficiency, steatorrhea, and other forms of malabsorption all significantly decrease thiamine's absorption. This malabsorption has even greater clinical relevance in alcoholics.4,68 In experimental studies, when healthy volunteers were given small amounts of ethanol, a 50% reduction in gastrointestinal thiamine absorption resulted.68 Thiamine is eliminated from the body largely by renal clearance, which consists of a combination of glomerular filtration, flowdependent tubular secretion, and saturable tubular reabsorption.74 In an animal model, furosemide, acetazolamide, chlorothiazide, amiloride, mannitol, and salt loading all significantly increased urinary elimination of thiamine.39 This nonspecific flow-dependent elimination was confirmed in humans given small doses of furosemide.52 Additionally, both furosemide and digoxin appear to inhibit thiamine uptake into myocardial cells.79

Thiamine

Deficiency

Pathophysiology Mice develop signs of encephalopathy 10 days after being rendered thiamine deficient. Immunohistochemistry in these animals demonstrates a breakdown of the blood-brain barrier with resultant extravasation of albumin.24 Similarly, rats develop symptoms after 10 days of thiamine deficiency, and subsequently demonstrate deterioration of the blood–brain barrier with hemorrhage into the mammillary bodies and other areas of the brain.11 This pattern is similar to findings described in humans with Wernicke encephalopathy.49 The exact cause of Wernicke encephalopathy is unclear. In human autopsy studies, brain samples from alcoholic patients with Wernicke-Korsakoff syndrome demonstrate decreased levels of pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase when compared to controls.10 However, a similar decrease in enzyme activity of neuronal tissue was demonstrated in alcoholics who died from hepatic coma without ever manifesting signs of Wernicke encephalopathy.38 Likewise, the activity of thiamine-requiring Kreb cycle enzymes is reduced in thiaminereplete patients with neurodegenerative diseases.7 Thus, while thiamine deficiency produces deficits in critical enzymes in humans, it is P.1163 unclear whether these deficits are either necessary or sufficient to produce clinical disease.

Figure A22-1. Thiamine links anaerobic glycolysis to the Krebs cycle. Anaerobic glycolysis only yields 2 moles of ATP as each mole of glucose is metabolized to 2 moles of pyruvate. To

obtain the 36 additional ATP equivalents that can be derived as the Krebs cycle converts pyruvate to CO2 and H2 O , pyruvate must first be combined with CoA to form acetyl-CoA and CO2 . This process is dependent on the thiamine-requiring enzyme system known as pyruvate dehydrogenase complex.

Animal models offer insight into the mechanisms involved in developing thiamine-deficient neurologic injury. While the exact chain of events leading to these structural abnormalities is unclear, several models demonstrate key portions of the pathway. Thiamine deficiency in rats produces 200–640% increases in levels of glutamate, an excitatory amino acid.37 This excess of glutamate presumably results from blockade of α-ketoglutarate dehydrogenase, which shunts α-ketoglutarate, a natural precursor of glutamate away from subsequently develop increases in the brain marked by the induction Both the histochemical lesions and

the Krebs cycle. Rats lactate in vulnerable regions of of the protooncogene c-fos. the gene induction can be

blocked by the administration of the calcium channel blocker nicardipine.42 This suggests a strong role for excitatory amino acid-induced alterations in calcium transport in the genesis of thiamine-deficient encephalopathy. In other animal models of thiamine deficiency, neuronal tissues are also directly injured by oxidative stress and lipid peroxidation.12 Additional lines of investigations demonstrate roles for triggered mast cell degranulation,20 histamine,36 and nitric oxide31 in the generation of neuronal injury. The final common pathway is localized cerebral edema, which may result from altered expression of aquaporin.16

Clinical

Manifestations

When thiamine is completely removed from the human diet, clinical manifestations of thiamine deficiency typically develop within 2–3 weeks, although tachycardia, the first sign of

deficiency, may occur as early as 9 days after cessation of thiamine intake.76 The clinical symptoms of thiamine deficiency present as two distinct patterns: “wet― beriberi or cardiovascular disease, and “dry― beriberi, the neurologic disease known as Wernicke-Korsakoff syndrome. Although some patients display symptoms consistent with both disorders, usually either the cardiovascular or the neurologic manifestations predominate. A genetic variant of transketolase activity, combined with low physical activity and low-carbohydrate diet, may predispose to neurologic symptoms, whereas high-carbohydrate diets and increased physical activity lead to cardiovascular symptoms.6,76 Thus, cardiovascular disease is more common in Asians, and neurologic disease predominates in northern Europeans. Wet beriberi results from high-output cardiac failure induced by peripheral vasodilation and the formation of arteriovenous fistulae secondary to thiamine deficiency. These patients complain of fatigue, decreased exercise tolerance, shortness of breath, and peripheral edema. The classic triad of oculomotor abnormalities, ataxia, and global confusion defines Wernicke encephalopathy. Other manifestations include hypothermia and the absence of deep-tendon reflexes.73 Additionally, patients develop a peripheral neuropathy with paresthesias, hypesthesias, and an associated myopathy, all related to axonal degeneration.61 Laboratory studies may reflect a lactic acidosis brought on by excessive anaerobic glycolysis resulting from blocked entry of substrate into the Kreb cycle.17,29,30,35,54,73 Korsakoff psychosis, an irreversible disorder of learning and processing of new information characterized by a deficit in short-term memory and confabulation, often occurs together with Wernicke encephalopathy.71 A 10–20% mortality rate is associated with Wernicke encephalopathy, with survivors having an 80% risk of developing Korsakoff psychosis.51

Populations

at

Risk

In the United States, a healthy diet and mandatory thiamine supplementation of numerous food products protect most people from the manifestations of thiamine deficiency. This is, unfortunately, not true in other countries. A survey of the 17 major public hospitals in the Sydney, Australia area, identified more than 1000 cases of either acute Wernicke encephalopathy or Korsakoff psychosis between 1978 and 1993.40 Similarly, a single Australian hospital identified 32 cases of Wernicke encephalopathy during a 33-month period.77 In Australia, mandatory supplementation of flour with thiamine in 1991 resulted in a dramatic reduction in hospitalized cases during 1992 and 1993,40 as well as of those subsequently identified by postmortem studies.25 Current areas at risk include Ireland and New Zealand where lack of a mandatory supplementation program is correlated with a high prevalence of biochemical evidence of thiamine deficiency.45 The alcoholic patient, whose consumption of ethanol is his or her major source of calories, is the best described and most easily recognized patient at risk for thiamine deficiency. 51 Consequential thiamine deficiency is also described in inmates; postoperative patients; in those patients with hyperemesis gravidarum or anorexia nervosa; in those patients receiving parenteral nutrition; in patients with acquired immunodeficiency syndrome (AIDS); in patients with malignancies; in the institutionalized elderly;34,35 foreign laborers from the Far East; patients P.1164 with congestive heart failure on furosemide therapy; and in patients receiving hemodialysis; among others. Thus, despite routine dietary supplementation, many people are still at risk because of dietary limitations, alcohol abuse, or underlying medical conditions.

Thiamine

Replacement

Thiamine hydrochloride is included in the initial therapy for any patient with an altered mental status, potentially acting as both treatment and prevention of Wernicke encephalopathy. Many patients with altered levels of consciousness have had or will have a poor nutritional status, or will be hospitalized without oral intake for a number of days because of gastrointestinal disorders or altered mental status. Although thiamine levels can be measured, either directly or functionally, by measuring their erythrocyte transketolase activity at baseline and in response to thiamine diphosphate,26 these tests are unavailable for clinical use. Likewise, although clinical prediction models have been developed, they are cumbersome and unvalidated. 59 Glucose loading increases thiamine requirements, which can exacerbate marginal thiamine deficiencies or even precipitate coma in the absence of parenteral thiamine supplementation.51 Although it is commonly believed that acute glucose loading, in the form of a bolus of hypertonic dextrose, can precipitate Wernicke encephalopathy several hours in normal individuals, there is only evidence to support this effect in patients who already have grave

over

manifestations of thiamine deficiency.73 Previously healthy patients require prolonged dextrose administration in order to develop Wernicke encephalopathy. Because the morbidity and mortality associated with Wernicke encephalopathy are so severe, and treatment is both benign and inexpensive, thiamine hydrochloride should be included in the initial therapy for all patients who receive dextrose, for all patients with altered consciousness, and for every potential alcoholic or nutritionally deprived individual who presents to the emergency department or other clinical setting. Initial therapy consists of the immediate parenteral administration of 100 mg of thiamine hydrochloride. This can be given either intramuscularly or intravenously, but the oral route should be

avoided because of its unpredictable absorption. In countries where thiamine propyl disulfide (a lipid-soluble thiamine preparation) is available, the oral route may be considered equally efficacious for the replacement of serious thiamine deficiencies.4,68,69,2 In some patients, symptoms such as ophthalmoplegia are reported to respond rapidly to as little as 2 mg of thiamine; however, the other neurologic and cardiovascular manifestations of thiamine deprivation may necessitate higher doses and may respond more slowly, if at all. Although virtually every source recommends that daily doses of 100 mg of thiamine are sufficient as preventive therapy, a recent trial suggested improved cognitive function when a daily dose of 200 mg was compared to lower doses.1 Because of the safety of thiamine hydrochloride, and the urgency to correct the manifestations of thiamine deficiency, up to 1000 mg of thiamine hydrochloride can be used in the first 12 hours if a patient demonstrates persistent neurologic abnormalities.43 The practice of requiring the administration of parenteral thiamine prior to hypertonic dextrose in patients with altered consciousness is illogical.22 Besides the fact that the first dose of dextrose is unlikely to cause thiamine deficiency, thiamine uptake into cells and activation of enzyme systems is slower than that of glucose uptake, which suggests that even pretreatment with thiamine offers little benefit over posttreatment.66 Despite these limitations it is prudent to administer 100 mg of parenteral thiamine at the time of initial dextrose administration. The biochemical link between dextrose and thiamine is obvious, which demonstrates to the clinician the scientific basis for the administration of thiamine. Although thiamine is unlikely to offer immediate benefits for patients with altered consciousness, it will offer some long-term protection for these individuals at risk and initiate therapy for an uncommon, serious, insidious and easily overlooked disorder. A supplementary indication for the administration of thiamine hydrochloride occurs in patients with ethylene glycol poisoning. As

shown in Figure 103-2, a minor pathway for the elimination of glyoxylic acid involves its conversion to α-hydroxy-β-ketoadipate by α-ketoglutarate:glyoxylate carboligase, a thiamine and magnesium-requiring enzyme. There are no data to support an increase in α-hydroxy-β-ketoadipate formation following thiamine administration in ethylene glycol-poisoned animals or humans. However, animal models of primary hyperoxaluria show increases in urinary oxalate during thiamine deficiency, suggesting at least a potential importance of this pathway.23,65 Because therapy is benign and inexpensive, it is prudent to administer standard doses of thiamine to patients with suspected or confirmed ethylene glycol poisoning. If magnesium supplementation is considered, caution is required because of the potential for renal compromise in ethylene glycol poisoned patients. Routine thiamine administration should also be considered in patients with congestive heart failure and long-term use of diuretics. Diuretics enhance renal thiamine elimination. In one randomized trial, 200 mg of daily intravenous thiamine was able to increase cardiac ejection fraction by 22% at 7 weeks.60

Adverse

Events

Very few complications are associated with the parenteral administration of thiamine. The older literature emphasized intramuscular administration because of numerous reports of anaphylactoid reactions associated with intravenous thiamine delivery.19,50,56,63,75 It is generally believed that these reactions resulted from responses to the vehicle (chlorbutanol) or its contaminants rather than thiamine itself. Despite the availability of purer, aqueous preparations of thiamine, rare adverse reports still occur.3,41,48,62 Although the intramuscular route is theoretically comparably efficacious in a healthy individual, many patients requiring thiamine may have diminished muscle mass or a

coagulopathy, exacerbating the potential for pain and unpredictable absorption. The safety of thiamine use was evaluated in a large case series in which nearly 1000 patients received parenteral doses of up to 500 mg of thiamine without significant complications.78 This study suggests that if anaphylaxis to thiamine exists, its occurrence is exceedingly rare, permitting the safe intravenous administration of thiamine to most patients.

Pregnancy

Category

Thiamine hydrochloride is listed as pregnancy A and is also considered safe for use in lactating mothers. P.1165

Availability Multiple manufacturers formulate thiamine hydrochloride for intravenous or intramuscular administration. Typical concentrations are either 50 or 100 mg/mL. Although more concentrated solutions are available, their use is usually reserved for preparation of total parenteral nutrition solutions.

References 1. Ambrose ML, Bowden SC, Whelan G: Thiamin treatment and working memory function of alcohol-dependent people: Preliminary findings. Alcohol Clin Exp Res 2001;25:112–116. 2. Arici C, Tebaldi A, Quinzan GP, et al: Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART. Int J Std AIDS 2001;12:407–409. 3. Assem ESK: Anaphylactic reaction to thiamine. Practitioner 1973; 322:565.

4. Baker H, Frank O: Absorption, utilization and clinical effectiveness of allithiamines compared to water-soluble thiamines. J Nutri Sci Vitaminol 1976;22(Suppl):63–68. 5. Barbato M, Rodriguez PJ: Thiamine deficiency in patients admitted to a palliative care unit. Palliat Med 1994;8:320–324. 6. Blass JP, Gibson GE: Abnormality of a thiamine-requiring enzyme in patients with Wernicke-Korsakoff syndrome. N Engl J Med 1977;297:1367–1370. 7. Bubber P, Ke ZJ, Gibson GE: Tricarboxylic acid cycle enzymes following thiamine deficiency. Neurochem Int 2004;45:1021–1028. 8. Butterworth RF, Gaudreau C, Vincelette J, et al: Thiamine deficiency and Wernicke's encephalopathy in AIDS. Metab Brain Dis 1991;6: 207–212. 9. Butterworth RF, Gaudreau C, Vincelette J, et al: Thiamine deficiency in AIDS. Lancet 1991;338:1086. 10. Butterworth RF, Kril JJ, Harper CG: Thiamine-dependent enzyme changes in the brains of alcoholics: Relationship to the Wernicke-Korsakoff syndrome. Alcohol Clin Exp Res 1993;17:1084–1088. 11. Calingasan NY, Baker H, Sheu KF, Gibson GE: Blood-brain barrier abnormalities in vulnerable brain regions during thiamine deficiency. Exp Neurol 1995;134:64–72.

12. Calingasan NY, Chun WJ, Park LC, Uchida K, Gibson GE: Oxidative stress is associated with region-specific neuronal death during thiamine deficiency. J Neuropathol Exp Neurol 1999;58:946–958. 13. Centers For Disease Control: Deaths associated with thiamine-deficient total parenteral nutrition. MMWR Morb Mortal Wkly Rep 1989;38:43–46. 14. Centers For Disease Control: Lactic acidosis traced to thiamine deficiency related to nationwide shortage of multivitamins for total parenteral nutrition—United States, 1997. MMWR Morb Mortal Wkly Rep 1997;46:523–528. 15. Chadda K, Raynard B, Antoun S, et al: Acute lactic acidosis with Wernicke's encephalopathy due to acute thiamine deficiency. Intensive Care Med 2002;28:1499. 16. Chan H, Butterworth RF, Hazell AS: Primary cultures of rat astrocytes respond to thiamine deficiency-induced swelling by downregulating aquaporin-4 levels. Neurosci Lett 2004;366:231–234. 17. Cho YP, Kim K, Han MS, et al: Severe lactic acidosis and thiamine deficiency during total parenteral nutrition—Case report. Hepatogastroenterology 2004;51:253–255. 18. Descombes E, Dessibourg CA, Fellay G: Acute encephalopathy due to thiamine deficiency (Wernicke's encephalopathy) in a chronic hemodialyzed patient: A case report. Clin Nephrol 1991;35:171–175.

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27. Jeyakumar D: Thiamine responsive ankle oedema in detention centre inmates. Med J Malaysia 1995;50:17–20. 28. Kern D, Kern G, Neef H, et al: How thiamine diphosphate is activated in enzymes. Science 1997;275:67–70. 29. Kitamura K, Takahashi T, Tanaka H, et al: Two cases of thiamine deficiency-induced lactic acidosis during total parenteral nutrition. Tohoku J Exp Med 1993;171:129–133. 30. Klein M, Weksler N, Gurman GM: Fatal metabolic acidosis caused by thiamine deficiency. J Emerg Med 2004;26:301–303. 31. Kruse M, Navarro D, Desjardins P, Butterworth RF: Increased brain endothelial nitric oxide synthase expression in thiamine deficiency: Relationship to Neurochem Int 2004;45:49–56.

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32. Kuba H, Inamura T, Ikezaki K, et al: Thiamine-deficient lactic acidosis with brain tumor treatment. report of three cases. J Neurosurg 1998; 89:1025–1028. 33. Kwok T, Falconer-Smith JF, Potter JF, Ives DR: Thiamine status of elderly patients with cardiac failure. Age Ageing 1992;21:67–71. 34. Laforenza U, Patrini C, Alvisi C, et al: Thiamine uptake in human intestinal biopsy specimens, including observations from a patient with acute thiamine deficiency. Am J Clin Nutr

1997;66:320–326. 35. Lange R, Erhard J, Eigler FW, Roll C: Lactic acidosis from thiamine deficiency during parenteral nutrition in a two-yearold boy. Eur J Pediatr Surg 1992;2:241–244. 36. Langlais PJ, McRee RC, Nalwalk JA, Hough LB: Depletion of brain histamine produces regionally selective protection against thiamine deficiency-induced lesions in the rat. Metab Brain Dis 2002;17:199–210. 37. Langlais PJ, Zhang SX: Extracellular glutamate is increased in thalamus during thiamine deficiency-induced lesions and is blocked by MK-801. J Neurochem 1993;61:2175–2182. 38. Lavoie J, Butterworth RF: Reduced activities of thiaminedependent enzymes in brains of alcoholics in the absence of Wernicke's encephalopathy. Alcohol Clin Exp Res 1995;19:1073–1077. 39. Lubetsky A, Winaver J, Seligmann H, et al: Urinary thiamine excretion in the rat: Effects of furosemide, other diuretics, and volume load. J Lab Clin Med 1999;134:232–237. 40. Ma JJ, Truswell AS: Wernicke-Korsakoff syndrome in Sydney hospitals: Before and after thiamine enrichment of flour. Med J Aust 1995;163:531–534. 41. Morinville V, Jeannet-Peter N, Hauser C: Anaphylaxis to parenteral thiamine (vitamin B1 ). Schweiz Med Wochenschr 1998;128:1743–1744.

42. Munujos P, Vendrell M, Ferrer I: Proto-oncogene c-fos induction in thiamine-deficient encephalopathy. Protective effects of nicardipine on pyrithiamine-induced lesions. J Neurol Sci 1993;118:175–180. 43. Nakada T, Knight RT: Alcohol and the central nervous system. Med Clin North Am 1984;68:121–131. 44. O'Keeffe ST, Tormey WP, Glasgow R, Lavan JN: Thiamine deficiency in hospitalized elderly patients. Gerontology 1994;40:18–24. P.1166 45. O'Keeffe ST: Thiamine deficiency in elderly people. Age Ageing 2000;29:99–101. 46. Oriot D, Wood C, Gottesman R, Huault G: Severe lactic acidosis related to acute thiamine deficiency. JPEN J Parenter Enteral Nutr 1991; 15:105–109. 47. O'Rourke NP, Bunker VW, Thomas AJ, et al: Thiamine status of healthy and institutionalized elderly subjects: Analysis of dietary intake and biochemical indices. Age Ageing 1990;19:325–329. 48. Proebstle TM, Gall H, Jugert FK, et al: Specific IgE and IgG serum antibodies to thiamine associated with anaphylactic reaction. J Allergy Clin Immunol 1995;95:1059–1060. 49. Rao VL, Butterworth RF: Thiamine phosphatases in human brain: Regional alterations in patients with alcoholic cirrhosis. Alcohol Clin Exp Res 1995;19:523–526.

50. Reingold IM, Webb FR: Sudden death following intravenous injection of thiamine hydrochloride. JAMA 1946;130:491–492. 51. Reuler JB, Girard DE, Cooney TG: Current concepts. Wernicke's encephalopathy. N Engl J Med 1985;312:1035–1039. 52. Rieck J, Halkin H, Almog S, et al: Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med 1999;134:238–243. 53. Rindi G, Laforenza U: Thiamine intestinal transport and related issues: Recent aspects. Proc Soc Exp Biol Med 2000;224:246–255. 54. Romanski SA, McMahon MM: Metabolic acidosis and thiamine

deficiency.

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55. Rovelli A, Bonomi M, Murano A, et al: Severe lactic acidosis due to thiamine deficiency after bone marrow transplantation in a child with acute monocytic leukemia. Haematologica 1990;75:579–581. 56. Schiff L: Collapse following parenteral administration of solution of thiamine hydrochloride. JAMA 1941;117:609. 57. Schramm C, Wanitschke R, Galle PR: Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis. Eur J Anaesthesiol 1999;16:733–735.

58. Seligmann H, Halkin H, Rauchfleisch S, et al: Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: A pilot study. Am J Med 1991;91:151–155. 59. Sgouros X, Baines M, Bloor RN, et al: Evaluation of a clinical screening instrument to identify states of thiamine deficiency in inpatients with severe alcohol dependence syndrome. Alcohol Alcohol 2004;39: 227–232. 60. Shimon I, Almog S, Vered Z, et al: Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med 1995;98: 485–490. 61. Skelton WP 3rd, Skelton NK: Thiamine deficiency neuropathy. It's still common today. Postgrad Med 1989;85:301–306. 62. Stephen JM, Grant R, Yeh CS: Anaphylaxis from administration of intravenous thiamine. Am J Emerg Med 1992;10:61–63. 63. Stiles MH: Hypersensitivity to thiamine chloride with a note on sensitivity to pyridoxine hydrochloride. J Allergy 1941;12:507–509. 64. Svahn J, Schiaffino MC, Caruso U, et al: Severe lactic acidosis due to thiamine deficiency in a patient with B-cell leukemia/lymphoma on total parenteral nutrition during highdose methotrexate therapy. J Pediatr Hematol Oncol 2003;25:965–968.

65. Takasaki E: The urinary excretion of oxalic acid in vitamin B 1 -deficient rats. Invest Urol 1969;7:150–153. 66. Tate JR, Nixon PF: Measurement of Michaelis constant for human erythrocyte transketolase and thiamin diphosphate. Anal Biochem 1987;160:78–87. 67. Tesfaye S, Achari V, Yang YC, et al: Pregnant, vomiting, and going blind. Lancet 1998;352:1594. 68. Thomson AD, Baker H, Leevy CM: Patterns of 35S-thiamine hydrochloride absorption in the malnourished alcoholic patient. J Lab Clin Med 1970;76:34–45. 69. Thomson AD, Frank O, Baker H, Leevy CM: Thiamine propyl disulfide: Absorption and utilization. Ann Intern Med 1971;74:529–534. 70. van Zaanen HC, van der Lelie J: Thiamine deficiency in hematologic malignant tumors. Cancer 1992;69:1710–1713. 71. Victor M, Adams RD: The effect of alcohol on the nervous system. In: Meritt HH, Hare CC, eds. Metabolic and Toxic Diseases of the Nervous System. Baltimore, Williams & Wilkins, 1953, pp. 526–563. 72. Vortmeyer AO, Hagel C, Laas R: Haemorrhagic thiamine deficient encephalopathy following prolonged parenteral nutrition. J Neurol Neurosurg Psych 1992;55:826–829. 73. Watson AJ, Walker JF, Tomkin GH, et al: Acute Wernicke's encephalopathy precipitated by glucose loading. Ir J Med Sci

1981;150:301–303. 74. Weber W, Nitz M, Looby M: Nonlinear kinetics of the thiamine cation in humans: Saturation of nonrenal clearance and tubular reabsorption. J Pharmacokinet Biopharm 1990;18:501–523. 75. Weigand CG: Reactions attributed to administration of thiamine chloride. Geriatrics 1950;5:274–279. 76. Wilson JD, Madison LL: Deficiency of thiamine (beriberi), pyridoxine, and riboflavin. In: Isselbacher KJ, Adams RD, Braunwald E, et al, eds: Harrison's Principles of Internal Medicine, 9th ed. New York, McGraw-Hill, 1980, pp. 425–429. 77. Wood B, Currie J: Presentation of acute Wernicke's encephalopathy and treatment with thiamine. Metab Brain Dis 1995;10:57–72. 78. Wrenn KD, Murphy F, Slovis CM: A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med 1989;18:867–870. 79. Zangen A, Botzer D, Zangen R, Shainberg A: Furosemide and digoxin inhibit thiamine uptake in cardiac cells. Eur J Pharmacol 1998;361:151–155.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 76 - Ethanol Withdrawal

Chapter

76

Ethanol Jeffrey

Withdrawal

Gold

Lewis S. Nelson A 46-year-old man with a seizure disorder arrived in the emergency department requesting his daily phenytoin dose after being in police custody for 18 hours. He denied any physical complaints, and simply wanted to be seen and discharged. His triage vital signs were: blood pressure, 130/80 mm Hg; respiratory rate, 12 breaths/min; pulse, 105 beats/min, without orthostatic changes; and rectal temperature, 99.9°F (37.2°C). He was well developed, poorly nourished, and appeared older than his stated age. He was garrulous and somewhat anxious, although alert and oriented to time, place, and person. On physical examination he had fine hand and tongue tremors, scattered spider hemangiomata, and hepatomegaly of 14 cm. Blood was drawn for a complete blood count, serum chemistries, liver function tests, and blood alcohol and phenytoin concentrations. A bedside rapid reagent blood sugar was 70 mg/dL. One liter of 0.9% sodium chloride was administered at 500 mL/h. Multivitamins and

100 mg of thiamine were given intravenously. One hour later, the patient began to shout at nursing staff that he was being held against his will and that he must leave. He was unable to remember why he asked to be evaluated or who brought him to the hospital. Repeat vital signs were: blood pressure, 130/80 mm Hg; pulse, 130 beats/min; respiratory rate, 12 breaths/min; room air pulse oximetry, 98% saturation; and rectal temperature, 100.3°F (37.9°C). The patient was diaphoretic with a coarse tremor. The pupils were 5 mm, equal, and briskly reactive. The patient's clinical condition was unchanged after two separate doses of diazepam 10 mg IV 15 minutes apart. Diazepam was repeated as 10-mg IV boluses to a total of 100 mg, and the patient was placed in 4-point soft restraints after he began to remove his intravenous line and climb off the stretcher. His diaphoresis and tachycardia continued. He picked at the restraints, scratched his skin, and shouted nonsensical words occasionally. Diazepam administered to a total dose of 220 mg did not improve the patient's agitation; the pulse was 110 beats/min; respiratory rate, 12 breaths/min; and temperature, 101.0°F (38.3°C). Phenobarbital was administered as 130-mg boluses over 3 minutes and repeated 4 times (520 mg total), following which the patient was calm, and the heart rate was 100 beats/min. The patient was electively intubated, given thiopental, and attached to a mechanical ventilator for airway protection. The patient remained sedated and required an additional 40 mg of diazepam over the next 24 hours. He developed a right lower lobe infiltrate on day 2 of his hospitalization and was treated with ampicillin plus sulbactam. He recovered uneventfully and was extubated 48 hours later.

History

and

Epidemiology

The medical problems associated with alcoholism and alcohol withdrawal were first described by Pliny the Elder in the 1st century

B.C. In his work Naturalis Historia, the alcoholic and alcohol withdrawal were described as follows: “…drunkenness brings pallor and sagging cheeks, sore eyes, and trembling hands that spill a full cup, of which the immediate punishment is a haunted sleep and unrestful nights. …―63 Initial treatments as described by Osler were focused on supportive care, including confinement to bed, cold baths to reduce fever, and judicious use of potassium bromide, chloral hydrate, hyoscine, and, possibly, opium.62 Some of the initial large series of alcohol related complications in the early 20th century describe the alcohol withdrawal syndrome (AWS) as a major public health concern. At Bellevue Hospital in New York City, Jolliffe describes 7000–10,000 admissions per year for alcohol-related problems from 1902–1935, with an estimated rate of 2.5–5 admissions/1000 New York City residents.42 Moore et al describe similar numbers of admissions to Boston City Hospital, with up to 10% of alcoholics admitted with evidence of delirium tremens (DT). The mortality at the beginning of their study among patients with DT was 52% (1912), and DT was the leading cause of death among admitted alcoholics. Over the ensuing 20 years, this rate declined to approximately 10–12%, a decrease believed to be secondary to improved supportive care and nursing.57 Though widely recognized that alcoholics had a high incidence of delirium and psychomotor agitation, it remained controversial as to whether this was caused by ethanol use, ethanol abstinence, or coexisting psychological disorders. Isbell and colleagues, in 1955, proved that abstinence from alcohol was the cause of this syndrome when they subjected 9 male prisoners to chronic alcohol ingestion for a period of 6–12 weeks followed by 2 weeks of abstinence.40 During this latter period, 6 of the 9 men developed tremor, elevations in blood pressure, heart rate, diaphoresis, and varying degrees of either auditory or visual hallucinations, consistent with the diagnosis of DT.40 In addition, 2 of the 9 men developed convulsions, further linking alcohol abstinence to seizures. However, it should be noted that the high rate of development of

P.1168 DT (67%) is atypical and does not represent the true prevalence found in later epidemiologic studies.12 Currently, alcoholism and alcohol withdrawal syndromes still represent a major problem in both the inpatient and outpatient setting. In a 10-year epidemiologic study, the prevalence of selfreported symptoms of alcohol withdrawal, including morning tremors and sweating, in the general population was quite low, with only 1–3% of men describing 1 or more symptoms of alcohol withdrawal; rates were even lower among women.12 However, when the population in this study was enriched by those at risk for alcoholism, with at risk being defined as convicted for driving under the influence, nearly 19% met self-reported Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (DSM-IV) criteria for alcohol withdrawal. The prevalence was even higher among persons admitted for detoxification, with nearly 80% experiencing 1 or more withdrawal symptom.12 Similar results have been obtained in the inpatient setting. Alcoholrelated complications accounted for 21% of all medical ICU admissions, with alcohol withdrawal being the most common alcoholrelated diagnosis.54 In one study, 8% of all general hospital admissions, 16% of all postsurgical patients, and 31% of all trauma patients developed AWS.27,69 The development of AWS in postsurgical and trauma patients can increase the mortality in this population nearly 3-fold.68,70 Furthermore, alcohol was involved in nearly 86% of homicides, 37% of assaults, and 25–35% of nonfatal motor vehicle crashes.59

Pathophysiology Numerous studies over the past 2 decades have provided valuable insight into the mechanism of alcohol withdrawal, allowing for better understanding of both the clinical spectrum of the disorder and potential therapeutic interventions. Alcohol withdrawal is a

neurologic disorder with a continuum of progressively worsening symptoms caused by the effects of chronic ethanol use on the central nervous system, and often exacerbated by the clinical manifestations of alcoholism (eg, nutritional depletion, impaired immunity, anemia, cirrhosis, head trauma). The effects of chronic alcohol consumption on neurotransmitter function best explains the clinical findings. Persistent stimulation of the inhibitory γ-aminobutyric acid (GABA) receptor-chloride channel complex by ethanol, leads to downregulation of GABA receptor–chloride channel complex.11,44 This allows the alcohol user to maintain a relatively normal level of consciousness despite the presence of sedative concentrations of ethanol in the brain. A continued escalation of the steady-state ethanol concentration is required to achieve euphoria (ie, tolerance), which results in progressive desensitization of the GABA receptor–chloride channel complex.24 The exact mechanism by which this adaptive change occurs is undefined, but may involve substitution of an α4 for an α 1 receptor subunit on the GABAA receptor (Chap. 15) .13,49 A converse series of events occurs at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Binding by ethanol to the glycine binding site of this receptor inhibits the NMDA function, resulting in compensatory upregulation of these excitatory receptors.33,38 Thus withdrawal of alcohol is associated with both a decrease in GABAergic activity and an increase glutamatergic activity.33 This phenomenon of a concomitant increased excitation and loss of inhibition results in the clinical manifestations of autonomic excitability and psychomotor agitation. Repeated episodes of alcohol withdrawal may lead to poorly understood permanent alterations in neurotransmitters and their receptors. In rats, repeated episodes of alcohol withdrawal leads to persistent and progressive EEG abnormalities, with further episodes of withdrawal becoming increasingly resistant to benzodiazepines. Both clinical observation and in vitro data suggest that repeated episodes of alcohol withdrawal leads to permanent dysregulation of

GABA receptors. This understanding may be an explanation for the “kindling phenomena,― which is the clinical observation of increasing severity of alcohol withdrawal among individual subjects, and the development of benzodiazepine resistant alcohol withdrawal.10,30,84

Clinical

Syndromes

Alcohol withdrawal is defined in the DSM-IV as the cessation of heavy or prolonged alcohol use resulting, within a period of a few hours to several days, in the development of 2 or more of the clinical findings listed in Table 76-1. 26 Furthermore, these symptoms must have no other organic etiology. Alcohol withdrawal syndromes can be classified both by timing (early vs. late) and severity (complicated vs. uncomplicated). However, there are no adequate or fully accepted criteria by which to define these categories. Furthermore, the clinical course of AWS can vary widely among patients, and progression of individual patients through these different stages is extremely variable. In fact, some heavy alcohol users experience no withdrawal syndrome following the cessation of alcohol consumption. Recognizing these limitations, this conceptual framework still proves helpful in the clinical management of patients with alcohol withdrawal.

Early

Uncomplicated

Withdrawal

Alcohol withdrawal begins as early as 6 hours after the cessation of drinking. Early withdrawal is characterized by autonomic hyperactivity including tachycardia, tremor, hypertension, and psychomotor agitation. Although these symptoms are uncomfortable, they are not generally dangerous. Most patients who ultimately develop severe manifestations of AWS initially develop these findings, but this is not universal. At this “stage― of AWS, the symptoms are still readily amenable to treatment with ethanol, as is done daily by most heavy alcohol users.

TABLE 76-1. DSM-IV Criteria for Alcohol Withdrawal

A . Cessation of (or reduction in) alcohol use that has been heavy and prolonged. B . Two (or more) of the following, developing within several hours to a few days after criterion A: 1 . Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100) 2 . Increased hand tremor 3 . Insomnia 4 . Nausea or vomiting 5 . Transient visual, tactile, or auditory hallucinations or illusions 6 . Psychomotor agitation 7 . Anxiety 8 . Grand mal seizures C . The symptoms in criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D . The symptoms are not due to a general condition and are not better accounted for by another mental disorder.

P.1169

Alcoholic

Hallucinosis

Nearly 25% of patients with AWS will develop hallucinations, and a subset of these patients will develop alcoholic hallucinosis, a syndrome of persistent hallucinations.75,78 Although classically these hallucinations are tactile or visual, other types of hallucinations are described. Tactile hallucinations include formication, or the sensation of ants crawling on the skin, which can result in repeated itching and

excoriations. However, as opposed to what is observed with DT, alcoholic hallucinosis is associated with a clear sensorium. The presence of alcoholic hallucinosis is neither a positive or negative predictor of the subsequent development of DT.39

Alcohol

Withdrawal

Seizures

Approximately 10% of patients with AWS develop alcohol withdrawal seizures, or “rum fits.― For many patients, a generalized alcohol withdrawal seizure may be the first manifestation of the AWS.76 Approximately 40% of patients with alcohol withdrawal seizures have isolated seizures and 3% develop status epilepticus.76,77 Alcohol withdrawal seizures may occur in the absence of other signs of alcohol withdrawal and are characteristically brief, generalized, tonic–clonic events with a short postictal period. Rapid recovery and normal mental status belie the seriousness of an alcohol withdrawal seizure. However, for approximately one-third of patients with DT, the sentinel event is an isolated alcohol withdrawal seizure. Alcohol withdrawal seizures occurring in the presence of an elevated ethanol concentration may be a poor prognostic indicator for the development of DT because the relative protection against withdrawal of an elevated ethanol concentration will be lost as the concentration drops.74 Finally, clinicians should be cognizant that many alcoholics are prescribed anticonvulsant medications because they have a preexisting seizure disorder, often related to repetitive brain trauma.29 Conversely, the use of anticonvulsants does not unequivocally indicate the presence of a preexisting seizure disorder because of the difficulty in differentiating these seizures from those of alcohol withdrawal.

Delirium

Tremens

Delirium tremens is the most serious complication of the AWS, and it generally manifests between 48 and 96 hours after the cessation of drinking.76 Many of the clinical manifestations of DT are similar to

those of uncomplicated early alcohol withdrawal, differing only in severity, and include tremors, autonomic instability (hypertension and tachycardia), and psychomotor agitation. However, unlike AWS, DT, as defined in DSM-IV, is associated with either (a) disturbance of consciousness (such as reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention, delirium, confusion, and frank psychosis, or (b) a change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia.26 Unlike the early manifestations of alcohol withdrawal, which typically last for 3–5 days, DT can last for up to 2 weeks (Table 76-2) .76

TABLE 76-2. Diagnostic Criteria for Substance Withdrawal Delirium

A . Disturbance of consciousness (ie, reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. B . A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia. C . The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. D . There is evidence from the history, physical examination, or laboratory findings that the symptoms in criteria A and B developed during, or shortly after discontinuation of substance use.

Risk Factors for the Development of Alcohol Withdrawal Factors determining whether an individual will develop AWS are not well identified. The strongest predictor for the development of AWS is a history of prior episodes of AWS/DT and/or a family history.46 The influence of family history on the development of AWS suggests a strong role for genetic factors. Recent studies document a strong association between the A9 polymorphism of the dopamine transporter and the development of AWS/DT.31 Whether this finding represents a predisposition to greater ethanol consumption because of an enhanced mesolimbic reward system, or some other underlying pathophysiologic effect, is unclear. Similar results are observed with the C allele of the neuropeptide Y gene.45 Larger and more varied patient cohorts that include both women and nonwhite ethnic groups are required before any definitive conclusions can be drawn. Because of the subjective nature of many of these findings, we discourage the use of pure clinical descriptors, such as DT, tremors, rum fits, and the like, to classify the severity of alcohol withdrawal in any given patient. Furthermore, the necessity of having a standardized means of classification has enormous implications for epidemiologic, genetic, and treatment studies. One of the more commonly used means for accurately assessing alcohol withdrawal is the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) score (Fig. 76-1) .72 This scoring system contains 10 clinical categories and requires less than 5 minutes to complete. Scoring systems are not only essential for symptom-triggered therapy, but provide a basis for comparative analysis of clinical trials in ethanol withdrawal. Greater use of CIWA-Ar or a comparable validated scale will be essential for interpretation of both genetic and treatment trials in the future.

Clinical

and

Biochemical

Predictors

Alcohol concentrations, homocysteine concentrations, and liver function tests are often studied and loosely associated with the development of AWS, with frequently contradictory study results.8,46 Because many studies are based on small numbers of often highly selected subjects, their generalizability is extremely poor. Numerous attempts have been made to develop biochemical predictors for the presence and/or severity of alcohol withdrawal. Although consistent abnormalities in readily obtained laboratory values are observed in patients with AWS (eg, aminotransferases, magnesium, erythrocyte parameters), their role in predicting the severity of AWS is poorly described. In one study, an alanine aminotransferase (ALT) >50 U/L (odds ratio [OR] 9.0; 3.5–24), a chloride 150 mg/dL had an 81% positive predictive value for the need to use more than a single dose of chlordiazepoxide for the treatment of AWS.79 In addition, admission blood ethanol concentrations in patients with alcohol withdrawal seizures were 2-fold higher than in those without seizures, irrespective of whether or not they had a history of prior withdrawal seizures.79 However, these results should be interpreted with caution, as other studies yield conflicting results. In one study, an admission ethanol concentration 8), which demonstrates the usefulness of standardized scoring and evaluation tools. Finally, it should be noted that in both of these trials, patients had very mild withdrawal symptoms, with mean CIWA-Ar scores of 9–11, although experience suggests that this same regimen is also effective in patients with serious withdrawal and/or DT.

Resistant Delirium

Alcohol Withdrawal Tremens

and

There is a subgroup of patients with AWS who require very large doses of diazepam, or another comparable drug to achieve initial sedation.50,61,85 This same group often has exceedingly high benzodiazepine requirements to maintain this level of sedation. Subjects with resistant AWS and DT may have benzodiazepine requirements that exceed 2600 mg of diazepam within the first 24 hours, and generally require admission to an intensive care or

stepdown unit.85 Patients admitted to the Bellevue hospital medical ICU for resistant alcohol withdrawal had very high diazepam requirements, with a mean of 234 mg (range: 10–1490 mg) required in the first 24 hours, and individual doses of diazepam that often exceeded 100 mg, to control their agitation. At Bellevue, these patients comprise approximately 5% of all ICU admissions, with nearly 40% of patients requiring mechanical ventilation and a mean ICU length of stay of 5.7 days. The approach to the management of resistant AWS depends on several factors, including the availability of an intensive care unit bed. In the ICU, despite the perception of failure of high benzodiazepine requirements, we favor administration of benzodiazepines in a symptom-triggered fashion. Patients who receive this therapy generally respond to bolus doses of diazepam ranging from 10–100 mg, which results in a brief period of sedation followed by recrudescence of their AWS. This approach was confirmed in a study of patients who developed AWS postoperatively in the ICU.71 In this study, a symptom-triggered strategy resulted in a shorter length of stay and a lower incidence of mechanical ventilation than did continuous infusion of midazolam.71 In non-ICU settings, the ability to administer frequent intravenous doses of diazepam is limited, and the use intravenous infusions with secondary sedative agents may be more practical. In instances of extreme benzodiazepine resistance, patients often receive a second GABAergic drug because of “failure― of benzodiazepine therapy. Phenobarbital, given in combination with benzodiazepine, in intravenous doses of 130 mg, is a reasonable choice. Caution is required to avoid stacking doses of phenobarbital, as the onset of clinical effect takes approximately 20–40 minutes.35,41 Alternatively, propofol in standard doses may be administered. Although propofol has a rapid onset, it is difficult to titrate.19,56 The main drawback to the use of these drugs is their narrow therapeutic–toxic index, with the potential for profound respiratory depression. This is especially true for propofol, which

should generally only be used in the setting of mechanical ventilation. Both of these agents can act synergistically with benzodiazepines to enhance GABA-induced chloride channel opening. In P.1173 addition, propofol uniquely antagonizes NMDA receptors, thus reducing the excitatory component of AWS.

Ethanol Ethanol consumption is a common and effective means by which alcoholics can self-medicate to treat and/or prevent mild alcohol withdrawal. However, little controlled data exist on the role of ethanol, whether oral or by infusion, for the in-hospital treatment of AWS/DT. In one trial, 39 trauma patients without liver or CNS disease were successfully treated with 10% ethanol infusion for treatment of presumed AWS.20 Although the authors did not report any adverse effects in this trial, the necessity for frequent blood alcohol monitoring, unpredictable elimination kinetics, potential for significant hepatic complications, and the difficulty in safely administering this therapy makes it inappropriate to recommend this regimen.25,36,55,82

Adrenergic

Antagonists

Numerous studies have investigated the use of sympatholytics to control the autonomic symptoms of alcohol withdrawal. Both βadrenergic antagonists and clonidine reduced blood pressure and heart rate in randomized, placebo-controlled trials.4,48,86 However, the inability of these agents to address the underlying pathophysiologic mechanism of AWS, and subsequently control the neurologic manifestations, makes them suboptimal as sole therapeutic agents. There are additional concerns that by altering the physiologic parameters that serve as classic markers for AWS severity, there is a risk of underadministering necessary amounts of

benzodiazepines.86 Consequently, we do not recommend using these drugs for the treatment of alcohol withdrawal until it becomes clear that other standard therapies have failed.

Magnesium The benefits of magnesium supplementation are based both on the high prevalence of magnesium deficiency in alcoholics and its usefulness in preventing seizures in other disorders, including eclampsia.5,37 Furthermore, magnesium deficiency has many clinical similarities to AWS, clouding the differential diagnosis. Numerous studies have evaluated the efficacy of magnesium supplementation. However, in a randomized, placebo-controlled trial, magnesium sulfate had no effect on either severity of alcohol withdrawal or incidence of withdrawal seizures.83 Consequently, aside from repletion of electrolyte abnormalities, there is no indication for routine administration of magnesium for the treatment of AWS.

Anticonvulsants Carbamazepine has been used in multiple trials for treatment of mild AWS, more commonly in Europe where an intravenous preparation is available. In animal studies, carbamazepine increases both the central nervous system GABA concentrations and the seizure threshold in alcohol withdrawal.17 In humans, carbamazepine is superior to placebo and equally efficacious as benzodiazepines for treatment of mild to moderate AWS in both inpatients and outpatients.7,52,53 Similar data has been obtained with valproic acid, which appears to have a benzodiazepine-sparing effect in patients with mild withdrawal.66 These drugs may be reasonably recommended as adjuncts, but should not be used as monotherapy.

Newer

Agents

and

Future

Directions

There is a constant search for newer agents to treat alcohol

withdrawal, especially for agents that target NMDA receptors. In animal studies, NMDA antagonists have shown benefit in preventing AWS seizure, neurologic damage, and alcohol craving.6,58 In humans, one NMDA inhibitor, acamprosate, has undergone significant study in the prevention of relapse following alcohol detoxification.16,32 Its effects on AWS are less clear, although in one study of patients capable of outpatient detoxification, it had no adverse effects on CIWA-Ar scores.16

Summary Alcohol withdrawal is a complex physiologic process involving both enhanced neuronal excitation and reduced inhibition resulting in neuroexcitation. The manifestations of greatest concern are neurologic and include altered mental status and seizure, but the autonomic excess may be clinically consequential. Treatment includes supportive care and sedation with benzodiazepines. When benzodiazepines cannot produce adequate sedation, agents such as phenobarbital or propofol should be added.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 77 - Disulfiram and Disulfiramlike Reactions

Chapter

77

Disulfiram Reactions

and

Disulfiramlike

Edwin K. Kuffner

Disulfiram

A 40-year-old woman with a history of depression was found unresponsive by her husband. The husband stated that the patient

had a strange garlic odor on her breath and that she had complained of exhaustion and confusion for several days. The patient's medications included paroxetine, risperidone, and trazodone. The patient also had access to a supply of nonprescription vitamins, herbal preparations, muscle liniments, and an unknown Mexican medication. Emergency medical personnel transported the patient to the emergency department. Her vital signs were: blood pressure, 178/100 mm Hg; pulse, 56 beats/min; respiratory rate, 32 breaths/min; rectal temperature, 94.8°F (34.9°C); pulse oximetry on room air, 99%. A bedside rapid reagent blood glucose was 130 mg/dL and therefore dextrose was not administered. The physical examination revealed an unresponsive patient with a Glasgow Coma Score (GCS) of 6. No evidence of trauma was noted. Pupils were 3 mm and sluggishly reactive to light. Cardiac, pulmonary, and abdominal examinations were unremarkable. Neurologic examination revealed flexion withdrawal to painful stimuli, areflexia, and occasional myoclonic jerks. The patient's trachea was intubated. Fifty grams of activated charcoal was administered via a nasogastric tube. The 12-lead electrocardiogram (ECG) revealed peaked T waves but was otherwise normal. The serum electrolytes were significant for a bicarbonate of 4 mEq/L, a potassium of 6.0 mEq/L, and an anion gap of 26 mEq/L. The serum lactate was 16.9 mmol/L. Serum blood urea nitrogen (BUN), serum creatinine, and hepatic aminotransferases were normal. Serum acetaminophen, salicylate, and blood ethanol concentrations were undetectable. An arterial blood gas analysis on supplemental oxygen revealed a pH of 7.11, a PCO2 of 6.7 mm Hg, and a PO2 of 187 mm Hg. A complete blood count revealed a white blood cell count (WBC) of 15,600/mm3 (89% neutrophils and 9% lymphocytes) with a normal hematocrit and platelet count. A computed tomography scan of the head, a chest radiograph, and a lumbar puncture were normal.

Blood was sent for determination of ethylene glycol and methanol concentrations and the patient was treated with 50 mg of pyridoxine and 50 mg of folinic acid intravenously. Instead of using fomepizole, which was unavailable, the patient was started on intravenous ethanol. A loading dose of 800 mg/kg of ethanol was followed by a continuous infusion to maintain the blood ethanol concentration between 100 and 120 mg/dL. Shortly after the loading dose of ethanol was administered, the patient developed generalized flushing, tachycardia with a pulse of 120 beats/min, and a systolic blood pressure of 70 mm Hg. The blood pressure did not respond to IV crystalloid, but did respond to norepinephrine. Hemodialysis was performed. The ethylene glycol and methanol levels were eventually reported as negative. The severe metabolic acidosis was corrected with hemodialysis. Within a few hours of discontinuing the ethanol infusion, the patient's tachycardia and hypotension resolved. Within 24 hours of presentation, the patient's mental status had returned to baseline. The patient later admitted to ingesting a “nonprescription― Mexican medication for alcoholism that she purchased from a Mexican pharmacist in the United States. The unknown medication was later identified as disulfiram. A complete understanding of disulfiram toxicity is dependent on understanding the distinction between the different forms of disulfiram toxicity that are associated with acute ingestions, chronic therapy, and disulfiram–ethanol reactions. The preceding case is unique in that it involves both toxicity from an acute overdose of disulfiram and toxicity from an iatrogenic disulfiram–ethanol reaction. This chapter emphasizes the distinctions between these three different forms of disulfiram toxicity. P.1177

History

and

Epidemiology

Disulfiram, tetraethylthiuram disulfide, and related chemicals were used in the rubber industry as catalytic accelerators for the vulcanization (stabilization) of rubber by the addition of sulfur. In the early 1900s, workers exposed to disulfiram were observed to develop adverse reactions when exposed to ethanol, and this suggested that disulfiram might be a useful adjunct in the treatment of alcoholism. In the 1940s, two Danish physicians, Hald and Jacobsen, using disulfiram for its antihelmintic properties became ill after consuming alcohol.29 Subsequently, disulfiram treatment for alcoholism gained popularity.3 Although evidence to support the benefit of using disulfiram in a comprehensive alcohol treatment program is equivocal, disulfiram is still prescribed for this purpose today.36 Specific epidemiologic information about the three different forms of disulfiram toxicity is difficult to elucidate, even from an analysis of the American Association of Poison Control Centers (AAPCC) (Chap. 130) . Between 1982 and 2003 more than 10,000 patients exposed to disulfiram were reported to the AAPCC. Fewer than 200 of these patients developed major adverse effects. Unlike most xenobiotics reported to the AAPCC, the majority of the disulfiram exposures were in adults. All 12 deaths were adults and most involved a disulfiram–ethanol reaction. In many of the deaths, coingestants other than disulfiram and ethanol were involved. The best studied and the most commonly reported life-threatening adverse effect of chronic disulfiram therapy is hepatotoxicity. The frequency of disulfiram-related hepatotoxicity is also difficult to determine. As many as 25% of all alcoholics treated with disulfiram develop subclinical elevations in their hepatic aminotransferase levels, and the frequency of disulfiram-induced fatal hepatitis is estimated at 1 in 25,000–30,000 patients treated per year.75

Pharmacology and Pharmacokinetics Therapeutic doses of Disulfiram

of

The effectiveness of disulfiram in discouraging alcohol consumption is aversive in nature, as it is dependent on the patient's fear of developing a disulfiram–ethanol reaction. Disulfiram does not produce central nervous system effects that alter an alcoholic's drinking behavior. Therapeutic doses of disulfiram, used as part of a comprehensive alcohol treatment program, typically range from 125–500 mg/d.

Absorption Disulfiram is highly lipid soluble and very insoluble in water. Following ingestion, disulfiram is either absorbed as the parent compound or converted to diethyldithiocarbamic acid (diethyldithiocarbamate) in the acid environment of the stomach.13 Diethyldithiocarbamic acid is also very unstable in this acid environment, and either rapidly undergoes absorption and spontaneous decomposition to carbon disulfide and diethylamine, or chelates copper, forming a bis (diethyldithiocarbamate)-copper complex. The bis(diethyldithiocarbamate)-copper complex is more stable than diethyldithiocarbamic acid and also can be absorbed as it passes through the upper gastrointestinal tract. In fact, most disulfiram is absorbed from the small intestine as this bis(diethyldithiocarbamate)-copper complex. Approximately 70–90% of an ingested therapeutic dose of disulfiram is absorbed. The bioavailability of disulfiram varies with different preparations. In one study, the mean serum disulfiram concentration in humans following a 250-mg dose was reported to be 0.38 ± 0.03 µg/mL.22 Peak serum concentrations of disulfiram and its metabolites are achieved 8–10 hours following a 250-mg dose.40

Distribution Approximately 96% of disulfiram itself and approximately 80% of disulfiram metabolites are protein bound.40 Following absorption, disulfiram and its metabolites are uniformly distributed throughout body tissues. A specific volume of distribution for disulfiram is not recognized.

Metabolism Any absorbed disulfiram is rapidly converted to diethyldithiocarbamic acid by erythrocyte glutathione

reductase

and endogenous thiols. Diethyldithiocarbamic acid in the blood also reversibly chelates copper, forming a bis(diethyldithiocarbamate)-copper complex. Diethyldithiocarbamic acid is metabolized by a number of different pathways, including glucuronidation, methylation, nonenzymatic degradation, and oxidation. Nonenzymatic degradation of diethyldithiocarbamic acid produces diethylamine and carbon disulfide. Carbon disulfide can be further oxidized to carbonyl sulfide, which, in turn, can be further oxidized to carbon dioxide. Phase II methylation of diethyldithiocarbamic acid, which is mediated by an Smethyltransferase, produces diethyldithiomethylcarbamic acid. Diethyldithiomethylcarbamic acid can be oxidized to diethylthiomethylcarbamic acid. Diethylthiomethylcarbamic acid is further oxidized to sulfoxide and sulfone metabolites and undergoes demethylation to form diethylthiocarbamic acid. Although diethyldithiocarbamic acid can be converted back to disulfiram, and carbon disulfide and diethylamine can be converted back to diethyldithiocarbamic acid, these reactions are not clinically significant20 (Fig. 77-1) .

Figure

77-1. Disulfiram metabolism occurs in the liver and in

the erythrocyte. The most consequential metabolites are diethyldithiocarbamate and carbon disulfide.

P.1178

Elimination Following a 250-mg dose, the half-lives of disulfiram, diethyldithiocarbamate, and carbon disulfide are 7.3 ± 1.5 hours, 15.5 ± 4.5 hours, and 8.9 ± 1.4 hours, respectively. Approximately 20% of disulfiram is excreted unchanged in the

feces and another 20% or more is excreted by the lungs as carbon disulfide. The majority of disulfiram is excreted in the urine as the glucuronidated metabolite of diethyldithiocarbamic acid.40 At 48 hours after administration of a single 250-mg dose, there is a negligible amount of disulfiram and metabolites detectable in the serum.22,38

Disulfiram–Ethanol

Reaction

Pharmacology and Pharmacokinetics Disulfiram–Ethanol Reaction

of

Understanding the metabolism of ethanol is critical to understanding the mechanism of action of disulfiram as it relates to the disulfiram–ethanol reaction (Fig. 77-2). Disulfiram and its metabolites impair both cytosolic aldehyde dehydrogenase 1 (ALDH 1) and mitochondrial aldehyde dehydrogenase 2 (ALDH 2). The inhibition by disulfiram of ALDH 2 leads to a rise of acetaldehyde levels 5–10 times above baseline levels, and a few days of treatment with disulfiram can reduce baseline aldehyde dehydrogenase activity by 50%.6 Although aldehyde dehydrogenase is present throughout the body, inhibition of hepatic mitochondrial aldehyde dehydrogenase is most important in

the

disulfiram-ethanol

reaction.

The exact mechanism by which disulfiram and its metabolites inhibit ALDH 1 and ALDH 2 is still unclear. Disulfiram may inactivate aldehyde dehydrogenase by causing internal sulfursulfur bonds, or by competing for nicotinamide adenine dinucleotide.97 The metabolites of disulfiram, including diethylthiomethylcarbamic acid and its sulfoxide and sulfone metabolites, may also inhibit aldehyde dehydrogenase.29,40 Different metabolites may possibly inactivate different isoenzymes of aldehyde dehydrogenase. Diethylthiocarbamic acid is believed to

inactivate ALDH 2. Because aldehyde dehydrogenase inhibition is irreversible, new ALDH must be synthesized to metabolize acetaldehyde.40 This explains why disulfiram has a longer-lasting effect than would be predicted based upon its half-life. The duration of the inhibition of aldehyde dehydrogenase by disulfiram is partially dependent on the dose ingested and the route of administration. A 500-mg dose inhibits aldehyde dehydrogenase for up to 4 days, a 1000-mg dose for up to 6 days, and a 1500-mg dose up to 8 days.29 There are also sustainedrelease and depot disulfiram preparations, but none are readily available in the United States. A patient reacted to oral ethanol 21 days following the subcutaneous injection of 2 g of disulfiram.73 Although the severity of the disulfiram–ethanol reaction following subcutaneous disulfiram dosing is reported to be less than that following oral dosing, this has not been proven.

Figure 77-2. The site of action of disulfiram. The irreversible inactivation of aldehyde dehydrogenase results in an increased acetaldehyde level after ethanol is administered.

TABLE 77-1. Common Household Products that Contain Ethanol and May Cause a Disulfiram–Ethanol Reaction

Adhesives Alcohols: denatured alcohol, rubbing alcohol Detergents Foods: liquor-containing desserts, fermented vinegar, sauces Nonprescription medications: analgesics, antacids, antidiarrheals, cough and cold preparations, topical

some

anesthetics, vitamins Personal hygiene products: after-shave lotions, colognes, deodorants, liquid soaps, mouthwashes, perfumes, skin liniments and lotions Solvents

The accumulation of acetaldehyde, that is normally metabolized rapidly by aldehyde dehydrogenase, is responsible for many of the symptoms produced by the disulfiram–ethanol reaction. In fact, intravenous administration of acetaldehyde to humans produces symptoms similar to those experienced by patients on disulfiram who consume ethanol.4 Acetaldehyde may increase the release of histamine, which may also be responsible for some of the effects of the disulfiram–ethanol reaction. Disulfiram–ethanol reactions are reported following exposure to disulfiram by the oral and subcutaneous routes, and to ethanol by any route.88 Disulfiram–ethanol reactions may follow exposure to the ethanol contained in many products other than alcoholic beverages. Table 77-1 lists some common household products containing ethanol.

Other

Enzymes

Inhibited

by

Disulfiram

Disulfiram and its metabolites inhibit other enzymes besides aldehyde hydrogenase, especially those that contain sulfhydryl groups and metalloproteins.67 Importantly, disulfiram inhibits dopamine β-hydroxylase, an enzyme necessary for norepinephrine synthesis.27,65 The mechanism for this inhibition may be the chelation of copper by diethyldithiocarbamate, which is necessary for dopamine β-hydroxylase activity.81 Disulfiram also decreases urinary concentrations of vanillylmandelic acid in humans.32 Decreased norepinephrine in the presence of acetaldehyde, a potential vasodilator, may account for the hypotension associated with the disulfiram–ethanol reaction. Increased concentrations of dopamine, as a consequence of dopamine β-hydroxylase inhibition, may also explain the psychiatric effects following both acute disulfiram overdose and chronic disulfiram therapy. Although it has been theorized that some of the neurologic effects following both acute disulfiram overdose and chronic disulfiram therapy may be related to the metabolite carbon disulfide, this has not been confirmed in a well-controlled trial.76

Disulfiram Sys tem

and

the

Cytochrome

P450

Disulfiram and its metabolites are inhibitors of cytochrome P450 (CYP) 2E1.42 Single doses of disulfiram administered to healthy humans result in 50% inhibition of baseline CYP2E1 activity for at least 3 days, with some inhibition for longer than 1 week.19,21 Although animal studies suggest that disulfiram alters acetaminophen metabolism, a human study found that disulfiram did not P.1179 significantly alter the metabolism of a therapeutic dose of acetaminophen, in either healthy patients or in patients with

alcoholic liver disease.74 Disulfiram may be an inducer of CYP2B1 and CYP2A1, but it does not appear to affect CYP2C9, CYP2C19, CYP2D6, or CYP3A4 activity.40,42 Disulfiram inhibits the metabolism and/or decreases the clearance of phenytoin, theophylline and warfarin.55,67,69,82 The effects of disulfiram on the CYP system may be both dose and time dependent.

Disulfiram–Xenobiotic

Interactions

Disulfiram may decrease the clearance of benzodiazepines (chlordiazepoxide, diazepam, and oxazepam),56 caffeine, phenytoin,93 theophylline,14 and some tricyclic antidepressants (desipramine and imipramine).16 Disulfiram can increase the prothrombin time (international normalized ratio) in patients taking warfarin.69 Combined therapy of disulfiram with omeprazole can cause catatonia.28 Isoniazid and metronidazole may potentiate the neuropsychiatric effects of disulfiram, producing confusion and psychosis.83,100 Patients taking disulfiram therapeutically may develop hypotension following the administration of anesthetic agents. 18 There is a theoretical concern that disulfiram may decrease the metabolism of propylene glycol found in many liquid and parenteral drug formulations, but specific cases of toxicity have not been reported. Although animal studies suggest that disulfiram may increase the carcinogenicity of ethylene dibromide, this has not been substantiated in humans. 103

Use of Disulfiram as an Antidote Case reports suggest that disulfiram may be useful for the treatment of nickel dermatitis.15,41 However, a small double-blind, placebo-controlled study of patients with hand eczema and nickel allergy did not find a clinically significant difference between those treated with disulfiram and those treated with placebo. 41 Because the conditions of some patients have worsened with this therapy,45 and because some patients treated for nickel dermatitis

have developed disulfiram-induced hepatitis, this therapy is not generally indicated. Diethyldithiocarbamate, a disulfiram metabolite, is available as the chelator ditiocarb. Although animal data and human case series suggest that diethyldithiocarbamate may be an effective chelator for the treatment of nickel-carbonyl poisoning, no well-controlled human trial has evaluated this therapy. Because disulfiram increases nickel absorption in humans, it is prudent to only use diethyldithiocarbamate in the treatment of nickel-carbonyl poisoning and not for the treatment of elemental or inorganic nickel

poisoning.11,8

Clinical

Manifestations

Most patients taking disulfiram who are exposed to ethanol develop symptoms of the disulfiram–ethanol reaction within 15 minutes. The symptoms usually peak within 30 minutes to 1 hour, and then gradually subside over the next few hours. Signs and symptoms of a disulfiram–ethanol reaction include facial and generalized body warmth and flushing, conjunctival injection, pruritus, urticaria, diaphoresis, lightheadedness, vertigo, headache, nausea, vomiting, and abdominal pain. Cardiac effects include palpitations, chest pain, and dyspnea. Tachycardia and hypotension, including orthostatic hypotension, are common. Rare complications include shock, myocardial ischemia,62 hypertension, bronchospasm, and methemoglobinemia.104 Esophageal rupture and intracranial hemorrhage, secondary to profound vomiting, may occur.23,64,92,104 Deaths attributed to the disulfiram-ethanol reaction occur but are rare.5,39,64 There is significant interindividual and intraindividual variation in the intensity and duration of a disulfiram–ethanol reaction.

TABLE 77-2. Xenobiotics Reported to Cause a Disulfiramlike Reaction with Ethanol

Antimicrobials Cephalosporins, especially those that contain a methylthiotetrazole (MTT) side chain, such as cefotetan, cefoperazone, cefamandole, and cefmenoxime. Metronidazole Moxalactam Trimethoprim-sulfamethoxazole Possible reactions with chloramphenicol, griseofulvin, quinacrine, procarbazine, phentolamine, Sulfonylurea oral hypoglycemics Chlorpropamide Tolbutamide

nitrofurantoin

Chemicals Calcium carbimide (citrated) Carbon disulfide Carbon tetrachloride Chloral hydrate Dimethylformamide Nitrefazole Tetraethylthiuram disulfide (disulfiram) Tetramethylthiuram disulfide (thiram) Thiram analogs (fungicides) Copper, mercuric, and sodium diethyldithiocarbamate Zinc and ferric dimethyldithiocarbamate Zinc and disodium ethylenebis [dithiocarbamate] Trichloroethylene Mushrooms Coprinus mushrooms including C. atramentarius, C. insignis, C. variegatus, and C. quadrifidus, Boletus luridus, Clitocybe clavipes, Polyporus sulphureus, Pholiota

squarosa,

Tricholoma

aurantum, and Verpa

Disulfiram–Ethanollike

bohemica

Reactions

The term disulfiramlike reaction is commonly used to describe a presentation similar to the typical disulfiram–ethanol reaction when the patient has not been exposed to both disulfiram and ethanol. Most disulfiramlike reactions involve an exposure to ethanol.30,51,53,101 Ingestion of ethanol following ingestion of various Coprinus species of mushrooms can cause symptoms of a disulfiram–ethanol reaction (Chap. 113) .80,89 Many xenobiotics in combination with ethanol also produce symptoms of the disulfiram–ethanol reaction (Table 77-2) . Alcohols other than ethanol and organic solvents, including mineral spirits, can also cause symptoms of a disulfiram–ethanol reaction.87

Management

of

Disulfiram–Ethanol

Reactions For most patients experiencing suspected disulfiram–ethanol reactions, it is frequently useful to confirm the presence of ethanol, P.1180 either with an exhaled ethanol concentration or by obtaining a blood ethanol concentration. Because only small amounts of ethanol can precipitate a disulfiram–ethanol reaction, some patients, especially those with small ingestions or dermal exposures, may still manifest reactions in the absence of detectable ethanol concentrations at the time of evaluation. Elevated acetaldehyde concentrations in the blood will occur

during a disulfiram–ethanol reaction, but acetaldehyde concentrations are not readily available, and thus are not clinically useful in managing most patients.31 Symptomatic and supportive care is the mainstay of treatment. Gastrointestinal decontamination aimed at removing ethanol is unlikely to have any clinically significant effect on limiting the severity or duration of the disulfiram–ethanol reaction, because even small amounts of ethanol can cause toxicity in the presence of disulfiram. Additionally, because nausea and vomiting are common, patients often experience spontaneous gastric emptying. Antiemetics may improve nausea and vomiting, and histamine (H1 ) receptor antagonists, such as diphenhydramine, may lesson cutaneous flushing.91 Most patients with hypotension respond to intravenous crystalloid administration. Symptomatic hypotension refractory to these measures rarely occurs. If hypotension is refractory to crystalloid administration, a vasopressor should be administered. There is a theoretical benefit to administering a direct-acting vasopressor such as norepinephrine, because disulfiram inhibits dopamine β-hydroxylase, an enzyme necessary for norepinephrine synthesis. Indirect-acting vasopressors, such as dopamine, that require functioning dopamine β-hydroxylase to create a releasable pool of norepinephrine, may be less effective in the setting of disulfiram toxicity. Patients with cardiovascular instability should have an electrocardiogram performed.62 Most patients with a typical disulfiram-ethanol reaction who have normal vital signs can be safely discharged following resolution of symptoms. More prolonged observation is essential for patients with persistent symptoms, ECG abnormalities, or any potentially life-threatening effect. Fomepizole, an inhibitor of alcohol dehydrogenase, prevents the metabolism of ethanol to acetaldehyde.10 Theoretically, by preventing the production of acetaldehyde, fomepizole could limit the effects of the disulfiram–ethanol reaction. A patient on disulfiram experiencing a disulfiram–ethanol reaction was given

fomepizole experimentally, with an almost immediate decrease in the serum acetaldehyde concentration, and a rapid clinical improvement.54 Fomepizole normalized blood acetaldehyde concentrations and relieved the symptoms of the disulfiram–ethanol reaction in 4 volunteers given calcium carbimide and ethanol.54 Fomepizole should be considered for patients with life-threatening signs or symptoms of a disulfiram–ethanol reaction who are unresponsive to standard treatment (see Antidotes In Depth: Fomepizole) .

Clinical Acute

Manifestations Disulfiram

Overdose

Acute overdose of disulfiram is uncommon and typically does not cause life-threatening toxicity. Most patients will develop symptoms within the first 12 hours following ingestion, with resolution of symptoms within 24 hours of ingestion.79 Nausea, vomiting, and abdominal pain are common. A spectrum of central nervous system depression—from drowsiness to coma—may occur.79 Metabolic acidosis is rare.57 Dysarthria and movement disorders, including myoclonus, ataxia, dystonia, and akinesia, occur rarely. The movement disorders may be related to direct effects on the basal ganglia.50,52,57 Sensorimotor neuropathy, subacute weakness, and psychosis are uncommon.34,44,84,105 Hypotonia may be a prominent feature in children. 6 Persistent neurologic abnormalities, lasting for weeks to months, are reported in both children and adults, but are rare.11,57,79

Chronic

Disulfiram

Therapy

Most of the known adverse effects are derived from case reports. Despite the widespread international use of disulfiram, there are

few well-controlled human trials evaluating chronic disulfiram toxicity. Toxicity from chronic disulfiram therapy correlates poorly with dose, and there is a wide variability in latency period between the time therapeutic dosing is initiated and when symptoms develop. Side effects of chronic disulfiram therapy, unsurprisingly, occur most commonly in alcoholic patients. Adverse effects most typically involve the liver, the skin, or the central nervous system. Common effects include nausea, drowsiness, dizziness, headache, a metallic taste in the mouth, halitosis, and skin odor described as having a sulfur or garlic smell,

decreased

libido,

impotence,

and

hypertension.32,58,98

Disulfiram therapy causes a spectrum of hepatotoxicity ranging from asymptomatic minor elevations of the aminotransferase levels, to fulminant hepatic failure and death. The hepatotoxicity is clinically indistinguishable from alcoholic hepatitis. The mechanism of disulfiram-induced hepatotoxicity is poorly understood and may be idiosyncratic. Injury may be caused by a hypersensitivity reaction or by direct hepatotoxicity related to a metabolite, or to an immunologic reaction.25 Histologic patterns of toxicity are predominantly hepatocellular, specifically centrilobular in nature.8 The onset of hepatotoxicity usually varies from 2 weeks to 6 months after initiation of disulfiram therapy.8 Although disulfiraminduced hepatotoxicity may be exacerbated by concurrent alcohol consumption, nonalcoholic patients taking disulfiram as a treatment for nickel dermatitis also developed hepatotoxicity.37,52,43 Elevated aminotransferases are a relative contraindication to disulfiram therapy. They cannot be used to confidently predict which patients will develop disulfiram-induced hepatotoxicity.86 Dermatoses associated with disulfiram therapy include exfoliative dermatitis, contact dermatitis, urticaria, pruritus, acne, and yellow palms.59,85 Interestingly, thiram and its analogs, which are found in rubber, are also potent skin sensitizers.89 Some patients with rubber sensitivity develop localized and generalized dermatitis following ingestion of

disulfiram, whereas other patients can be treated with disulfiram without dermatologic complications.68,99,101 Disulfiram can also cause exacerbations of nickel and cobalt dermatitis.45,63 Disulfiram may exacerbate nickel dermatitis because diethyldithiocarbamate complexes with nickel and increases its absorption. 35 Reported neuropsychiatric side effects include headache, dizziness, confusion,77 memory impairment,58 ataxia, parkinsonian symptoms,52 seizures,17 optic neuropathy,1 coma,58 peripheral neuropathy, psychosis,7,32 depression, catatonia,24 and organic brain syndrome.48,84 Confusion, memory impairment, peripheral neuropathy, and psychiatric diagnoses are common in alcoholic patients who are not taking disulfiram. Alcohol-induced and disulfiram-induced peripheral neuropathy are difficult to distinguish clinically. Disulfiram-induced peripheral neuropathy usually involves motor nerves more than sensory and autonomic nerves, is worse distally, and is usually bilateral. A small prospective study of alcoholics taking therapeutic doses of disulfiram did reveal abnormalities of peripheral P.1181 function.70

nerve Neurologic symptoms may be related to both dose and duration of therapy, but these issues are not well studied.21 Although case reports suggest an increased incidence of psychiatric complications, one prospective randomized study did not find an increased incidence of psychiatric complications in alcoholic patients taking disulfiram.12 Disulfiram therapy may result in increases in serum cholesterol.60 Although patients with occupational exposures to carbon disulfide, a metabolite of disulfiram, have an increased risk of atherosclerosis and ischemic heart disease, this has not been proven for patients taking disulfiram. One case report suggests that disulfiram may cause thrombocytopenia.95 Disulfiram is not believed to be teratogenic or carcinogenic.

Diagnostic

Testing

Disulfiram serum concentrations are not useful when managing most patients with suspected disulfiram toxicity following an acute overdose, chronic therapy, or a disulfiram–ethanol reaction. When interpreting a disulfiram serum concentration, it is important to note that because of rapid metabolism, only a small proportion of ingested disulfiram appears in the blood as the parent compound. Metabolites of disulfiram, including diethyldithiomethylcarbamic acid and diethylthiomethylcarbamic acid, can also be measured in the serum. Other markers of ingestion of disulfiram include carbon disulfide on the breath and diethylamine in the urine. The activity of hepatic mitochondrial aldehyde dehydrogenase can be determined by liver biopsy, but this is impractical and dangerous. Leukocyte aldehyde dehydrogenase activity correlates most closely with hepatic mitochondrial aldehyde dehydrogenase activity. Decreased erythrocyte ALDH 1 activity and leukocyte ALDH 2 activity are markers of disulfiram exposure, although neither enzyme assay is commonly available.

Chronic

Disulfiram

Therapy

Monitoring aminotransferase levels, both before the initiation of therapy to establish a baseline and during the course of therapy, is recommended. Unfortunately, no well-controlled trial has specifically addressed the issue of the timing or frequency of routine aminotransferase monitoring. There is indirect evidence that continued use of disulfiram in the face of elevated aminotransferase levels increases the risk of developing lifethreatening hepatotoxicity.25 If an alcoholic patient has increased aminotransferase concentrations from chronic alcohol use, it is appropriate to delay the administration of disulfiram until the aminotransferase concentrations have normalized, as it is never obligatory to emergently initiate therapy. Common, but not

uniform, recommendations for asymptomatic patients include monitoring aminotransferases at 2 weeks following initiation of disulfiram therapy, and at 3–6 months intervals thereafter, or as needed.102 Unfortunately, even conservative monitoring regimens may fail to detect patients who develop hepatitis during the testing intervals, so clinicians should educate patients about the signs and symptoms of hepatitis. As a method of determining compliance with chronic disulfiram therapy, some authors have advocated using ethanol patch testing to produce cutaneous vasodilation. Studies demonstrate that patch testing is not a reliable measure of compliance with disulfiram therapy. Measuring leukocyte aldehyde dehydrogenase activity, serum concentrations of disulfiram and/or its metabolites, are better measures of compliance with disulfiram therapy.

Management Acute

of

Disulfiram

Disulfiram

or

Toxicity

Overdose

Symptomatic and supportive care is the mainstay of treatment. There is no antidote for disulfiram toxicity. No studies have specifically addressed gastrointestinal decontamination in the setting of an acute disulfiram overdose. Unless otherwise contraindicated, activated charcoal, 1 g/kg of body weight, should be administered. It would be unusual for a patient with an isolated disulfiram ingestion to require either orogastric lavage or wholebowel irrigation. Emesis is not indicated, especially because some emetics contain ethanol, which could precipitate a disulfiram–ethanol reaction.

Chronic

Disulfiram

Toxicity

If a patient on chronic disulfiram therapy develops hepatotoxicity related to disulfiram, the drug should be discontinued. In addition,

patients should be instructed to have their aminotransferase concentrations measured if they develop any signs or symptoms of hepatitis, including anorexia, nausea, vomiting, abdominal pain, generalized weakness, malaise, fever, pruritus, scleral icterus, or jaundice. If aminotransferase concentrations rise during disulfiram therapy, the drug should be discontinued. Although in some cases rechallenge with disulfiram can confirm the role of disulfiram in causing hepatotoxicity, the benefit is not substantial enough to outweigh the risk.8 Because the evidence to support the use of disulfiram therapy as part of a comprehensive alcohol treatment program is equivocal using the standards of evidence-based medicine, the risks of continuing disulfiram therapy usually outweigh the benefits. Following discontinuation of disulfiram therapy, hepatic aminotransferase levels usually return to baseline values. Rarely, patients may develop fulminant hepatic failure. Supportive care is the mainstay of treatment for disulfiraminduced hepatic failure. Liver transplantation has been successfully performed for disulfiram-induced hepatic failure.75

Summary Because disulfiram is still used in comprehensive alcohol treatment programs, it is critical to understand the distinction between the different forms of disulfiram toxicity, including toxicity from an acute overdose, from chronic therapy, and from a disulfiram–ethanol reaction. Disulfiram toxicity following an acute overdose is unlikely to be life-threatening unless a massive amount is ingested, an event that usually only occurs in suicidal adults. Although death is reported following disulfiram–ethanol reactions, most patients do not develop life-threatening toxicity. With the recent widespread availability of fomepizole, its role in treating life-threatening disulfiram–ethanol reactions requires further study. The most common adverse effects of disulfiram that

most clinicians, including toxicologists, encounter are secondary to chronic disulfiram therapy. These adverse effects on the liver and the central and peripheral nervous systems are often difficult to distinguish from the effects of chronic alcohol abuse. The effects, including life-threatening disulfiram-induced hepatotoxicity, are rare, and may be limited by closely monitoring patients prescribed disulfiram and by discontinuing disulfiram therapy as soon as any evidence of toxicity develops. P.1182

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64. Motte S, Vincent JL, Gillet JB, et al: Refractory hyperdynamic shock associated with alcohol and disulfiram. Am J Emerg Med 1986;4:323–325. 65. Musacchio JM, Goldstein M, Anagnoste B, et al: Inhibition of dopamine-b-hydroxylase by disulfiram in vivo. J Pharmacol Exp Ther 1966;152:56–61. 66. Neu HC, Prince AS: Interaction between moxalactam and alcohol. Lancet 1980;1:1422. 67. Olesen OV: Disulfiram (Antabuse) as inhibitor of phenytoin metabolism. Acta Pharmacol Toxicol 1966;24:317–322. 68. Olfson M: Disulfiram and allergy to rubber. Am J Psych 1988;145:651–652. 69. O'Reilly RA: Interaction of sodium warfarin and disulfiram (Antabuse) in man. Ann Intern Med 1973;78:73–76. 70. Palliyath SK, Schwartz BD, Gant L: Peripheral nerve functions in chronic alcoholic patients on disulfiram: A sixmonth follow-up. J Neurol Neurosurg Psychiatry 1990;53:227–230. 71. Pattison EM: Is there a formaldehyde-disulfiram reaction. J Stud Alcohol 1982;43:1257–1259. 72. Petroni NC, Cardoni AA: Alcohol content of liquid medicinals. Clin Toxicol 1979;14:407–432.

73. Phillips M: Persistent sensitivity to ethanol following a single dose of parenteral sustained-release disulfiram. Adv Alcohol Subst Abuse 1987;7:51–61. 74. Poulsen HE, Ranek L, Jorgensen L: The influence of disulfiram on acetaminophen metabolism in man. Xenobiotica 1991;21:243–249. 75. Rabkin JM, Corless CL, Orloff SL, et al: Liver transplantation for disulfiram-induced hepatic failure. Am J Gastroenterol 1998;93:830–831. 76. Rainey JM: Disulfiram toxicity and carbon disulfide poisoning. Am J Psychiatry 1977;134:371–378. 77. Rathod NH: Toxic effects of disulfiram therapy, with two case reports. Q J Study Alcohol 1958;19:418–427. 78. Refojo MF: Disulfiram-alcohol reaction caused by contact lens wetting solution. Contact Intraocul Lens Med J 1981;7:172. 79. Reichelderfer TE: Acute disulfiram poisoning in a child. Q J Study Alcohol 1969;30:724–728. 80. Reynolds WA, Lowe FH: Mushrooms and a toxic reaction to alcohol. N Engl J Med 1965;272:630–631. 81. Rogers WK, Benowitz NL, Wilson KM, et al: Effect of disulfiram on adrenergic function. Clin Pharmacol Ther 1979;25:469–477.

82. Rothstein E: Warfarin effect enhanced by disulfiram (Antabuse). JAMA 1972;22:1052. 83. Rothstein E, Clancy DD: Toxicity of disulfiram combined with metronidazole. N Engl J Med 1969;280:1006–1007. 84. Ryan TV, Sciara AD, Barth JT: Chronic neuropsychological impairment resulting from disulfiram overdose. J Stud Alcohol 1993;54:389–392. 85. Santonastaso M, Cecchetti E, Pace M, et al: Yellow palms with disulfiram. Lancet 1997;350:1176. 86. Saxon AJ, Sloan KL, Reoux J, et al: Disulfiram use in patients with abnormal liver function test results. J Clin Psychiatry 1998;59:313–316. 87. Scott GE, Little FW: Disulfiram reaction to organic solvents other than ethanol. N Engl J Med 1985;312:790. 88. Shelly WB: Golf-course dermatitis due to thiram fungicide. JAMA 1964;188:115–117. 89. Spoerke DG, Rumack BH, eds: Handbook of Mushroom Poisoning— Diagnosis and Treatment. Boca Raton, FL, CRC Press, 1994. 90. Stoll D, King LE Jr: Disulfiram-alcohol skin reaction to beer-containing shampoo. JAMA 1980;244:2045. 91. Stowell A, Johnson J, Ripel Å, et al: Diphenhydramine and the calcium carbimide-ethanol reaction: A placebo-controlled

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92. Stransky G, Lambing MK, Simmons GT, et al: Methemoglobinemia in a fatal case of disulfiram–ethanol reaction. J Anal Toxicol 1997; 21:178–179. 93. Sunderman FW: Use of sodium diethyldithiocarbamate in the treatment of nickel carbonyl poisoning. Ann Clin Lab Sci 1990;20:12–21. 94. Svendsen TL, Kristenson MB, Hansen JM, et al: The influence of disulfiram on the half-life and metabolic clearance rate of diphenylhydantoin and tolbutamide in man. Eur J Clin Pharmacol 1976;9:439–441. 95. Sweetman PM, Taylor SWC, Elwood PC: Exposure to carbon disulphide and ischaemic heart disease in a viscose rayon factory. Br J Indus Med 1987;44:220–227. 96. Syed J, Moarefi G: An unusual presentation of a disulfiram alcohol reaction. Del Med J 1995;67:183. 97. Thompson CC, Tacke RB, Woolley LH, et al: Purpuric oral and cutaneous lesions in a case of drug-induced thrombocytopenia. J Am Dent Assoc 1982;105:465–467. 98. Truitt EB, Puritz G, Morgan AM, et al: Disulfiram-like actions produced by hypoglycemic sulfonylurea compounds. Q J Stud Alcohol 1962;23:197–207. 99. Vallari RC, Pietruszko R: Human aldehyde dehydrogenase: Mechanism of inhibition of disulfiram. Science

1982;216:637–639. 100. Volicer L, Nelson KL: Development of reversible hypertension during disulfiram therapy. Arch Intern Med 1984;144:1294–1296. 101. Webb PK, Gibbs SC, Mathias CT, et al: Disulfiram hypersensitivity and rubber contact dermatitis. JAMA 1979;241:2061. 102. Whittington HG, Grey L: Possible interaction between disulfiram and isoniazid. Am J Psychiatry 1969;125:1725–1729. 103. Williams EE: Effects of alcohol on workers with carbon disulfide. JAMA 1937;109:1472–1473. 104. Wilson H: Side effects of disulfiram. Br Med J 1962;2:1610. 105. Wright C, Vafier JA, Lake CR: Disulfiram-induced fulminating hepatitis: Guidelines for liver-panel monitoring. J Clin Psychiatry 1988;49:430–434. 106. Yodaiken RE: Ethylene dibromide and disulfiram—A lethal combination. JAMA 1978;239:2783. 107. Zapata E, Orwin A: Severe hypertension and bronchospasm during disulfiram–ethanol test reaction. 1992;305:870.

BMJ

108. Zorzon M, Mase G, Biasutti E, et al: Acute encephalopathy

and polyneuropathy after disulfiram Alcohol 1995;30:629–631.

intoxication.

Alcohol

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 78 - γ-Hydroxybutyric Acid

Chapter

78

γ-Hydroxybutyric

Acid

Lawrence S. Quang

Figure. No Caption Available.

An ambulance was called to provide assistance for a comatose 17-yearold student in a college campus dormitory. The paramedics found the patient completely unresponsive, hypoventilating (4 breaths/min), and lying in a pool of urine and feces. Earlier that same evening the patient had attended a dormitory party where, reportedly, there was “heavy― alcohol and “liquid E― consumption. Physical examination in the emergency department, revealed a minimally responsive young man with the following vital signs: blood pressure, 98/40 mm Hg; pulse, 43 beats/min; respirations, 4 breaths/min; rectal temperature, 95.9°F (35.5°C). Miosis and intermittent myoclonic

movements of his extremities were also noted. The patient was ventilated by bag-valve-mask. While preparations were made to perform endotracheal intubation, naloxone 0.4 mg IV was administered without effect. The patient was subsequently intubated uneventfully. An electrocardiogram (ECG) demonstrated sinus bradycardia with prominent U waves, and a basic metabolic panel, and serum and urine toxicology screens were unremarkable. The patient was admitted to the pediatric intensive care unit where he required mechanical ventilation for 4 hours before being extubated. On recovery he admitted to his first experimentation with γ-hydroxybutyric acid. Since its scientific discovery as a γ-aminobutyric acid (GABA) mimetic neurochemical, gamma-hydroxybutyric acid (GHB) has been transformed from an investigational drug with legitimate research applications and licit medical uses to the toxic ingredient in banned nutritional supplements and illicit recreational drugs. GHB and its numerous chemical precursors and structural analogs, most notably γ-butyrolactone (GBL) and 1,4butanediol (1,4-BD), represent an emerging group of drugs among the broad class of recreational drugs known as “club drugs.― Like most other “club drugs,― GHB, GBL, and 1,4-BD are physically and psychologically addictive with acute and chronic toxicity that may be severe or lethal. GHB, GBL, and 1,4-BD are consumed by a diverse population of acute and chronic abusers, who have misused them as sports supplements with touted anabolic effects; as dietary health supplements, with numerous unsubstantiated “natural health benefits―, such as sleep and sexual enhancement; or as recreational drugs, with purported euphoriant and psychedelic effects. Despite a federal proscription on GHB since 1990, state and federal legislative efforts to regulate and curb GHB abuse have proven to be more difficult to effect than with other “club drugs― because of the lawful availability of GHB chemical precursors, which are widely used by industry (GBL and 1,4-BD), and because of the unabating supply of alternative GHB analogs that include such drugs as γ-

valerolactone (GVL), γ-hydroxyvaleric acid (GHV), and tetrahydrofuran (THF). Perhaps more than any other contemporary drug of abuse, GHB and its analogs heralded the age of electronic drug trafficking, as purveyors exploited the Internet to popularize, market, and distribute GHB and its analogs. Recently, there has been a conspicuous increase in case reports of GHB, GBL, and 1,4-BD use leading to a severe, potentially life-threatening withdrawal syndrome, a clinical feature of toxicity that has not been described with other “club drugs.― With the notable exception of ketamine, GHB is one of the only “club drugs― that has licit medical uses, having recently received approval from the US Food and Drug Administration (FDA) as a therapy for narcolepsy.

History Before their recent emergence as popular recreational drugs, GHB, GBL, and 1,4-BD had a relatively quiescent history of medical research and licit therapeutic use that spanned more than 6 decades. The toxic effects of GBL were first reported in 1947, when it was noted to completely suppress

cortical

electroencephalographic P.1185 failure.35

(EEG) activity and cause death from respiratory Simultaneously, it was demonstrated that sublethal doses of GBL produced a reversible inhibition of voluntary movements in mice and chickens. GHB was subsequently discovered in 1960, when it was synthesized as a structural analog of the inhibitory neurotransmitter, GABA, and found to be capable of traversing the blood–brain barrier after peripheral administration.53 , 54 , 55 Three years later, GHB was determined to be a naturally occurring neurochemical in the mammalian brain.5 , 6 In 1966, the first association of the effects of 1,4-BD with GHB were made. Noting the close structural similarity of 1,4-BD with GHB, researchers demonstrated that 1,4-BD could produce an anesthetic response similar to GHB and GBL. In rodents, GHB, GBL, and 1,4-BD all produce anesthesia that is characterized by the loss of voluntary movement, righting reflex, struggle response, and body and limb tone, as well as myoclonic jerking.

EEG tracings of animals treated with GHB, GBL, or 1,4-BD have very similar wave patterns.95 As a result of these discoveries, GHB found its first clinical application as an anesthetic in the early 1960s.53 , 54 , 55 Several studies in the 1960s, involving a total of 376 patients, confirmed the potential of GHB to serve as an adjuvant to anesthesia.7 , 94 However, those same studies also documented adverse effects, including the occurrence of gross muscular movements when rapidly administered,7 as well as inadequate analgesia (abrupt rise in systolic and diastolic pressure during surgical incision), emergence delirium, and bradycardia.94 Although GHB continues to be investigated and used as an anesthetic adjuvant abroad,50 , 51 , 52 it has never gained widespread acceptance in the United States for this clinical application. An important research milestone in GHB history was reached in 1977, when it was reported that GHB use resulted in a significant increase in plasma growth hormone and rapid eye movement sleep in 6 healthy male human subjects.98 This discovery launched concerted efforts to study and develop GHB as a potential therapeutic agent for sleep disorders such as narcolepsy. However, as an unintended and misappropriated consequence of this and similar studies, GHB became popular as a sports supplement and “natural― soporific. Subsequently, in the late 1980s, GHB was introduced to the health and dietary supplement market with dubious claims that it could metabolize fat, enhance muscle building, and improve sleep. However, it was quickly associated with severe adverse effects and deaths. 11 , 23 Accordingly, the FDA intervened in November 1990 to prohibit further nonprescription sales of GHB in nutritional supplements.32 , 33

Despite the known dangers from overdoses and FDA regulations, GHB became fashionable and trendy as a recreational drug during the 1990s, as reports of its “natural― euphoric and hallucinogenic properties popularized its misuse at “dance raves― and nightclubs. The rapid expansion of the Internet during the 1990s helped to fuel the emergence of GHB as a widespread recreational drug. The Internet allowed GHB

purveyors to circumvent the FDA ban on nonprescription sale of GHBcontaining products by shifting their distribution from over-the-counter sales to online sales. This FDA ban was further circumvented by substitution of GBL for GHB as the active ingredient in dietary supplements. Soon after its substitution into dietary health supplements, toxic effects similar to GHB, including deaths, were attributed to GBL.10 , 45 , 60 , 82 Consequently, the FDA issued a voluntary recall of GBLcontaining health supplements in February 1999.31 As was the case with the initial recall of GHB, purveyors of GBL-containing dietary health supplements willingly complied with the FDA order because of the availability of yet another GHB precursor, 1,4-BD. Predictably, the consequences of 1,4-BD misuse and abuse including death were clinically similar to that of GHB and GBL.14 , 24 , 87 , 90 , 110 In the midst of its emergence as an illicit drug, GHB received both orphan drug and investigational new drug (IND) status from the FDA for clinical trials as a therapeutic drug for narcolepsy. Confounding and nearly preventing its clinical development as a narcolepsy treatment, GHB also developed forensic notoriety as a chemical submission agent used in the commission of drug-facilitated sexual assault. After several highly publicized GHB-related “date rape― deaths, a federal statute gave GHB dual status as a Schedule III drug for IND use in clinical trials for narcolepsy, and as a Schedule I drug for illicit purposes.20 Authority was also granted to federal law enforcement agencies to monitor the commercial and industrial sale and distribution of GBL for potential diversionary activity.19 In response to several deaths in 1999, 1,4-BD was classified by the FDA as a Class I Health Hazard.31 This FDA categorization recognizes 1,4-BD to be a potentially life-threatening health hazard but does not impose any regulatory actions on its commercial sale or distribution. The current legal status of GHB under federal law has rendered GHB more difficult to obtain, and subsequently increased trafficking and abuse of its chemical precursors and structural analogs.

Epidemiology Illicit use of GHB and its analogs have primarily occurred in 1 of 4 settings: in the recreational setting of raves or night clubs; in the athletic setting of bodybuilding gyms and fitness centers; in the home consumer setting of individuals seeking its “natural health benefits―; and in the criminal setting of drug-facilitated sexual assault. Products containing GHB, GBL, or 1,4-BD marketed for these purposes are generally no longer sold because of law enforcement pressure; however, comparable products with similar brand names are available.31 , 32 National statistics demonstrate a trend of escalating GHB abuse and poisoning throughout the last decade. In 2002, there were 1386 exposures with GHB and its analogs and precursors reported to the American Association of Poison Control Centers–Toxic Exposure Surveillance System, representing more than a 2-fold increase from approximately 600 GHB cases reported in 1996. Among these, 1181 exposures (85%) required treatment in a healthcare facility and resulted in 272 major outcomes and 3 deaths (Chap. 130 ).108 Eighty-five percent of these exposures involved individuals older than age 19 years. According to the Drug Abuse Warning Network, emergency department (ED) mentions related to GHB increased significantly from 1994–1999, and GHB mentions increased dramatically from 1997–2000.96 Almost half (46%) of these ED mentions of GHB were attributed to patients age 20 to 25 years, nearly 90% were white, and two-thirds were male. Seventy-four percent of ED visits for GHB toxicity involved another club drug. Alcohol was the most frequently mentioned coingestant in visits with GHB (54%), followed by marijuana (14%) and 3,4methylenedioxymethamphetamine (ecstasy, 12%). Although most GHB abusers are young adults, adolescents have also abused GHB, and the 2002 “Monitoring the Future― study reported an annual prevalence rate of GHB use of 0.8%, 1.4%, and 1.5% in grades 8, 10, and 12, respectively.48 P.1186 While the illicit use of GHB and its precursors appears to have reached a

plateau in the United States, recent worldwide statistics have reported GHB abuse to be on the rise internationally. For example, in Spain, GHB was responsible for 3.1% of all toxicologic emergencies in an urban public hospital ED during a 15-month study period, and ranked second in illicit drugs requiring emergency consultation.72 While European and Asian countries have reported recent rises in acute poisonings from GHB and its chemical precursors and structural analogues, virtually all of the reports of GHB dependence and withdrawal have been from the United States.

Pharmacology GHB has a dual pharmacologic profile, with the intrinsic neuropharmacology of endogenous GHB being distinct and divergent from that of exogenously administered GHB. The principal difference between their profiles is that the intrinsic neuropharmacologic activity of endogenous GHB appears to be mediated by the GHB receptor, whereas the neuropharmacologic activity of exogenously administered GHB is likely mediated by the GABAB receptor.

Endogenous

GHB

Although the precise physiologic function of endogenous GHB is unknown, GHB is a putative neurotransmitter or neuromodulator because it possesses the requisite pharmacologic properties for recognition as such. That is, (a) it has a discrete regional and subcellular distribution in the CNS; (b) it has subcellular systems for synthesis, vesicular uptake, and storage in presynaptic terminals; (c) it is released in a Ca2 + -dependent manner following depolarization of neurons; (d) subsequent to neuronal release, GHB binds to GHB-specific receptors and modulates neurotransmitter systems; (e) following neuronal release, GHB activity is terminated by active uptake from the synaptic cleft for metabolism by specific cytosolic and mitochondrial enzymes; and (f) localized application of GHB can produce a response that mimics the action of endogenous GHB released by nerve stimulation.

Although GHB is heterogeneously distributed throughout the mammalian CNS, its highest concentrations are found in the hippocampus, basal ganglia, hypothalamus, striatum, and substantia nigra.64 , 66 , 103 A s shown in Figure 78-1 , the subcellular presynaptic synthesis of endogenous GHB involves 3 precursors (GABA, GBL, and 1,4-BD) and 5 enzymes (GABA-transaminase, succinic semialdehyde reductase [SSA reductase], alcohol dehydrogenase [ADH], aldehyde dehydrogenase [ALDH], and serum and peripheral tissue lactonases). The extracellular release of GHB from presynaptic GHB terminals occurs by neuronal depolarization in a Ca2 + -dependent manner.61 , 62 In the early 1980s, three independent studies collectively proposed the existence of a putative GHB-specific receptor.4 , 63 , 93 Although the existence of a GHB-specific receptor has been speculated and disputed for some time, its existence was recently verified by the cloning of a Gprotein–coupled receptor in the rat that is activated by endogenous GHB.1 This newly cloned receptor exhibits no binding affinity for GABA, baclofen, or glutamate, which have no capacity to displace radioactive GHB from this binding site. In fact, a family of GHB receptors in the brain is now identified. Activation of the GHB receptor alters second-messenger systems in the hippocampus by increasing cyclic guanosine monophosphate (cGMP) turnover and stimulating inositol phosphate turnover, which subsequently modulate the activity of other neurotransmitter systems.104 From a toxicologic perspective, perhaps the most important neurotransmitter system altered by GHB binding is the GABA system at the GABAB receptor. Low-dose GHB inhibits GABA release in the thalamus, which may implicate a role for GHB in producing absence seizures,2 and decreases the extracellular GABA concentration in the frontal cortex.37 However, higher doses of GHB enhance GABA concentrations in the frontal cortex.37

Figure 78-1. The synthesis and metabolism of γ-hydroxybutyric acid. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; SSA reductase, succinic semialdehyde reductase; SSAD, succinic semialdehyde dehydrogenase.

GHB also exerts a prominent modulatory effect on dopamine neurotransmission. Acute administration of GHB inhibits dopamine release and results in the accumulation of dopamine in the presynaptic cells. This effect is mediated by GHB inhibition of dopamine neuron firing in the substantia nigra and mesolimbic regions,41 , 47 , 84 and the subsequent autoreceptor-mediated stimulation of tyrosine hydroxylase activity, resulting in increased presynaptic dopamine production.73 , 107 The attenuation of dopamine neurotransmission following GHB administration

may be the pharmacologic basis for the loss of locomotor activity in experimental animals and overdose patients. Other systems modulated by GHB include the serotonin system, cholinergic system, and opioid system. GHB modulates the serotonin system by increasing its turnover rate, without altering total brain serotonin concentrations, likely by elevating presynaptic tryptophan concentrations.43 , 64 , 106 GBL, but not GHB itself, increases total brain acetylcholine concentrations by decreasing firing of cholinergic neurons.36 , 56 , 89 Such an increase in brain acetylcholine might underlie the pharmacologic basis for the reported analeptic effect of GHB in narcolepsy. Despite having no binding affinity for opioid receptors, GHB increases the release of endogenous opioids in various brain regions.30 , 38 , 41 , 57 Furthermore, despite naloxone having no affinity for the GHB receptor, administration of the opioid antagonists naloxone and naltrexone

can

P.1187 attenuate or reverse the electrophysiologic and behavioral actions of GHB on dopamine neuron firing and catalepsy in experimental animals.29 , 92 After its release from GHBergic presynaptic membranes, GHB activity is terminated by an active vesicular uptake system driven by the vesicular inhibitory amino acid transporter (the same transporter that mediates the vesicular uptake of GABA and glycine) or by an active cellular uptake from the synaptic cleft by means of a high-affinity, Na+ -dependent, transport protein specific for GHB and its analogs.3 , 40 , 75 Once within the cell, the degradation of endogenous GHB in the mammalian brain can occur via 4 pathways, leading to succinic acid (SSA) which enters the tricarboxylic acid cycle, GABA, trans -4-hydroxycrotonic acid, or 4,5-dihydroxyhexanoic acid. In the first degradative pathway, which is the most significant quantitatively, GHB is oxidized to SSA by the nicotinamide adenine dinucleotide, phosphate-dependent, high Km SSR (succinic semialdehyde reductase), which is now commonly referred to as GHB dehydrogenase (GHB-DH) (Fig. 78-1 ).

Exogenous

γ-Hydroxybutyric

Acid

Although accumulating evidence favors the role of endogenous GHB as a neuromodulator, the study of the pharmacologic profile of exogenous GHB is still in its infancy. However, current data suggest that the GABAB receptor is a major component of the neural substrate mediating the pharmacologic, behavioral, clinical, and toxicologic actions of exogenous GHB and its precursors. When the brain GHB concentration exceeds its physiologic concentration by 2–3 orders of magnitude, it will saturate GHB-specific receptors and produce GABAB receptor-mediated brain perturbations.59 Similarly, only millimolar concentrations of GHB can mimic the postsynaptic electrophysiologic effects of baclofen on the GABAB receptor, which can be blocked by GABAB receptor-selective antagonists but not by GHB receptor-selective antagonists such as NCS 382.26 , 28 It is theorized that under conditions of excess exogenous administration, GHB may act both directly as a partial GABAB receptor agonist and indirectly through a GHB-derived GABA pool.42 GHB itself is a weak GABAB receptor agonist with an affinity in the mmol/L range, which far exceeds the 1–4 µmol/L physiologic concentrations of GHB in the brain.18 , 59 , 69 Therefore, the supraphysiologic concentration of GHB that could accumulate after its exogenous administration may exert its effects through a weak, direct agonistic effect on GABAB mediated mechanisms.

GHB

and

Endogenous

receptor-

Analogs

GHB has several endogenous structural analogs (GABA, trans -4hydroxycrotonic acid [T-HCA]) and chemical precursors (GBL, 1,4-BD, γcrotonolactone [GCL]), as well as several well synthetic structural analogs (5-hydroxyvaleric acid, γ-methyl-GHB, γ-phenyl-GHB, γ-(p chlorophenyl)-GHB, γ-(p -methoxyphenyl)-GHB, γ-benzyl-GHB, R -γbenzyl-GHB, S -γ-benzyl-GHB, γ-(p -methoxybenzyl)-GHB [NCS 435]), and precursors (GVL, THF). Of these analogs, illicit abuse has only been reported with GBL, 1,4-BD, γ-methyl-GHB, GVL, and THF. GHB itself usually exists as either a free acid (a colorless liquid) or as a

sodium salt (generally a white powder). The molecular formulas of GHB for its free acid and sodium salt are C4 H8 O3 (molecular weight [MW] 104.11 g/mol) and C4 H7 NaO3 (MW 126.09 g/mol), respectively. 4Hydroxybutyric acid is the chemical name for its free acid, and sodium oxybate is the national nonproprietary name for its sodium salt, which is also a prescription drug. Synonyms for its chemical name are important because illicit GHB products often intentionally list obscure alternative chemical synonyms to conceal the identity of GHB. Synonyms include γhydroxybutyric acid, 4-hydroxybutyric acid sodium salt, γ-hydroxybutyric acid sodium salt, sodium 4-hydroxybutyrate, and 4-hydroxybutanoic acid. GBL, the lactone ring precursor analog of GHB, is an endogenous substance in the mammalian brain at concentrations of approximately 10% that of GHB.17 Chemically, it is most commonly referred to as γbutyrolactone, but it also has numerous obscure chemical synonyms, which are often intentionally listed on illicit GBL product labels to conceal the identity of GBL, such as 2(3 H)-furanone dihydro; butyrolactone; 4butyrolactone; dihydro-2(3 H)-furanone; 4-butanolide; 2(3 H)-furanone; tetrahydro-2-furanone; 4-deoxytetronic acid; butyrolactone-γ; 4hydroxbutyric acid lactone; γ-hydroxybutyric acid lactone; butyryl lactone; butyric acid lactone; butyrolactone; hydroxybutanoic acid lactone; tetrahydro-2-furanone; 1,4-butanolide; and 1,4-lactone. Based on behavioral and analytical observations, GBL is best described as a precursor to the pharmacologically active metabolite GHB. 1,4-BD, the other naturally occurring GHB precursor analog, is usually referred to by the chemical name 1,4-butanediol, but it has several additional chemical synonyms, including 1,4-butylene glycol, 1,4-dihydroxybutane, and 1,4tetramethylene glycol. CNS depression by 1,4-BD is mediated through metabolism to GHB.85

Synthetic

Analogs

Numerous pharmacologically active synthetic GHB structural analogs have been produced in the laboratory. In general, lengthening of the GHB carbon chain and introduction of functional groups to the γ-carbon both

can yield potent compounds with respect to affinity for [3 H]GHB-labeled binding sites. Although the list of pharmacologically active GHB structural analogs appears to be ever increasing, only GHV (γ-methyl-GHB) abuse is reported to date. Nevertheless, the possibility exists for future illicit introduction of these GHB structural analogs, as law enforcement pressure continues to increase for GHB, GBL, and 1,4-BD.

Synthetic

Precursor

Analogs

GVL and THF have been illicitly used as synthetic precursor analogs of GHV and GBL/GHB, respectively. GVL is the structural analog of GBL produced by the methylation of GBL in the γ (4-carbon) position. It has the chemical synonyms 4-hydroxypentanoic acid lactone, 4,5-dihydro-5methyl-2(3 H)-furanone, and γ-methyl-GHB. When administered, GVL undergoes hydrolysis to yield the GHB structural analog GHV.67 , 77 , 78 Furthermore, GVL is reported to be used in the illicit synthesis of GHV.22 THF is the cyclic ether structural analog of GBL. THF can serve as the key precursor ingredient in the illicit synthesis of GBL.80 , 86 Because THF is a widely employed industrial solvent, human toxicity is generally available in the context of occupational exposure and poisoning, where THF causes nausea, headache, blurred vision, dizziness, narcosis, tinnitus, chest pain, and coughing.9 , 81 Acute poisonings and fatalities from THF are rare; only 2 published references are available. In the first case, a 50-year-old man ingested a drink offered by a stranger and abruptly developed abdominal pain, nausea, and vomiting. He was hospitalized 16 hours postingestion, developed hepatorenal syndrome, and died on hospital day 5. THF was detected in the patient's urine by gas chromatography-mass spectrometry (GC/MS).76 In the second case, a 55-year-old woman intentionally ingested an organic solvent and psychoactive medications, and presented to an ED with P.1188 coma. She required endotracheal intubation, and a chest radiograph was consistent with aspiration pneumonitis. She had a complete recovery on hospital day 4 and was discharged after 8 days, without any sequelae. Toxicologic screening by high-performance liquid chromatography (HPLC)

revealed the presence of zolpidem and fluoxetine. Quantitative nuclear magnetic resonance (NMR) analysis was performed, demonstrating THF and GHB in serum and urine at concentrations of 813 and 850 mg/L, and 239 and 2977 mg/L, respectively. A GC/MS method confirmed the NMR observations.9

Pharmacokinetics

and

Toxicokinetics

GHB is rapidly and near completely absorbed from the gastrointestinal tract with an onset of action of about 15 minutes,105 and reaches its peak effect by 90–120 minutes.46 The steady-state volume of distribution is approximately 0.58 L/kg.44 GHB is eliminated very rapidly, with a half-life of 30 minutes.8 Less than 5% of the parent compound is recovered in the urine. In comparison, GBL is more rapidly absorbed and has a longer duration of action, a result of higher lipid solubility. Because 1,4-BD is metabolized by alcohol dehydrogenase (ADH), coingestion with ethanol can prolong its clinical effects because of competitive inhibition of ADH.79 , 87

Clinical

Manifestations

The clinical manifestations of overdose of GHB and related xenobiotics can be predicted based on known pharmacologic activity and kinetics. Specifically, effects on the GABA and opioid neurotransmitter symptoms seem to predominate. In volunteers undergoing sleep studies, a clear oral dose–response effect for GHB is noted: 30 mg/kg produces CNS depression and myoclonus, 50 mg/kg produces unconsciousness, and 60 mg/kg produces coma.33 , 65 Again, tolerance has the ability to shift this dose–response curve to the right. These clinical manifestations of overdose are highlighted by a number of well-documented cases.23 , 24 , 90 , 99 , 110 Although the constellation of signs and symptoms are best reported for GHB, the following is most likely applicable to the entire class of xenobiotics. The onset of action is very rapid, with effects noted as early as 15 minutes postingestion. Vital

signs typically reveal hypotension, bradycardia, bradypnea, and hypothermia. Bradypnea is the most consequential of these effects, and apnea is the most likely cause of death. Pupils are typically miotic and poorly responsive to light. Salivation and vomiting are common, especially when CNS depression is prominent. These effects compound bradypnea and hypoventilation in that they increase the risk for aspiration. CNS effects can range from hallucinations, disorientation, and agitation to lethargy, followed by stupor and coma. These findings most likely represent disinhibition of higher cortical areas and are consistent with other sedative–hypnotics such as ethanol. In contrast to ethanol and other sedative–hypnotics, however, patients with GHB overdose often have a characteristic violent arousal that accompanies attempts to assess their gag reflex or perform intubation, which is somewhat suggestive of a clonidine overdose (Chap. 60 ). Motor abnormalities are also common, and there is debate whether they represent seizures, myoclonus or both. In animal models, GHB can produce seizures, yet EEG monitoring in humans suggests that repetitive movements most likely represent myoclonus.27 Clinically, these events are often called “seizures― because, in the absence of consciousness or EEG monitoring, it is difficult to distinguish these two disorders. Other findings include prominent U waves on the ECG.13 Electrolytes, anion gap, and other standard tests are usually normal. The duration of effect is characteristically short. Many patients will abruptly awaken within a few hours of presentation and appear completely normal. Even those patients who require endotracheal intubation are usually able to be extubated within 8 hours. As long as aspiration and hypoxia have not occurred, most patients suffer no sequelae.

Diagnostic

Testing

The presence of GHB and related xenobiotics can be determined,

quantitatively and qualitatively, in both serum and urine, using a variety of analytical techniques.39 , 102 , 109 The most important caveat is that appropriate cutoff values must be selected to distinguish use and overdose from endogenous levels.16 , 25 , 49 , 74 In general, unconsciousness occurs when serum concentrations reach 50 µg/mL, and levels above 260 µg/mL typically produce deep coma.90 Attempts to relate concentrations to clinical effects in any individual might not be valid because of the potential for tolerance. Due to rapid metabolism and elimination, concentrations return to endogenous values shortly after nontolerant patients become clinically normal. Most clinical hospital laboratories do not routinely test for the presence of GHB and related xenobiotics, and recovery is typically rapid, so results of analytical testing are not useful for clinical care. They may, however, have forensic implications. Other routine tests that should be obtained in patients with depressed levels of consciousness include a rapid evaluation of blood glucose, an ethanol concentration, and an ECG. When intentional overdose or selfharm is suspected, a determination of acetaminophen concentration is also indicated. Other studies should be obtained based on the clinical condition of the patient.

Treatment The provision of good supportive care remains the mainstay of therapy. The decision to perform endotracheal intubation should be made at the bedside and based on a clinical assessment of oxygenation and ventilation. Despite deep coma, many patients will have adequate respirations and airway-protective reflexes. Because the duration of unconsciousness is relatively brief, coma, in and of itself, should not be considered an absolute indication for endotracheal intubation. Hypotension usually responds to fluids, and bradycardia rarely requires pharmacologic intervention. Hypothermia is mild and typically responds to passive rewarming. Dextrose and thiamine should be given, as clinically indicated. Although

no clinically available GHB antagonists exist, both naloxone and physostigmine have been used. A trial of naloxone is often clinically reasonable in the undifferentiated patient, based on the findings of small pupils and CNS and respiratory depression. Although in animal models some of the effects of GHB are reversed by naloxone, naloxone administration to GHB-toxic humans is largely unsuccessful.58 Likewise, while P.1189 anecdotal reports suggest some utility for physostigmine, a systematic review of available data failed to find any convincing supporting evidence.101 There is no role for any form of gastrointestinal decontamination. GHB and related xenobiotics are rapidly absorbed and can produce significant airway compromise. It is unlikely that a significant percentage of the ingested dose will be present in the stomach at the time of presentation, and the use of activated charcoal will only increase the risk of vomiting and aspiration. However, if a coingestant is suspected, appropriate decontamination techniques can be used, as long as there are no contraindications.

GHB

Withdrawal

Severe and life-threatening manifestations follow abrupt cessation or reduction in intake of GHB or any of its precursors or analogs.15 , 21 , 70 , 88 , 100 Because GHB and related xenobiotics have a short duration of effect, symptoms usually develop very rapidly and are clinically consistent with sedative hypnotic withdrawal. Patients develop agitation, disorientation, hallucinations, hypertension, tachycardia, hyperthermia, tremor, and seizures, often within hours of their last use.12 , 83 Treatment principles involve sedation, cooling, volume resuscitation, and a search for other medical and traumatic causes of alterations in behavior. Although benzodiazepines appear to be the safest initial pharmacologic agent to control behavior, excessively large doses may be required. When patients appear resistant to benzodiazepines, either

barbiturates or propofol can be given.91 Endotracheal intubation is often required when barbiturates or propofol are used.

Summary GHB is a unique xenobiotic in that it is an endogenous neurotransmitter, a licensed pharmaceutical, and a drug of abuse. Complex pharmacologic effects with multiple receptors produce rapid coma with hypotension, bradycardia, respiratory depression, and miosis. Treatment is largely supportive, and because the duration of effect is short, there is essentially no value in attempting to antagonize receptors or enhance elimination. Although fatality is possible, most patients recover rapidly, with no long-standing effects.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 79 - Inhalants

Chapter

79

Inhalants Heather

Long

A mother returned home from a parent–teacher conference regarding her 11-year-old daughter; both the parent and the teacher had become concerned about some behavioral changes noted in the girl over the past few months. The mother found her daughter in the bathroom, holding a can of air freshener aerosol spray. Upon discovery, the girl immediately collapsed and lost consciousness. She had some short-lived twitching movements of her extremities that were not rhythmic. On arrival of emergency medical services (EMS), the girl was unresponsive and the electrocardiogram revealed ventricular tachycardia. A white residue was noted around her mouth. EMS initiated resuscitation following the Pediatric Advanced Life Support protocol, which included three stacked, unsynchronized defibrillations at 200, 300, and 360 joules, followed by the administration of intravenous epinephrine (0.01 mg/kg). The patient was endotracheally intubated and given 100% oxygen. Chest compressions were continued throughout transport to the emergency department (ED). On arrival to the ED, the child was asystolic. Resuscitative efforts,

including chest compressions and the intravenous administration of epinephrine (0.1 mg/kg) and atropine (0.02 mg/kg), were continued in the ED. After approximately 30 minutes, the patient was pronounced dead. Inhalant abuse is defined as the deliberate inhalation of vapors for the purpose of changing one's consciousness or becoming “high.― It is also referred to as volatile substance abuse and was first described in 1951.30 Inhalants are appealing to adolescents because they are inexpensive, readily available, and sold legally. Initially, inhalant abuse was viewed as physically harmless, but reports of “sudden sniffing death― began to appear in the 1960s.6 Shortly thereafter, evidence surfaced of other significant morbidities, including organic brain syndromes and peripheral neuropathy.

Epidemiology The demographics of inhalant abuse differ markedly from that of other traditional substances of abuse. The 2003 Monitoring the Future Study found that more than 2 million youths between the ages of 12 and 17 years used inhalants at least once in their lifetime.126 The 2000 National Household Survey on Drug Abuse showed that the number of new inhalant users in the United States increased more than 50%, from 618,000 to 979,000, between 1994 and 2000.126 Youths ages 12–17 years had higher rates of past-year use than did adults ages 18 years and older. The lifetime prevalence of inhalant use peaked among 8th graders at 15%. The median age of first use is 13 years.4 Although long considered to be a problem among boys, there has been a steady increase of inhalant abuse among girls, and their lifetime prevalence now equals that of boys.8 In the United States, the problem is greatest among children of lower socioeconomic groups; non-Hispanic white adolescents are the most likely and black adolescents the least likely to use inhalants.80 Although inhalant use is a problem in both urban and rural communities, its prevalence is higher in rural settings.105 This may relate to the easier access teens in urban areas have to other drugs

of abuse. Inhalant abuse includes the practices of sniffing, huffing, and bagging. Sniffing entails the inhalation of a volatile substance directly from a container, as occurs with airplane glue or rubber cement. Huffing involves pouring a volatile liquid onto fabric, such as a rag or sock, and placing it over the mouth and/or nose while inhaling. Huffing is the method used by more than 60% of volatile-substance abusers.80 Bagging refers to spraying a solvent into a plastic or paper bag and rebreathing from the bag several times; spray paint is among the xenobiotics commonly used with this method.

Agents

Used

There are myriad xenobiotics abused as inhalants (Table 79-1 ), most of which are volatile hydrocarbons. Hydrocarbons are organic compounds comprised of carbon and hydrogen atoms and are divided into two basic categories: aliphatic (straight, branched, or cyclic chains) and aromatic. Most of the commercially available hydrocarbon products are mixtures of hydrocarbons; for example, gasoline is a mixture of aliphatic and aromatic hydrocarbons that may consist of more than 1500 compounds. Substituted hydrocarbons contain halogens or other functional groups (eg, hydroxyl or nitrite), other than carbon and hydrogen, that are substituted for hydrogen atoms in the parent structure. Solvents are themselves a heterogeneous group of chemical compounds that are used to dissolve other chemical compounds or provide a vehicle for their delivery. The most commonly inhaled volatile hydrocarbons are fuels, such as gasoline, and solvents, such as toluene.105 Other commonly inhaled hydrocarbon-containing products include spray paints, lighter fluid, air fresheners, and glue. In most reported cases of inhalant use, the inhalant is identified not by its chemical name (eg, butane, toluene) but rather by its form (eg, lighter fluid, paint thinner). Because exact components may vary between commercial products, this method is inaccurate and imprecise.

Although volatile alkyl nitrites are technically substituted hydrocarbons, they have pharmacologic and behavioral effects, P.1193 as well as patterns of abuse that are distinct from the other volatile hydrocarbons. For this reason, researchers usually classify them as a separate category among abused inhalants. Amyl nitrite is the prototypical volatile alkyl nitrite.4 Amyl nitrite became popular in the 1960s with the appearance of “poppers,― small glass capsules containing the chemical in a plastic sheath or gauze. When crushed, the ampules release the amyl nitrite. When over-the-counter sales of amyl nitrite were restricted in 1968, sex and drug paraphernalia shops began selling small vials of butyl and isobutyl nitrites marketed as room deodorizers or liquid incense.4 , 75 Because of further restrictions on sales of alkyl nitrites, most of these products now contain chemicals that are not technically alkyl nitrites, such as cyclohexyl nitrite.4 Glues/adhesives Toluene, n -hexane, benzene, xylene, trichloroethane, trichloroethylene, tetrachloroethylene, ethyl acetate, methylethyl ketone, methyl chloride Spray paint Toluene, butane, propane Hair spray, deodorants, air fresheners Butane, propane, fluorocarbons Cigarette lighter fluid Butane Paint thinner Toluene, methylene chloride, methanol Gasoline Aliphatic and aromatic hydrocarbons Carburetor cleaner Methanol, methylene chloride, toluene, propane Dry cleaning agents, spot removers, degreasing agents Tetrachloroethylene, trichloroethane, trichloroethylene Typewriter correction fluid Trichloroethane, trichloroethylene

Nail polish remover Acetone Paints, lacquers, varnishes Trichloroethylene, toluene, n-hexane “Poppers― Amyl nitrite, isobutyl nitrite Room deodorizers Butyl nitrite, isobutyl nitrite, cyclohexyl nitrite Whipped cream dispensers “whippets― Nitrous oxide Inhalant

Chemical

TABLE 79-1. Common Inhalants and the Constituent Chemicals The most commonly used nonhydrocarbon inhalant is nitrous oxide. Nitrous oxide, or “laughing gas,― is used medicinally as an inhalational anesthetic. It is the propellant in supermarket-bought whipped cream canisters, and cartridges of the compressed gas are sold for home use in whipped cream dispensers. These battery-sized metal containers of compressed gas may be used as “whippets,― in which the container is punctured using a device known as a “cracker,― and the escaping gas is either inhaled directly or collected in a balloon and then rebreathed.

Pharmacology Although chemically heterogeneous, inhalants are generally highly lipophilic and gain rapid entrance into the central nervous system (CNS). Little is known about the cellular basis of the effects of inhalants and it is unclear whether these actually represent a single pharmacologic group. Their effects are probably best represented by the model for ethanol in which multiple different cellular mechanisms explain diverse pharmacologic and toxicologic effects.4

Volatile

Hydrocarbons

The clinical effects of the volatile hydrocarbons are likely mediated through stimulation of the γ-aminobutyric acid (GABA) receptor complex, the primary system responsible for inhibitory neurotransmission within the CNS. Like ethanol, both toluene and TCE enhance GABAA receptormediated synaptic currents as well as glycine receptor-activated ion function; stimulation of these receptors acts to increase chloride permeability, hyperpolarizing the cell membrane and inhibiting excitability. Despite very different molecular structures, ethanol, enflurane, chloroform, toluene, and 1,1,1-trichloroethane (TCE) compete for binding sites in glycine α1 receptors.9 Additionally, toluene, like ethanol, interferes with glutamate-mediated excitatory neurotransmission by inhibiting N -methyl-D-aspartate (NMDA) a concentration-dependent manner.32

receptor-mediated

currents

in

Toluene is the prototypical volatile hydrocarbon and the best studied. In animal models, differences in pharmacologic action are demonstrated between toluene and other alkylbenzenes, and halogenated hydrocarbons such as TCE, and acetone.17 , 18 , 113 These differences may represent evidence that specific cellular sites for their actions exist. Additionally these differences may explain the variation in their abuse potential or their intoxicating effects.4 Despite these distinctions, there are marked similarities in the behavioral and pharmacologic effects of the volatile hydrocarbons. Moreover, the clinical effects profile shared by the volatile hydrocarbons, subanesthetic concentrations of general anesthetics, ethanol, and benzodiazepines suggests that they share cellular mechanisms. Shared clinical effects include anxiolytic effects,19 anticonvulsant effects,125 impaired motor coordination,85 and evidence of physical dependence on withdrawal.36 , 37 There are scant data on the pharmacokinetics of the inhalants. Most data are derived from studies on occupational and environmental exposures and have limited applicability to the intentional inhalation. More relevant to the understanding of inhalants are the similarities with the inhalational anesthetic agents, many of which are halogenated hydrocarbons. Factors

determining pharmacokinetic and pharmacodynamic effects of a given inhalational anesthetic include concentration in inspired air; its partition coefficient; interaction with other inhaled substances, alcohol, and drugs; the patient's respiratory rate and blood flow; their percent body fat; and individual variation in drug metabolism (Chap. 65 ).46 Whereas the pharmacokinetics of the inhalational anesthetics are extensively studied, the intentional inhalation of variable concentrations of abused inhalants for variable periods of time remains unstudied. Partition coefficients measure the relative affinity of a gas for two different substances at equilibrium and are used to predict the rate and extent of uptake of an inhaled substance. The blood:gas partition coefficient is most commonly referenced. The higher the number, the more soluble the substance is in blood. Substances with a low blood:gas partition coefficient, like nitrous oxide, are rapidly taken up by the brain and, conversely, are rapidly eliminated from the brain once exposure is ended (Table 79-2 ). In a rodent model of inhalation abuse of toluene and acetone,24 the rapidity of onset and the depth of CNS depression were dependent on the concentration of the solvent inhaled. There was a parallel relationship between brain concentration and pharmacologic effect during induction (inhalation) and postexposure. Brain and liver concentrations dropped rapidly after exposure; concentration in blood decreased at the slowest rate. Elimination was biphasic: rapid elimination during the first step was a result of tissue redistribution, P.1194 alveolar ventilation, and metabolic clearance. During the second phase there was a slow decrease in tissue concentrations as a result of the gradual mobilization from adipose tissue with subsequent exhalation or metabolism. Acetone, which is more water-soluble than toluene, is less potent and more slow acting than toluene, but is eliminated much more slowly than toluene and has a much longer duration of action.24 Positron emission tomography (PET) studies using (11 C) radiolabeled toluene in nonhuman primates showed rapid uptake of radioactivity in striatal and frontal regions of the cortex followed by rapid clearance from brain.

Whole-body PET scans in mice showed excretion through the kidneys and liver.44 Acetone 243–300 Largely unchanged via exhalation 95% and urine 5% None n - Butane 0.019 Largely unchanged via exhalation None Carbon tetrachloride 1.6 50% unchanged via exhalation; 50% hepatic metabolism and urinary excretion CYP2E1 to trichloromethyl radical, trichloromethyl peroxy radical, phosgene n -Hexane 2 10–20% exhaled unchanged; hepatic metabolism and urinary excretion CYP2E1 to 2-hexanol, 2,5-hexanedione, γ-valerolactone Methylene chloride 5–10 92% exhaled unchanged; hepatic metabolism and urinary excretion (1) CYP2E1 to CO and CO2 (2) Glutathione transferase to CO2 , formaldehyde, and formic acid Nitrous oxide 0.47 >99% exhaled unchanged None Toluene 8–16 80% hepatic metabolism and urinary excretion CYP2E1 to benzoic acid, then

(1) glycine conjugation to form hippuric acid (68%) (2) glucuronic acid conjugation to benzoyl glucuronide (insignificant pathway except following large exposure to toluene) 1,1,1-Trichloroethane 1–3 91% exhaled unchanged; hepatic metabolism and urinary excretion CYP2E1 to trichloroethanol, then (1) conjugated wih glucuronic acid (urochloralic acid) or (2) further oxidized to trichloracetic acid Trichloroethylene 9 16% exhaled unchanged; 84% hepatic metabolism and urinary excretion CYP2E1 to epoxide intermediate (transient); chloral hydrate (transient); trichloroethanol (45%), trichloroacetic acid (32%)

Xenobiotic

Blood:Gas Partition Coefficient (98.6°F/37°C)

Routes of

Important

Elimination

Metabolites

TABLE 79-2. Blood: Gas Partition Coefficients, Routes of Elimination and Important Metabolites of Selected Inhalants The inhalants are eliminated unchanged via respiration, undergo hepatic metabolism or both (Table 79-2 ). For some the percentage that is metabolized versus eliminated unchanged varies with the exposure dose. Nitrous oxide and the aliphatic hydrocarbons are frequently eliminated unchanged in the expired air. The aromatic hydrocarbons are usually metabolized extensively via the cytochrome P450 (CYP) system, particularly CYP2E1, which has a substrate spectrum that includes a number of aliphatic, aromatic, and halogenated hydrocarbons.15 Extrahepatic expression of CYP2E1 occurs to a lesser extent but may be of toxicologic significance, particularly in the kidneys and the dopaminergic cells of the substantia nigra. 16 , 56 , 116 In humans, there appears to be no significant gender differences in CYP2E1; however, it is

polymorphic and, as such, allelic distributions vary among different human populations.15 , 103 Moreover, this polymorphism may explain the varying degrees of toxicity exhibited following inhalant abuse. Although little is known about the cellular actions of the inhalants, even less is known about the reward mechanisms and consequently the abuse potential of inhalants. Animal research on toluene suggests that similar to other drugs of abuse, activation of mesolimbic dopaminergic pathways may play an important role.13 , 44 , 96

Volatile

Alkyl

Nitrites

Unlike other volatile hydrocarbons, the volatile alkyl nitrites are not thought to have any direct effects on the CNS. Their effects are mediated through smooth muscle relaxation in the central and peripheral vasculature and they share a common cellular pathway with other nitric oxide (NO) donors like nitroglycerin and sodium nitroprusside.65 A rat model of inhalation of isobutyl nitrite found a half-life of 1.4 minutes with almost 100% biotransformation to isobutyl alcohol. following inhalation was estimated to be 43%.

Nitrous

Bioavailability

Oxide

The pharmacokinetics and pharmacodynamics of nitrous oxide (N2 O) abuse are derived from its use as an inhalation anesthetic. Anesthetic uptake or induction, as well as emergence with N2 O, is rapid because of its low solubility in blood, muscle, and fat.107 There is no appreciable metabolism of N2 O in human tissue.38 An animal study found N2 O significantly inhibited excitatory NMDA-activated currents and had no effect on GABA-activated currents.57 N 2 O is also known to stimulate dopaminergic neurons, but the significance of this in mediating its anesthetic effects remains unclear.62 , 86 Animal studies suggest the analgesic effects (or more accurately the antinociceptive effects because it refers to animals) of N2 O appear to be mediated through opioid peptide release in the midbrain. These

antinociceptive effects can be reversed by the opiate antagonist naloxone. 12 However, the anesthetic effects are not attenuated by naloxone, and, in humans, the subjective and psychomotor effects of N2 O are not extinguished by even high doses of naloxone.104 , 127

Clinical

Manifestations

Signs and symptoms of inhalant use may be subtle, tend to vary widely among individuals, and generally resolve within two hours P.1195 of exposure. Following acute exposure, there may be a distinct odor of the abused inhalant on the patient's breath or clothing. Depending on the inhalant used and the method, there may be discoloration of skin around the nose and mouth. Mucus membrane irritation may cause sneezing, coughing, and tearing. Patients may complain of dyspnea and palpitations. Gastrointestinal complaints include nausea, vomiting, and abdominal pain. After an initial period of euphoria, patients may have residual headache and dizziness.

Volatile

Hydrocarbons

The central nervous system is the intended target of the inhalants and is most susceptible to adverse effects. Initial CNS effects include euphoria and hallucinations (both visual and auditory) as well as headache and dizziness. As toxicity progresses, CNS depression worsens and patients may develop slurred speech, confusion, tremor, and weakness. Transient cranial nerve palsies are reported.111 Further CNS depression is marked by ataxia, lethargy, seizures, coma, and respiratory depression. These acute encephalopathic effects generally resolve spontaneously and associated neuroimaging abnormalities are not reported.40 As can be expected given the high lipophilicity of most inhalants, toxicity from chronic use is manifested most strikingly in the central nervous system. Toluene leukoencephalopathy, characterized by dementia, ataxia, eye movement disorders, and anosmia, is the prototypical manifestation

of chronic inhalant neurotoxicity. Patients with toluene leukoencephalopathy display characteristic neurobehavioral deficits reflecting white matter involvement: inattention, apathy, and impaired memory and visuospatial skills with relative preservation of language.40 Autopsy studies reveal white matter degeneration including cerebral and cerebellar atrophy and thinning of the corpus callosum.66 , 97 O n microscopy, there is diffuse demyelination with relative sparing of the axons. Abundant perivascular macrophages containing coarse or laminar myelin debris found in areas of the greatest myelin loss is a characteristic pathologic feature.40 This targeting of myelin, which is 70% lipid, may be explained by toluene's lipophilicity.40 As myelination continues at least through the second decade of life, the typical toluene abuser who begins inhaling during adolescence may be particularly susceptible to its toxic CNS effects.39 Advances in magnetic resonance imaging with gadolinium, which allow enhanced visualization of the cerebral white matter, demonstrate that the extent of white matter injury in the brain directly corresponds to the clinical severity of toluene leukoencephalopathy.40 I t is postulated that reactive oxygen species generated either by toluene or its metabolite benzaldehyde induce lipid peroxidation.77 , 78 Genetic polymorphisms and host susceptibility among chronic abusers are also hypothesized to play a role.49 Acute cardiotoxicity associated with hydrocarbon inhalation is manifested most dramatically in “sudden sniffing death.― In witnessed cases, sudden death occurred when sniffing was followed by some physical activity. Examples include running or wrestling or a stressful situation like being caught sniffing by parents or police. 6 It is thought that the inhalant “sensitizes the myocardium― by blocking the potassium current (IK R ), thereby prolonging repolarization.88 This produces a substrate for dysrhythmia propagation; the activity or stress then causes a catecholamine surge that initiates the dysrhythmia (Chap. 23 ).88 Cardiac dysrhythmias following the inhalation of hydrocarbons were documented with the halogenated inhalational anesthetics in the early 1900s, and this association was subsequently confirmed in both animal and human studies.42 , 112 Multiple case reports of ventricular fibrillation follow

intentional inhalation of other hydrocarbons as well, such as butane fuel, 51 , 123 Freon (Dupont trade name for fluorinated hydrocarbons), and Glade Air Freshener (SC Johnson), which contains a mixture of shortchain aliphatic hydrocarbons.71 Although cardiotoxic effects of inhalant abuse are generally acute, dilated cardiomyopathy is reported with chronic abuse of toluene and with trichloroethylene.81 , 124 Microscopy reveals evidence of chronic myocarditis with fibrosis.124 The typical clinical presentation of a patient with hydrocarbon cardiotoxicity includes palpitations, shortness of breath, syncope, and ECG abnormalities, including atrial fibrillation, premature ventricular contractions, QTc prolongation, and U waves. The primary respiratory toxicity complication of inhalational substance abuse is hypoxia, which is either caused by rebreathing of exhaled air, as occurs with bagging, or displacement of inspired oxygen with the inhalant, reducing the FiO2 . Direct pulmonary toxicity associated with inhalants is most often a result of inadvertent aspiration of a liquid hydrocarbon (Chap. 102 ). Aspiration injury is associated with acute lung injury and the acute respiratory distress syndrome, a continuum of lung injury characterized by increased permeability of the alveolar-capillary barrier and the resulting influx of edema into the alveoli, neutrophilic inflammation, and an imbalance of cytokines and other inflammatory mediators.119 Reports of asphyxiation initially ascribed to inhalant abuse were later found to be caused by suffocation by a plastic bag, mask, or container pressed firmly to the face, and not specifically by toxicity of the inhaled vapor.6 , 27 , 118 Irritant effects on the respiratory system are frequently transient, but patients may develop chemical pneumonitis. This syndrome is characterized by tachypnea, fever, tachycardia, rales/rhonchi, leukocytosis, and radiographic abnormalities, including perihilar densities, bronchovascular markings, increased interstitial markings, infiltrates, and consolidation. Rebreathing of exhaled air, as occurs with bagging, may lead to hypercapnia and hypoxia. Acute eosinophilic pneumonia following abuse of a fabric protector containing 1,1,1-trichloroethane, is also

reported.63 Barotrauma emphysema.100

presents

as

pneumomediastinum

or

subcutaneous

Hepatoxicity is associated with exposure to halogenated hydrocarbons, particularly carbon tetrachloride, but also chloroform, trichloroethane, trichloroethylene, and toluene. 76 Intentional inhalation of carbon tetrachloride is rarely reported, but its toxic metabolite, the trichloromethyl radical, created by the cytochrome CYP2E1, can covalently bind to hepatocyte macromolecules and cause lipid peroxidation.95 The resultant depletion of glutathione and the potentially fatal centrilobular necrosis mimic acetaminophen toxicity and have led to a postulated role for N -acetylcysteine (NAC) in preventing carbon tetrachloride hepatoxicity. Animal studies on the efficacy of NAC in preventing carbon tetrachloride-induced hepatoxicity have yielded mixed results.31 , 33 , 34 There are no clinical trials in humans, but case series suggest a protective role for NAC.98 Two cases of centrilobular hepatic necrosis following inhalation of trichloroethylene are reported. Inhalation of either toluene or one of the many halogenated hydrocarbons is associated with elevated liver enzymes and hepatomegaly that generally return to baseline within 2 weeks of abstinence.3 , 55 , 60 , 70 , 87 , 89 Renal toxicity is most frequently described following inhalation of toluene. Traditionally, prolonged toluene inhalation was said to cause a distal renal tubular acidosis (RTA), resulting in hypokalemia. However, distal RTA is associated classically with a hyperchloremic metabolic acidosis and a normal anion gap, and P.1196 toluene abuse may be associated with an increased anion gap. Production of hippuric acid, a toluene metabolite, plays a more important role in the genesis of the metabolic acidosis than was previously thought.28 Hippurate excretion, usually expressed as a ratio to creatinine, rises dramatically with toluene inhalation.82 The excretion of abundant hippurate in the urine unmatched by ammonium mandates an enhanced rate of excretion of sodium and potassium cations. Continued loss of potassium in the urine leads to hypokalemia. Toluene is rapidly metabolized to hippuric acid, and the hippurate anion is swiftly cleared by

the kidneys, leaving the hydrogen ion behind. This prevents the rise in anion gap that would normally occur with an acid anion other than chloride, generating a normal anion gap. In some cases, the loss of sodium causes extracellular fluid volume contraction and a fall in the glomerular filtration rate, which may transform the metabolic acidosis with a normal anion gap into one with a high anion gap caused by the accumulation of hippurate and other anions.28 Through unclear mechanisms, other renal abnormalities occur with toluene inhalation, including hematuria, albuminuria, and pyuria. Glomerulonephritis associated with hydrocarbon inhalation is also reported and is a result of antiglomerular basement membrane antibody-mediated immune complex deposition.115 , 128 Toluene-abusing patients may present with profound hypokalemic muscle weakness. In a study of 25 patients admitted to the hospital following inhalant abuse, 9 presented with muscle weakness. The mean serum potassium concentration was 1.7 mEq/L and 6 of these patients had elevated creatine phosphokinase concentrations, ranging from 118–4350 IU/L (normal: Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 80 - Hallucinogens

Chapter

80

Hallucinogens Kavita M Babu Robert P. Ferm A 17-year-old boy was taken to the emergency department (ED) by his friends because he was acting bizarrely on the way home from school. He told a friend that he had “dropped acid― after school and now could not stop staring at the bright lights. He encouraged his friends to enjoy the “peace of the lights.― Physical examination revealed that the patient was agitated, and staring at the overhead lights. Vital signs were: blood pressure, 150/100 mm Hg; pulse, 112 beats/min; respiratory rate, 28 breaths/min; oral temperature, 100.4°F (38°C); and room air pulse oximetry 97%. A rapid bedside blood glucose was 120 mg/dL. His skin was moist and pale. Examination of the eyes revealed slowly reactive 6-mm pupils without nystagmus. He had occasional faint, scattered end-expiratory wheezes. Cardiac auscultation was normal. The abdomen was soft and nontender with hyperactive bowel sounds. There was no clubbing, cyanosis, or edema. Neuropsychiatric examination revealed that the patient was oriented, but was frightened by the visual hallucinations, and was “hearing purple and blue― from the overhead lights. The remainder of the

neurologic examination was intact except for the presence of a fine tremor. The patient stated that he had previously taken lysergic acid diethylamide (LSD), although this was the first time that he had used it while alone. He understood that he was experiencing drug effects; however, he was extremely anxious and afraid of “losing his mind.― The patient was moved to a quiet location with minimal stimuli and an intravenous line was inserted. He received diazepam 10 mg via slow IV push, and had some subsequent improvement of his anxiety. After approximately 8 hours of observation, the patient returned to his baseline functional status, without hallucinations or anxiety. After obtaining permission from the patient regarding disclosure, the ED staff notified his pediatrician and parents. A referral was made for drug counseling, and the patient was discharged to home with family members.

Epidemiology Hallucinogens are a diverse group of xenobiotics that alter and distort perception, thought, and mood without clouding the sensorium. They have been used for thousands of years by many different cultures, largely during religious ceremonies. The ancient Indian holy book RigVeda , written more than 3500 years ago, describes a sacramental xenobiotic called Soma both as a god and as an intoxicating xenobiotic. Although debated for many years, the source of Soma is now believed to be the juice of the mushroom Amanita muscaria .84 , 90 The Aztecs used the psilocybin-containing teonanacatl (flesh of the gods) and Ololiuqui (morning glory species) in their religious ceremonies. To this day, the Native American Church uses peyote in religious ceremonies. Synthetic hallucinogen use is often said to have begun with the discovery of lysergic acid diethylamide (LSD). The synthesis of LSD resulted from extensive research on the ergot alkaloids derived from the fungus Claviceps purpurea. From medieval times through recent years, several large-scale epidemics of vasospastic ischemia, gangrene, and hallucinations (collectively called ergotism) have

resulted from C. purpurea contamination of cereal crops.117 C . purpurea is suggested as the cause of the mass hysteria leading up to the Salem Witch trials. Many of these adverse effects after ingestion of C. purpurea are attributed to its serotonergic agonist effects. 35 In 1938, Albert Hofmann, a Swiss chemist, synthesized LSD-25, the 25th substance in a series of lysergic acid derivatives being researched as new arousal, or analeptic, agents. These lysergic acid compounds were based on ergot extracts from C. purpurea. Five years later, LSD25 was “tested― when Hofmann had an unintentional exposure in his laboratory, and subsequently developed hallucinations.54 , 98 Soon thereafter, Sandoz laboratories began marketing LSD under the trademark name Delysid as an adjunct for analytic psychotherapy. In the 1950s, a small number of psychiatrists began using LSD to release the repressed memories of patients, and as an experimental model for schizophrenia.103 The Central Intelligence Agency reportedly experimented with using LSD as a tool for interrogating suspected communists and as a mind-control agent.23 , 98 In the 1960s, the concept of the “fifth freedom― emerged. As individuals explored this “right― to alter their consciousness as they saw fit, LSD (also called “acid―) became a fashionable recreational drug. In one of the most famous slogans of the 1960s, Dr. Timothy Leary popularized LSD with the phrase, “Tune in, Turn on, Drop out.―98 By 1966, federal law banned the use of LSD.80 Initial reports of LSD-induced chromosomal damage appeared in the 1960s, although further studies of pregnant women who had taken LSD did not demonstrate an increased risk of abortions or birth defects.29 , 39 , 56 , 64 , 67

LSD use diminished in the late 1970s and early 1980s, perhaps because of users' concerns regarding potential health risks of brain damage, “bad trips,― and flashbacks.83 In the meantime, there was a rise in the use of the “designer― hallucinogens. Exploiting a loophole in drug enforcement laws, these synthetic tryptamine and amphetamine hallucinogens were chemically similar to, but legally

distinct

from,

their

outlawed

counterparts.

A resurgence in LSD use was reported among high school teens in the late 1990s, with more prevalent use in the suburbs than P.1203 the inner In 1997, two studies of adolescents showed a lifetime prevalence of LSD use at 13 and 14%.57 , 83 However, in 2000, DEA agents seized an LSD-production lab and apprehended two men involved in massive production of LSD in the United States. Their incarceration resulted in a more than 90% decrease in LSD availability nationwide.107 city.4 , 81 , 91

The use of contemporary hallucinogens has grown in venues like allnight dance clubs and “rave parties.―14 While the impact of these parties and clubs on the growth of hallucinogen use in the United States is unclear, many of the newer hallucinogens have been christened “club drugs― because of this association.48 I n addition, the Internet has developed as a vehicle for the rapid and facile sharing of information on the synthesis of emerging drugs, user experiences, and adverse effects.21

Specific

Hallucinogens

The term hallucination can be defined as false perception that has no basis in the external environment. The term is derived from the Latin “to wander in mind.― A hallucination is distinct from an illusion, which refers to mental impressions derived from the misinterpretation of an actual experience. Hallucinogenic substances may also have illusogenic effects. Although the term psychedelic has been used for years to refer to the recreational and nonmedical effects of hallucinogens, other terms, like entheogen, and entactogen, frequently appear in Internet discussions. Entheogens are “substances which generate the god or spirit within,― whereas entactogens create an awareness of “the touch within.―37 Hallucinogens can be categorized by their chemical structures, and

further divided into natural and synthetic members of each family (Table 80-1 ). The major structural classes of hallucinogens include the lysergamides, indolealkylamines (tryptamines), phenylethylamines (amphetamines), arylhexamines, cannabinoids, harmine alkaloids, and the tropane alkaloids. In addition, there are several unique hallucinogens, such as Salvinorin A. This chapter focuses on lysergamides, tryptamines, phenylethylamines, and Salvinorin A. Further discussion of the other classes of hallucinogens can be found in Chaps. 73 and 8 1 .

Lysergamides Lysergamides are derivatives of lysergic acid, a substituted tetracyclic amine based on an indole nucleus (Fig. 80-1 ). Naturally occurring lysergamides are found corymbosa , Ipomoea (Argyreia nervosa ). 52 including lysergic acid

in several species of morning glory (Rivea violacea ) and Hawaiian baby wood rose Morning glory seeds contain multiple alkaloids, hydroxyethylamide and ergonovine. The morning

glory seeds were called Ololiuqui in ancient Mexico, where Aztecs and other indigenous populations used them in religious rites.101 However, in one volunteer study, Ololiuqui use predominantly caused sedation rather than hallucinations.55 Lysergamides D-Lysergic acid diethylamide (LSD) Lysergic acid hydroxyethylamide Ipomoea violacea (morning glory) Ololiuqui (South American morning glory) Ergine Argyreia (Hawaiian baby wood rose) Indolalkylamines/Tryptamines 5-Methoxy-N,N -dimethyltryptamine N,N -Dimethyltryptamine Psilocin Psilocybin

Phenylethylamines Mescaline MDMA (3,4-methylenedioxymethamphetamine) 2CB 2CT-7 Tetrahydrocannabinoids Marijuana Hashish Belladonna alkaloids Jimsonweed (Datura stramonium ) Henbane (Hyoscyamus niger ) Deadly nightshade (Atropa belladonna ) Brugmansia species Miscellaneous Salvia divinorum Ketamine Phencyclidine

(PCP)

TABLE 80-1. Xenobiotics Classified as Hallucinogens

Figure 80-1. Hallucinogens of the lysergamide class and their chemical similarity to serotonin.

Ingestion of 200–300 morning glory seeds is required to achieve hallucinogenic effects. Hawaiian baby wood rose seeds contain ergine, and only 5–10 seeds are required to produce hallucinations. Ten

seeds may cost as little as 2 dollars. After ingestion of wood P.1204 rose seeds, the effects typically last for 6–8 hours, and produce tranquility without marked euphoria.6 Both morning glory and Hawaiian baby wood rose seeds can be purchased legally in garden stores and on the Internet. The synthetic lysergamide, LSD, is derived from an ergot alkaloid of the fungus C. purpurea. Although four LSD isomers exist, only the d isomer is active. Lysergic acid diethylamide is a water-soluble, colorless, tasteless, and odorless powder. Currently, LSD is typically sold as liquid-impregnated blotter paper, microdots, tiny tablets, “window pane― gelatin squares, liquid, powder, or tablets.91 Although LSD use has been reported via intravenous and intramuscular routes, ingestion of blotter paper is the most common route of abuse. The minimum effective oral dose is 25 µg.60 The Drug Enforcement Administration reports that the current street dose of LSD ranges from 20–80 µg, which is lower than the 100–200 µg quantities reported during the 1960s and early 1970s.32 The onset of effects may occur 30–60 minutes after exposure, with a duration of 10–12 hours after ingestion. LSD users typically experience heightened awareness of auditory and visual stimuli with size, shape, and color distortions. Auditory and visual hallucinations may occur, as well as synesthesia, a confusion of the senses, where users may describe “hearing colors― or “seeing sounds.― Other more complex perceptual effects may include depersonalization and a sensation of enhanced insight or awareness. A “bad trip― may occur with any dose of LSD, and produce anxiety, bizarre behaviors, and combativeness. LSD is classified as a Schedule I agent, with a high abuse potential, a lack of established safety even under medical supervision, and no known use in medical treatment.110

Indolealkylamines

(Tryptamines)

Indolealkylamines, or tryptamines, represent a class of natural and synthetic compounds that structurally share a substituted monoamine group (Fig. 80-2 ). Endogenous tryptamines include serotonin and melatonin. Naturally occurring exogenous tryptamines include psilocybin, bufotenine, and dimethyltryptamine (DMT). Psilocybin is found in three major genera of mushrooms: Psilocybe, Panaelous , and 90 Conocybe . Other hallucinogenic mushrooms include A. muscaria and A. pantherina , which contain ibotenic acid, muscimol, and muscazone.52 Toxic and hallucinogen mushrooms are discussed at length in Chapter 113 . Psilocybin-containing mushrooms, or “magic mushrooms,― grow in the Pacific Northwest and the southern United States, usually in cow pastures. The mushroom may be recognized by a green-blue color that it assumes after bruising, but misidentification is common.12 In the gastrointestinal tract, psilocybin is converted to psilocin, the active hallucinogen.50 The effects of psilocin are similar to LSD, but with a shorter duration of action of about four hours. DMT is a potent short-acting hallucinogen. It is found naturally in the bark of the Yakee plant (Virola calophylla ), which grows in the Amazon basin and is used by shamans as a hallucinogenic snuff to “communicate with the spirits.―90 DMT is also found in the hallucinogenic tea, Ayahuasca, which is used by indigenous healers in the Amazon Basin. In Ayahuasca, dimethyltryptamine-containing plants (eg, Psychotria viridis ) are combined with plants containing harmine alkaloids (eg, Banisteriopsis caapi ) that inhibit hepatic monoamine oxidases to increase the oral bioavailability of DMT (Chap. 69 ).73 For current recreational purposes, DMT is typically smoked, snorted, or injected. By this route, its hallucinogenic effects peak in 5–20 minutes, with a duration of 30–60 minutes. This short duration of action has earned DMT the nickname “businessman's trip.―

Figure 80-2. Hallucinogens of the indolalkylamine class and their chemical similarity to serotonin.

The use of toads in religious ceremonies and witchcraft dates back thousands of years. All species of the toad genus Bufo have parotid glands on their backs that produce a variety of xenobiotics, including dopamine, epinephrine, and serotonin.70 Many of these toads produce

bufotenine, a tryptamine, which causes hypertension, but does not cross the blood–brain barrier. Interest in bufotenine grew out of reports of a toad-licking fad in the 1980s, in which individuals would reportedly lick toads for recreational purposes.69 However, further review suggests that bufotenine is not the hallucinogenic substance found in toad secretions. Instead, 5-methoxydimethyl tryptamine (5MeO-DMT), has been identified as the psychoactive substance.116 5 MeO-DMT is only found in one species of toad, Bufo alvarius (Sonoran Desert toad or Colorado River toad).69 Although bufotenine is currently classified as a Schedule I substance by the United States Drug Enforcement Administration, 5-MeO-DMT is not scheduled.77 , 105 Like DMT, 5-MeO-DMT is rapidly metabolized by intestinal monoamine oxidase enzymes; licking or ingesting toads skins would thus have limited potential as a route of recreational use.21 Methods for extracting and drying B. alvarius secretions for smoking are available and on the Internet. The toad venom glands also produce cardioactive steroids, called bufadienolides, which may cause cardioactive steroid toxicity (Chap. 62 ), and in some species, can secrete tetrodotoxin.75 , 119 Death has resulted from wrongful use of Bufo secretions for purposes

of

aphrodisia.28 , 49 P.1205

Two of the more important synthetic tryptamines include N,N diisopropyl-5-methoxytryptamine (5-MeO-DiPT, Foxy Methoxy), and α-methyltryptamine (AMT, IT-290). Since 2001, law enforcement authorities in more than 10 states have seized large amounts of 5MeO-DiPT and AMT.106 These xenobiotics are often sold surreptitiously as methylenedioxymethamphetamine (MDMA). 5-MeO-DiPT is usually ingested, but it can be smoked or insufflated. Effects begin 20–30 minutes after ingestion, and include disinhibition and relaxation. There is a dose-dependent response and at higher doses symptoms may be similar to LSD or MDMA, with mydriasis, euphoria, auditory and visual hallucinations, nausea, diarrhea, and jaw clenching.79 , 95 The hallucinogenic effects are reported to last from 3–6 hours.74 , 95 , 106 Other substances, such as sildenafil, γ-

hydroxybutyrate, benzodiazepines, and marijuana, may be used to heighten or prolong the hallucinogenic effects of 5-MeO-DiPT.68 5-MeODiPT received Schedule I status in 2004.109 AMT is a monoamine oxidase inhibitor that was initially marketed as an antidepressant in the former Soviet Union.94 , 106 AMT is available as a white powder that can be ingested, smoked, or insufflated. Despite its chemical similarity to DMT, the effects of AMT may last from 12–16 hours.66 AMT was given Schedule I status by the DEA in September 2004.109

Phenylethylamines Endogenous

phenylethylamines

(Amphetamines) include

dopamine,

norepinephrine,

and

tyrosine. Exogenous phenylethylamines are known for their ability to stimulate catecholamine release and cause a variety of physiologic and psychiatric effects, including hallucinations. Substitution on the phenylethylamine structure has important effects on both the hallucinogenic and stimulant potential of the xenobiotic. The of a methyl group in the side chain of the phenylethylamines associated with a higher degree of hallucinogenic effect (Fig. MDMA, amphetamine and methamphetamine are well-known of this family and are discussed in detail in Chap. 73 .

presence is 80-3 ).59 members

Figure

80-3. Hallucinogens of the phenylethylamine class.

The best recognized of the naturally occurring phenylethylamines is mescaline. Mescaline is found in peyote (Lophophora williamsii ), a small, blue-green spineless cactus that grows in dry and rocky slopes throughout the southwestern United States and northern Mexico. Peyote buttons are the round, fleshy tops of the cactus that have been sliced off and dried. The bitter-tasting buttons are eaten whole or can be dried and crushed into a powder, which is reconstituted into a tea.52 Nausea, vomiting, and diaphoresis often precede the onset of hallucinations. Six to 12 peyote buttons, or 270–540 mg of mescaline, are commonly required to produce hallucinogenic effects.89 The legal use of peyote in the United States is restricted to the Native

American Church, where peyote buttons are used in religious ceremonies, and for medical treatment of physical and psychological ailments.24 , 26 Other nonindigenous cactus species containing significant amounts of mescaline include the San Pedro cactus (Trichocereus pachanoi ) and Peruvian torch cactus (Trichocereus peruvianus ). These plants can be purchased in garden stores and on the Internet for ornamental purposes.52 However, the synthesis and effects of hundreds of other congeners of amphetamine have been described.93 The best known of these synthetic hallucinogenic amphetamines are 4-bromo-2,5dimethoxyphenethylamine (2CB, Nexus, Bromo, Spectrum), and 2,5dimethoxy-4-N

-propylthiopheneethylamine

(2CT-7,

Blue

Mystic).

During the 1980s, 2CB gained popularity as a legal alternative to MDMA. When 2CB was given Schedule I status in 1995, 2CT-7 emerged as another legal designer amphetamine.11 In March received Schedule I status. 31 Low doses of 2CB and hypertension, tachycardia, and visual hallucinations, doses are associated with shifts in color perception,

2004, 2CT-7 also 2CT-7 can produce while elevated enhanced auditory

and visual stimulation, and even morbid hallucinations.

Salvia

divinorum

Salvia divinorum is a perennial herb classified as a member of the mint family or Labiatae. Although there are more than 500 species of Salvia , S. divinorum is most recognized for its hallucinogenic properties. The plant is characterized by a height greater than 1 m, large green leaves, hollow square stems, and white flowers with purple calyces.111 S . divinorum is a native to areas of Oaxaca, Mexico, and grows well in sunny, temperate climates (Fig. 80-4 ). Since the 16th century, the Mazatec Indians have employed S . divinorum in religious rites as a means of producing visions.111 The Mazatecs continue to revere S. divinorum as an incarnation of the

Virgin Mary, referring to the plant as Ska Maria Pastora. S. divinorum may be chewed, smoked, or ingested as tea. Hallucinations occur immediately after exposure to the xenobiotic and are typically quite vivid. Synesthesia, a confusion of the senses, like hearing colors or smelling sounds, has been reported among Salvia users. 33 However, this effect is not specific to S. divinorum , and has been reported with multiple other hallucinogens. Hallucinogenic effects after S. divinorum use are typically brief, lasting only 1–2 hours. Currently, the Controlled Substances Act does not prohibit use of S . divinorum or its active ingredients. Nationwide regulation of this xenobiotic exists in Australia, and there is local legislation in some midwestern towns where use among teenagers is rampant.108 There is widespread marketing of this hallucinogen on the Internet as a “legal hallucinogen.―33 Plants, leaves, and extracts may be purchased online, and tips for cultivation of plants are easily accessible. P.1206

Pharmacokinetics LSD is the most studied hallucinogen, and there is extensive information about its pharmacokinetics. Ingestion is the most common route of exposure, and the gastrointestinal tract rapidly absorbs LSD. Other routes of administration include intranasal, parenteral, sublingual, smoking, and conjunctival instillation. Plasma protein binding is greater than 80% and volume of distribution is 0.28 L/kg. It is concentrated within the visual cortex, as well as the limbic and reticular activating systems. LSD is metabolized in the liver via hydroxylation and glucuronidation, and excreted predominantly as a pharmacologically inactive compound. LSD has an elimination half-life of about 2.5 hours. Only small amounts are eliminated unchanged in the urine. Tolerance to the psychological effects of LSD occurs within 3 days with daily dosing, but rapidly dissipates if the xenobiotic is withheld for 2

days. Psychological cross-tolerance among mescaline, psilocybin, and LSD is reported in humans.15 There is no evidence for physiologic tolerance, physiologic dependence, or a withdrawal syndrome with LSD. Limited tolerance is demonstrated between psilocybin and cannabinoids such as marijuana.22 There is little information about 2CB and 2CT-7 in the medical literature. Both drugs may be used via oral, intranasal, and intrarectal routes. Both 2CB and 2CT-7 exert their hallucinogenic effects within 1 hour of use, and physiologic and psychologic effects may persist for 6–10 hours. While specific pharmacokinetic data on 2CB and 2CT-7 are not available, the pharmacokinetics of other phenylethylamines may be similar. Amphetamine, methamphetamine, and MDMA are well absorbed through the GI tract. The elimination half-life ranges from 8–30 hours for members of this class, and is dependent on urine pH.13 , 30 Amphetamines are weak bases, and undergo more rapid elimination in an acidic urine environment.92 The volume of distribution ranges from 3–5 L/kg for amphetamine, 3–4 L/kg for methamphetamine, and is likely more than 5 L/kg for MDMA.13 , 30 , 65 , 92 Elimination of other amphetamines occurs through multiple mechanisms including aromatic hydroxylation, aliphatic hydroxylation, and N -dealkylation.65 Tolerance has been demonstrated in chronic amphetamine

users.61

Pharmacokinetic data for S. divinorum have been described in one volunteer study. Psychoactive effects were typically experienced 5–10 minutes after absorption of Salvinorin A via the buccal mucosa, reaching a plateau during the first hour after exposure, and resolving within 2 hours. Vaporization and inhalation of Salvinorin A led to more rapid effects at 30 seconds after exposure. These effects would plateau at 5–10 minutes, and typically subside after 20–30 minutes. In this study, ingestion of S. divinorum leaves did not produce the same effects as buccal or inhalational administration, leading to the theory that gastrointestinal deactivation of Salvinorin A occurs after ingestion.96 The pharmacokinetic characteristics of hallucinogens are summarized in Table 80-2 .

Ultrashort acting DMT IV 1 min 5 min 30 min Short acting DMT IM 5–15 min 15–60 min 1–2 h Intermediate acting Psilocybin 15–30 min 1–3 h 6 h Long acting LSD; Mescaline 30–90 min 3–5 h 8–12 h Ultralong acting Ibogaine 2–4 h 4–8 h 18–24 h Classification

TABLE

80-2.

Xenobiotic

Onset

Pharmacokinetic

Pharmacology

Peak effect

Classification

Duration of effect

of

Hallucinogens

Although the lysergamide, indolealkylamine, and phenylethylamine hallucinogens are structurally distinct, the similarities in their effects on cognition have led scientists to postulate a shared mechanism of action. Studies support a common site of action on central serotonin receptors.5 , 20 , 25 , 53 , 102 Serotonin (5-HT) modulates many psychological and physiologic processes, including mood, personality, affect, appetite, motor function, sexual activity, temperature regulation, pain perception, sleep induction, and antidiuretic hormone release. There are more than 14 known 5-HT receptor subtypes; differing affinity for these subtypes occurs based on the structure of the hallucinogen, and may account for the subtle differences between their effects. Another theory held by hallucinogen researchers was that the common site of action within the brain itself would involve the cerebral cortex, the area of the brain responsible for higher functions like cognition and mood. Alternatively, hallucinogens could affect subcortical areas, like the locus coeruleus found in the upper pons. The locus coeruleus is the part of the brain that responds to new stimuli and has projections throughout the entire cortex which affect cortical functioning.72 The

lysergamide,

indolealkylamine,

and

phenylethylamine

hallucinogens all bind to the 5-HT2 class of receptors. There is a good correlation between the affinity of both indolealkylamine and phenylethylamine hallucinogens for 5-HT2 receptors in vitro and hallucinogenic potency in humans in vivo.5 , 46 , 82 , 102 Of the multiple subtypes of 5-HT2 receptors, 5-HT2 A receptors are found with highest density in the cerebral cortex, making the 5-HT2 A receptor the most likely common site of hallucinogen action.72 This theory is bolstered by an animal study that shows that a selective 5-HT2 A antagonist can inhibit the effects of LSD and a phenylethylamine, 2,5dimethoxy-4-iodo-amphetamine (DOI). The response to high doses of LSD and DOI suggest that both lysergamides and phenylethylamines are partial agonists at cortical 5-HT2 A receptors.47 , 72 , 87 Although the majority of investigation has focused on the role of

serotonin for drug-induced hallucinations, other neurotransmitters are involved. Stimulation of 5-HT2 A receptors enhances release of glutamate in the cortical layer V pyramidal cells.5 , 10 LSD and other lysergamides stimulate both D1 and D2 dopamine receptors.9 , 45 , 115 In animal models, LSD and phenylethylamine hallucinogens modulate N -methyl-D-aspartate (NMDA) receptor-mediated effects, and may have a protective effect against neurotoxicity secondary to phencyclidine (PCP) and ketamine.10 , 38 Another theory that incorporates these other neurotransmitters revolves around “thalamic filtering.― The thalamus receives input and output from the cortex and reticular activating system, and functions to filter relevant sensory input. This theory has been explored as an explanation for organic psychosis and the effects of hallucinogens. Multiple neurotransmitters, including dopamine, acetylcholine, γ-aminobutyric acid (GABA), and P.1207 glutamate, exert their actions on the thalamus. Increased excitatory or decreased inhibitory neurotransmitter in this region of the brain may lead to “sensory overload,― which manifests itself clinically as symptoms of psychosis.44

Figure

80-4. Salvinorin A.

The psychological effects of hallucinogens seem to represent a complex and elusive interaction between different neurotransmitters, including

the serotonergic and dopaminergic systems. Based on this serotonergic mechanism, serotonin syndrome could theoretically occur after the use of any of the lysergamide, indolealkylamine, or phenylethylamine hallucinogens. Animal studies have documented LSD and tryptamine-induced serotonin syndrome.97 , 112 Case reports have linked phenylethylamine use to fatal serotonin syndrome in recreational users.78 , 114 Salvinorin A, the psychoactive component of S. divinorum , is thought to be one of the most potent natural hallucinogens. The effect of Salvinorin A occurs via binding at the δ opioid receptor, making it structurally and mechanistically unique (Fig. 80-4 ). 86 , 118 The δ opioid receptor is distinct from the µ opioid receptor, which generally mediates euphoria and analgesia (Chap. 38 ).

Clinical

Effects

Physiologic changes accompany and often precede the perceptual changes induced by lysergamides, tryptamines, and phenylethylamines. The physical effects may be caused by direct drug effect or by a response to the disturbing or enjoyable hallucinogenic experience. Sympathetic effects mediated by the locus coeruleus include mydriasis, tachycardia, hypertension, tachypnea, hyperthermia, and diaphoresis. They may occur shortly after ingestion and often precede the hallucinogenic effects. Other reported clinical findings include piloerection, dizziness, hyperactivity, muscle weakness, ataxia, altered mental status, coma, and hippus, a rhythmic dilation and constriction of the pupils.62 Nausea and vomiting often precede the psychedelic effects produced by psilocybin and mescaline. Potentially life-threatening complications, such as hyperthermia, coma, respiratory arrest, hypertension, tachycardia, and coagulopathy, were described in a report of 8 patients with a massive LSD overdose.58 Sympathomimetic effects are generally less prominent in LSD ingestion than in phenylethylamine toxicity. Similar sympathetic symptoms have

been described after the use of 2CB and 2CT-7. Three deaths are associated with 2CT-7 use; anecdotal reports suggest that 1 death may have resulted from seizures or aspiration.31 , 36 , 104 The vast majority of morbidity from hallucinogen use stems from trauma. Hallucinogen users frequently report lacerations and bruises sustained during their “high.― Additionally, dysphoric reactions may drive patients to react to stimuli with unpredictable, and occasionally aggressive, behaviors. Many Internet sites advise readers to take hallucinogens only while under the supervision of a “sitter.― The psychological effects of hallucinogens are dose-related and affect changes in arousal, emotion, perception, thought process, and selfimage. The response to the xenobiotic is related to the user's mindset, emotions, or expectations at the time of exposure, and can be altered by the group or setting.2 A person experiencing the effects of a hallucinogen is usually fully alert, oriented, and aware that he or she is under the influence of a drug. Euphoria, dysphoria, and emotional lability may occur. Perceptual distortions are common, typically involving distortion of body image and alteration in visual perceptions. Hallucinogen users may display acute attention to details with excessive attachment of meaning to ordinary objects and events. Usual thoughts seem novel and profound. Many people report an intensification of their sensory perceptions such as sound magnification and distortion. Colors often seem brighter with halolike lights around objects. Frequently, hallucinogen users relate a sense of depersonalization and separation from the environment, commonly called an “out-of-body― experience. Synesthesia, or sensory misperception, occurs frequently and may include “hearing― color or “seeing― sounds. True hallucinations may occur and can be visual, auditory, tactile, or olfactory. Acute adverse psychiatric effects of hallucinogens include panic reactions, true hallucinations, psychosis, and major depressive

dysphoric reactions. Acute panic reaction, the most common adverse effect, presents with frightening illusions, tremendous anxiety, apprehension, and a terrifying sense of loss of self-control.46 These psychiatric effects may cause patients to seek care in the emergency department.

Differential

Diagnosis

Hallucinosis is the abnormal organic mental condition of persistent hallucinations. The major causes of hallucinosis can be divided by etiology into structural, infectious, functional, and toxic–metabolic. The diagnosis of hallucinogen exposure often must be established on the basis of history and physical examination alone. The person who has ingested hallucinogens typically is oriented and will often give a history of hallucinogen use. This stands in stark contrast to patients with xenobiotic-induced delirium, in whom orientation is, by definition, altered. Xenobiotics such as amphetamine, cocaine, PCP, and anticholinergics produce delirium or psychosis at doses capable of producing hallucinations. Psychiatric or “functional― causes of perceptual changes, such as schizophrenia, typically present with auditory hallucinations. Patients with central anticholinergic toxicity usually present with disorientation, combative behavior, and incoherent mumbling, and may be unaware that the hallucinations are druginduced.60 The presence of marked hyperthermia, uncontrollable behavior, or extreme agitation should suggest phenylethylamine use, or an alternative drug exposure, such as cocaine or PCP. Evaluation for other causes of altered mental status and hallucinations should include early exclusion of hypoglycemia, meningitis, intracerebral hemorrhage, thyrotoxicosis, sepsis, decompensated P.1208 psychiatric disease, withdrawal states and other toxic exposures. A lumbar puncture and computed tomography of the head are adjunctive tests that may be required in a case where the history of hallucinogen

exposure is unclear.

Laboratory Routine drug-of-abuse screens do not detect LSD or other hallucinogens. Although LSD exposure can be detected by radioimmunoassay, confirmation by high-performance liquid chromatography or gas chromatography is necessary. These tests are rarely used in the clinical setting, but are much more common for forensic matters.15 , 34 False-positive urine testing for LSD has been reported after exposure to several medications including fentanyl, sertraline, haloperidol, and verapamil.42 , 85 Depending on their structure, phenylethylamines may cause positive qualitative urine testing for amphetamines. However, amphetamine drug testing is associated with numerous false-positive results, particularly after the use of cold medications that contain ephedrine, pseudoephedrine, or phenylpropanolamine.99 Gas chromatographymass spectrometry testing methods for detection of 5-MeO-DiPT, DMT, AMT, 2CT-7, and 2CB have been described.113 There is currently no information on laboratory drug testing for S . divinorum.

Treatment Most hallucinogen users do not seek medical attention because they experience only the desired effect of the drug. For any hallucinogen user who does present to the ED, initial treatment must begin with attention to airway, breathing, circulation, level of consciousness, and abnormal vital signs. Even when hallucinogen exposure is suspected, the basic approach to altered mental status should include dextrose, naloxone, and oxygen therapy as indicated, along with a vigorous search for other etiologies. Hallucinogens rarely produce life-threatening toxicity. Sedation with benzodiazepines is usually sufficient to treat hypertension, tachycardia,

and hyperthermia. Benzodiazepines remain the cornerstone of therapy, as the sedating effect can diminish both endogenous and exogenous sympathetic effects.76 Autonomic instability and hyperthermia may be a feature of phenylethylamine use, as well as tryptamine use or massive LSD overdose.41 , 58 , 76 Hyperthermia resulting from agitation or muscle rigidity requires urgent sedation with benzodiazepines and rapid cooling. While CNS depression is unlikely to be severe enough to require endotracheal intubation in a patient with a pure hallucinogen exposure, intubation and paralysis may be required in the patient with intractable hyperthermia.18 Seizures may occur with tryptamine or phenylethylamine use, and can be initially treated with benzodiazepines. Morbidity and mortality typically result from the complications of hyperthermia including rhabdomyolysis and myoglobinuric renal failure, hepatic necrosis, and disseminated intravascular coagulopathy. For the most part, however, hydration, sedation, a quiet environment, and meticulous supportive care will prove adequate to prevent mortality in recreational use or overdose.27 The patient with a dysphoric reaction can be placed in a quiet location with minimal stimuli. A nonjudgmental advocate should attempt to reduce the patient's anxiety, provide reality testing, and remind the individual that a drug was ingested and the effect will wear off in a couple of hours.100 Significant agitation, dysphoria, or a “bad trip,― combined with signs of autonomic instability, can usually be treated by the administration of a benzodiazepine.1 The role of antipsychotics in controlling hallucinogen-induced agitation is unclear. Haloperidol, risperidone, and ziprasidone may help control the acutely agitated patient. However, haloperidol and risperidone may worsen panic and visual symptoms, and increase the incidence of hallucinogen persisting perception disorder.3 The safety of ziprasidone in hallucinogen users has not yet been reported. Although further study on these xenobiotics is required, prolonged psychosis may require treatment with long-term antipsychotic therapy. Gastrointestinal decontamination with activated charcoal may be considered for asymptomatic patients with recent ingestions, but is

probably not helpful after clinical symptoms appear, and attempts may lead to further agitation. Excessive physical restraint should be avoided out of concern for hyperthermia and rhabdomyolysis. Serotonin syndrome may occur after hallucinogen use, and has been described after LSD, tryptamine, and phenylethylamine use.35 , 78 , 97 , 112 Diagnosis begins with early identification of serotonin syndrome based on the constellation of symptoms. Treatment is largely supportive and symptomatic, and includes the avoidance of further administration of serotonergic medications. Specific therapy with agents like cyproheptadine may be warranted (Chap. 70 ).19 In comparison to the other hallucinogens, the high produced by S . divinorum is relatively mild. Symptoms severe enough to require treatment in the emergency department are uncommon, but may include agitation and confusion. Gastrointestinal decontamination with activated charcoal may be considered if presentation is early after ingestion or if coingestants are suspected. Agitation may be managed through administration of benzodiazepines. To date, no significant toxicity or death from S. divinorum use or overdose has been reported.

Long-Term

Effects

Long-term consequences of LSD use include prolonged psychotic reactions, severe depression, and exacerbation of preexisting psychiatric illness.51 , 88 When LSD was initially popularized, some patients were noted to behave in a manner similar to schizophrenia and required admission to psychiatric facilities. In volunteer studies, panic reactions, hallucinogen persisting perception disorder, and extended psychoses were noted. When the xenobiotic was used for alleviation of anxiety and personality abnormalities, flashbacks and extended psychosis were reported.40 Several authors have suggested that individuals who reacted this way to hallucinogen use may have had preexisting, compensated psychological disturbances.5 , 71 Flashbacks have been reported in up to 80% of LSD users.7

Anesthesia, alcohol intake, and medications can precipitate flashbacks.43 These abnormal perceptions can be triggered during times of stress, illness, and exercise, and are often a virtual recurrence of the initial hallucinations. Hallucinogen-persisting perception disorder (HPPD) is a chronic problem associated with LSD abuse. According to the Diagnostic and Statistical Manual 4th Edition , the diagnosis of HPPD requires the recurrence of perceptual symptoms that were experienced while intoxicated with the hallucinogen that causes functional impairment and is not caused by a medical condition.8 The etiology of HPPD is still unknown, and the reported incidence varies widely. P.1209 Symptoms are primarily visual, and reality testing is typically intact in HPPD. Common perceptual and visual disturbances in HPPD include geometric forms; false, fleeting perceptions in the peripheral fields; flashes of color; intensified color; and halos around objects.71 One finding described after LSD use is palinopsia, or “trailing,― which refers to the continued visual perception of an object after it has left the field of vision. Interestingly, these visual perceptions are associated with normal ophthalmologic examinations and abnormal EEG evaluations, suggesting a cortical etiology for the visual symptoms. Although many drugs have been tried to treat patients with HPPD, most have not proven beneficial. However, there have been no randomized trials to compare the efficacy of different pharmacologic interventions in HPPD. Clonazepam reportedly improved symptoms of LSD-induced HPPD in one study of 16 patients.63 Haloperidol and risperidone are associated with an exacerbation of panic and visual symptoms.3 , 7 Clonidine may also be a therapeutic option for HPPD. Patients being treated with tricyclic antidepressants or selective serotonin reuptake inhibitors have an inconsistent response to therapy.16 , 17

Summary Hallucinogens are a diverse group of xenobiotics that alter and distort

perception, thought, and mood without clouding the sensorium. The lysergamide, phenylethylamine, and tryptamine hallucinogens share a serotonergic mechanism of action; however, other neurotransmitters may be responsible for the complex effects of these hallucinogens. Salvinorin A, a novel hallucinogen, exerts its effects via the δ opioid receptor. Acute adverse psychiatric effects of hallucinogens include panic reactions, true hallucinations, psychoses, and major depressive dysphoric reactions. Hallucinogens rarely produce life-threatening problems, but have been known to cause autonomic instability, seizures, and hyperthermia, particularly in overdose. Meticulous supportive care with attention to abnormal vital signs is often the only therapy required. Long-term consequences of LSD use may include prolonged psychotic reactions, severe depression, exacerbation of preexisting psychiatric illnesses, and hallucinogen-persisting perception disorder.

Acknowledgment Cynthia K. Aaron, MD, and Jeffrey R. Tucker, MD, contributed to this chapter in previous editions.

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73. McKenna DJ: Clinical investigations of the therapeutic potential of ayahuasca: Rationale and regulatory challenges. Pharmacol Ther 2004;102:111–129. 74. Meatherall R, Sharma P: Foxy, a designer tryptamine hallucinogen. J Anal Toxicol 2003;27:313–317. 75. Mebs D, Schmidt K: Occurrence of tetrodotoxin in the frog Atelopus

oxyrhynchus . Toxicon 1989;27:819–822.

76. Miller PL, Gay GR, Ferris KC, Anderson S: Treatment of acute, adverse psychedelic reactions: “I've tripped and I can't get down.― J Psychoactive Drugs 1992;24:277–279. 77. Most A: Bufo Desert. 1984.

alvarius : The Psychedelic Toad of the Sonoran

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79. National Drug Intelligence Center: Foxy Fast Facts. Fast Facts September, 2003. 80. Neill JR: “More than medical significance―: LSD and American psychiatry 1953 to 1966. J Psychoactive Drugs 1987;19:39–45. 81. O'Malley P, Johnston L, Bachman J: Adolescent substance use: Epidemiology and implications for public policy. Pediatr Clin North Am 1995;42.

82. Rasmussen K, Glennon RA, Aghajanian GK: Phenethylamine hallucinogens in the locus coeruleus: Potency of action correlates with rank order of 5-HT2 binding affinity. Eur J Pharmacol 1986;132:79–82. 83. Rickert VI, Siqueira LM, Dale T, Wiemann CM: Prevalence and risk factors for LSD use among young women. J Pediatr Adolesc Gynecol 2003;16:67–75. 84. Riedlinger TJ: Wasson's alternative candidates for soma. J Psychoactive Drugs 1993;25:149–156. P.1211 85. Ritter D, Cortese CM, Edwards LC, et al: Interference with testing for lysergic acid diethylamide. Clin Chem 1997;43:635–637. 86. Roth BL, Baner K, Westkaemper R, et al: Salvinorin A: A potent naturally occurring nonnitrogenous kappa opioid selective Proc Natl Acad Sci U S A 2002;99:11934–11939.

agonist.

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1980;4:363–369.

96. Siebert DJ: Salvia divinorum and Salvinorin A: New pharmacologic findings. J Ethnopharmacol 1994;43:53–56. 97. Silbergeld EK, Hruska RE: Lisuride and LSD: Dopaminergic and serotonergic interactions in the “serotonin syndrome.― Psychopharmacology (Berl) 1979;65:233–237. 98. Stevens J: Storming Heaven. New York, Harper and Row, 1987.

99. Stout PR, Klette KL, Horn CK: Evaluation of ephedrine, pseudoephedrine and phenylpropanolamine concentrations in human urine samples and a comparison of the specificity of DRI amphetamines and Abuscreen online (KIMS) amphetamines screening immunoassays. J Forensic Sci 2004;49:160–164. 100. Strassman RJ: Human hallucinogenic drug research: Regulatory, clinical, and scientific issues. NIDA Res Monogr 1994;146: 92–123. 101. Taber WA, Heacock RA: Location of ergot alkaloid and fungi in the seed of Rivea corymbosa (L.) Hall. f., “ololiuqui.― Can J Microbiol 1962;8:137–143. 102. Titeler M, Lyon RA, Glennon RA: Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology (Berl) 1988;94:213–216. 103. Ulrich RF, Patten BM: The rise, decline, and fall of LSD. Perspect

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 81 - Cannabinoids

Chapter

81

Cannabinoids Michael

McGuigan

A 25-year old man was arrested for erratic driving on a city street. He was not involved in a crash or injured. On initial questioning the man stated that he was not drinking or using any other mind-altering substances. The police noted inappropriate smiling and atypical answers to their battery of standard questions. Although the man claimed that he was not intoxicated he was asked by the police to take a breath alcohol test, which was negative. However, his behavior was of sufficient concern to the police that they brought him to the emergency department (ED). In the ED the patient was alert, oriented, and compliant with all requests. He stated that he had no medical problems and took no medication. He mentioned that he had used marijuana infrequently in the past, but that it had been at least 6 months since his last use. He denied the use of other drugs. The patient had normal vital signs, including temperature. His pupils were normal and reactive, extraocular movements were intact, there was no nystagmus, and his sclera were minimally injected. He had a

supple neck and clear lungs. His neurologic examination including his gait, was normal. A bedside rapid glucose was 95 mg/dL. At the request of the police, the patient's urine was sent to the hospital laboratory for analysis for drugs of abuse. The analysis results were positive for cannabinoids and negative for all other drugs assayed. The patient was charged with driving under the influence of drugs. In court, the man was convicted of the charges on the grounds that in his deposition testimony he reiterated his claim that he had not used drugs for 6 months, yet had a positive urine toxicology test. Even if he was a heavy marijuana user, this 6 months was too long for an assay to remain positive. The man sued the hospital. See Chapter

135 for further discussion.

Cannabis is a collective term referring to the bioactive substances from Cannabis sativa. The C. sativa plant contains a group of more than 60 chemicals (C21 group) called cannabinoids. In this chapter, the term cannabis encompasses all cannabis products. The major cannabinoids are cannabinol, cannabidiol, and tetrahydrocannabinol. The principal psychoactive cannabinoid is Δ9 -tetrahydrocannabinol (THC). Marijuana is the common name for a mixture of dried leaves and flowers of the plant. Hashish and hashish oil are the pressed resin and the oil expressed from the pressed resin, respectively. The concentration of THC varies from 1% in low-grade marijuana up to 50% in hash oil. Pure THC and a synthetic cannabinoid are available as prescription drugs with the generic names of dronabinol and nabilone, respectively.

History

and

Epidemiology

Cannabis has been used for more than 4000 years. The earliest documentation of the therapeutic use of marijuana is the 4th century B.C. in China.74 Cannabis use spread from China to India to North Africa, reaching Europe around 500 A.D.63 In colonial North America,

cannabis was cultivated as a source of fiber. Marijuana was used as an intoxicant from the 1850s until the 1930s when the US Federal Bureau of Narcotics began to portray marijuana as a powerful, addicting substance. Despite this, marijuana was listed in the United States Pharmacopoeia from 1850 to 1942. In 1970, The Controlled Substances Act classified marijuana as a Schedule I drug. Currently, marijuana is the most commonly used illicit drug in the United States. A recent study by the Substance Abuse and Mental Health Services Administration107 reported that 95 million persons age 12 years and older (40% of that population) had tried marijuana at least once. Of these, 94.6% were age 18 years and older. Approximately 14.6 million persons used marijuana in the month prior to the survey, 4.8 million of whom used it on 20 or more days in the month prior to the survey. The number of first-time users was estimated to be 2.6 million in 2001. These incidence figures have remained essentially unchanged since 1995.

Medical

Uses

Cannabinoids are proposed for use in the management of many clinical conditions (Table 81-1), but have only been approved for the control of chemotherapy-related nausea and vomiting that are resistant to conventional antiemetics, for breakthrough postoperative nausea and vomiting, and for appetite stimulation in HIV patients with anorexia-cachexia syndrome. The claims of benefit in the other medical conditions in Table 81-1 are not supported by robust evidence.5,36,56,120

Pharmacology

and

Pathophysiology

Î ”9 -THC (sometimes referred to in the literature as Δ 1 -THC) was isolated in 1964. In the early 1990s, two specific cannabinoidbinding receptors were identified: CB1 (or Cnr1) and CB2 (or Cnr2) .

Subsequent research identified endogenous cannabinoid receptor ligands (anandamide, palmitoylethanolamide), as well as cannabinoid receptor agonists and antagonists.27,42,108 P.1213 CB1 receptors are distributed throughout the brain with high densities in the basal ganglia, substantia nigra, globus pallidus, cerebellum, hippocampus, and cerebral cortex (particularly the frontal regions). CB2 receptors are located peripherally in immune system tissues (splenic macrophages), peripheral nerve terminals, and the vas deferens. Both receptors inhibit adenylyl cyclase and stimulate potassium channel conductance.88 CB1 receptors are located on the presynaptic side and their activation inhibits the glutamate, γ-aminobutyric acid, hydroxytryptamine.52,57,99 CB2

of central nervous system synapses release of acetylcholine, Lnoradrenaline, dopamine, and 5receptors are believed to participate

in the regulation of immune responses and inflammatory reactions.

TABLE 81-1. Medical Conditions Proposed for Cannabinoid Use

Anorexia-cachexia syndrome secondary Asthma Glaucoma Nausea and vomiting (resistant)a Neurologic disorders Anxiety Depression Epilepsy Head injury Insomnia Migraine headaches Multiple sclerosis

to

HIV

infectiona

Muscle spasticity and spasms Pain Parkinson disease Tourette syndrome a

FDA approved use.

The neuropharmacologic mechanisms by which cannabinoids produce their psychoactive effects have not been fully elucidated.43,52,88 Nevertheless, activity at the CB1 receptors is believed to be responsible for the clinical effects of cannabinoids,10,27,52,108 including the regulation of cognition, memory, motor activities, nociception, and nausea and vomiting. Chronic administration of a cannabinoid agonist reduces CB1 receptor density in several regions of the rat brain.11

Pharmacokinetics

and

Toxicokinetics

The pharmacokinetics of cannabinoids have been extensively reviewed.35

Absorption The rate and completeness of absorption of cannabinoids depend on the route of administration and the type of cannabis product. Inhalation of smoke containing THC results in the onset of psychoactive effects within minutes. From 10–35% of available THC is absorbed during smoking and peak plasma concentrations of THC occur an average of 8 (range: 3–10) minutes after the onset of smoking marijuana. Peak plasma levels depend on the dose; a marijuana cigarette containing 1.75% THC produces a peak plasma THC concentration of approximately 85 ng/mL.46 Ingestion of cannabis results in an unpredictable onset of

psychoactive effects in 1–3 hours. Because of THC's instability in acidic gastric fluid and first-pass hepatic clearance,85 5–20% of available THC reaches the systemic circulation following ingestion. Peak plasma concentrations of THC usually occur 2–4 hours after ingestion but delays up to 6 hours are described.31,64 The therapeutic serum concentration of THC for the treatment of nausea and vomiting is greater than 10 ng/mL.17 Dronabinol has an oral bioavailability of approximately 10% with high interindividual variability.35,85 Peak plasma concentrations occur 2–3 hours after ingestion. Nabilone has an oral bioavailability estimated to be greater than 90% and reaches peak plasma concentrations 2 hours after ingestion.98

Distribution THC has a steady-state volume of distribution of approximately 2.5–3.5 L/kg. 35 Previous estimates of up to 10 L/kg are considered erroneous because of inaccuracy of the quantitative method used. THC is 98% bound, primarily to plasma lipoproteins. Cannabinoids are lipid soluble and accumulate in fatty tissue in a biphasic pattern. Initially, THC is distributed to highly vascularized tissues (eg, liver, kidneys, heart, muscle). Following smoking or intravenous administration, the distribution half-life is less than 10 minutes.46,85 After the initial distribution phase, THC accumulates more slowly in less vascularized tissues and body fat. Repeated administration of Î ”8 -THC (an isomer of Δ9 -THC) to rats over 2 weeks resulted in steadily increasing concentrations of Δ8 -THC in body fat and liver, but not in brain tissue. Once administration of Δ8 -THC stopped, the cannabinoids were slowly released from fat stores as adipose tissue turned over.84 THC crosses the placenta and enters the breast milk. Concentrations in fetal serum are 10–30% of maternal concentrations. Daily marijuana smoking by a nursing mother resulted in concentrations of THC in breast milk that are 8-fold higher than concomitant maternal

serum concentrations; THC metabolites do not accumulate in breast milk.90

Metabolism THC is nearly completely metabolized by hepatic microsomal hydroxylation and oxidation by the cytochrome P450 (CYP) system (primarily CYP2C).35 The primary metabolite (11-hydroxy-Δ9 -THC or 11-OH-THC) is active and is subsequently oxidized to the inactive 11nor-Δ9 -THC carboxylic acid metabolite (THC-COOH) and many other metabolites.1,3,93 The plasma concentrations of THC and its metabolites change over time. Smoking a marijuana cigarette results in peak plasma concentrations of THC before finishing the cigarette. In 6 volunteers, peak plasma concentrations of THC occurred at 8 (range: 6–10) minutes after onset of smoking, of 11-OH-THC at 13 (range: 9–23) minutes, and of THC-COOH at 120 (range: 48–240) minutes46 (Fig. 81-1). Approximately 1 hour after beginning to smoke a marijuana cigarette, the THC–to–11-OH-THC ratio is 3:1 and the THC–to–THC-COOH ratio is 1:2; at approximately 2 hours the ratios are 2.5:1 and 1:8, respectively; at 3 hours the ratios are 2:1 and

1:16,

respectively. 46

Ingestion of cannabis results in much more variable concentrations and time courses of THC and metabolites (Fig. 81-1). Nonetheless, at 2–3 hours postingestion the ratios are similar to those after smoking: THC–to–11-OH-THC is 2:1 and THC–to–THC-COOH ranges from 1:7 to 1:14.31,116

Figure 81-1. Estimated relative time course of THC and its major metabolite based on the route of exposure. ----------THC (single

smoking

----------THC oral

(single

smoking

exposure);----------THC-COOH

exposure);

(single

oral

exposure);----------THC-COOH

(single

exposure);

----------THC-COOH

(chronic

exposure).

P.1214

Excretion Reported elimination half-lives of THC and its major metabolites vary considerably. Following intravenous doses of THC, the mean elimination half-life ranges from 1.6–57 hours.35 Elimination half-

lives are expected to be similar following inhalation.35,46 The elimination half-life of 11-OH-THC is 12–36 hours and the elimination half-life of THC-COOH ranges from 1–6 days.58,116 THC and its metabolites are excreted in the urine and the feces. In the 72 hours following ingestion, approximately 15% of a THC dose is excreted in the urine and roughly 50% is excreted in the feces.1,15,116 Following intravenous administration, approximately 15% of a THC dose is excreted in the urine and only 25–35% is excreted in the feces.116 Inhalation is expected to produce results similar to intravenous administration.35,46 In 5 days, 80–90% of a THC dose is excreted from the body.40,50 Cannabinoids were measured in the urine following smoking a marijuana cigarette containing 27 concentrations peaked at 2 hours 3.2–53.3 µg/L) after smoking ng/mL) in 5 of the 8 subjects by

mg of THC 70 (Fig. 81-1). THC urine (mean: 21.5 µg/L; range: and were undetectable ( Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 82 - Nicotine and Tobacco Preparations

Chapter Nicotine

82 and

Tobacco

Preparations

Morton E. Salomon

Nicotine

At 8:15 A.M. an 11-month-old boy was found eating cigarette butts out of an ashtray. The parents cleaned his lips and mouth with cold water. Twenty minutes later the child vomited 3 times. The parents contacted their regional poison center, which advised them to bring the child immediately to an emergency department (ED). En route, via ambulance, the child vomited again. On presentation to the ED at 9:00 A.M., the child was noted to be tremulous and diaphoretic with excessive salivation. He had a glassy-eyed look and did not interact with his parents. His vital signs were: blood pressure, 128/78 mm Hg; pulse, 150 beats/min; respiratory rate, 28 breaths/min; and temperature, 99.7°F (37.6°C). Pulse oximetry measured 96% saturation on room air.

Pupils were 3 mm and reactive to light. The skin was pale without rashes or bruises. The anterior fontanel was appropriately open (1 cm) and flat. The mouth was clear of particulate matter. Examination of the chest, heart, and abdomen were normal, as were his pulses. The neurologic examination was nonfocal; however, at 9:10 A.M., approximately 1 hour after the ingestion, the child had a generalized seizure lasting less than 15 seconds. There was no incontinence, eye rolling, or focal neurologic findings. The ED staff placed a 28-French orogastric tube into the child's stomach and lavaged with 100-mL aliquots of 0.9% sodium chloride. Lavaging produced a scant amount of brown particulate material along with other stomach contents. After the stomach contents were cleared, 10 g of activated charcoal with sorbitol were delivered through the orogastric tube, which was then replaced by a nasogastric tube. Over the next 30 minutes, the child became increasingly lethargic. Neurologic examination demonstrated progressively more hypotonia, and his deep tendon reflexes became undetectable. The blood pressure decreased to 76/50 mm Hg, the pulse decreased to 84 beats/min and his respiratory rate decreased to 18 breaths/min. His skin was mottled and cool. The pulse oximeter registered 88–89% on room air. An arterial blood gas analysis done prior to placing the child on oxygen showed: pH 7.44; PCO2 , 46 mm Hg; and PO2 , 57 mm Hg. By 9:45 A.M. the child was intubated and placed on a ventilator. Copious clear secretions were noted from both the mouth and endotracheal tube and the child was given 0.2 mg of atropine intravenously. The complete blood count (CBC), electrolytes, glucose, calcium, magnesium, and renal function tests done at the time of admission were all within normal limits. Four hours after presentation, the child was more alert and breathing more effectively and began fighting the ventilator. He was sedated with a continuous midazolam infusion, and was gradually weaned from the respirator and extubated 11 hours after the ingestion. He was discharged home 48 hours after ingestion in stable condition and his parents were counseled regarding poison prevention. Followup examination 15 days later revealed no apparent sequelae.

Fifty million Americans—25% of the adult population—smoke cigarettes despite antismoking public education campaigns, widespread knowledge of its health consequences, and decreasing social acceptance.6 , 78 In the United States, 350,000 deaths annually are attributable to cigarette smoking, making it the single most important cause of preventable premature mortality.57 It is now widely accepted that tobacco use is addictive and that nicotine is the component primarily responsible for dependency.72 Nicotine is a tertiary amine, that is a colorless, bitter-tasting, and a highly water-soluble volatile liquid that is weakly alkaline (pKa = 8.0–8.5).6 The principal source of nicotine is the tobacco plant, Nicotiana tabacum , from which nicotine was first isolated in 1826.13 Nicotine also can be isolated from multiple plant species in the Solanaceae family. N. tabacum is not the only tobacco plant in this family. The first tobacco to be brought back from the New World to P.1222 Europe was N. rustica , which contains a much higher concentration of nicotine (approximately 18%) and which is still found in “Turkish tobacco.― 39 Nicotine is also found in small concentrations in plants outside the Nicotiana genus, and even in plants outside the Solanaceae family. In addition, there are a number of alkaloids with chemical structures and physiologic activity similar to that of nicotine in tobacco plants and botanical species related to tobacco.39 Nornicotine, anabasine, and anabatine are structurally similar alkaloids also found in tobacco. Anabasine is the principal alkaloid found in N . glauca .65 Lobeline, derived from Lobelia inflata , or “Indian tobacco,― is frequently used as a nicotine substitute.32 Cystisine, found in mescal beans, is used for its mind-altering properties. Coniine, the lethal alkaloid in “poison hemlock,― is also chemically related to nicotine.

History

and

Epidemiology

The principal sources of nicotine exposure and poisoning are tobacco

products: cigarettes, cigars, pipe tobacco, chewing tobacco, and snuff. Nicotine is also the essential component of smoking-cessation products such as nicotine gum, nicotine patches, nicotine nasal and oral sprays, and nicotine lozenges. Nicotine had a brief application as an animal tranquilizer and was used extensively as an agricultural insecticide in the 1920s and 1930s; formulations of this product are still used by “organic― gardeners.

Sources and Uses of Nicotine Cigarettes Cigarettes are the most widely used tobacco products in Western culture and the most likely to be implicated in nicotine poisoning. When a cigarette is burned, the smoker inhales both gaseous and particulate matter. Nicotine is found in the particulate phase of cigarette smoke, along with tar. The total nicotine content of a “regular― American cigarette varies between 13 and 20 mg. “Low nicotine― cigarettes contain half this amount, and many European cigarettes contain up to 30 mg of nicotine.8 , 20 , 70 When a cigarette is smoked, more than half the nicotine escapes in the sidestream smoke and a large fraction remains in the butt and filter.2 As a result, a typical cigarette delivers 0.5–2.0 mg of nicotine (average: 1.0 mg) to the smoker.32 This amount depends on the total nicotine content of the cigarette as well as the individual's smoking technique. The nicotine content written on a cigarette package is determined by burning cigarettes on mechanical smoking machines in a standardized manner.45 A smoker, on the other hand, extracts variable amounts of nicotine from a cigarette to maintain a steady blood nicotine concentration. Smokers vary the degree of nicotine extraction by altering the rate of puffing, the puff volume, the depth and duration of inhalation, and the size of the residual butt.6 , 45 African Americans extract, on average, 30% more nicotine per cigarette smoked than whites.58 When smokers switch from “regular― to “low-tar― cigarettes, they often maintain a similar nicotine intake by increasing

the number of cigarettes they smoke and by puffing in a more vigorous manner (Table 82-1 ).45 Not all cigarettes are made from pure tobacco. It is common, especially in Asia, to create cigarettes out of a mixture of tobacco and other products. “Kreteks― are cigarettes composed of 60% tobacco and 40% ground clove. In the United States, they are especially popular with adolescents because of their pleasant odor and euphorigenic effect. Unfortunately, kreteks are more addicting than tobacco alone.39 Moreover, eugenol, the major active ingredient in cloves, is believed to be the probable cause of the severe lower respiratory complications of acute lung injury and hemorrhage that occur in some users.39 1 whole cigarette 13–30 0.5–2.0 1 low-yield cigarette 3–8 0.1–1.0 1 cigarette butt 5–7 — 1 cigar 15–40 0.2–1.0 1 g of snuff (wet) 12–16 2.0–3.5 1 g of chewing tobacco 6–8 2.0–4.0 1 piece of nicotine gum 2 or 4 1.0–2.0 1 nicotine patch

8.3–114 5.0–22/24 h 1 nicotine nasal spray 0.5 0.2–0.4 a Delivered through intended use of standard dose. Source

Content

(mg)

Delivered

(mg)a

TABLE 82-1. Sources of Nicotine

Smokeless

Tobacco

Smokeless tobacco, especially snuff, has regained popularity in the United States. Because smoking is not involved, and with the present laws in many states making it illegal to smoke in public places, the public generally believes that smokeless tobacco is more socially acceptable and less of a health risk.23 , 39 In fact, in comparison to nonsmokers, there is as much as 48 times the risk of oropharyngeal cancers among longtime users of smokeless tobacco, in addition to other oral and nonoral health hazards.12 , 13 , 39 Smokeless tobacco comes in two varieties: chewing tobacco and snuff. Snuff is a finely cut tobacco powder packaged dry or moist. In Europe, especially Great Britain, small pinches of dry snuff are inhaled through the nostrils. In the United States, dry and wet snuff are usually “dipped.― This involves placing a bite-size amount of tobacco (a “quid―) between the mucous membranes and the gums. Chewing tobacco is generally packaged as “twists―—leaf tobacco twisted into ropelike portions—or “plugs―—shredded tobacco pressed into cakes. These forms are chewed or simply placed in the gingival recess. Generally, the nicotine from smokeless tobacco dissolves in the saliva and is absorbed through the mucous membranes of the mouth. However, approximately one-third of smokeless tobacco users swallow their saliva, absorbing additional nicotine in the intestinal tract.12 , 13 ,

69

Snuff contains approximately 14 mg of nicotine per gram of tobacco. A typical quid contains 1.5–2.5 g of tobacco, which the user “dips― for 20–30 minutes. Ten percent of the available nicotine crosses the oral mucosa, producing a total nicotine dose of 2.0–3.5 mg/dip. Tobacco chewers use approximately 7 g of tobacco at a time. The nicotine content of a typical “chaw― is 7.8 mg/g of tobacco. Only 8% of this nicotine is absorbed through the oral mucosa, because the pH of chewing tobacco is only 6.5. Ultimately, the tobacco chewer gets approximately the same dose of nicotine or slightly more than the tobacco snuffer.11 The smokeless tobacco user who takes 8–10 dips or chaws per day gets a nicotine dose equivalent to 30–40 cigarettes per day, and cotinine (nicotine metabolite) concentrations found in their urine are similar to those found in the urine of smokers.5 , 11

Less

Common

Sources

Although poisoning from smokeless tobacco usually occurs by ingestion in children, 1 case report of nicotine poisoning occurred when a child licked the contents of a spittoon.21 Another unusual source of nicotine poisoning is tobacco enemas, where tobacco is soaked in water and the juice of this extract is added to enemas for the treatment of pinworm. This practice has produced at least 1 reported case of severe nicotine poisoning.20 P.1223 Green-leaf tobacco sickness occurs when a tobacco harvester handles dew-laden tobacco leaves. The nicotine dissolves in the water and is absorbed through the worker's skin, if cutaneous precautions are not taken.6 , 39 Transcutaneous nicotine poisoning is also reported in smugglers who hide tobacco leaves under their clothing.39 Nicotine salts, such as nicotine sulfate, were popular pesticides in the 1920s and 1930s. These compounds generally contain 40% nicotine; when they come in contact with moist skin, significant doses of nicotine are absorbed. Several cases of severe nicotine poisoning from skin exposure or ingestion, including deaths, have occurred.9 , 39 , 55

Although industrial scale manufacture of nicotine insecticides was discontinued by 1950, these products are available through catalogues and web sites catering to the organic gardener.

Gum Nicotine is prepared in the form of gum to assist abstinent smokers with withdrawal symptoms. Nicotine resin gum is packaged in 2 strengths: 2 mg and 4 mg per stick. It is designed to be chewed slowly and intermittently. When used correctly, blood concentrations of nicotine are less than those achieved through cigarette smoking, even when 4-mg gum is chewed. Because of alkaline buffers, approximately 53–72% of the nicotine in the gum is absorbed through the buccal mucosa. Additional amounts can be absorbed through swallowed saliva.6 However, when the gum is chewed rapidly and vigorously, nicotine concentrations in the blood can rise rapidly, producing adverse effects, especially in children.70 Severe nicotine poisoning in a 20-month-old child occurred from the use of nicotine gum.68 Moreover, adverse effects are reported in adults who have used the gum while continuing to smoke.50 , 70 If the gum is swallowed, it is less likely to be toxic because the nicotine is released in an acidic milieu resulting in an ionized state and absorbed slowly during GI transit, producing low blood concentrations.6

Patches There are currently four nicotine-releasing adhesive patches available to aid in the treatment of smoking cessation. These patches, designed for 16–24 hours of use, vary in size and nicotine release rates, and contain 8.3–114 mg of nicotine per patch. Only a portion of the total nicotine load of the patch is actually absorbed during the cutaneous application.

Nasal

Spray

and

Inhaler

In 1996, a nicotine nasal spray was released in the United States as

another treatment modality for withdrawal symptoms during smoking cessation. The metered-dose inhaler contains 100 mg of nicotine in a concentration of 10 mg/mL, and is designed to deliver 200 equivalent puffs. Each puff contains 0.5 mg of nicotine of which slightly more than half will pass into the circulation through the nasal mucosa.49 Absorption is diminished slightly by rhinitis and delayed by the use of α-adrenergic decongestants.40 The recommended dose is 2 sprays (1 mg)—1 in each nostril—every 30–60 minutes. The user titrates the dosing frequency to withdrawal symptoms, using a maximum of 40 doses (80 puffs) per day and creating a steady-state serum nicotine concentration of 6–18 ng/mL. A nicotine metered-dose oral inhaler for smoking cessation is now available. The device is designed to mimic smoking by providing airway stimulation as well as nicotine replacement. Absorption of nicotine occurs primarily through the buccal and pharyngeal mucosa, but slow, deep inhalation can redirect some nicotine into the pulmonary tree and achieve absorption there. Typical use achieves an average steady-state serum nicotine concentration of 7 ng/mL.41 Absorption Lungs, oral mucosa, skin, intestinal tract, gastric acidity inhibits absorption Volume of distribution 1 L/kg Protein binding 5–20% Metabolism 80–90% hepatic, remainder in lung and kidney; principle metabolites are cotinine, nicotine-′-N -oxide Half-life 1–4 h, shorter in smokers (average, 2h); half-life of cotinine is 19 h Elimination 2–35% excreted unchanged in urine

TABLE

82-2.

Pharmacologic

Pharmacology

and

Characteristics

of

Nicotine

Pharmacokinetics

Table 82-2 summarizes the pharmacologic characteristics of nicotine.

Absorption The typical cigarette smoker will adjust his or her use of cigarettes and pattern of smoking to maintain an average nicotine concentration of 30 ng/mL.6 Nicotine is readily absorbed from the buccal mucosa, respiratory tract, intestinal tract, and skin. The usual site of absorption is the lungs. Inhaled nicotine from cigarette smoke reaches the brain in approximately 8 seconds, with central nervous system (CNS) concentrations of nicotine rising rapidly and then declining rapidly as the drug is redistributed to other tissues.6 , 32 The cigarette smoker achieves a serum nicotine concentration of 5–30 ng/mL after a single cigarette.6 Nicotine from cigar and pipe tobacco, as well as from chewing tobacco, snuff, and nicotine resin chewing gum, is generally absorbed through the buccal mucosa. Pipe and cigar tobacco are air-cured to achieve an alkaline pH of 8.5. Smokeless tobaccos and nicotine gum are buffered. The alkaline pH of all of these products enhances buccal absorption.6 Smokeless tobacco users generally achieve nicotine concentrations comparable to those of cigarette smokers. Pipe and cigar smokers usually average lower nicotine concentrations, unless they inhale the smoke from these products. 6 Nicotine generally achieves a volume of distribution of 1 L/kg. It readily crosses the placenta and is also transmitted in small concentrations in breast milk.6

Metabolism

and

Elimination

Habitual tobacco users generally metabolize 80–90% of their nicotine intake, excreting 10–20% in urine unchanged. Metabolism takes place primarily in the P450 system of the liver, but also, to a lesser extent, in the kidney and lung.9 , 32 The two major oxidative metabolites of nicotine are cotinine and nicotine-1-N -oxide. Both of these compounds are pharmacologically inactive and are excreted primarily by the kidney. 6 , 32 The half-life of nicotine is 1–4 hours but generally averages 2 hours in chronic users.6 , 32 Because nicotine metabolism in the liver is an inducible transformation, smokers metabolize the drug more rapidly than nonsmokers. The elimination half-life of cotinine is approximately 19 hours, making cotinine levels in the urine a better marker of recent tobacco use and total tobacco exposure.6 , 32 Clearance of cotinine is slower in African Americans than in whites.58 β-Adrenergic antagonists Nicotine Benzodiazepines Opioids Caffeine Phenacetin Cyclic antidepressants Theophylline H 2 -histamine

antagonists

TABLE 82-3. Xenobiotics with Enhanced Metabolism in Smokers P.1224 Renal excretion of unchanged nicotine can vary from 2–35% of the total dose,6 depending on urine flow and urine pH. Experimentally, acidification of the urine traps nicotine ions and enhances direct elimination.6 , 20 Nonsmokers eliminate a larger proportion of nicotine unchanged in the urine because of their slower hepatic metabolism.35

Drug

Interactions

A number of studies demonstrate that smokers have altered metabolism of many commonly used xenobiotics. Smokers metabolize via autoinduction the xenobiotics listed in Table 82-3 more quickly than do nonsmokers. 32 , 35 Nicotine itself is metabolized more rapidly in smokers. The therapeutic effectiveness of opioids, benzodiazepines, nifedipine, and β-adrenergic antagonists is diminished in smokers. 32 Smokers with peptic ulcer disease are also more likely to fail treatment with H2 antagonists and antacids.6 The presumed mechanism for this change in drug metabolism is induction of microsomal enzyme systems. However, because there are 3000 components to tobacco smoke, it is difficult to know exactly which components affect metabolism. In all likelihood, nicotine is not responsible for the induction. For example, IV nicotine does not affect theophylline metabolism in humans.6 It is more likely that polycyclic aromatic hydrocarbons (PAH), released by the combustion of tobacco, are responsible for the induction of P448 microsomal enzymes in the liver.35 Xenobiotics whose metabolism is affected by smoking are in part metabolized by this system. In contrast, xenobiotics using the P450 system exclusively are not affected by chronic smoking.35 This conclusion would be further supported by demonstrating the absence of xenobiotic interactions in users of smokeless tobacco, nicotine gum, and transdermal nicotine patch users. Nicotine and ethanol are frequently used concurrently, and animal studies demonstrate that pretreatment with ethanol exaggerates cardiovascular responses to IV nicotine. Heart rate and blood pressure increase in an additive way. Smokers are more apt to suffer from dysrhythmias and sudden death during alcohol use. It is likely that this is the result of increased oxygen demand triggered by additive cardiovascular stimulation. 7 Because ethanol does not influence the rate of nicotine metabolism, the etiology of this additive response is unclear.

Pathophysiology Nicotine binds stereospecifically to select acetylcholine receptors, generally referred to as nicotine receptors (Chap. 14 ).6 , 32 There are nicotine receptors throughout the body, particularly in the autonomic

ganglia, adrenal medulla, central nervous system, spinal cord, neuromuscular junctions, and chemoreceptors of the carotid and aortic bodies. 6 , 32 In the CNS, the highest density of nicotine receptors can be found in the limbic system, midbrain, and brainstem.6 The physiologic effects on the CNS are multiple, complex, and dose-dependent. At doses commonly encountered with tobacco use there is stimulation of the reticular activating system and an alerting pattern on electroencephalogram (EEG).32 , 68 There is a facilitation of memory and attention, with a decrease in aggression and irritability.32 Although nicotine might reduce skeletal muscular tone and decrease deep-tendon reflexes, its central and neuromuscular stimulatory effects can also produce tremor.32 , 65 At very high doses, nicotine induces seizures. Studies in mice suggest that nicotine-induced seizures can be controlled by the neuroinhibitory agent 5-α-pregnan-3α-ol-20-one. It is therefore postulated that nicotine produces seizures at high doses by a CNS disinhibition mechanism at CNS nicotine receptor synapses.42 Gastrointestinal effects are probably mediated by nicotine stimulation of vagal centers in the medulla oblongata. Even at low doses, nicotine exposure produces nausea and vomiting in the naive tobacco user. Nicotine also increases gastroesophageal reflux, probably by either lowering sphincter pressure or increasing acid secretion.62 Diarrhea can be stimulated by larger doses of nicotine, which is probably mediated by both central and parasympathetic excitation.20 , 32 Nicotine exerts a number of endocrinologic effects either by acting directly on nicotine receptors in the endocrine gland or by stimulating neurohumoral pathways in the CNS. It enhances the release of catecholamines, and stimulates the production of vasopressin (antidiuretic hormone), growth hormone, adrenocorticotropin, cortisol, prolactin, serotonin, and β-endorphins. It also affects pancreatic exocrine functions in rats. In rats pretreated with nicotine doses comparable to exposures that moderate smokers receive there is an increase in amylase, trypsin, and chymotrypsin activity.15 With repeated exposure, tolerance develops to many of these effects.6

Nicotine is an anorexiant, especially to sweet foods, while increasing basal energy expenditures. It also causes moderate increases in serum glucose by reducing insulin sensitivity.51 These effects explain why nicotine promotes weight loss. Smokers weigh, on average, 6–10 lbs less than nonsmokers. With repeated exposure, tolerance develops to many of these effects.6 , 32 Habitual use of nicotine also decreases estrogen levels in female smokers, probably by promoting hydroxylation of estradiol. As a result, women who smoke are at increased risk for osteoporosis.

Clinical

Manifestations

More than 60% of reported nicotine exposures produce no toxicity and only 1% produced moderate to major toxicity. This low proportion of serious poisoning is not surprising, because 98% of these exposures are unintentional and more than 90% occur in children younger than 6 years of age (Chap. 130 ).8 Nonetheless, serious exposures do occur, even in young children, and seem to be dose related. In one report, 23 (45%) of 51 childhood exposures to nicotine resulted in some degree of symptomatology. Only 8 (16%) of these 51 children required evaluation by a physician and only 4 children (8%) developed significant symptoms of lethargy, unresponsiveness, and limb jerking.70 Similarly, another study reported that only 1 (5%) of 20 children who ingested nicotine became moderately ill and required 24 hours of hospitalization.8 Most unintentional exposures in small children result from the ingestion of tobacco products. The tobacco itself usually induces spontaneous vomiting, which limits its own absorption. Early (15–60 min) Abdominal pain Bronchorrhea Hypertension Agitation/anxiety Headache Nausea

Hyperpnea Tachycardia Ataxia/dizziness Hyperactivity Salivation Pallor Blurred vision Muscle fasciculations Vomiting

Confusion Distorted hearing Seizures Tremors Delayed (0.5–4 h) Diarrhea Apnea Bradycardia Coma Lethargy Hypoventilation Dysrhythmias Hypotension Shock Hyporeflexia Hypotonia Weakness Muscle paralysis Gastrointestinal

Respiratory

Cardiovascular

Neurologic

TABLE 82-4. Signs and Symptoms of Acute Nicotine Poisoning

P.1225 A child who ingests 1 or more cigarettes or 3 or more cigarette butts has a 90% chance of becoming symptomatic. Conversely, ingestion of smaller amounts will produce symptoms only half the time.78 In a retrospective review of cigarette ingestions by 10 children, each of the 4 children who became severely poisoned had ingested at least 2 whole cigarettes.44 One-half piece or more of 2-mg nicotine chewing gum usually produces symptoms in a child.70 Table 82-4 outlines the symptoms associated with acute nicotine exposure. Clinical signs of low concentrations of nicotine, such as those occurring routinely in smokers, include tremor and increased heart rate, respiratory rate, blood pressure, and alertness. In marked contrast to these relatively mild effects associated with cigarette smoking, when nicotine is taken in “toxic― quantities, as in an insecticide exposure, for example, the effects are more severe. The symptoms may follow a biphasic pattern in which there is initial stimulation followed quickly by inhibition. 65 Early symptoms of toxicity often include nausea, vomiting, diaphoresis, and increased salivation. Cardiovascular signs include tachycardia, hypertension, and pallor secondary to vasoconstriction. Early neurologic manifestations include headache, dizziness, ataxia, and, in moderately severe cases, confusion as well as visual and auditory distortions.8 , 65 In the most severe exposures, these generally mild symptoms can be quickly overshadowed by signs of more extreme stimulation, such as seizures, muscle fasciculations, and atrial fibrillation.8 , 65 , 68 Although seizures do occur, there are no reports of nicotine-induced status epilepticus in nonexperimental conditions. These symptoms are often succeeded by signs of multisystem depression, such as bradycardia and hypotension, and a curarelike neuromuscular blockade that leads to muscle paralysis, particularly respiratory paralysis.55 , 65 , 68 Death is generally attributable to respiratory depression or paralysis of the intercostal muscles complicated by increased bronchial secretions or to cardiovascular collapse.9 , 55 , 65 Timely and adequate respiratory and

cardiovascular support generally leads to full recovery without sequelae.9 , 55 Vomiting is the most common symptom of nicotine poisoning, occurring in more than 50% of symptomatic patients. However, it is not a reliable sign of toxicity.70 Patients can present with lethargy and respiratory depression without prior vomiting or any other signs of CNS stimulation.9 Moreover, nicotine chewing gum ingestions in children produce vomiting less frequently (20% incidence) than do cigarette ingestions.70 Following the ingestion of tobacco products, children usually manifest symptoms within 30–90 minutes. When children chew nicotine gum, symptoms are usually apparent within 15–30 minutes, a result of more rapid absorption through the buccal mucosa.68 , 70 When death occurs, it usually occurs within 1 hour of exposure, however with mild poisonings, symptoms generally last only 1–2 hours after exposure. With severe toxicity, however, full recovery might take 48–72 hours.68 As little as 1 mg of nicotine can produce symptoms in a young child. Four to 8 mg of nicotine might produce symptoms in an adult, especially a nonhabituated victim.20 Nicotine doses of 0.8–1.0 mg/kg are considered to be lethal dose in adults.20 , 21 , 44 In a prospective study of nicotine ingestions in children, the 3 most severely poisoned infants ingested a minimum of 1.4 mg/kg. The 25 asymptomatic children ingested a mean of 0.5 mg/kg, and all asymptomatic children ingested less than 1 mg/kg.70 These numbers indicate a very narrow range between nontoxic and significantly toxic doses. Green-leaf tobacco sickness generally produces a mild to moderate illness consisting of nausea, vomiting, headaches, dizziness, pallor, and diaphoresis.6 , 39 However, in two recent outbreaks of green-leaf tobacco sickness in Kentucky, nearly 25% of the affected tobacco workers required hospitalization. A significant portion of these poisoned workers were younger than age 18 years.3 , 48 One study exposed dogs transdermally and orally to 3 different

commercially available nicotine patch systems. The topical administration provided 1–2 mg/kg over 24 hours, producing serum concentrations as high as 43 ng/mL. Two of 12 topical applications elicited salivation and vomiting. Oral exposure up to 13 mg/kg produced maximal serum concentrations of 73 ng/mL, with only vomiting in 2 of 12 oral challenges.47 Published reports from a 2-year postmarketing surveillance study by 34 poison centers describe toxicity from misuse or from unintentional exposure to transdermal nicotine patches. Transdermal application of 2–20 transdermal nicotine patches in 9 adults resulted in very serious toxicity. Eight patients were admitted to intensive care; 4 had refractory seizures; and 4 required assisted ventilation. However, 7 of the 9 patients ingested cointoxicants in suicide attempts, and the maximum nicotine level recorded was only 27 ng/mL.81 Thirty-six exposures in children were less severe. Half the children had topical exposures and half had bitten, chewed, or swallowed the patches. Nearly 40% developed symptoms, but only 27% required medical evaluation and only 5% were hospitalized for 24 hours or more.80 It seems, therefore, that unintentional exposure to nicotine patches has not yet produced serious toxicity.

Diagnostic

Testing

Toxicologic assay for nicotine or its metabolites is of limited value in the management of a patient with an acute poisoning. The presence P.1226 of nicotine or cotinine in the urine might reflect coincidental active or passive smoke exposure and therefore does not confirm nicotine as the cause of poisoning.68 Serum nicotine levels must be determined shortly after exposure and are difficult to interpret. A serum nicotine level greater than 50 ng/mL generally predicts serious toxicity, but lower levels can also be significant in the nontolerant patient.65

Management

Unintentional ingestions of nicotine in small children almost invariably involve small amounts, with spontaneous vomiting providing adequate decontamination. Thus many patients do not need medical evaluation. Individuals who ingest 1 or more whole cigarettes or 3 or more cigarette butts, who acquire their exposures from a more toxic source (a nicotine insecticide or a tobacco enema), who develop symptoms other than vomiting, or who are potentially suicidal should be referred to an ED without delay. Patients with mild symptoms and no complicating circumstances can generally be observed for 4 hours in the ED and released if symptoms have resolved. 65

Initial

Management

The patient with a significant recent oral exposure, who has not vomited prior to presentation, should be decontaminated by orogastric lavage. Emesis induced by syrup of ipecac should be avoided because nicotine poisoning may cause unexpected seizures or respiratory depression.9 , 70

Activated charcoal effectively binds nicotine and should be used to reduce absorption in gastrointestinal (GI) exposures. Pharmacokinetic studies indicate that nicotine appears in the GI tract, even when administered intravenously.70 Because this suggests that nicotine undergoes enteroenteric or enterohepatic circulation, multiple-dose activated charcoal should be considered in patients with serious exposures. In cases of skin exposure to wet tobacco leaves, concentrated nicotine liquid, or nicotine pesticide powder, the patient's clothing should be promptly removed, bagged, and not returned to the patient and the skin thoroughly washed with soap and water. The medical staff must wear impervious gloves and gowns during these procedures to avoid secondary exposure.

Symptom-Directed

Treatment

Because of the variety of stimulatory and depressant effects in the

neuromuscular, sympathetic, parasympathetic, and central nervous systems, treatment of nicotine toxicity is a complex therapeutic problem. Treatment is based on a symptom analysis with primary emphasis on respiratory support. Seizures are usually treated with a benzodiazepine. Loading the patient with longer-acting anticonvulsants is generally unnecessary.9 , 44 , 65 Cardiovascular compromise is treated with atropine for symptomatic bradycardia and fluids for hypotension.65 If hypotension does not respond to fluids, a vasopressor such as dopamine or norepinephrine is recommended.68 By reversing bradycardia with atropine, there is some risk of further exacerbating the vasoconstrictive effects. For this reason, some authors also suggest using concomitant phentolamine, an α-adrenergic antagonist, in the treatment of nicotine overdose.20 , 65 Such combined therapy is unnecessary, however, as adrenergic stimulation is rarely lifethreatening in nicotine poisoning, and adrenergic antagonism can exacerbate hypotension in the delayed phase. Respiratory compromise, caused by respiratory depression is generally treated with oxygen, intubation, and positive pressure ventilation as indicated.

Enhancing

Elimination

Although nicotine is a weak base (pKa = 8.0–8.5) and excretion can theoretically be enhanced by acidification of the urine, this approach is to be condemned,9 , 65 because the potential risks of acidification in a patient with seizures and possible rhabdomyolysis outweigh any of the theoretical benefits.65 Furthermore, because the symptoms in nicotine poisoning are generally short-lived, acidification is unnecessary. Fluid diuresis may also enhance elimination and is safer but also is unnecessary because of the limited urinary elimination.9

Antidotes There is no specific antidote for nicotine poisoning. Pempidine and mecamylamine demonstrate both competitive and noncompetitive antagonism to the central effects of nicotine,46 and hexamethonium, a

ganglionic blocker, prevents nicotine-induced seizures in animals.65 None of these blockers has been reported as used, either experimentally or clinically, to treat overdoses in humans. Although their application is theoretically of interest, new approaches with these blockers are unlikely to be developed because severe nicotine poisoning is rare and nonspecific supportive measures are almost always adequate when initiated in a timely manner.

Nicotine

Withdrawal

Tobacco use meets all definitions of addiction. taking the drug. There and therefore to keep

and

Treatment

of the World Health Organization (WHO) There is an overpowering compulsion to continue is a tendency to develop tolerance to its effects increasing the dosage. Psychological and physical

dependency develops, and the absence of tobacco produces discomfort in the smoker. Finally, tobacco has detrimental consequences for both the individual user and society at large.52 Tobacco addiction occurs with other forms of tobacco besides cigarettes, especially with smokeless tobacco. Of course, many smokeless tobacco users switch to this product to wean themselves from cigarettes.52 , 59 Individuals dependent on tobacco, like any other substance-dependent individuals, go through multiple cycles of quitting and relapsing. While spontaneous quitting without any special treatment program is the most common route to abstinence, the achievement rate by this method is only 1% of users per year.6 , 36 Women cigarette smokers have a lower rate of quitting success than men.56 Smokers are much more likely than nonsmokers to have other substance dependencies.36 Conversely, 80–95% of alcohol and drug abusers also smoke cigarettes. It has been suggested that nicotine use promotes the release of endogenous endorphins. Therefore, withdrawal from nicotine might have a strong biochemical resemblance to withdrawal from opioids.16 In fact one study was able to precipitate withdrawal symptoms in nicotine-dependent rats with subcutaneous naloxone and then reverse

the abstinence symptoms with morphine sulfate.43 On the other hand, nicotine's neurochemical effects on the brain, and on other neurotransmitters P.1227 such as dopamine, closely resemble that of other psychostimulants. (For an in-depth discussion of the physiology of withdrawal see Chap. 15 .) With so many substances involved in cigarette smoking, it is quite likely that tobacco dependency is a complex addiction, involving both psychological components, such as oral gratification, and physical dependency. It is now widely accepted that the primary addictive component of tobacco is nicotine,53 , 59 , 78 but this is the subject of some controversy and is supported primarily by indirect evidence.

Clinical Manifestations Withdrawal

of

Nicotine

Manifestations of nicotine withdrawal can occur within 2–8 hours of the last cigarette. In fact, most moderate to heavy smokers experience some withdrawal symptoms as they wake up each morning. Withdrawal reaches maximum intensity at 24–48 hours, and then diminishes over a 2-week period of abstinence. After 1 month, symptoms are gone, except for the cravings for cigarettes and an increase in appetite.6 , 66 Approximately 80% of smokers experience withdrawal symptoms when quitting, and withdrawal is nearly universal among smokers using 20 or more cigarettes per day.6 Nicotine withdrawal is not confined to cigarette smokers alone. The same syndrome is reported in smokeless tobacco users and chronic users of nicotine chewing gum.6 , 52 Most of the symptoms associated with tobacco withdrawal are subjective, leading to an overall feeling of dysphoria. These manifestations, widely described in the literature, are summarized in Table 82-5 .14 , 27 , 32 , 38 , 52 The most dramatic and intense symptom of tobacco abstinence is a craving for cigarettes, which can continue for months to years.6 Cravings for cigarettes are less intense and diminish

more quickly in people who are totally abstinent, as compared to those who are only partially abstinent.66 One study evaluated 7 smokers in a battery of computerized performance tasks over a 24-hour period of abstinence. With increasing abstinence, the smoker's responses showed increased latencies and decreased accuracy.71 Moreover, EEG studies evaluating smokers in withdrawal show a decrease in high-frequency activity and an increase in low-frequency activity, consistent with diminished arousal.32 Anger/aggression/hostility Decreased arousal pattern on EEG Anxiety Decreased blood pressure Blurred vision Decreased heart rate Confusion Diminished psychomotor performance Constipation Impaired short-term memory Craving for cigarettes Reduced plasma catecholamines Drowsiness Weight gain Gastrointestinal upset Headache Hunger Impaired concentration Irritability/impatience Moodiness Restlessness Sleep disturbance Subjective

Objective

TABLE 82-5. Clinical Manifestations of Nicotine Withdrawal The most common objective physical manifestation of nicotine abstinence is a decrease in heart rate by a mean of 9 beats/min within the first day of abstinence; it is a unique feature of nicotine withdrawal syndrome.27 This decrease remains constant when measured over the next 5 weeks of abstinence, suggesting that heart rate reduction in tobacco abstinence reflects the absence of stimulation from nicotine, rather than withdrawal symptomatology.79 Concentrations of epinephrine and norepinephrine also decrease in abstinent smokers. This is probably another manifestation of the absence of nicotine effect and undoubtedly contributes to the reduction in mean heart rate.17

Management

of

Acute

Nicotine

Withdrawal

In clinical practice, nicotine withdrawal syndrome is encountered when tobacco users attempt to quit in the interest of their long-term health or when acute illness forces abstinence. The discomfort is a primary obstacle to smoking cessation and contributes significantly, but not solely, to the low success rate of attempts to quit smoking. Therefore, any treatment approach that lessens nicotine withdrawal symptoms, without reinitiating the use of tobacco products, is more likely to aid the effort to quit, which in turn will have many long-term health benefits. An in-depth discussion of smoking cessation management falls outside the purview of a textbook on toxicologic “emergencies.― Physician counseling, behavioral interventions, nicotine replacement therapies, and select antidepressants raise cessation rates. A brief overview is included because of the current medical and public health significance of this subject.

Nicotine

Replacement

Therapy

One approach to the treatment of nicotine abstinence syndrome is to provide nicotine without tobacco. This therapy offers nicotine in a safer,

more clinically controllable form that minimizes nicotine withdrawal symptoms. After the patient breaks the smoking habit, the nicotine replacement agent is gradually tapered.63 Nicotine gum is the oldest of the nicotine substitution therapies. It ameliorates many symptoms of nicotine withdrawal, especially feelings of irritability, aggression, and dysphoria. However, it seems less effective in eliminating cigarette craving and increased hunger.10 The effectiveness of nicotine chewing gum in promoting long-term smoking abstinence has been extensively studied.33 , 74 , 75 A metaanalysis of all these studies, with special emphasis on double-blind, randomized, placebo-controlled trials with 1 or more years of followup study, indicates that nicotine chewing gum in conjunction with a formal program of behavioral therapy can produce 1-year abstinence rates of 29–49%.1 , 6 , 77 On the other hand, when nicotine gum is used in general medical practice, without structured behavioral interventions, improvement in smoking abstinence is short-lived and smoking cessation rates at 6–12 months are similar to those of placebo-treated patients.4 , 6 , 33 Unfortunately, many smokers who use nicotine gum to quit develop dependency on the gum itself. As an adjuvant to smoking cessation, nicotine gum should be used for a maximum of 3 months. However, several studies have reported continued use of the gum at 1-year followup (6–38% of users).6 , 25 , 26 Self-administration of the gum may reinforce some of the behavioral patterns that sustain smoking. It can be argued that the behavioral components of the P.1228 addictive process must be decisively interrupted for successful treatment of the addiction.59 Transdermal nicotine patches have supplanted chewing gum as the preferred nicotine-replacement therapy. Because nicotine patches are easier to use, requiring only once-a-day application, compliance is better. The dose of nicotine delivered to the patient is more predictable, nicotine steady-state concentrations are higher, and different dose

patches make tapering easier to control. Finally, because no specific behavioral action is required of the patient, other than putting the patch on in the morning, a transdermal nicotine patch does not require selfadministration of nicotine by the user and therefore does not mimic oral smoking behavior.59 , 63 There are four patch systems currently available, each of which comes in several different doses of nicotine. Three of the patch systems are designed for 24-hour use, and the newest is made for 16-hour use to approximate more closely nicotine intake patterns of the smoker.54 The patches generally deliver steady-state nicotine serum concentrations of 10–15 ng/mL, which are maintained throughout the application of the patch.24 Several double-blind, placebo controlled at 6–12-month follow-up, transdermal abstinence 2–4 times more frequently 77 , 78 Many studies have demonstrated

studies have demonstrated that, nicotine patch users achieve than placebo users.14 , 19 , 22 , that long-term efficacy is

present even with little or no formal behavioral intervention accompanying the program.1 , 14 , 77 The most consistent adverse effect of the transdermal nicotine patch is skin irritation at the site of the patch. In one trial, approximately 5% of patients withdrew from the study because they could not tolerate the cutaneous irritation.1 Both nicotine nasal spray and nicotine oral inhaler reduce withdrawal symptoms and promote abstinence more effectively than placebo.41 , 73 , 76 Both treatment modalities are based on the belief that airway stimulation will mimic smoking more closely and therefore be more effective in reducing cigarette cravings. Furthermore, the application of nicotine to mucous membranes provides a rapid transient rise in serum nicotine and thus reduces cigarette cravings more promptly than slower forms of nicotine delivery.30 Although these characteristics are probably real, the replication of smoking's airway sensations might actually make long-term abstinence more difficult to achieve.

To date there have been no head-to-head comparisons of any of the nicotine-replacement therapies. Both transdermal nicotine patch and nicotine nasal spray seem to be more effective than nicotine gum in reducing cigarette craving and increased appetite.30 , 63 A meta-analysis of 103 nicotine-replacement therapy trials, with data from more than 30,000 patients, concluded that all nicotine-replacement therapy modalities were better than placebo in promoting abstinence at 6 or more months. Abstinence odds ratios were highest for nicotine nasal spray and lowest for nicotine gum.67 Clearly, nicotine replacement therapies are moderately effective in promoting smoking cessation, especially in the short term. To be successful, the patient must eventually face the inevitable—withdrawal from nicotine itself. Theoretically, if other treatment modalities promote tobacco abstinence effectively without the use of nicotine replacement, they would have a substantial advantage.

Antidepressant

Therapy

Antidepressant medications such as bupropion offer an encouraging alternative to nicotine replacement in smoking cessation. The idea of using antidepressants for smoking cessation grows out of the observations that nicotine has antidepressive effects; that anxiety and depression are frequent comorbid conditions in nicotine-addicted patients; that dysphoria is a common symptom of nicotine withdrawal; and that women have a more difficult time with nicotine abstinence.31 In a randomized double-blinded placebo-controlled comparison study of sustained-release bupropion, smoking abstinence at 52 weeks was 12% in the placebo group and 23% in the 300-mg per day bupropion group.31 A subsequent trial, compared bupropion SR and nicotine patch, and both together, for smoking cessation efficacy in 893 subjects. The 1-year cessation rate was 16% in the patch group—roughly equivalent to placebo—but was 30% in the bupropion group and 35% in the bupropion-plus-patch group. The bupropion-plus-patch group also had the smallest weight gain.34 Another study of 211 adolescent smokers

also showed modest benefit from the combination of bupropion plus patch compared with patch alone.37 The sustained-release bupropion dose currently recommended is 150 mg twice a day. Patients should be started on treatment at least 1 week prior to their smoking quit date and continued on treatment for 8 weeks. There is an increased seizure risk with bupropion, but generally not at the doses recommended for smoking cessation unless patients are otherwise prone to seizures.34 Other antidepressants, including monoamine oxidase inhibitors and selective serotonin reuptake inhibitors, have no proven long-term benefit in smoking cessation.28

Summary Nicotine, a tertiary amine from N. tobacum and other tobacco plants, is found commercially in a number smoking products and smokingcessation treatment pharmaceuticals. It is commonly absorbed through the buccal mucosa or respiratory epithelium of the lungs, but can also be absorbed from the skin and intestine. Up to 90% of a nicotine “dose― is metabolized by an inducible P450 hepatic biotransformation, producing 2 inactive metabolites that are slowly excreted by the kidneys. It exerts its physiologic effects on selective acetylcholine receptors, primarily in neural tissue. Although the vast majority of reported nicotine exposures are unintentional and occur in children and produce mild or no toxicity, severe poisoning and even death can result, and there is a narrow range between nontoxic and significantly toxic doses. Clinical manifestations of consequential poisoning are complex but can be characterized as biphasic, with initial excitation followed quickly by inhibition. Management is symptom directed with special emphasis on seizure control and respiratory support. In terms of smoking cessation management, it should be noted that although several xenobiotics will reduce the severity of nicotine

withdrawal, long-term smoking cessation is more difficult to achieve. In many approaches to smoking treatment, the overall mean 6–12-month success rate seems to be approximately 25%.59 This is, of course, much better than the spontaneous abstinence rate of 1%, but as many as 70% of patients who achieve initial abstinence will be smoking again after 1 year.16 Whatever approach is taken to treat tobacco abstinence, it seems the patient must start with a strong desire to quit, avoid unusually stressful situations, and have a social support network that encourages the effort to stop smoking. The most successful programs are multimodality treatments that combine counseling or other behavioral therapies with one or more pharmacologic interventions. P.1229

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49. McNeil Consumer Products Co: Manufacturer's Product Information. Nicotrol. Fort Washington, PA. March 1996. 50. Mensch AR, Holden M: Nicotine overdose after a single piece of nicotine gum. Chest 1984;86:801–802. 51. Morgan TM, Crawford L, Stoller A, et al: Acute effects of nicotine on serum glucose insulin growth hormone and cortisol in healthy smokers. Metab Clin Exp 2004;53:578–82. P.1230 52. Morse RM, Norvich RC, Graf JA: Tobacco chewing: An unusual case of drug dependence. Mayo Clin Proc 1977;52:358–360. 53. Mulligan SC, Masterson JG, Devane JG, Kelly JG: Clinical and pharmacokinetic properties of a transdermal nicotine patch. Clin Pharmacol Ther 1990;47:331–337. 54. Nicotine

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Psychopharmacology

80. Woolf A, Burkhart K, Caraccio T, Litovitz T: Childhood poisoning involving transdermal nicotine patches. Pediatrics 1997;99:724(e4). 81. Woolf A, Burkhart K, Caraccio T, Litovitz T: Self-poisoning among adults using multiple transdermal nicotine patches. J Toxicol Clin Toxicol

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > H - Substances of Abuse > Chapter 83 - Phencyclidine and Ketamine

Chapter

83

Phencyclidine Ruben

and

Ketamine

Olmedo

Figure. No Caption Available.

A 17-year-old boy was brought to the emergency department (ED) by his school supervisor and 2 police officers. The boy was extremely agitated, but having transient periods of blank staring

and myoclonic movements of both arms. It took several members of the ED staff to keep him on a stretcher. Initially, no history was obtainable from the patient, who responded to verbal stimuli with inappropriate physical gestures and a few nonsensical words. The school supervisor reported that the boy had become suddenly agitated and had created a disturbance in the lunchroom, throwing chairs about the room. His vital signs were: blood pressure, 130/90 mm Hg; pulse, 110 beats/ min; respiratory rate, 18 breaths/min; and temperature, 99.9°F (37.2°C). He was well developed and well nourished, anicteric, and acyanotic. The head and neck examination were normal. His breath sounds were clear to auscultation. He had a normal heart exam. His abdomen was soft and nontender and his bowel sounds were normal. The skin was cool and diaphoretic. Conjunctivae were normal; extraocular movements were intact, but there was persistent vertical and horizontal nystagmus; pupils were equal at 4 mm and reactive to light; fundi were normal. The patient moved all extremities, had good strength and normal, symmetric deep-tendon reflexes; muscle tone seemed increased and there were periodic myoclonic jerks; plantar flexion was elicited; a sensory examination could not be performed because of the patient's lack of response and agitation. Blood was drawn for initial laboratory tests and an intravenous infusion of 5% dextrose in 0.45% sodium chloride solution was started at 200 mL/h. Fifty milliliters of 50% dextrose and 100 mg of thiamine were given IV. He was placed on 6 L of oxygen via nasal cannula. Fifty grams of activated charcoal were given together with 50 g of sorbitol by mouth. The initial laboratory data, including complete blood count, electrolytes, arterial blood gas analysis, and urinalysis, were all normal. An ECG revealed a sinus tachycardia at 110 beats/min and was otherwise normal.

By the time the physical examination and laboratory tests were completed, the patient had become calm and cooperative. He related that while at lunch, one of his friends had put mustard on his sandwich and that it tasted “terrific.― He recalled finishing the sandwich and then slowly “freaking out― and losing control of his mind and body. By the time the patient's mother arrived in the ED, his clinical condition had significantly improved. Within 3 hours after the patient's arrival, he was cooperative and his neuropsychiatric examination was entirely normal. Because he had no prior history of drug abuse, he was discharged home and arrangements were made for a followup examination with his pediatrician.

History

and

Epidemiology

Phencyclidine (PCP) was discovered in 1926, but it was not developed as a general anesthetic until the 1950s. At the time, the Parke Davis drug company was searching for an ideal intravenous anesthetic that would rapidly achieve analgesia and anesthesia with minimal cardiovascular and respiratory depression.36 It was marketed under the name Sernyl because it rendered an apparent state of serenity when administered to laboratory monkeys. Its surgical P.1232 use began in 1963, but PCP was rapidly discontinued when a 10–30% incidence of postoperative psychoses and dysphoria was documented over the subsequent 2-year period.79 By 1967 the use of PCP was limited exclusively to veterinary medicine as a tranquilizer marketed under the name Sernylan. Simultaneously, in the 1960s, PCP was developing as a San Francisco street drug called “the PeaCe Pill.―66 Numerous street names have been given to phencyclidine: on the West Coast it was called “Angel Dust, PCP, crystal, crystal joints (CJs)―; Chicago called it “THC― or “TAC―; the East Coast

opted for “the sheets,― “Hog,― or “elephant tranquilizer.― 120 Ironically, the drug was initially unpopular with drug users because of its dysphoric effects and unpredictable oral absorption.154 With time, however, its use spread in a similar geographic pattern to that of marijuana and lysergic acid diethylamide (LSD), from the coastal United States to the Midwest region.66 Phencyclidine abuse became widespread during the 1970s.25 The relatively easy and inexpensive synthesis coupled with the common masking of PCP as LSD, mescaline, psilocybin, cocaine, amphetamine, and/or “synthetic THC― (tetrahydrocannabinol) added to its allure and consumption.120 By the late 1970s PCP abuse had reached epidemic proportions.7 The Drug Abuse Warning Network (DAWN) reported that the number of PCP related emergencies and deaths more than doubled in the two years from 1975 to 1977. In 1978 the National Institute of Drug Abuse reported that of the young adults (18–25 years old), 13.9% had used PCP.50 The manufacture of phencyclidine was ultimately prohibited in 1978 when the drug was added to the list of federally controlled substances. Classifying PCP as a Schedule II drug led to its decrease in availability and, consequently, a decrease in its use. Although the 1980s brought about a cocaine epidemic that eclipsed PCP, PCP has remained consistently available on the streets, primarily regionalized to large cities in the northeastern United States and in the Los Angeles area, 103 where PCP use continues to rise and fall with societal trends. Because many of the PCP congeners made during the manufacturing process were being abused in place of PCP, the Controlled Substance Act of 1986 made these derivatives illegal and established that the use of PCP's precursor, piperidine, necessitated mandatory reporting. With this new law in place, those possessing similar but not identical illegal substances could be prosecuted. This led to a further decline in the popularity of phencyclidine. Beginning in 1984, the overall use of PCP remained

flat, reaching a nadir in 1994.182 Since 1994, however, there has been an increase of reported PCP abuse. DAWN reported that the number of PCP-related emergencies increased 28% in the years between 1995 and 2002. According to the 2002 the National Survey on Drug Use and Health (NSDUH), lifetime use of PCP was highest among those 26 years of age and older (3.5%) compared with people ages 18–25 years (2.7%) and those ages 12–17 years (0.9%).182 In the 2003 NSDUH report, the number of PCP users remained at approximately 200,000.183 Laboratory investigation of phencyclidine derivatives led to the discovery of ketamine, a chloroketone analog. Ketamine was introduced for general clinical practice in 1970 and was marketed as Ketalar, Ketaject, and, for veterinary use, Ketavet. Because ketamine has approximately 5–10% of the potency of PCP and a much shorter duration of action, it provides greater control in clinical use. Thirty-five years of clinical experience have established that ketamine provides adequate surgical anesthesia, a rapid recovery, and less prominent emergence reactions than does PCP.56,81,157,195 Because of the simplicity and efficacy of its use it is regularly employed in operating rooms, emergency departments, and throughout the developing world where little clinical monitoring is available during surgical and emergency procedures.53,78,79,80,81,82,158,194 Abuse of ketamine was first noted on the West Coast in 1971.168 During the 1980s there were reports of its abuse internationally, as well as among physicians.3,68 The nonmedical use of dissociative anesthetics has continued to increase throughout the 1990s, and into the 2000s in spite of the common complications associated with their use.181 At present, ketamine, methylenedioxyamphetamine (MDA), and methylenedioxymethamphetamine (MDMA) have regained popularity with today's youth. The same pharmacologic qualities that made ketamine more popular than PCP clinically are also responsible for its nonmedical popularity. Ketamine is regularly

consumed at all-night “rave parties― and in nightclubs because of its “hallucinatory― and “out-of-body― effects, relatively inexpensive price, and short duration of effect (a single snort lasting between 15 and 20 minutes).11,44,92,96,196 The use of ketamine is not limited to the inner city. In the past decade, the media reports police arrests in affluent suburban communities for possession and sale of ketamine, as well as more in-depth and frequent reporting of the effects of its toxicity among users.44,92,155,196 In contrast to PCP, ketamine is not manufactured illegally, but rather, diverted illicitly from legitimate medical, dental, and veterinary sources. Additionally, with the advent of the Internet, its availability has dangerously grown nationwide; a sham “biotech― Internet company was seized by New York City police in the year 2000 for selling so-called daterape drugs, including ketamine.131 Adverse reactions do occur, although, there are few reports of fatalities secondary to ketamine during this period of increased use.72,111,136 Because of its abuse potential, ketamine was placed in Schedule III of the Controlled Substance Act in 1999.157 In 2002, DAWN reported that there was a dramatic rise (more than 2000%) of ketamine-related ED visits between 1994 and 2001. Despite any clear reason, after a peak of 679 ketamine-related ED visits in 2001, there was a decline to 260 visits in 2002.183

Pharmacology Chemistry Phencyclidine's chemical name 1-(1-phenylcyclohexyl) piperidine provided the basis for its street acronym PCP. During its unlawful chemical synthesis, numerous analogs are made which have similar effects on the central nervous system (CNS) and which have been used as PCP substitutes. These “designer―

arylcyclohexylamines are aliphatic- or aromatic-substituted amines, ketones, or halides, and appear similar to the parent compound. More than 60 psychoactive analogs are mentioned in the medical literature and the following salient points of the 5 most prevalent compounds are worth mentioning. TCP and PCC are piperidine derivatives. Piperidine, the synthetic precursor, was formerly easily purchased for manufacturing PCP and its derivatives. TCP, a thiophene analog (1-[1-(2-thienyl)cyclohexyl] piperidine), produces even more intense effects than PCP. An intermediate of PCP synthesis, PCC (1-piperidinocyclohexanecarbonitrile) was a constituent of up to 22% of illicit drug preparations analyzed for phencyclidine. This most likely resulted from a poor manufacturing process.14,167 PCC degrades to piperidine, which is recognizable by its strong fishy odor. The presence of its carbonitrile group adds to its toxicity by generating cyanide when smoked.12,14,174,175 The pyrrolidine derivative, PHP (phencycloclohexylpyrrolidine), is comparable clinically to PCP and is not detected by many of the available drug-screening methods.27,89 More potent than PCP, PCE (1-phenylcyclohexylethylamine) was commonly available on the street as a white powder indistinguishable from PCP.167 P.1233 Ketamine and tiletamine, two legal congeners of PCP, are used clinically for sedation and anesthesia. In large quantities, both are also used in veterinary medicine for animal sedation. Ketamine (Ketaset and Ketalar) is the only dissociative anesthetic product manufactured for human use for the purpose of anesthesia, conscious sedation, and the treatment of bronchospasm. The development of a mechanistic approach to pain therapy in the last 15 years has brought a renewed interest in the use of ketamine as an adjuvant to multimodal pain treatment. Ketamine is used prophylactically and therapeutically in children and adults in the management of postoperative pain. For the treatment of pain ketamine is administered intravenously (median dose: 0.4 mg/kg;

range: 0.1–1.6), orally, intramuscularly, rectally, subcutaneously, intraarticularly, caudally, epidurally, transdermally, intranasally, or added to a patient-controlled analgesia device.61,90,107,160 The molecular structure of ketamine [2-(ortho-chlorophenyl)-2methylaminocyclohexanone] contains a chiral center, producing a racemic mixture of 2 resolvable optical isomers or enantiomers, the D(+)-isomer and L(–)-isomer. Commercially available preparations of ketamine contain equal concentrations of the 2 enantiomers. These 2 molecules differ in their pharmacodynamic effects. In a randomized, double-blind evaluation of patients undergoing surgery, the D(+)-isomer of ketamine was a more effective anesthetic, but manifested a higher incidence of psychotic emergence reactions than the L(–)-isomer. In other studies, the D(+)-isomer causes a greater increase in both blood pressure and pulse than the D(–)-isomer, as well as more bronchodilating effects.158,195

Pharmacokinetics

and

Toxicokinetics

Phencyclidine is a white, stable solid that is readily soluble in both water and ethanol. It is a weak base with a pKa between 8.6 and 9.4 with a high lipid-to-water-partition coefficient. It is rapidly absorbed from the respiratory and the gastrointestinal tracts; as such, it is typically self-administered by oral ingestion, nasal insufflation, smoking, or intravenous and subcutaneous injection. The effects of PCP are dependent on routes of delivery and dose. Its onset of action is most rapid from the intravenous and inhalational routes (2–5 minutes) and slowest (30–60 minutes) following gastrointestinal absorption.42,43 Sedation is commonly produced by doses of 0.25 mg intravenously, whereas oral ingestion typically requires 1–5 mg to produce similar sedation. Signs and symptoms of toxicity usually last 4–6 hours, and large overdoses generally resolve within 24–48 hours, but

effects may persist in a chronic user.16,54,57,119,141,154 However, in the PCP-intoxicated patient, the relationships between dosage, clinical effects, and serum levels are not reliable or predictable. There are several explanations for PCP's protracted CNS effects. It has a large volume of distribution of 6.2 L/kg.42,200 Its high lipid solubility accounts for its entry and storage in adipose and brain tissue. Also on reaching the acidic CSF, PCP becomes ionized, producing CSF concentrations approximately 6–9 times greater than those of serum.133 PCP undergoes first-order elimination over a wide range of doses. It has an apparent terminal half-life of 21 ± 3 hours under both control and overdose settings.42,95 More prolonged toxicity has been reported in patients who “body-pack― PCP in plastic bags.95,203 Ninety percent of PCP is metabolized in the liver and 10% is excreted in the urine unchanged. Evidence indicates that PCP undergoes hepatic oxidative hydroxylation into 2 monohydroxylated and 1 dihydroxylated metabolites. All 3 compounds are conjugated to the more water-soluble glucuronide derivatives and then excreted in the urine. Urine pH is an important determinant of renal elimination of PCP. In acidic urine, PCP becomes ionized and then cannot be reabsorbed. Acidification of the urine increased renal clearance of PCP from 1.98 ± 0.48 L/h to 2.4 ± 0.78 L/h.42 Additional studies have found a much higher renal clearance (8.04 ± 1.56 L/h) if the urine pH was decreased to 101.8°F [38.8°C]).129 In an experimental animal model, PCP failed to increase body temperature.36,57 When hyperthermia does occur, all the known

complications, including encephalopathy, rhabdomyolysis, myoglobinuria, electrolyte abnormalities, and liver failure, occur (Chap 16) .8,19,39,151 Most PCP- and ketamine-toxic patients demonstrate mild sympathomimetic effects. PCP consistently increases both the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a dose-dependent fashion.36,57 (Doses of 0.06 mg/kg of PCP IV increased the SBP and DBP by 8 mm Hg, whereas 0.25 mg/kg produce a 26 and 19 mm Hg increase in SBP and DBP, respectively.) PCP also increases the heart rate, although inconsistently.84 Likewise, ketamine produces mild increases in blood pressure, heart rate, and cardiac output via this same mechanism.49,121,176,186,195

Cardiopulmonary Rarely are cardiovascular catastrophes encountered in PCP toxicity.60,130 These complications may result from direct vasospasm of blood vessels,5,35 causing severe systemic hypertension61 and cerebral hemorrhage.22 Hypertension, abnormal behavior, and miosis in children strongly suggest PCP poisoning.105 The effect of PCP and ketamine on cardiac rhythm is controversial. Dysrhythmias are only observed in animals poisoned with very large doses of PCP. Ketamine is observed to both enhance and diminish epinephrine-induced dysrhythmias in animals.21,58,85,106 The considerable experience in the use of ketamine anesthesia on humans undergoing surgery or cardiac catheterization has not demonstrated prodysrhythmic effects.65,142 As these dissociative anesthetics were designed to retain normal ventilation, hypoventilation is uncommon. In clinical studies, PCP increased the minute ventilation, tidal volume, and respiratory rate of volunteers.84 Clinically, in PCP-toxic patients, irregular

respiratory patterns occur with tachypnea much more often than P.1236 bradypnea.8,129

with Hypoventilation, when present, is usually secondary to the use of particularly high doses of PCP. Pulmonary edema secondary to respiratory depression is also a rare occurrence. Large doses of PCP (20 mg/kg) administered to laboratory animals produced respiratory depression.36 Although respiratory depression in humans is an extremely rare event, it has been reported with fast or high-dose infusions of ketamine.77,195 In fact, ketamine has been used successfully to prevent intubation in patients with refractory asthma.71,159,181,195

Neuropsychiatric The majority of patients with PCP and ketamine toxicity who are brought to medical attention manifest diverse psychomotor abnormalities.12,18,28,68,100,188 As dissociative anesthetics, these drugs produce a lack of response to external stimuli by dissociating various elements of the mind. Consciousness, memory, perception, and motor activity appear dissociated from each other. This dissociation prevents the user from attaining cognition and properly assembling all this information to construct a reality. Clinically the person may appear inebriated, either calm or agitated, and sometimes violent. In large overdoses, the drug's anesthetic effect causes patients to develop stupor or coma. In recreational use, “dissociatives― are not taken for these effects, but rather for so-called out-of-body experiences. In addition patients often have disordered thought processes (including disorientation as to time, place, and person) or amnesia, paranoia, and dysphoria.67 The manifestations of PCP and ketamine toxicity are better illustrated by the results of their effects in controlled human studies. Volunteers who took oral PCP doses of up to 7.5 mg/d, or ketamine 0.1 mg/kg, exhibited inebriation, but higher doses (PCP

>10 mg/d; ketamine 0.5 mg/kg) generally caused a more severe impairment of mental function.57,109 Intravenous doses of 0.1 mg/kg of PCP16,54,119,141,162 or 0.5 mg/kg of ketamine109,149 causes diminution in all sensory modalities (pain, touch, proprioception, hearing, taste, and visual acuity) in a dose–dependent fashion. Both drugs also cause feelings of apathy, depersonalization, hostility, isolation, and alterations in body image.16,54,70,109,119,149 The deficits in sensory modalities are evident prior to the development of the psychological effects of PCP, with pain perception disappearing first. This alteration in analgesic perception is caused by a blocking action on the thalamus and midbrain (Fig. 83-1) .141 Abnormal stereognosis and proprioception occur in a dose–dependent manner. This disturbed perception results in body image distortions described as “numbness,― “sheer nothingness,― and “depersonalization.― The decrease of proprioceptive sensation to gravity probably gives the sensation of “tripping― or “flying.― Because all sensory modalities are affected, visual, auditory, and tactile illusions and delusions are common. Hallucinations are typically auditory rather than visual, which are more common with LSD use. Ketamine's hallucinogenic effects on healthy human volunteers are linearly related to steady-state concentrations between 50 and 200 ng/mL.23 The majority of ketamine users report experiencing a “k-hole,― a slang term to the intense psychological and somatic state experienced while under the influence of ketamine. This experience varies with the individual, but can include buzzing, ringing or whistling sounds, traveling through a dark tunnel, intense visions and out-of-body or near-death sensations.55 The reaction to the misperceived or disconnected reality may result in unintentional actions and violent behavior. The hallmark of PCP toxicity is the recurring delusion of superhuman strength and invulnerability resulting from both the anesthetic and dissociative properties of the drug. There are case reports of

patients presenting with trauma either from jumping from high altitudes, fighting large crowds or the police, or self-mutilation. The true extent and incidence of violence is probably less than previously suggested.24

Figure 83-1. Clinical effects of phencyclidine and ketamine. Phencyclidine and ketamine bind to different receptors in the CNS with varying degrees of affinity; that is an increasing concentration is necessary to achieve the consequential clinical effects. ACh = acetylcholine.

Typically, neurologic signs include rotatory nystagmus, ataxia, and

altered gait. Initially, except for ataxia, motor movement is not impaired, until the patient becomes unconscious. On physical examination, use of dissociative agents typically produces relatively small pupils and (horizontal, vertical, and/or rotatory) nystagmus, and diplopia. In the largest case series reported to date, nystagmus and hypertension were noted in 57% of patients who had taken PCP.129 Smaller and more limiting studies have found an incidence of nystagmus of 89% or higher.18 Other cerebellar manifestations were also encountered, most notably dizziness, ataxia, dysarthria, and nausea. A pooled data compilation of 35 reports demonstrated that emesis occurred 8.5% of the time.81 In fact, Internet chat groups devoted to substance abuse commonly direct users to “mix dissociatives with marijuana― for its antiemetic effect. Larger doses of PCP produce loss of balance and confusion, the latter characterized by inability to repeat a set of objects, frequent loss of ideas, blocking, lack of concreteness, and disordered linguistic expression.51,57,109,119,162 Similarly, ketamine users report a high incidence of incoordination, confusion, unusual thought content and an inability to speak.55 In general, dissociative anesthetics stimulate the central nervous system but seizures rarely occur, except at high doses. The largest case series of PCP-toxic patients detected a 3.1% incidence of seizures.129 Although PCP- and ketamine-toxic patients also present with motor disturbances, it is not clear to what extent PCP and ketamine are actually responsible for these manifestations. The most common of the reported disturbances are dystonic reactions: opisthotonos, torticollis, tortipelvis, and risus sardonicus (facial P.1237 grimacing). Myoclonic movements, tremor, hyperactivity, athetosis, stereotypies, and catalepsy also occur.12,29,68,129 A slight increase in muscle tone results from a dopaminergic effect.119 Laryngospasm requiring intubation has been reported after the use of ketamine anesthesia. The incidence of this

complication is less than 0.017%.81 In comparison, the incidence of laryngospasm following traditional general anesthesia is 2%.147

Emergence

Reaction

The acute psychosis, observed during the recovery phase of PCP anesthesia, limits its clinical use. This bizarre behavior, characterized by a confused state, vivid dreaming, and hallucinations, is termed an “emergence reaction.― These reactions occur most frequently in middle-age males, with a reported incidence of 17–30%.84,104 The most violent emergence reactions follow an intravenous dose of approximately 0.25 mg/kg (total: 20 mg) of phencyclidine.57 The mildest degrees of agitation produced by phencyclidine resemble the effects of ethanol intoxication. These same postanesthetic reactions also limit the clinical use of ketamine. The incidence of emergence reactions following ketamine administration may approximate 50% in adults and 10% in children.81 Patients older than age 10 years, females, and persons who normally dream frequently and/or have a prior personality disorder incur the greatest risk.81 The incidence of the occurrence of emergence reactions appears to be exacerbated when the drugs are rapidly administered intravenously, and in those patients who are exposed to excessive stimuli during recovery. Although it has not been proved in a controlled study, reducing external stimuli during the recovery phase might reduce emergence reactions. Both cholinergic and anticholinergic clinical manifestations occur in the PCP- or ketamine-toxic patient. Miosis, mydriasis, blurred vision, profuse diaphoresis, hypersalivation, bronchospasm, bronchorrhea, and urinary retention occur.12,18,116,128,129 Clinically, ketamine stimulates salivary and tracheobronchial secretions; both of which are equally and effectively inhibited by atropine and glycopyrolate.137 Furthermore, in a randomized, double-blind trial, after infusion of 1.5 mg/kg of ketamine in

healthy volunteers, physostigmine decreased vision, and the time to recovery.185

nystagmus,

blurred

Ironically, the very characteristics that were thought to make phencyclidine ideal for anesthesia—the preservation of muscle tone and cardiopulmonary function—magnify the difficulties in managing an individual who manifests dysphoria after an overdose. The course of delirium, stupor, and coma associated with PCP and ketamine is extremely variable, although the manifestations are much milder and shorter acting following ketamine use.

Diagnostic

Testing

Most hospital laboratories do not perform quantitative analysis of PCP, but many can do a qualitative urine test for the presence of the drug. Qualitative testing is more important than a quantitative determination as serum concentrations do not correlate closely with the clinical effects. PCP may not be part of a routine toxicologic screening and it therefore may be necessary to request a specific analysis if confirmation is required. When a routine toxicologic screen is reported as negative this result should not lead to the erroneous conclusion that PCP exposure has been excluded. If it is necessary to confirm the suspicion that PCP is the offending agent, urine is most commonly used for analysis, although serum, and possibly gastric contents, can be employed. Rarely is it essential to make this determination. PCP is qualitatively detected by an enzyme immunoassay at a sensitivity of 10.00 ng/mL. High-affinity antibodies were once studied as specific PCP antagonists that may reverse PCP-induced toxicity.148,187 The detection of PCP is thus dependant on the concentration of PCP in the body fluid tested and the affinity of the antibody for the PCP molecule. As such, the immunoassay antibody binding to a molecule similar to PCP can anticipate false-positive

reactions. Metabolites of PCP, such as PCE, PHP, TCP and its pyrrolizidine derivative TCPy, cross-react with the immunoassay at concentrations 30 times higher than those used to detect PCP. Because of its similar structure to PCP, dextromethorphan and its metabolite dextrorphan, also cross-react with Syva enzymemultiplied immunoassay and fluorescence polarization PCP assays (Chap. 7) .92 Although nonspecific, laboratory findings resulting from PCP use can include leukocytosis, hypoglycemia, and elevation of muscle enzymes, myoglobin, BUN, and creatinine.129 The EEG reveals diffuse slowing with θ and δ waves, which may return to normal before the patient improves clinically. There is no commercially available immunoassay for ketamine. When necessary, ketamine is detected by gas chromatography and mass spectroscopy. The increase in popularity in ketamine use in certain parts of the world has led to the development of rapiddetection urine assays that are sensitive, specific, and accurate.37,192 There is anecdotal evidence that ketamine also cross-reacts with the urine PCP immunoassay because of their structural similarity.165 Other authors, including the manufacturer who tests the reactivity of the commercially available PCP immunoassay with ketamine, do not find such results.32,188

Management Agitation Conservative management is indicated for PCP and ketamine toxicity and includes maintaining adequate respiration, circulation, and thermoregulation. The psychobehavioral symptoms observed during acute dissociative reactions and during the emergence reaction are similar. To treat the symptoms of agitation and alteration of mental status of acutely toxic PCP patients, it is

helpful to recognize that both pharmacologic1,33,38,41,64,81,82,123,127 and behavioral40,41,81,110 modalities have been employed to diminish agitation and emergence phenomena during conscious sedation with ketamine. To prevent self-injury, a common form of PCP-induced morbidity and mortality, the patient must be safely restrained, initially physically, and then chemically. An intravenous line must be established and blood drawn for electrolytes, glucose, BUN, and creatinine determinations. The use of 0.5–1.0 g/kg of body weight of dextrose and 100 mg of thiamine HCl intravenously should be considered if indicated. Psychomotor agitation from PCP toxicity may cause hyperthermia and should be identified early on. Treatment should be accomplished immediately with adequate sedation to control motor activity. Physical restraint should only be used temporarily, if necessary, until chemical sedation is achieved. Rapid immersion in an ice water bath may be necessary because body temperatures greater than 106°F (41.1°C) place the patient at a great risk for end-organ injury. These patients will need volume repletion and P.1238 electrolyte supplementation loss from sweat.

because

hyperthermia

increases

fluid

In the pharmacologic treatment of emergence reactions, butyrophenones and benzodiazepines have been employed with benzodiazepines demonstrating the most success. A benzodiazepine such as diazepam, administered in titrated doses of up to 10 mg intravenously every 5–10 minutes until agitation is controlled, is usually safe and effective. Numerous studies demonstrate the benefits of benzodiazepines, although under certain conditions, 38,81 they may prolong recovery time. Midazolam may be more effective than diazepam under certain circumstances.33,127 In contrast, phenothiazines may lower the seizure threshold, and both phenothiazines and butyrophenones may cause acute dystonic reactions. Phenothiazines may also

cause significant hypotension, worsen hyperthermia, and exacerbate any anticholinergic effects from these drugs. Some behavioral modalities have also been implemented in the treatment. Early studies demonstrated that the psychotomimetic effects of PCP were diminished when external stimulation was reduced by environmental sensory deprivation.40 The practice of placing patients in a quiet room with minimal sensory stimulation is recommended by many, but has never been formally studied in a double-blind, controlled trial. Conversely, it is observed in patients undergoing ketamine anesthesia that emergence reactions are less violent when patients are talked to or when music is played. 110,171 Although it is always important to ask the patient the names, quantities, times, and route of all drugs taken, the information obtained from such a patient is notoriously unreliable. Even when the patient is trying to cooperate and give an accurate history, many street psychoactive xenobiotics are drug mixtures whose contents are unknown to the patient. Consequently, pharmacologic management is complex and often sign- or symptom-dependent. Although some authors have attempted to define the appropriate therapy for specific PCP congeners and for ketamine-induced psychosis, no single approach has been consistently efficacious.73,108,124

Decontamination Patients with a history of recent oral use of PCP are candidates for gastrointestinal decontamination, but they should be considered too unstable for induced emesis, as uncontrolled agitation or respiratory compromise can rapidly develop. Although there is rarely, if ever, an indication, if congestion is suspected, orogastric lavage may be initiated but the patient may need to be sedated. Activated charcoal, 1 g/kg, should be administered as soon as possible, and repeated every 4 hours for several doses. Activated

charcoal will effectively adsorb PCP and increase its nonrenal clearance; even without prior gastric evacuation this approach is usually adequate.155 Unless there are specific contraindications, a single dose of a cathartic, such as sorbitol, can be given. Theoretically, xenobiotics that are weak bases, such as PCP, can be eliminated more rapidly if the urine is acidified. Although urinary acidification with ammonium chloride was previously recommended, 9 we do not recommend this approach. The risks associated with acidifying the urine—simultaneously inducing a systemic acidosis, thereby potentially increasing urinary myoglobin precipitation—outweigh

any

perceived

benefits

(Chap. 10) .

As opposed to the problems in applying ion-trapping to renal excretion, ion-trapping results in the active mobilization of PCP into gastric secretions. Phencyclidine is in a substantially ionized (and therefore non–lipid-soluble) form in the acid of the stomach and can be absorbed only when it reaches the more alkaline intestine. As a result, gastric suction can remove a significant amount of the drug, as well as interrupt the gastroenteric circulation (by which the drug is secreted into the acid environment of the stomach only to be reabsorbed again in the small intestine).9 Continuous gastric suction, however, can also be dangerous and unnecessary. It should be considered only in comatose patients. Continuous suction may result in trauma to the patient as well as in fluid and electrolyte loss, which can further complicate management and possibly interfere with the efficacy of activated charcoal. For these reasons the administration of multiple-dose activated charcoal rather than continuous nasogastric suction appears to be the safest and most effective way of removing ion-trapped drug from the stomach. Most patients rapidly regain normal CNS function anywhere from 45 minutes to several hours after using these drugs. However, those who have taken exceedingly high doses or who have an underlying psychiatric disorder may remain comatose or exhibit

bizarre behavior for days, or even weeks, before returning to normal. Those who regain normal function rapidly should be monitored for several hours and then, after a psychiatric consultation, should receive drug counseling and any additional social support available. Patients whose recovery is delayed should be treated supportively and monitored carefully in an intensive care unit. Many patients become depressed and anxious during the “posthigh― period, and chronic users may manifest a variety of psychiatric disturbances.201 These individuals typically present with repeated drug use, hospitalizations, and poor psychosocial functioning in the long term. The major toxicity of PCP appears to be behaviorally related: selfinflicted injuries, injuries resulting from exceptional physical exertion, and injuries sustained as a result of resisting the application of physical restraints are frequent. Patients appear to be unaware of their surroundings and sometimes even oblivious to pain because of the dissociative anesthetic effects. In addition to major trauma, rhabdomyolysis and resultant myoglobinuric renal failure account in large measure for the high morbidity and mortality associated with PCP intoxication. If significant rhabdomyolysis39,151 has occurred, myoglobinuria may be present. Early fluid therapy should be used to avoid deposition of pigment into the kidneys, leading to renal failure. Urinary alkalinization as part of the treatment regimen for rhabdomyolysis would potentially increase PCP reabsorption and deposition in fat stores, but this is only theoretical and is not recommended. Although the clinical experience with recreational use of ketamine is limited, toxic manifestations appear to be similar, yet milder and shorter-lived, when compared to PCP. In a study of 20 patients who presented with acute ketamine toxicity, all were treated conservatively and successfully with intravenous hydration, and sedation with benzodiazepines.188

Summary As “dissociative― anesthetics became clinically available, their abuse potential was also discovered. The popularity of PCP and ketamine results from their ability to produce an “out-ofbody experience― with seemingly hallucinatory effects. The action of these drugs is largely mediated by the NMDA receptor. Their toxicity, in great part neuropsychiatric in nature, is managed by supportive P.1239 care. The popularity of ketamine may be related to its lesser toxicity and milder distortion of the personality.

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > I - Metals > Chapter 84 Antimony

Chapter

84

Antimony Asim F. Tarabar Antimony (Sb) Atomic number = 51 Atomic weight = 121.75 Normal concentrations Serum

= 0.8–3 µg/L Urine (24 hour) = 0.5–6.2 µg/L Urine (24 hour) = 35 µg/g creatinine A 19-year-old Hispanic man with a history of alcoholism presented to the emer

(ED) complaining of 1 day of repeated vomiting, diarrhea, and abdominal cramp history was significant for multiple failed attempts to achieve alcohol abstinence. help him attain sobriety, his parents sent him an aversive medication from Gua “Soluto Vital.― On the day prior to admission the patient ingested the ent of the bottle that was labeled to contain tartar emetic and small amounts of qui Strophanthus. The normal dose was listed as 20–25 drops. His estimated dose was 500 mg. Approximately 30 minutes after ingestion he experienced abdomina vomited multiple times. Massive diarrhea rapidly ensued.

Physical examination revealed a young man in distress with the following vital s pressure, 104/71 mm Hg; pulse, 96 beats/min; respirations, 18 breaths/min; r 96.6°F (35.9°C). The remainder of the examination was remarkable for dry a clear chest, and a normal heart examination. His abdomen was tender in the but there was no rebound tenderness or guarding. Neurologic examination was was no indication of suicidality. His stool tested negative for occult blood.

An intravenous line was inserted, and the patient was resuscitated with 0.9% s solution. Specimens were sent for a complete blood count, electrolytes, and glu

enzymes. An electrocardiogram was interpreted as normal. In the ED, the patien episodes of vomiting despite antiemetic therapy. His diarrhea also continued. B studies were consistent with volume loss and possibly renal injury (blood urea creatinine, 2.4 mg/dL; hematocrit, 60%; urinalysis, 2+ protein) the patient was hospital.

The vomiting gradually subsided and a single dose of 50 g of activated charcoa without a cathartic. By 12 hours after admission, his creatinine had improved to total urine output was only 500 mL for the first 24 hours. The following day the was discharged. Subsequently, his 24-hour urine reported an antimony concentr or 682 µg/g creatinine. The patient never returned for followup care.

Chemistry

Antimony (Sb) is located in the same group on the periodic table as arsenic (As) shares many chemical, physical, and toxicologic properties. Because it can react nonmetal, antimony is classified as metalloid (Chap 12 ). 77 Pure antimony is a white, brittle, hard metal that is easily pulverized.61 , 89 However, because elem

rapidly converted to either antimony oxide or antimony trioxide, it is extremely

P.1245 rare to find isolated elemental antimony in nature. It has been suggested that e originates from anti monon (enmity to solitude) because antimony is almost alw other metal.59 Thus, for the purposes of this chapter, the term antimony refers nature, antimony can be found in more than 100 different minerals,59 , 49 includ cervantite, valentine, and kermesite. 30 The sulfide ore (stibnite) is the most ab Bolivia and South Africa are among the leading producers.89 Like arsenic, antim both organic and inorganic compounds with trivalent and pentavalent oxidation inorganic trivalent antimony compounds include antimony trioxide (SbO3 ), ant (SbS3 ), antimony trichloride (SbCl3 ), antimony potassium tartrate (C8 H4 K2 O (SbH3 ). Antimony pentasulfide (Sb2 S5 ) and pentoxide (Sb2 O5 ) are pentaval compounds that can act as oxidizing agents. 40 From an industrial perspective, t

application of antimony is the use of antimony oxychloride (Sb6 O6 Cl4 ) as a fl

Tartar emetic (antimony potassium tartrate) is an odorless trivalent antimony co

potent emetic effect40 and a sweet metallic taste.41 Antimony potassium tartrate one of the most toxic antimony compounds, with minimal lethal doses reported and 1200 mg.59 There are large species variations of the LD50 (median lethal do subjects) in experimental animals, with a reported range of 115 mg/kg in rabbits

mg/kg in mice. In comparison, because of a low water solubility, antimony triox practically, to be nontoxic, with an LD50 >20,000 mg/kg.32

History

In spite of the fact that antimony and its compounds are regarded as among th remedies in the practice of medicine, they remain unfamiliar to most people.59 discovered during exploration of old Mesopotamian civilization (3rd and 4th mil suggested that both the Sumerians and the Chaldeans were able to produce pu The reference to eye paint in the Old Testament suggested the use of antimony thousand years, Asian and Middle Eastern countries used antimony sulfide in the cosmetics, including rouge and black paint for eyebrows, also known as kohl or Because of the scarcity of antimony sulfide, lead replaced antimony as a main c modern cosmetic preparations. One of the first monographs on metals, written in the 16th century, included a

antimony.84 The medicinal use of antimony for the treatment of syphilis, whoop dates to the medieval period. Paracelsus (1493–1541) was credited with esta compounds as therapeutic agents and increasing their popularity. In spite of bei potential, many of the disciples of Paracelsus enthusiastically continued the use Various antimony compounds were used also as topical preparations for the tre leprosy, mania, and epilepsy.89 Orally administered tartar emetic (antimony pot used for treatment of fever, pneumonia, and inflammatory conditions, but was of its significant toxicity.11 , 27 , 39 Historically, the therapeutic dose range for tartrate was from 20 mg every 10 minutes (until vomiting occurred) to 4000 mg The use of antimony as a homicidal poison80 was recognized, and this practice the 20th century (Chap 1 ).

The current medical use of antimony is limited to the treatment of leishmaniasis

kala-azar, and schistosomiasis, and to sporadic use as aversive therapy for sub Pentavalent compounds are used because they are better tolerated. In spite of in vitro,27 there is no current oncologic use of antimony.

Some contemporary homeopathic35 and anthroposophical75 practices still recom antimonial compounds as home remedies; however, these practices are rare.59

Because of its poor physical properties (eg, inflexible metal), the elemental form very few industrial uses. In contrast, its alloys with copper, lead, and tin have applications. Industrial and occupational exposure to antimony occurs mainly by dust or fumes during the processing or packaging of antimony compounds.59 Sm

also be occupationally exposed to antimony.34 Antimony concentrations in cigare from 10–60 mg/kg.34 , 63 This may be an additional factor contributing to the concentrations of antimony found in workers' lungs.34

In developed countries, antimony poisoning rarely occurs following intentional i preparations.89

Toxicokinetics Absorption

Antimony may be absorbed by inhalation, ingestion, or transcutaneously. Absorp

gastrointestinal tract begins immediately on ingestion, and the oral bioavailabilit ranges from 15–50%.33 , 85 This poor gastrointestinal absorption in humans, i concomitant emesis, necessitates parenteral administration of many antimony-b pharmaceuticals. Pulmonary absorption of many inorganic antimony compounds i limited by low solubility.59 In contrast, animal data suggest that inhaled trivalen absorbed from the lung, distributed to various organs, and subsequently excrete urine.26

Distribution

Distribution apparently depends on the oxidation state of antimony. In animals, trivalent antimony is incorporated into the red blood cells within 2 hours of expo similar time frame, 90% of pentavalent antimony will still be found in the serum administered intravenously or orally, antimony is predominantly distributed amo

organs, including liver, kidneys, thyroid, and adrenals.66 , 89 Uptake by the live mechanisms of diffusion and saturable binding. Repeated exposures cause accum independent of the concentration in red cells.74 In a hamster model, following a organic antimonials, the greatest concentration of antimony was found in the liv

inhalation, antimony accumulates predominantly in red blood cells, and to a sig extent in liver and spleen.26 , 28 The fact that elevated urine and serum antim are measured more than 2 years after the treatment suggests that antimony can for a prolonged period of time. 58 P.1246

Excretion

Although antimony and arsenic share many toxicokinetic properties, unlike arse trivalent antimony is not methylated in vivo.3 Trivalent antimony is excreted in conjugation with glutathione. A significant proportion of excreted antimony und recirculation.3 The remainder is excreted in urine. The overall elimination is very 10% of a given dose cleared in the first 24 hours, 30% in the first week,5 and s antimony is still detected in the urine 100 days after administration.57 , 89 Penta much more rapidly excreted by the kidneys than trivalent antimony (50–60% 24 hours).89 In workers, urine concentrations of pentavalent antimony correlate intensity of exposure.3

Pathophysiology

Elemental antimony is considered to be more toxic than its salts, but because e elemental form is relatively uncommon, this fact is of limited clinical relevance. metals, antimony binds to sulfhydryl groups to inhibit a variety of metabolic fu Trivalent antimony compounds are more toxic than the pentavalent compounds higher affinity for erythrocytes and sulfhydryl groups. 54 Tartar emetic and other also considered local irritants of the gastrointestinal tract. One proposed mechan activation of enterochromaffin cells that are located in the gastrointestinal muco secrete serotonin. Released serotonin acts on the 5-HT3 receptors, stimulating

and activating the vomiting center.38 , 87 In addition, there is apparent direct action, particularly after administration of higher doses of antimony.89 From a perspective, trivalent antimony compounds also inhibit phosphofructokinase, dis energy for schistosomes.14 , 89

Clinical

Manifestations

Data on human toxicity of antimony are very limited, and are largely extrapolat occupationally exposed patients and from the reports of adverse effects during leishmaniasis with antimony. There are very few case reports of intentional ant For didactic purposes, we recognize three distinct populations that may present toxicity.

Workers with occupational exposures usually present with subtle clinical sympto

toxicity develops slowly over time. It is important to recognize that antimony or concentration of arsenic as impurity, making it difficult to distinguish whether e are caused by contaminants or by the antimony. Therapeutic side effects of an may have a somewhat subacute to acute clinical picture, as some patients with require prolonged treatment with antimony to achieve cure,82 exposing them, ov large cumulative doses.

Patients with oral ingestions present with acute symptoms mimicking the toxicity other metal salts. Several cases were described after the use of old porcelain h use of antimony compounds as home remedies.1 , 53 , 62 , 79

Local

Irritation

The majority of antimony toxicity is based on local irritation. In sufficient conc acts as an irritant to the eyes, skin, and mucosa. Chronic exposure can cause 72

Irritation of the upper respiratory tract can lead to pharyngitis.

Systemic

Gastrointestinal in acute exposures, antimony can rapidly produce nausea, vom pain, and diarrhea. Some patients may report a metallic taste in the mouth. In gastrointestinal irritation can progress to hemorrhagic gastritis. Workers chronic antimony dusts have a much higher incidence of gastrointestinal ulcers in comp

(63 per 1000 vs. 15 per 1000).12 A large series of patients developed chemical pancreatitis following treatment with pentavalent antimonial agents.31 Because cases improved despite continuation of treatment, the authors presumed a mec direct toxicity. In another series, several patients with HIV who were treated wit meglumine antimonate developed severe pancreatitis and died.24

Cardiovascular

In animals, antimony decreases myocardial contraction, decreases coronary vas producing decreased systolic pressure,89 and causes bradycardia.23 The majority cardiac effects are related to changes on the electrocardiogram (ECG). Prolongat

interval, inversion or flattening of T waves, and ST segment changes are frequ during treatment of visceral leishmaniasis with pentavalent antimonial compoun stibogluconate and meglumine antimonate).18 , 90 Torsades de pointes was des treated with pentavalent antimonial preparations.65 , 81 In patients with underl disease (eg, cardiomyopathy), ECG changes can occur even with antimony doses considered to be therapeutic.37 These changes are not necessarily associated w cardiac function.44 However, it is important to recognize that pentavalent antim the treatment of leishmaniasis are associated with sudden deaths, probably as a development of ventricular dysrhythmias.16 , 78

Thrombophlebitis is common after IV use of antimony, but has been reported e occurs orally.55

Res p ir ator y

Local irritation from antimony trioxide can produce laryngitis, tracheitis, and p lung injury was reported after acute exposure to antimony pentachloride.21 , 22

Although antimony oxides are capable of causing metal fume fever,29 this is mu comparison to exposure to zinc oxide.2 , 29 Antimony metal fume fever is report concentrations below 5 mg/m 3 .20

Renal

Patients treated with sodium stibogluconate can develop varied manifestations o ranging from renal cell casts, proteinuria, and increased blood urea nitrogen co renal failure.4 , 70 Some patients can also develop renal tubular acidosis47 and necrosis.71

Hem atologic

Severe anemia was reported in HIV-positive patients during the treatment with stibogluconate, with documented transient severe bone marrow dyserythropoies complete recovery on discontinuation of the therapy.46

Patients treated with sodium stibogluconate for visceral leishmaniasis occasiona thrombocytopenia. 9 , 45 , 51 Rare cases of epistaxis are described during the tre unclear if they are associated with thrombocytopenia.52 Visceral leishmaniasis

P.1247 itself is known to be associated with pancytopenia, probably as a result of incre peripheral blood cells.69 It may be difficult to determine whether this phenomen disease itself or is secondary to the treatment, although some authors suggeste immune thrombocytopenia.69

Leukopenia is frequently observed in patients treated with antimonial compound authors speculate that antimony-induced lymphopenia is associated with an incr herpes zoster in HIV patients.91

Dermatologic Antimony

spots76 are papules and pustules that develop around sweat and seba

may resemble varicella. A similar skin rash was described in the 18th century a application of antimony tartrate for medicinal use.59 Interestingly, these eruptio interpreted as a sign of cure.39

Neurologic

A patient with cutaneous leishmaniasis who was treated with sodium stibogluco antimony) developed a reversible, peripheral sensory neuropathy in temporal a treatment.13 The authors suggested that neuropathy may be the result of idios antimony.

Reproductive

In animal studies, antimony exposure causes ovarian atrophy, uterine metaplas conception.7 Limited information from the Russian literature describes an assoc spontaneous abortion and premature births in women who were occupationally salts. Antimony was found in the blood, urine, placenta, amniotic fluid, and brea women.7

Carcinogenicity

Initial studies in female rats reported lung tumors after inhalational exposure to trioxide.36 , 86 Likewise, a survey among antimony smelter workers suggested a

cancer, with a latency of 20 years, in comparison to a nonexposed population. concomitant exposure to arsenic and its effects could not be excluded and the d inadequately controlled for workers' smoking habits.50

Patients with schistosomiasis have an increased incidence of bladder tumors, an compounds are considered to be one potential cause.89

Stibine

Antimony compounds can react with nascent hydrogen forming an extremely tox (SbH3 ), which resembles arsine (AsH3 ) (Chap. 85 ). Stibine is probably the m compound. It is a colorless gas with a very unpleasant smell that rapidly decom temperatures above 302°F (150°C). 43 , 89 Historically, stibine release was re

charging of lead storage batteries.89 In addition to GI symptoms that include n abdominal pain, stibine has strong oxidative properties capable of producing m (Chap. 24 ). Similar to arsine,73 severe stibine exposure may result in hematu and death. Maintenance workers are advised to avoid use of drain cleaners (eg, capable of releasing hydrogen in situations where antimony may be present.67

Diagnostic

Testing

Standard laboratory testing to help identify volume depletion and renal injury is patients with acute antimony toxicity. A complete blood count, electrolytes, ren and a urinalysis should be obtained. When there is a known or suspected expos additional studies should include tests for hemolysis, such as determinations of haptoglobin. Blood should also be obtained for a blood type and cross-match, as likely to be required.

An ECG should be obtained to evaluate for QTc prolongation and other changes. myocardial disease should have more frequent monitoring of cardiac function an

Antimony concentration in a 24-hour urine collection can be used for assessmen exposure to either trivalent or pentavalent antimony.3 A normal urinary antimo nonexposed patients is reported in the range of 0.5–6.2 µg/L.58 , 88 The geo

US population is 0.128 µg/L, with concentrations of the 95th percentile of 0.42 serum antimony concentration is impractical because it cannot be determined in However, it is suggested that normal serum concentration of antimony is in the µg/L,58 although some laboratories use higher values.64

Treatment Decontamination

Following a significant acute ingestion, the majority of the patients develop vom emesis is unlikely to offer any additional benefit. In contrast, gastric lavage ma especially if performed before the onset of spontaneous emesis. Although it is antimony is adsorbed to activated charcoal, based on experience with salts of a mercury, administration of activated charcoal seems reasonable. Additionally, b a documented enterohepatic circulation, multiple-dose activated charcoal may be

patients exposed to stibine, decontamination involves removal from the exposure administration of high-flow oxygen. Theoretically, severe stibine exposures may transfusion for removal of stibine–hemoglobin complex.73

Supportive

Care

The mainstay of treatment for antimony poisoning is good supportive care. Clin anticipate massive volume depletion and begin rehydration with isotonic crysta Electrolytes and urine output should be followed closely. A central venous pressu required in patients with cardiovascular instability. Antiemetics are indicated bot comfort and to facilitate the administration of activated charcoal. Following stib hematocrit should be followed closely and blood should be transfused based on

Chelation

Human experience with regard to chelation of antimony is rather limited because serious toxicity and the rarity of instances when patients have received chelation

available data are based on animal experimentation. Dimercaprol, succimer, and dimercaptopropane-sulfonic acid (DMPS) all improve survival of experimental a One animal study that compared survival after treatment with multiple chelator P.1248 concluded that the most effective antidotes were DMPS and succimer.6

A single case series documented survival in 3 of 4 patients exposed to tartar e intramuscular dimercaprol at a dose of 200–600 mg/d. All 4 patients had incr excretion of antimony.55 In another case report, a patient survived after chelat but without evidence of enhanced antimony excretion in urine.3 Although specif are difficult to make, it is reasonable to begin therapy with intramuscular dimer certain that antimony is removed from the gastrointestinal tract, at which time switched to oral succimer. Because chelation doses for antimony poisoning are chelators should be administered in doses and regimens that are determined to effective for other metals (see Antidotes in Depth: Dimercaprol [British Anti-Lew Antidotes in Depth: Succimer [2,3-Dimercaptosuccinic Acid] ).

Summary

Antimony is an element whose physical, chemical, and toxicologic properties clo arsenic. Although uncommon, antimony toxicity does occur. The hallmarks of to gastrointestinal manifestations leading to profound volume depletion and renal Electrocardiographic findings may assist in the identification of this xenobiotic. supportive, although chelation may be indicated in life-threatening cases.

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

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> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > I - Metals > Chapter 85 Arsenic

Chapter

85

Arsenic Marsha Arsenic

Ford (As)

Atomic

number

=

33

Atomic

weight

=

74.92

Normal Whole

concentrations blood

=


MMAV = DMAV . Thus, toxicity increases with the formation of MMAI I I. Urinary elimination of unchanged arsenic and its methylated metabolites occurs via glomerular filtration and tubular secretion; active reabsorption does occur.161 Human studies demonstrate renal arsenic elimination of 46–68.9% within the first 5 days postingestion.20,77,126 Approximately 30% is eliminated with a halflife of greater than 1 week, while the remainder is slowly excreted with a half-life of greater than 1 month.20,109 Fecal elimination is considerably less, with reported amounts ranging from 0.21–6.1% in humans.110,154 Arsenobetaine is also well absorbed and is excreted unchanged in the urine.165 Elimination occurs more rapidly than with inorganic arsenic. In a study involving human volunteers, 25% was excreted within 2–4 hours, 50% by 20 hours, and 70–83.7% after 166 hours. A two-component exponential model shows nearly 50% of the arsenobetaine eliminated, with a first component t1 / 2 of 6.9–11.0 hours and a second component t1 / 2 of 75.7 hours.77

Pathophysiology Investigations of the pathophysiologic effects induced by toxic doses of arsenic, in contradistinction to therapeutic doses, have elucidated the toxic mechanisms discussed below. The apoptotic mechanisms thought to be responsible for some therapeutic effects of arsenic trioxide have not been studied in toxicity models.

Trivalent

Arsenic

The primary biochemical lesion of As3 + is inhibition of the pyruvate dehydrogenase (PDH) complex (Fig. 85-2). Normally,

dihydrolipoamide is recycled to lipoamide, a necessary cofactor in the conversion of pyruvate to acetyl-coenzyme A (CoA). As3 + binds the sulfhydryl groups of dihydrolipoamide, blocking lipoamide regeneration.131 Acetyl-CoA is a central molecule in metabolism, and the resulting decrease leads to several deleterious effects: Decreased citric acid cycle activity and thus decreased adenosine triphosphate (ATP) production. Disruption of oxidative phosphorylation leads to production of hydrogen peroxide and oxygen radicals. Decreased gluconeogenesis that can worsen hypoglycemia. Pyruvate carboxylase catalyzes the conversion of pyruvate to oxaloacetate (initial step in gluconeogenesis), and this reaction requires the carboxylation of biotin, a CO2 carrier attached to pyruvate carboxylase. Biotin cannot be carboxylated unless acetyl-CoA is attached to the enzyme.132,152 In the citric acid cycle, oxidation of α-ketoglutarate to succinyl-CoA uses an α-ketoglutarate dehydrogenase complex that contains the same cofactors as the PDH complex, including lipoamide. Arsenic also blocks the dihydrolipoamide–lipoamide recycling in this complex, thus interfering with citric acid cycle activity at a second point. Succinyl-CoA is necessary for production of porphyrins and amino acids, and deficiency may contribute to the anemia and wasting seen with chronic arsenic poisoning. Arsenic inhibition of thiolase, the catalyst for the final step in fatty acid oxidation, also impairs ATP production. Diminished fatty acid oxidation results in decreased acetyl-CoA, in the loss of the reduced form of nicotinamide adenine dinucleotide (NADH) and the reduced form of flavin adenine dinucleotide (FADH2 ) (electron carriers reduced during fatty acid breakdown whose subsequent oxidation yields ATP). Trivalent arsenic also inhibits glutathione synthetase, glucose 6-phosphate dehydrogenase (required to produce nicotinamide adenine dinucleotide phosphate [NADPH]), and glutathione reductase.5 These

inhibitions result in decreased levels of reduced glutathione, which is required to facilitate arsenic metabolism, protect RBCs from oxidative damage, maintain P.1255 hemoglobin in the ferrous state, and scavenge hydrogen peroxide and other organic peroxides.

Figure 85-2. Effect of trivalent arsenicals (As3 +) on pyruvate dehydrogenase (PDH) complex. A . The PDH complex is composed of the three enzymes, which use thiamine pyrophosphate (TPP) and lipoamide as cofactors to decarboxylate pyruvate and form acetyl CoA. B . Arsenic interferes with the regeneration of lipoamide from dihydrolipoamide, thereby altering the function of the PDH complex.

Arsenic affects cardiac repolarization currents. When toxicity occurs, the result is ventricular dysrhythmias, including torsades de pointes. An in vitro study of cells exposed to As3 + demonstrated blockade of the delayed rectifier channels IK s and IKr . Interestingly, activation of

I K-ATP, a weak inward rectifier channel, also occurred; this activation could potentially counteract some of the effects of As3 + on the IK s and IKr channels.41 Animal experiments with phenylarsine oxide, a trivalent arsenical, demonstrate inhibition of insulin-induced glucose transport involving vicinal sulfhydryl groups, as well as β-cell damage in pancreatic islets attributed to inhibition of the α-ketoglutarate dehydrogenase complex.17 These findings support a link between exposure to arsenic and the development of diabetes mellitus.91,128 The impaired glucose transport, plus the inhibited gluconeogenesis (discussed above), can lead to glycogen depletion and hypoglycemia.133 Several animal experiments indicate improved central nervous system (CNS) glucose content132 and an increase in survival time with glucose treatment.34,166

Pentavalent

Arsenic

Several mechanisms can cause toxicity from As5 +; pentavalent arsenic can be transformed to As3 +. 73,168 Pentavalent arsenic also resembles phosphate chemically and structurally, may share a common transport system for cellular uptake with phosphate,73 and can uncouple oxidative phosphorylation by substituting for inorganic phosphate (Pi) in the glycolysis reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase (Fig. 85-3). The resulting unstable product, 1-arseno-3-phosphoglycerate, spontaneously hydrolyzes to 3-phosphoglycerate, so glycolysis continues, but the ATP normally produced during conversion of 1,3-bisphosphoglycerate to 3phosphoglycerate is lost. Uncoupling may also occur if adenosine diphosphate (ADP) forms ADP-arsenate, instead of ATP, in the presence of As5 +. The ADP-arsenate rapidly hydrolyzes, thus uncoupling oxidative phosphorylation. Effects on RBCs include decreased membrane fluidity and ATP depletion.177 Chronic arsenic exposure is associated with vascular disease; in vitro studies demonstrate inhibition of endothelial cell

proliferation and glycoprotein synthesis in addition to lipid peroxidation.27 A study or rodent and human platelets demonstrates increased platelet aggregation and arterial thrombosis.95 Noncirrhotic hepatic portal fibrosis can develop. In a controlled study where mice chronically ingested water containing equal parts As3 + and As5 + for up to 15 months, the development of portal fibrosis was preceded by decreased hepatic glutathione (GSH), increased lipid peroxidation, and diminished levels or activities of numerous enzymes involved in regenerating GSH or scavenging free radicals.139 Proposed mechanisms by which arsenic induces cancer include DNA damage induced by a dimethyl sulfide (DMS)-derived peroxyl radical, gene amplification, replacing phosphate in DNA during replication, and increased cell proliferation.80,180 Experimental evidence and human studies support a number of etiologic or contributing factors for skin keratosis and cancer,1 including chronic stimulation of keratinocytederived growth factors such as transforming growth factor-α (TGFα); impaired methylation; mutation in the p53 tumor-suppressor gene; inhibition of poly(ADP-ribose) polymerase vital for DNA repair; and interference with mitotic spindle and microtubular function.56,72,179 P.1256 Pigmentary changes also occur, and hyperpigmentation is attributed to increased melanin.

Figure

85-3. Pathophysiologic effects of pentavalent arsenic

(As5 +). A . As 5 + substitutes for inorganic phosphate (*), bypassing the formation of 1,3-bisphosphoglycerate (1,3-BPG), and thus losing the ATP formation that occurs when 1,3-BPG is metabolized to 3-phosphoglycerate. B . Energy loss also occurs if A s5 + substitutes for Pi and blocks the formation of ATP + AMP from two ADPs. ADP = adenosine diphosphate; AMP = adenosine monophosphate; ATP = adenosine triphosphate.

Clinical Toxic

Manifestations Effects:

Inorganic

Arsenicals

Toxic manifestations vary, depending on the amount and form of arsenic ingested, as well as the chronicity of ingestion. Other influencing factors include individual variations in methylation and excretion. Larger doses of a potent compound, such as arsenic

trioxide, will rapidly produce manifestations of acute toxicity, whereas chronic ingestion of substantially lower amounts of pentavalent arsenic in groundwater will slowly result in a different clinical picture. Manifestations of subacute toxicity can develop in patients who survive acute poisoning, as well as in patients who are slowly poisoned environmentally. To avoid misdiagnosis, the physician must be aware of these differences.

Acute

Toxicity

Gastrointestinal signs and symptoms of nausea, vomiting, abdominal pain, and diarrhea, which occur 10 minutes to several hours following ingestion, are the earliest manifestations of acute poisoning by the oral route. The diarrhea has been compared to that seen with cholera and may resemble “rice water.― Severe multisystem illness can ensue in the extensive exposure. Cardiovascular signs, ranging from sinus tachycardia and orthostatic hypotension to shock, can develop. Reported cases have mimicked myocardial infarction or systemic inflammatory response syndrome, with intravascular volume depletion, capillary leak, myocardial dysfunction, and diminished systemic vascular resistance.10,14,16,60,78,143 Acute encephalopathy can develop and progress over several days, with delirium, coma, and seizures attributed to cerebral edema and microhemorrhages.22,50,143 Seizures may be secondary to dysrhythmias, and the underlying cardiac rhythm should be assessed. In 3 cases, seizures secondary to torsades de pointes associated with a prolonged QTc interval developed 4 days to 5 weeks after acute arsenic ingestion. 14,58,149 Acute lung injury, acute respiratory distress syndrome and respiratory failure, hepatitis, hemolytic anemia, acute renal failure, rhabdomyolysis, other ventricular dysrhythmias, and death can occur.16,48,63,112,153 Three people died after suddenly developing bradycardia, followed by asystole.16,78,101 Fever may develop, misleading the practitioner to diagnose sepsis. 43,78 Hepatitis can occur and may be a result of altered intrahepatic heme metabolism causing an increased synthesis of

bilirubin or a result of altered protein transport between hepatocytes.3 Acute renal failure may be secondary to ischemia caused by hypotension, tubular deposition of myoglobin or hemoglobin, renal cortical necrosis, and direct renal tubular toxicity.18,55,140,162 Glutathione depletion may be contributory.70 Unusual complications include phrenic nerve paralysis, unilateral facial nerve palsy, pancreatitis, pericarditis, and pleuritis.11,187 Fetal demise has been reported, with toxic arsenic levels found in the fetal organs.16,100 Acutely poisoned patients with less severe illness may experience gastroenteritis and mild hypotension that persist despite antiemetic and intravenous crystalloid therapies. Hospitalization and continued intravenous fluids may be required for several days.93 The prolonged character of the gastrointestinal symptoms is atypical for most viral and bacterial enteric illnesses and should alert the physician to consider arsenic poisoning, especially if there is a history of repetitive gastrointestinal illnesses. A metallic taste or oropharyngeal irritation can occur; the latter can mimic pharyngitis.16,67 The garlicky breath odor attributed to inorganic arsenicals has also been reported with exposure to arsine gas. Gastrointestinal ulcerative lesions and hemorrhage have been reported.50,60 Toxic erythroderma and exfoliative dermatitis result from a hypersensitivity reaction to arsenic.155

Subacute

Toxicity

In the days and weeks following an acute exposure, prolonged or additional signs and symptoms in the nervous, gastrointestinal, hematologic, dermatologic, pulmonary, and cardiovascular systems can occur. Encephalopathic symptoms of headache, confusion, decreased memory, personality change, irritability, hallucinations, delirium, and seizures may develop and persist. 43,52 Sixth cranial nerve palsy and bilateral sensorineural hearing loss are reported.33,58 Peripheral neuropathy typically develops 1–3 weeks

after acute poisoning, although in one series 9 patients developed maximal neuropathy within 24 hours of exposure.33,67,93 Sensory symptoms develop first, and diminished to absent vibratory sense may be present. Progressive signs and symptoms include numbness, tingling, and formication with physical findings of diminished to absent pain, touch, temperature, and deep-tendon reflexes in a stocking-glove distribution. Superficial touch of the extremities may elicit severe or deep, aching pains, a finding that also occurs with thallium poisoning. Motor weakness may then develop. The most severely affected patients manifest an ascending flaccid paralysis that mimics Guillain-Barré syndrome.33,67,93 Respiratory problems can include dry cough, rales, hemoptysis, chest pain, and patchy interstitial infiltrates.67,123 These findings may be misinterpreted as viral or bronchitic disease. Leukopenia, and less commonly anemia and thrombocytopenia, occur from days to 3 weeks after an acute exposure, but resolve as bone marrow function returns.74,97 Dermatologic lesions can include patchy alopecia, oral herpetiform lesions, a diffuse pruritic macular rash, and a brawny nonpruritic desquamation. Diaphoresis and edema of the face and extremities can develop. Mees lines (transverse striate leuconychia of the nails) are 1–2-mm-wide horizontal nail bands that represent disturbed nail matrix keratinization. (See ILMEESUNES in the Image Library at http://www.goldfrankstoxicology.com) They are uncommon in arsenic poisoning. In one series of 74 patients with acute and chronic toxicity, Mees lines were found in only 5% of the patients. Mees lines are also reported with thallium poisoning, chemotherapy, Hodgkin disease, helminthic infections, renal failure, and systemic lupus erythematosus.1,179 A minimum of 30 days after exposure is required for the lines to extend visibly beyond the nail lunulae. Contact dermatitis has been reported from topical exposure in an occupational setting. Other possible toxic manifestations of subacute inorganic arsenic toxicity include nephropathy, fatigue, anorexia with weight loss, torsades de pointes, and persistence of gastrointestinal symptoms.10,105

Chronic

Toxicity

Chronic low-level exposure to inorganic arsenicals typically occurs from occupational or environmental sources. Malignant and nonmalignant skin changes, hypertension, diabetes mellitus, peripheral vascular disease, and several internal malignancies are associated with drinking water containing arsenic that is consumed by study populations.121,183 The skin is very susceptible to the toxic effects of arsenic; multiple dermatologic lesions have been reported in populations suffering from hydroarsenicism.108,183 Alterations in pigmentation occur first, with hyperpigmentation being the most common. Hypopigmentation (“raindrop― pattern) can also occur. (See ILARSENIC1 in the Image Library.) Hyperkeratoses typically develop on the palms and soles, but can be diffuse. (See ILARSENIC2 in the Image Library.) Squamous and basal cell P.1257 carcinomas and Bowen disease may occur. Bowen disease usually proliferates in multiple sites, especially on the trunk, and is noted for developing on sun-protected areas. Latency periods for developing keratoses, Bowen disease, and squamous cell carcinoma were 28, 39, and 41 years, respectively, in 17 patients chronically exposed to environmental or medicinal arsenic.178 Gastrointestinal symptoms of nausea, vomiting, and diarrhea are less likely but can occur. Hepatomegaly was present in 190 of 248 patients with hydroarsenicism; liver biopsy in 69 cases revealed a noncirrhotic portal fibrosis in 91.3%.139 Portal hypertension and hypersplenism have occurred. Hepatic angiosarcomas have been linked to arsenic exposure.32,79,92 Population studies in areas of Bangladesh and Taiwan with arsenic contaminated water show an increased prevalence of diabetes mellitus.128,160 Restrictive lung disease was reported in 9 of 17 patients, and a restrictive plus obstructive pattern occurred in another 7 cases.108 Aplastic anemia and agranulocytosis are documented in patients exposed to arsenic.43 A dose–response relationship between arsenic exposure and vascular

disease is reported in several populations. After adjusting for age, sex, hypertension, diabetes mellitus, cigarette smoking, and alcohol consumption, a significant relationship was observed with cerebrovascular disease in a region of Taiwan. 31 Blackfoot disease, an obliterative arterial disease of the lower extremities, occurring in Taiwan, is linked to chronic arsenic exposure,159 as is ischemic heart disease.23 Incidence of Raynaud phenomenon and vasospasm was reported to be increased in smelter workers exposed to arsenic compared to a control group.90 Encephalopathy and peripheral neuropathy are the neurologic manifestations most commonly reported.13,66 Electromyographic studies of 33 patients with chronic ingestion of arsenic-contaminated water revealed 10 patients with findings consistent with sensory neuropathy. The minimum time for exposure was 2 years. Interestingly, 3 patients consumed water with an arsenic concentration that slightly exceeded the contaminant level of 50 ppb Arsenic is Agency for Toxicology

that was previously permissible in classified as a definite carcinogen Research on Cancer (IARC, Group Program (NTP). Cancers known to

the United States.69 by the International 1) and the National develop include lung

(adenocarcinomas and oat cell carcinomas) and skin. Bladder carcinoma is strongly associated; transitional cell carcinoma was the most common type in one large epidemiologic study.30 Suprisingly perhaps, a critical literature review of animal and human studies found that exposure to environmental arsenic was unlikely to cause reproductive or developmental toxicity.40

Me lar s oprol The therapeutic use of melarsoprol can produce many of the toxic effects that occur with inorganic arsenic, including fever, encephalopathy, and acute cerebral edema with seizures and coma. Whether these effects are caused by drug toxicity or by an immune reaction elicited by trypanosomal antigens is unknown.122,158 Other adverse effects include vomiting, abdominal pain, peripheral neuropathy with hypersensitivity reactions, hypertension, myocardial

damage, and albuminuria. Hemolysis can occur in patients with glucose-6-phosphate dehydrogenase deficiency, and erythema nodosum in patients with leprosy. In a study of the usefulness of melarsoprol as a treatment for refractory or advanced leukemia, reported adverse effects included fatigue, vomiting, diarrhea, vertigo, fever, seizures, headache, back pain, and injection site pain.148

Adverse

Drug

Effects:

Arsenic

Trioxide

The most common adverse effects are dermatologic (skin dryness, pigmentary changes, maculopapular eruptions with or without pruritus), gastrointestinal (nausea, vomiting, anorexia, diarrhea and dyspepsia), hematologic (leukemoid reactions), hepatic (elevation of aminotransferase concentrations typically ≤10 times the upper limit of normal values; with a reported incidence of 20% with lowdose and 31.9% with conventional-dose therapy144), cardiac (prolonged QTc interval in 40–63% of patients, first-degree atrioventricular block, ventricular ectopy, monomorphic nonsustained ventricular tachycardia, torsades de pointes, sudden asystole, and death),138,144,147,163,176 facial edema, and neurologic (paresthesias, peripheral neuropathy, and headache). All of these effects occurred more commonly in one case series with conventional-dose therapy (0.16 mg/kg/d) when compared to low dose therapy. They are usually treated symptomatically without discontinuing As2 O 3 treatment. Leukemoid reactions, defined as white blood cell counts greater than 10 × 109 /L, develop in approximately 50% of patients between 14 and 42 days of beginning treatment. Such patients are at risk for intracerebral hemorrhage or infarction and for the APL syndrome. This syndrome is similar to the retinoic acid syndrome; the remission induction treatment phase is the period of greatest risk.145 Approximately 20–25% of patients will develop one or more signs or symptoms of this syndrome, including pulmonary interstitial infiltrates and/or pleural effusions, dyspnea, tachypnea, fluid retention, myalgias, arthralgias, fever, and weight

gain.106,116,138,144,145

Diagnostic

Testing

Timing of testing for arsenic must be correlated with the clinical course of the patient and whether the poisoning is acute, subacute, chronic, or remote with residual clinical effects. To properly interpret laboratory measurements, confounding factors, such as food-derived organic arsenicals or accumulated arsenic (DMA and arsenobetaine) in patients with chronic renal failure, must be considered.37,189,190 Failure to understand potential confounders, as well as the time course of arsenic metabolism, clearance, and effect on laboratory parameters, can complicate the assessment of possible arsenic poisoning.

Urine and Blood Diagnosis ultimately depends on finding an elevated urinary arsenic concentration. In an emergency, a spot urine may be sent prior to beginning chelation therapy. A markedly elevated arsenic concentration verifies the diagnosis in a patient with characteristic history and clinical findings, whereas a low level does not exclude arsenic toxicity.171 In 9 acutely symptomatic patients, initial spot urine arsenic levels ranged from 192 to 198,450 µg/L.81 Because urinary excretion of arsenic is intermittent, definitive diagnosis hinges on finding a 24-hour urinary concentration equal to or greater than 50 µg/L, 100 µg/g creatinine, or 100 µg total arsenic. All urine should be collected in metal-free polyethylene containers; acidrinsed containers are no longer necessary. If testing is performed by an outside reference laboratory, specimens from acutely ill patients should be sent via express transportation with a request for a rapid result. When interpreting slightly elevated urinary arsenic levels, laboratory findings must also be correlated with the history and clinical findings,

because seafood ingestion is reported to transiently elevate urinary arsenic excretion up to 1700 µg/L.9 When seafood arsenic is a consideration, speciation of arsenic can be accomplished P.1258 by high-performance liquid chromatography (HPLC) separation, followed by inductively coupled plasma-mass spectrometry (ICPMS), HPLC via ion-pair chromatography coupled with hydride-generation atomic-fluorescence spectrometry (HGAFS), or by hydride generation coupled with cold-trap gas chromatography-atomic absorption spectrometry. These techniques separate arsenobetaine (AsB), As3 +, A s5 +, MMA, and DMA.47 Arsenobetaine can also be directly measured by silica-based cation-exchange separation, followed by atomic absorption spectrometry.117 Two other methods, selective hydridegeneration atomic-absorption spectrometry (HGAAS) and resin-based ion-exchange chromatography, do not directly measure AsB; instead, they indirectly derive this value by subtracting the sum of all measured arsenic species from the total arsenic concentration.117 If arsenic speciation cannot be done, the patient can be retested after a 1-week abstinence from fish, shellfish, and algae food products. Conditions under which urine is stored can affect total arsenic recovery, as well as proportionality of the species. The various arsenic species—arsenate (As5 +), arsenite (As3 +), MMA, DMA, and AsB—remain stable for 2 months in urine stored without preservatives at either –4°F (–20°C; freezer) or 39.2°F (4°C; refrigerator); AsB is stable for 8 months under these conditions. Storage for longer than 2 months can alter the recovery of various species. Addition of 0.1% hydrochloric acid (HCl) facilitates reduction of arsenate to arsenite and also decreases MMA and DMA levels. Acid-washed collection containers should not be used if measurement of the various arsenic species is planned. Total arsenic recovery can be diminished by any of the following: specimen storage for greater than 2 months, acidification, or testing using the HPLC-ICPMS and HPLC-HGAFS methods, in which samples are filtered prior to undergoing HPLC separation.47

Diagnostic evaluation of chronic toxicity should include laboratory parameters that may become abnormal within days to weeks following an acute exposure. Tests should include a complete blood count, renal and liver function tests, urinalysis, and 24-hour urinary arsenic determinations. Complete blood count findings can include a normocytic, normochromic, or megaloblastic anemia; an initial leukocytosis followed by development of leukopenia, with neutrophils depressed more than lymphocytes, and a relative eosinophilia; thrombocytopenia; and a rapidly declining hemoglobin, indicative of hemolysis or a gastrointestinal hemorrhage.89 Basophilic stippling of RBCs can be seen; this can occur in other toxic and clinical disorders. Karyorrhexis, a rupture of the RBC cell nucleus with chromatin disintegration into granules that are extruded from the cell, and dyserythropoiesis are reported in both lead- and arsenic-toxic patients. Both findings are caused by arsenic-induced inhibition of DNA synthesis and damage to the nuclear envelope.45 The karyorrhexis can occur within 4 days and resolve by 2 weeks after poisoning, and may be an early indication of arsenic toxicity.89 Elevated serum creatinine, aminotransferases, and bilirubin, as well as depressed haptoglobin concentrations, may develop. Urinalysis may reveal proteinuria, hematuria, and pyuria. Cerebrospinal fluid examination in patients with CNS findings can be normal or exhibit mild protein concentration elevation, measured at 26.5 mg/dL in one case.67 Urinary arsenic excretion in subacute and chronic cases varies inversely with the postexposure time period, but low-level excretion can continue for months after exposure. In a study of 41 cases of arsenic-induced peripheral neuropathy, most patients with a neuropathy of 4–8 weeks duration had total 24-hour urinary arsenic measurements of 100–400 µg.67

Hair and Nail Testing In cases of suspected arsenic toxicity, in which the urinary arsenic measurements fall below accepted toxic levels, analysis of hair and nails may yield the diagnosis. Arsenic can be detected in the

proximal portions of hair within 30 hours of ingestion. 184 Inorganic arsenic is the form best absorbed by these tissues and the form most commonly found in human poisoning cases; small amounts of methylated metabolites may also be detected.127 Arsenobetaine has not been found in hair and tissues in human and animal studies.181,182 Hair grows at rates varying from 0.7–3.6 cm per month, with a mean rate of 1 cm per month.173 The Society of Hair Testing has made the following recommendations for collection of hair specimens, in the context of testing for drugs of abuse: (a) collect approximately 200 mg of hair from the posterior vertex region of the scalp using scissors to cut as close to the scalp as possible, and (b) tie the hairs together, wrap in aluminum foil to protect from environmental contamination, and store at room temperature.173 Nails grow approximately 0.1 mm per day. Total replacement of a fingernail requires 3–4 months, whereas toenails require 6–9 months of growth. These facts, plus the frequency of hair cutting, should be considered when estimating the usefulness of measuring arsenic levels in these tissues. The normal values of the testing laboratory should be used to determine whether arsenic levels are elevated. In cases of remote toxicity, hair and nail arsenic measurements may or may not be elevated, depending on the time elapsed since exposure. Sequential hair analysis to assess the time(s) of exposure can be performed by solid sampling graphite furnace atomic absorption spectrophotometry, or by x-ray fluorescence spectrometry.82,156,157

Challenge

Testing

The role of challenge testing is unclear. In a study of people chronically exposed to elevated levels of arsenic in groundwater, a baseline urine was collected at –2 to zero hours in an exposed group (whose groundwater contained arsenic 510–660 µg/L), and in a control population (whose groundwater contained arsenic 0–21 µg/L). Sodium 2,3-dimercapto-1-propane sulfonate (DMPS) 300 mg was then administered, and urines were collected in 2-hour aliquots

for the next 6 hours. Total concentrations of inorganic arsenic, MMA, and DMA were elevated in the post-DMPS aliquots in both groups, more so in the exposed group. On a percentage basis, MMA levels were elevated the most.8 It is unknown whether a DMPS challenge could assist in diagnosing an acute or a remote exposure with nondiagnostic urine, hair, and nail measurements.

Other

Tests

Abdominal radiographs might demonstrate radiopaque material in the gastrointestinal tract soon after an ingestion; 2,29,60,61,68 however, even after an acute ingestion the absence of radiopaque materials on abdominal radiographs is reported.36 The incidence of positive radiographs after an ingestion is unknown, and a negative radiograph should not eliminate arsenic as a diagnostic consideration. Electrocardiographic changes reported include QRS widening, QTc prolongation, ST segment depression, T-wave flattening, ventricular premature contractions, nonsustained monomorphic ventricular tachycardia, and torsades de pointes.12,119,147,163 Nerve conduction studies (NCS) can confirm or diagnose clinical or subclinical axonopathy. Both the sensory nerve action potential P.1259 (SNAP) and the motor compound muscle action potential (CMAP) measure the number of axons that can conduct impulses. However, the sensory studies are more sensitive than motor studies in detecting axonal degeneration and demyelination; decreased SNAP measurements can indicate subclinical neuropathy. In motor nerve studies, the amplitude (height of the CMAP) is a more sensitive measure of the number of axons that can conduct impulses than is the conduction velocity; this can be explained by the pattern of axonal destruction. Nerve biopsies have confirmed disintegration of both axons and myelin in patients with arsenic-induced peripheral neuropathy; the axonal loss begins distally in the lower extremities and is initially scattered. Thus, conduction along the remaining functional axons can be sufficient to produce normal or only slightly

decreased conduction measurements on NCS.57,67,83,93,114,118

Management General Acute arsenical toxicity is life-threatening and mandates aggressive treatment. Advanced life support monitoring and therapies should be initiated when necessary, but with a few caveats. Careful attention to fluid balance is important because cerebral and pulmonary edema may be present. Xenobiotics that prolong the QTc, such as the class IA, class IC, and class III antidysrhythmics, should be avoided. Potassium, magnesium, and calcium concentrations should be maintained within normal range to avoid exacerbating a prolonged QTc. Glucose concentrations and glycogen stores should be maintained parenterally with dextrose and hyperalimentation solutions, or with enteral feedings, in view of their beneficial effects, in experimental models of arsenic poisoning.98,132,133,152 Arsenic poorly adsorbs to activated charcoal, cholestyramine, and bentonite. Activated charcoal should be administered in the presence of significant ingestions. If radiopaque material is visualized in the gastrointestinal tract, whole-bowel irrigation can be administered until the radiopaque material is no longer seen on repeat abdominal radiograph. Continuing nasogastric suction may be important in removing arsenic resecreted in the gastric or biliary tract. Arsenite was still detectable in the gastric aspirate in 3 patients 5–7 days following an ingestion.103 There is no clinical experience with the use of N-acetylcysteine to increase glutathione levels; an animal experiment suggested a protective effect.129 In cases of chronic toxicity, patients should be removed from the arsenic source and gastric decontamination should be performed if there is evidence of arsenic in the gastrointestinal tract. Arsenic can be readily removed from skin with soap, water, and vigorous scrubbing. In all cases, when homicidal intent is suspected, patients

should be advised against accepting food or drink from anyone who might be responsible. Also, the hospital visitors should be closely monitored and outside nutritional products should be forbidden.

Chelation

Therapy

The decision to initiate chelation therapy should depend on the clinical condition of the patient as well as the laboratory results for arsenic in urine, hair, or nails. A severely ill patient with known or suspected acute arsenic poisoning should be chelated immediately, prior to laboratory confirmation. In a series of 33 patients who had coma, seizures, or both, 24 patients were treated with British antiLewisite (BAL) within 6 hours (mean: 1 hour) and 75% survived, compared with a survival rate of 45% of 9 patients who were treated later (range: 9–72 hours; mean: 30 hours).43 Cases of subacute and chronic toxicity can await rapid laboratory confirmation prior to beginning chelation, unless the clinical condition deteriorates.

Figure DMSA.

85-4. 1,2,5-Arsadithiolane adducts with BAL, DMPS, and

Specific

Chelators Dimercaprol (BAL) and 2,3-dimercaptosuccinic acid (succimer) are the 2 chelators available in the United States. A third drug, DMPS, is distributed by Heyl, a German pharmaceutical company, as Dimaval, but it is not approved or marketed in the United States (see Antidotes in Depth: Succimer [2,3-Dimercaptosuccinic Acid]). All contain vicinal dithiol moieties that bind arsenic to form stable 1,2,5arsadithiolanes (Fig. 85-4), and all are most effective when administered in doses equimolar to the arsenic burden.113 Dosing regimens and adverse effects are listed in Table 85-3.

TABLE 85-3. Chelators

Dosage

Adverse febrile

Effects

BAL

Hypertension;

reaction;

3–5 mg/kg every 4–6 h

diaphoresis; nausea; vomiting; salivation; lacrimation; rhinorrhea; headache; painful injection; injection site sterile abscess; hemolysis in G6PDdeficient patients; chelation of essential metals (prolonged course)

SUCCIMER 10 mg/kg/dose every 8 h for 5 d, then 10 mg/kg/dose every 12 h

Nausea; vomiting; diarrhea; abdominal gas and pain; transient elevations of hepatic aminotrans-ferases and alkaline phosphatase; rash; pruritus; sore throat; rhinorrhea; drowsiness; paresthe-sias; thrombocytosis; eosinophilia

DMPS Dose: 5 mg/kg/dose IM, administered as a 5% solution Day 1: q6–8h Day 2: q8–12h Day 3 and thereafter: q12–24h

Allergic reactions; increased copper and zinc excretion; nausea; pruritus; vertigo; weakness, toxic epidermal necrolysis

End point: for chelation is a 24 hour urinary arsenic of < 50 µg/L

P.1260 In the United States, BAL remains the initial chelating drug for acute arsenical toxicity.113 It is the only intracellular and extracellular chelator available in the United States. BAL is administered parenterally and thus is not affected by the patient's gastrointestinal motility. Its therapeutic-to-toxic ratio is narrow, with adverse effects likely to occur in patients receiving doses of 4 mg/kg or greater. It is administered intramuscularly in peanut oil; the injections are painful and can lead to sterile skin abscesses. In a cellular study of glucose uptake impaired by a lipophilic arsenical, BAL was superior to succimer and DMPS in restoring cellular equilibrium.113 A human case series found increased survival with early use of BAL and improvement in encephalopathy within 24 hours of initiating therapy.43 However, other acute cases treated promptly with BAL developed peripheral neuropathy.93 In a study of subacute cases with peripheral neuropathy, BAL accelerated neurologic recovery but did not affect the overall recovery rate.33 Despite starting BAL therapy 8 hours postexposure, a man who had ingested 2.15 g of arsenic

developed severe toxicity and neurologic deficits.49 Most concerning are the animal experiments indicating that BAL shifts arsenic into the brain and testes, two organs that have blood–organ barriers susceptible to this lipophilic drug.7,71,85 It is clear that BAL has limitations, and that we need a safer, more effective intracellular/extracellular parenteral chelator. Succimer is an oral choice for subacute animal studies and exposed to sodium

hydrophilic analog of BAL and is the chelator of and chronic toxicity. It has proven effective in in reported human cases.7,84,96,102,146 In mice arsenite, succimer was more effective than either

DMPS or BAL in decreasing lethality, and more potent than BAL in restoring activity in the pyruvate dehydrogenase complex.7 It is equal or superior to BAL in speeding arsenic elimination.113 Liver function tests and essential metal levels should be monitored in patients

requiring

prolonged

therapy. 51,62

DMPS is also a water-soluble analog of BAL. Although not approved for use in the United States, it has been used on an investigational basis in a few cases (Karen Simone, PharmD, and Anthony Tomassoni, MD, personal communication). It can be administered by the oral, intravenous, and intramuscular routes. It is eliminated from the body more slowly than succimer and has the advantage of intracellular as well as extracellular distribution.4 It predominantly binds MMA3 + and possibly removes the MMA3 + from endogenous ligands. The DMPS–MMA3 + complex is eliminated in the urine.6,8,59 It may also work by synergistically increasing the nonenzymatic methylation of As3 +. 185 Two brothers ingested nearly pure arsenic trioxide (1 and 4 g each) and were treated with intravenous and oral DMPS. The brother who ingested 4 g developed hypotension, renal failure, respiratory insufficiency, and asystolic cardiac arrest. DMPS was started 32 hours postingestion, and the patient survived with normal renal function and no neurologic dysfunction. His sibling had a milder course; DMPS was started 48 hours postingestion, and there were no neurologic sequelae on followup examination.112 DMPS significantly increased biliary excretion of arsenic in a guinea pig

model, but did not increase fecal excretion. The latter is most likely a result of enterohepatic recirculation of the DMPS–As complex. 130 D-Penicillamine has not demonstrated efficacy in chelating or reversing the biochemical lesions of arsenic and should not be used. Its previous advantage of oral administration is no longer relevant with the availability of succimer.

Hemodialysis Hemodialysis removes negligible amounts of arsenic, with or without concomitant BAL therapy, and is not indicated in patients with normal renal function.15,65 In patients with renal failure, hemodialysis clearance rates have ranged from 76–87.5 mL/min, with or without concomitant BAL therapy.107,170 In 2 acutely toxic patients with renal failure, total arsenic removed during a 4-hour dialysis measured 4.68 mg in one and 3.36 mg in the other. Concomitant 24hour urinary arsenic excretions were 3.12 mg and 2.03 mg, respectively. When renal function returned, however, the 24-hour urinary excretion of arsenic far exceeded that recovered with dialysis, with reported levels of 18.99 mg in the first patient and 75 mg in the second patient.170 There are no published rigorous data regarding hemodialysis removal of a water-soluble complex such as DMPS–As.86

Summary Arsenicals produce multisystem toxicity by a variety of pathophysiologic mechanisms. A thorough understanding of inorganic arsenic metabolism and excretion as well as the different clinical manifestations of acute, subacute, and chronic toxicity are necessary to avoid misdiagnosis. Chelation therapy with BAL in the United States, or with DMPS elsewhere, if available, should be started immediately in the severely ill patient. Treatment can await laboratory results for patients with subacute or chronic toxicity, unless clinical deterioration intervenes. Environmental contamination

of water sources has become a major health problem in many countries, including the United States.

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183. Yoshida T, Yamauchi H, Fan SG: Chronic health effects in people exposed to arsenic via the drinking water: Dose-response relationships in review. Toxicol Appl Pharmacol 2004;198:243–252. 184. Young EG, Smith RP: Arsenic content of hair and bone in acute and chronic arsenical poisoning: Review of 2 cases examined posthumously from medico-legal aspect. Br Med J 1942;1:251–253. 185. Zakharyan RA, Aposhian HV: Arsenite methylation by methylvitamin B12 and glutathione does not require an enzyme. Toxicol Appl Pharmacol 1999;154:287–291. 186. Zakharyan RA, Aposhian HV: Enzymatic reduction of arsenic compounds in mammalian systems: The rate-limiting enzyme of

rabbit liver arsenic biotransformation is MMA(V) reductase. Chem Res Toxicol 1999;12:1278–1283. 187. Zaloga GP, Deal J, Spurling T, et al: Case report: Unusual manifestations of arsenic intoxication. Am J Med Sci 1985;289:210–214. 188. Zhang P, Wang SY, Hu LH, et al: Treatment of 72 cases of acute promyelocytic leukemia by intravenous arsenic trioxide. Chin J Hematol 1996;17:58–62. 189. Zhang X, Cornelis R, De Kimpe J, et al: Accumulation of arsenic species in serum of patients with chronic renal disease. Clin Chem 1996;42 (8 Pt 1):1231–1237. 190. Zhang X, Cornelis R, Mees L, et al: Chemical speciation of arsenic in serum of uraemic patients. Analyst 1998;123:13–17.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > I - Metals > Antidotes in Depth - Dimercaprol (British Anti-Lewisite or BAL)

Antidotes in Depth Dimercaprol (British Lewisite or BAL) Mary Ann Howland

Principles

of

2,3-Dimercaptopropanol

Chelation

(BAL)

Anti-

Prior to a discussion of chelators, it is critical to understand the principles of chelation. Soft metal ions, such as Hg2 +, Au+, Cu+, and Ag+ have large ionic radii with a large number of electrons in their outer shell. Accordingly, they form the most stable complexes with sulfur donors and are referred to as sulfur seekers (Chap. 12) .1,5,28 The chelator or ligand, in this case, a sulfurcontaining compound such as British anti-Lewisite (BAL), forms a coordinate bond with the metal by donating a pair of free electrons. Hard metals such as Na+, K+, Mg2 +, Ca2 +, and Al3 + are referred to as oxygen seekers and form the best complexes with hard ligands containing a carboxyl (COO- ) group, such as edetate calcium disodium (CaNa2 EDTA). Borderline metal ions, such as Pb2 +, Cd2 +, Cu2 +, As3 +, and Zn2 +, prefer nitrogen-donating ligands but will also react with both hard and soft ligands. Antidotes for metal poisoning often contain more than one type of donating group, making them effective for more than one type of metal. BAL has two adjacent sulfur groups, thus the term dithiol; the presence of these two sulfur groups permits the formation of a ring structure with the metal, thereby enhancing chelator stability.1,5,28 The most useful chelators have relatively low intrinsic toxicity, form stable complexes with the chelated metals, have tissue distribution characteristics similar to the metal to be chelated, and effect a favorable clinical outcome when administered.1,5,28 Other desirable aspects of the metal–chelator complex are elimination from the body without breaking and no redistribution to the brain or other critical organs. Unfortunately, there is no currently available chelator with all of these attributes. In addition, there are no published double-blind, randomized, placebo-controlled trials comparing outcomes with the use of metal chelators such as dimercaprol, CaNa2 EDTA, or succimer on lead, arsenic, or mercury poisoning in humans. The majority of efficacy data to date are derived from animal studies, several case series compared to historical controls, and several case reports. The most rigorous

human data usually describe a reduction in metal concentrations rather than improvements in clinical parameters. Redistribution characteristics of metal–chelator complexes are being rigorously investigated in animal models, because redistribution to vital tissues such as the brain is of great concern. Although BAL has been in use since the late 1940s,20 much of our current practice relies on opinion and historical precedence, and many pharmacokinetic and toxicokinetic questions remain unanswered.

History Investigation into the use of sulfur donors as antidotes was precipitated by the World War II threat of chemical warfare with lewisite (dichloro(2-chlorovinyl)arsine) and mustard gas (dichlorodiethyl sulfide). Both are vesicant gases that cause tissue damage when combined with protein sulfhydryl (SH) groups31 (Chap. 126). These investigations led to the discovery of the dithiol 2,3-dimercaptopropanol, called British anti-Lewisite, which combines with Lewisite to form a stable 5-membered ring.

Chemistry BAL has a molecular weight of 124.2 Daltons and a specific gravity of 1.21.32 BAL is an oily liquid with only 6% weight/volume water solubility, 5% weight/volume peanut oil solubility, and a disagreeable odor. Aqueous solutions are easily oxidized and therefore unstable. Peanut oil stabilizes BAL and benzyl benzoate (in the ratio of 1 part BAL to 2 parts of benzyl benzoate) renders the BAL miscible with peanut oil.32

Pharmacokinetics There are no recent pharmacokinetic studies with BAL. The limited amount of information available dates back to the late 1940s. Plasma concentrations of BAL peak about 30 minutes after IM

administration and distribution occurs quickly.32,35 Within 2 hours after IM administration to rabbits, plasma concentrations drop quickly. Urinary excretion of BAL metabolites, perhaps partially as glucuronic acid conjugates, accounted for nearly 45% of the dose within 6 hours and 81% of the dose within 24 hours.32,34 Very little is excreted unchanged in the urine.32 BAL is concentrated in the kidney, liver, and small intestine.30 BAL can also be found in the feces, strongly implying that enterohepatic circulation exists. Hemodialysis may be useful in removing the BAL–metal chelate in cases of renal failure.19,25,37

Use of BAL for Arsenic Poisoning Animal

Studies

The fear that Lewisite might be sprayed over the land and its population, causing skin lesions, led researchers to investigate the potential for cutaneous application of BAL.36 This was based on its limited water solubility and high lipid solubility. In a low concentrations of topical BAL were very effective preventing lewisite-induced toxicity and in reversing administered within 1 hour of skin exposure.29,31 In

rodent model, both in toxicity when rabbits,

ocular application of BAL proved effective in preventing eye destruction P.1266 exposure.19

if applied within 20 minutes of Additionally, urinary arsenic concentrations were significantly increased after the application of BAL. 31 The effectiveness of both parenteral single-dose and multiple-dose BAL against lewisite and other arsenicals was studied in rabbits. When begun within 2 hours of lewisite exposure, BAL injections of 4 mg/kg every 4 hours led to a 50% survival of exposed rabbits. This dose regimen was demonstrated to be one-seventh of the maximum tolerated dose of BAL.13

The most recent animal studies demonstrate that although studies with BAL increase the LD50 (median lethal dose for 50% of test subjects) of sodium arsenite, the therapeutic index of BAL is low and arsenic redistribution to the brain occurs.2,3,4,16,33 In these same animal models, succimer and the investigational agent 2,3dimercaptopropane sulfonate (DMPS) also increased the LD50, but with a better therapeutic index and without causing redistribution to the brain.

Human

Studies

Experiments in human volunteers who were given minute amounts of arsenic demonstrated that BAL increased urinary arsenic concentration by approximately 40%, with maximum excretion occurring 2–4 hours after BAL administration.38 BAL was subsequently used in the treatment of arsenical dermatitis resulting from syphilis therapy with organic arsenicals. When applied to affected skin, topical BAL produced erythema, pruritus, and dysesthesias, but had no adverse effects on unaffected skin. Intramuscular BAL produced both subjective and objective improvement, limited the duration of the arsenical dermatitis, and increased

urinary

arsenic

elimination.9,23,24

In a study of 227 patients with inorganic arsenic poisoning, maximal efficacy and minimal toxicity were achieved when 3 mg/kg of BAL was administered intramuscularly every 4 hours for 48 hours and then twice daily for 7–10 days. This regimen resulted in complete recovery in 6 of 7 patients with severe arsenic-induced encephalopathy and demonstrated the importance of administering BAL as soon as possible after the exposure. Of 33 patients with severe arsenic-induced encephalopathy, 18 of 24 (75%) treated within 6 hours survived, versus only 4 of 9 (44%) treated after a delay of at least 72 hours.12 Furthermore, the effectiveness of BAL was also demonstrated in 3 patients who were treated successfully after mistakenly receiving 10–20 times the

therapeutic dose of Mapharsen (oxophenarsine hydrochloride). A fourth patient, treated with inadequate doses of BAL, died.12 These cases also support the effectiveness of BAL in treating arsenic-induced agranulocytosis, encephalopathy, dermatitis, and probably arsenical fever.12 When BAL first became more widely available, 42 children who were treated following arsenic ingestions were compared to a historical group of 111 other children who had ingested arsenic.39 The percentage of children exhibiting symptoms on presentation were similar between groups (46%), but in the group of treated children there were fewer deaths (0 vs. 3), a shorter average hospital stay (1.6 vs. 4.2 days), and fewer cases of persistent symptoms at 12 hours (0% vs. 29.3%). Ocular damage caused by lewisite is partly a result of the liberation of hydrochloric acid, which results in an acid injury causing localized superficial opacity of the cornea and deep penetration of lewisite into the cornea and aqueous humor with resultant rapid necrosis. In an experimental model, a 5% BAL ointment or solution applied within 2 minutes of exposure prevented the development of a significant reaction; application at 30 minutes lessened the reaction, but did not prevent permanent damage.17

Mercury Because mercury also reacts with sulfhydryl groups, animal studies were performed to assess the affinity and ability of thiols to competitively chelate inorganic mercury and prevent toxicity. As in the case of arsenic, the dithiols BAL and BAL glucoside were more effective than the monothiol 1-thiosorbitol in preventing mercuryinduced death and uremia.15 The clinical efficacy of BAL in treating inorganic mercury poisoning was substantiated in patients who ingested mercuric chloride.22,21 Thirty-eight patients ingesting more than 1 g of mercuric chloride who were treated with BAL

within 4 hours of exposure were compared to historical controls.21 There were no deaths in the 38 patients treated with BAL as compared to 27 deaths in the 86 untreated patients. Death typically resulted from hemorrhagic gastritis and renal failure.21 BAL is particularly useful for patients who have ingested a mercuric salt, as the associated gastrointestinal toxicity of the mercuric salt limits the potential of an orally administered antidote such as succimer. Animal models demonstrate that when BAL is administered to chelate mercury following poisoning from elemental mercury vapor or exposure to short-chain organic mercury compounds, brain levels of mercury may increase.6,8 However, in a rat model, the initiation of BAL therapy within 1 day of exposure to short-chain organic mercury compounds prevented neurologic toxicity.40 When treatment was delayed for 12 days, no effect on established neurotoxicity could be demonstrated. As a result of these limited and somewhat contradictory data, BAL therapy is not recommended when patients are exposed to short-chain organic mercury compounds because it may increase brain concentrations of methyl mercury.5,19 Other therapies may have greater usefulness (Chap. 92) .

Lead BAL may be used in combination with CaNa2 EDTA to treat patients with severe lead poisoning. In all other cases, succimer has become the chelator of choice. When administering BAL in patients with lead encephalopathy, it is essential to administer the BAL first, followed 4 hours later by CaNa2 EDTA, concomitantly with the second dose of BAL. This regimen prevents the CaNa2 EDTA from redistributing lead into the brain (the converse with regard to arsenic).10,11 Providing two different chelators also reduces the blood lead level significantly faster than either one alone, and maintains a better molar ratio of chelator to lead.10 Once the

mobilization of lead has begun, it is important to provide uninterrupted therapy to prevent redistribution of lead to the brain.10

Adverse

Effects

and

Safety

Issues

The toxicity of BAL is dose dependent and affected by urinary pH. An acidic urine allows dissociation of the BAL–metal chelate. Less than 1% of 700 intramuscular injections resulted in minor reactions, such as pain at the injection site, among patients P.1267 who received 2.5 mg/kg of BAL every 4–6 hours for 4 doses.12 When doses of 4 mg/kg and 5 mg/kg were given, the incidence of adverse effects rose to 14% and 65%, respectively.12 At these higher doses, the following symptoms were reported in decreasing order of frequency: nausea; vomiting; headache; burning sensation of lips, mouth, throat, and eyes; lacrimation; rhinorrhea; salivation; muscle aches; burning and tingling of extremities; tooth pain; diaphoresis; chest pain; anxiety; and agitation.23 These effects were maximal within 10–30 minutes of exposure, and usually subsided within 30–50 minutes.12 Elevations in systolic and diastolic blood pressure and tachycardia commonly occurred and correlated with increasing doses.19,26 Thirty percent of children given BAL may develop a fever that can persist throughout the therapeutic period.19 A transient reduction in the percentage of polymorphonuclear leukocytes may also occur.19 Doses above 5 mg/kg should not be administered because of the high risk of adverse reactions. Doses above 25 mg/kg can be expected to produce a hypertensive encephalopathy with convulsions and coma.39 BAL is not very effective in the presence of arsenic-induced hepatotoxicity.24 Moreover, in rats, preexistent hepatotoxicity was exacerbated when BAL was used for treatment of arsenic poisoning. Therefore, unless the hepatotoxicity is considered

arsenic-induced, hepatic dysfunction is a contraindication to BAL use.31 BAL should not be used for patients poisoned by methylmercury because animal studies demonstrate a redistribution of mercury to the brain.5,19 Because dissociation of the BAL–metal chelate will occur in an acid urine, the urine of patients receiving BAL should be alkalinized with hypertonic NaHCO3 to a pH of 7.5–8.0 to prevent renal liberation of the metal.19 BAL should be used with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as it may cause hemolysis.18 In these cases, a risk-to-benefit analysis must be made because G6PD-deficiency syndromes are variably expressed in young cells. In addition, chelators are relatively nonspecific and may bind metals other than those desired, thus causing deficiency of an essential metal. For example, BAL given to mice increased copper elimination to 3 times normal.7 BAL is formulated in peanut oil; therefore, the patient should be questioned regarding any known peanut allergy. Limited evidence suggests that iron supplements should not be given to patients who are receiving BAL because the BAL–iron complex appears to cause severe vomiting and decreases metal chelation.10,11,14 Unintentional IV infusion of BAL could theoretically produce fat embolism, lipoid pneumonia, chylothorax, and associated hypoxia.34

Dos i n g Commercially available BAL is a yellow, viscous liquid with a sulfur odor. It is available in 3-mL ampules containing 100 mg/mL of BAL, 200 mg/mL of benzyl benzoate, and 700 mg/mL of peanut oil. This drug should only be administered by deep IM injection. The dose of BAL for lead encephalopathy is 75 mg/m2 IM every 4 hours for 5 days.10,11 As noted earlier, the first dose of

dimercaprol should precede the first dose of CaNa2 EDTA by 4 hours. Thereafter, intravenous CaNa2 EDTA, in a dose of 1500 mg/m2 /d (up to a maximum of 2–3 g) as a continuous infusion, or divided into 2–4 doses, should be administered. These daily doses are equimolar. The dose of BAL for severe inorganic arsenic poisoning has not been established. One regimen suggests the use of 3 mg/kg IM every 4 hours for 48 hours and then twice daily for 7–10 days.12 Another regimen uses 3–5 mg/kg IM every 4–6 hours on the first day and then tapers the dose and frequency, depending on the patient's symptomatology. A third regimen reduces the number of injections by day 2 and terminates therapy within 5–7 days.39 The dose of BAL for patients exposed to inorganic mercury salts is 5 mg/kg IM initially, followed by 2.5 mg/kg every 8–12 hours for 1 day, followed by 2.5 mg/kg every 12–24 hours until the patient appears clinically improved, up to a total of 10 days.

Summary BAL (dimercaprol) is an effective metal chelator used clinically in the treatment of inorganic mercury and arsenic toxicity, and in conjunction with edetate calcium disodium for lead encephalopathy and severe lead toxicity. 19,26

References 1. Aaseth J: Recent advances in the therapy of metal poisonings with chelating agents. Hum Toxicol 1983;2:257–272. 2. Aposhian HV, Tadlock CH, Moon TE: Protection of mice against the lethal effects of sodium arsenite—A quantitative comparison of a number of chelating agents. Toxicol Appl

Pharmacol

1981;61:385–392.

3. Aposhian HV, Mershon MM, Brinkley FB, et al: Anti-Lewisite activity and stability of meso-dimercaptosuccinic acid and 2,3dimercapto1-propanesulfonic acid. Life Sci 1982;31:2149–2156. 4. Aposhian HV, Carter DE, Hoover TD, et al: DMSA, DMPS, and DMPA as arsenic antidotes. Fundam Appl Toxicol 1984;4:S58–S70. 5. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, et al: Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;97:23–38. 6. Berlin M, Ullberg S: Increased uptake of mercury in mouse brain caused by 2,3-dimercaptopropanol. 1963;197:84–85.

Nature

7. Cantilena LR, Klaassen CD: The effect of chelating agents on the excretion of endogenous metals. Toxicol Appl Pharmacol 1982;63:344–350. 8. Canty AJ, Kishimoto R: British anti-Lewisite and organmercury poisoning. Nature 1972;253:123–125. 9. Carleton AB, Peters RA, Stocken LA, et al: Clinical uses of 2,3-dimercaptopropanol (BAL): VI. The treatment of complications of arseno-therapy with BAL. J Clin Invest 1946;25:497–527. 10. Chisolm JJ Jr: The use of chelating agents in the treatment

of acute and chronic lead intoxication in childhood. J Pediatr 1968;73:1–38. 11. Committee on Drugs: Treatment guidelines for lead exposure in children. Pediatrics 1995;96:155–160. 12. Eagle H, Magnuson HJ: The systemic treatment of 227 cases of arsenic poisoning (encephalitis, dermatitis, blood dyscrasias, jaundice, fever) with 2,3-dimercaptopropanol (BAL). Am J Syph Gonorrhea Vener Dis 1946;30:420–441. 13. Eagle H, Magnuson HJ, Fleischman R: Clinical uses of 2,3dimercaptopropanol (BAL): I. The systemic treatment of experimental arsenic poisoning (Mapharsen, lewisite, phenyl arsenoxide) with BAL. J Clin Invest 1946;25:451–466. 14. Edge WD, Somers GF: The effect of dimercaprol (BAL) in acute iron poisoning. Q J Pharm Pharmacol 1948;21:364–369. 15. Gilman A, Allen RP, Philips FS, et al: Clinical uses of 2,3dimercaptopropanol (BAL): X. The treatment of acute systemic mercury poisoning in experimental animals with BAL, thiosorbitol and BAL glucoside. J Clin Invest 1946;25:549–556. 16. Hoover TD, Aposhian HV: BAL increases the arsenic-74 content of rabbit brain. Toxicol Appl Pharmacol 1983;70:160–162. 17. Hughes WF: Clinical uses of 2,3-dimercaptopropanol (BAL): IX. The treatment of lewisite burns of the eye with BAL. J Clin

Invest

1946;

25:541–548. P.1268

18. Janakiraman N, Seeler RA, Royal JE, et al: Hemodialysis during BAL chelation therapy for high blood lead levels in two G6PD-deficient children. Clin Pediatr 1978;17:485–487. 19. Klaassen CD: Heavy metals and heavy metal antagonists. In: Hardman JG, Limbird LE, eds: The Pharmacological Basis of Therapeutics, 10th ed. New York, Macmillan, 2001, pp. 1851–1875. 20. Kosnett MJ: Unanswered questions in metal chelation. J Toxicol Clin Toxicol 1992;30:529–547. 21. Longcope WT, Luetscher JA: The use of BAL (British antiLewisite) in the treatment of the injurious effects of arsenic, mercury and other metallic poisons. Ann Intern Med 1949;31:545–554. 22. Longcope WT, Luetscher JA, Calkins F, et al: Clinical uses of 2,3-dimercaptopropanol (BAL): XI. The treatment of acute mercury poisoning by BAL. J Clin Invest 1946;25:557–567. 23. Longcope WT, Luetscher JA, Wintrobe MM, et al: Clinical uses of 2,3-dimercaptopropanol (BAL): VII. The treatment of arsenical dermatitis with preparations of BAL. J Clin Invest 1946;25:528–533. 24. Luetscher JA, Eagle H, Longcope WT: Clinical uses of 2,3dimercaptopropanol (BAL): VIII. The effect of BAL on the excretion of arsenic in arsenical intoxication. J Clin Invest

1946;25:534–540. 25. Maher JF, Schreiner GE: The dialysis of mercury and mercury-BAL complex. Clin Res 1959;7:298. 26. Mahieu P, Buchet JP, Roels HA, et al: The metabolism of arsenic in humans acutely intoxicated by As2 O 3 : Its significance for the duration of BAL therapy. J Toxicol Clin Toxicol 1981;18:1067–1075. 27. Oehme FW: British anti-lewisite (BAL): The classic heavy metal antidote. Clin Toxicol 1972;5:215–222. 28. Pearson RG: Hard and soft acids and bases; NSAB. Part II. Underlying theories. J Chem Educ 1968;45:643–648. 29. Peters RA: Biochemistry of some toxic agents. J Clin Invest 1955;34: 1–20. 30. Peters RA, Spray GH, Stocken LA, et al: The use of British anti-Lewisite containing radioactive sulfur for metabolism investigations. Biochem J 1947;41:370–373. 31. Peters RA, Stocken LA, Thompson RM: British anti-Lewisite (BAL). Nature 1945;156:616–618. 32. Randall RV, Seeler AO: BAL. N Engl J Med 1948;239:1004–1009, 1040–1048. 33. Schafer B, Kreppel H, Reichl FX, et al: Effect of oral treatment with BAL, DMPS or DMSA arsenic in organs of mice injected with arsenic trioxide. Arch Toxicol

1991;14(Suppl):228–230. 34. Seifert SA, Dart RC, Kaplan EH: Accidental, intravenous infusion of a peanut oil-based medication. J Toxicol Clin Toxicol 1998;36:733–736. 35. Spray GM, Stocken LA, Thompson RMS: Further investigations on the metabolism of 2,3-dimercaptopropanol. Biochem J 1947;41:363–366. 36. Stocken LA, Thompson RM: Reactions of British antiLewisite with arsenic and other metals in living systems. Physiol Rev 1949;29:168–194. 37. Vaziri ND, Upham T, Barton CM: Hemodialysis clearance of arsenic. Clin Toxicol 1980;17:451–456. 38. Wexler J, Eagle M, Tatum MJ, et al: Clinical uses of 2,3dimercaptopropanol (BAL): II. The effect of BAL on the excretion of arsenic in normal subjects after minimal exposure to arsenical smoke. J Clin Invest 1946;25:467–473. 39. Woody NC, Kometani JT: BAL in the treatment of arsenic ingestion of children. Pediatrics 1948;1:372–378. 40. Zimmer LJ, Carter DE: The effect of 2,3dimercaptopropanol and D-penicillamine on methyl mercuryinduced neurological signs and weight loss. Life Sci 1978;23:1025–1034.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > I - Metals > Chapter 86 Bismuth

Chapter

86

Bismuth Rama B. Rao Bismuth

(Bi)

Atomic

number

=

83

Atomic

weight

=

208.98

Normal

concentrations

Serum

=

2–11

mg/L(9.52

nmol/L)

Urine

=

100 µg/L, with the majority of these blood concentrations between 100 µg/L and 1000 µg/L.26 Twenty-two patients suffered encephalopathy at blood concentrations below 100 µg/L.26 In another report, 2 patients with encephalopathy had blood concentrations of 900 µg/L and 2500 µg/L, both of whom recovered when the concentration fell below 500 µg/L.5 Just as blood concentrations do not reflect severity of illness, tissue concentrations may also poorly correlate with severity of illness. An example was noted in a patient who recovered from a severe encephalopathy. On discharge, he had low blood bismuth concentrations and died 3 months later of unrelated trauma. At autopsy he was found to have an elevated central nervous system (CNS) bismuth burden, but no reported symptoms at the time of the trauma.9

The electroencephalographic (EEG) findings of patients with bismuth encephalopathy generally demonstrate nonspecific slow wave changes.14,17 In one study, the EEG findings were described in association with blood concentrations. At less than 50 µg/L, the EEG was normal or demonstrated diffuse slowing. In patients with blood concentrations of less than 1500 µg/L, the findings of sharp wave abnormalities were noted. At higher concentrations (>2000 µg/L), some patients with neurologic events, such as myoclonic jerks, did not have corresponding EEG changes. The authors proposed that an elevated body burden might have an inhibitory effect on the cerebral cortex.9 In encephalopathic patients with blood concentrations >2000 µg/L, diagnostic imaging, such as computed tomography, may demonstrate a diffuse cortical hyperdensity of the gray matter. These findings tend to resolve with recovery. Magnetic resonance imaging was normal in another encephalopathic patient.14

TABLE 86-2. Differential Diagnosis of Bismuth Encephalopathy

Creutzfeld-Jacob disease Ethanol withdrawal Lithium toxicity Neurodegenerative leukoencephalopathies Nonketotic hyperosmolar coma Postanoxic and posthypoglycemic encephalopathies Progressive multifocal ataxia Viral encephalopathies

Treatment

Typically, supportive care results in a complete recovery. Some authors suggest GI decontamination with activated charcoal and polyethylene glycol solution.44 Although evidence for this approach is lacking, it appears to be a reasonable initial intervention, especially in patients with severe encephalopathy. In patients with renal toxicity, resolution is generally observed with supportive care. The use of chelating agents in acute overdose without neurotoxicity is probably not indicated. Withdrawal of the source of bismuth often results in complete reversal of symptoms within days to weeks, even in severely ill patients. In general, the data regarding chelation are limited, and in vitro and animal models do not clearly predict in vivo human models. Chelation therapy with British anti-Lewisite (BAL) is beneficial in experimental models,44,47 reportedly beneficial in humans,30 and often recommended, although clear evidence of efficacy is lacking. BAL undergoes biliary elimination, offering a major advantage over other chelators in patients who may develop renal insufficiency. One study advocated the addition of dimercaptopropane sulfonate (DMPS), as BAL with hemodialysis did not affect clearance, whereas the addition of DMPS to patients needing hemodialysis was effective in enhancing elimination.47 It is uncertain whether the clinical course of the patients was improved. In human volunteers using colloidal bismuth subcitrate, succimer and DMPS, both at a dose of 30 mg/kg, increased urinary elimination of bismuth by 50-fold.45 In an animal model, D-penicillamine was most efficacious in enhancing elimination of bismuth. In a human volunteer model using therapeutic doses of TDC, however, a single dose of Dpenicillamine did not enhance urinary excretion.32 The precise timing, dosage, indications, and choice of chelator are unknown; however, chelation with succimer has few side effects and might limit the potentially fatal complications associated with

prolonged immobilization. BAL, which has more side effects, can be considered in encephalopathic patients with renal failure in whom no neurologic improvement is noted within 48 hours of bismuth withdrawal and whole-bowel irrigation. Prevention is the most effective means of avoiding neurotoxicity. Patients and their families should be taught to recognize the subtle manifestations of bismuth-induced neurotoxicity. Blood concentrations of bismuth are not routinely performed, but a bismuth concentration >100 µg/L, or symptoms at lower levels, warrant withdrawal of bismuth therapy.

Bismuth

Drug

Interactions

and

Reactions The coadministration of proton pump inhibitors (PPIs) may affect the absorption of some bismuth preparations. In a prospective evaluation of patients receiving different treatment regimens for Helicobacter pylori-induced dyspepsia or peptic ulcer disease, individuals taking PPIs had a statistically significant elevation in their blood bismuth concentrations. The authors suggest that the bismuth preparation used—colloidal bismuth subcitrate—is more soluble and absorbable at the higher gastric pH of patients on PPIs. All of these patients received short courses of therapy (2 weeks). Although the investigators did not attempt to follow neurobehavioral P.1272 or neuropsychiatric changes, none of the patients had clinically evident bismuth toxicity.35 Based on this investigation, coadministration of PPIs with longer courses of colloidal bismuth subcitrate should be avoided or only offered with extreme caution. Ranitidine, which is frequently prescribed with a bismuth compound for dyspepsia or ulcer disease, does not affect the pharmacokinetics of bismuth

absorption. 22 In the United States, where bismuth subsalicylate is the most common oral bismuth-containing compound, up to 90% of the salicylate is absorbed. 36 Salicylate toxicity has been reported and salicylate concentrations should be performed in both acute and chronic exposures. Methemoglobinemia from subnitrate salt of bismuth is uncommonly described.20

Summary The most likely manifestations of bismuth toxicity are either neuropsychiatric or renal, depending on the type of compound and whether the etiology is related to chronic therapy or acute overdose. The factors predisposing some individuals to neurotoxicity from therapeutic use of oral bismuth compounds are poorly understood. Thus patients using therapeutic bismuth with new movement disorders or alterations in mental status should be assessed

for

possible

bismuth-induced

encephalopathy.

References 1. Akpolat I, Kahraman H, Akpolat T, et al: Acute renal failure due to overdose of colloidal bismuth. Nephrol Dial Transplant 1996;11:1890–1898. 2. Barnett RN: Reactions to a bismuth compound. Toxic manifestations following the use of the bismuth salt of heptadienecarboxylic acid in suppositories. JAMA 1947;135:28–30. 3. Benet LZ: Safety and pharmacokinetics: Colloidal bismuth subcitrate. Scand J Gastroenterol 1991;25(Suppl 185):29–35.

4. Bennet JE, Wakefield JC, Lacey LF: Modeling trough plasma bismuth concentrations. J Pharmacokinet Biopharm 1997;25:79–106. 5. Bes A, Caussanel JP, Geraud G, et al: Encephalopathie toxique par les sels de bismuth. Rev Med Toulouse 1976;12:810–813. 6. Bierer DW: Bismuth subsalicylate: History chemistry, and safety. Rev Infect Dis 1990;12:S3–S8. 7. Boyette DP, Ahiskie NC: Bismuth nephrosis with anuria in an infant. J Pediatr 1946;28:493–497. 8. Bridgeman AM, Smith AC: Iatrogenic bismuth poisoning: Case report. Aust Dental J 1994;39:279–281. 9. Buge A, Supino-Viterbo V, Rancurel G, Pontes C: Epileptic phenomena in bismuth toxic encephalopathy. J Neurol Neurosurg Psychiatry 1981;44:62–67. 10. Burns R, Thomas DW, Barron VJ. Reversible encephalopathy possibly associated with bismuth ingestion. Br Med J 1974;1:220–223.

subgallate

11. Czerwinski AW, Ginn HE: Bismuth nephrotoxicity. Am J Med 1964;37:969–975. 12. Emile J, De Bray JM, Bernat M, et al: Osteoarticular complications in bismuth encephalopathy. Clin Toxicol 1981;18:1285–1290.

13. Goldenberg MM, Honkomp LJ, Davis CS: Antinauseant and antiemetic properties of bismuth subsalicylate in dogs and humans. J Pharmacol Sci 1976;65:1398–1400. 14. Gordon MF, Abrams RI, Rubin DB, et al: Bismuth subsalicylate toxicity as a cause of prolonged encephalopathy with myoclonus. Mov Disord 1995;10:220–222. 15. Gryboski JD, Gotoff SP: Bismuth nephrotoxicity. N Engl J Med 1961;265:1289–1291. 16. Hasking GJ, Duggan JM: Encephalopathy from bismuth subsalicylate. Med J Aust 1982;2:167. 17. Hudson M, Mowat NAG: Reversible toxicity in poisoning with colloidal bismuth subcitrate. BMJ 1989;299:159. 18. Hundal O, Bergseth M, Gharehnia B, et al: Absorption of bismuth from two bismuth compounds before and after healing of peptic ulcers. Hepatogastroenterology 1999;46:2882–2886. 19. Huwez F, Pall A, Lyons D, Stewart MJ: Acute renal failure after overdose of colloidal bismuth subcitrate. Lancet 1992;340:1298. 20. Jacobsen JB, Huttel MS: Methemoglobin after excessive intake of a subnitrate containing antacid. Ugeskr Laeger 1982;144:2340–2350. 21. Karelitz S, Freedman AD: Hepatitis and nephrosis due to soluble bismuth. Pediatrics 1951;8:772–777.

22. Koch KM, Kerr BM, Gooding AE, Davis IM: Pharmacokinetics of bismuth and ranitidine following multiple doses of ranitidine bismuth citrate. Br J Clin Pharmacol 1996:42:207–211. 23. Kruger G, Thomas DJ, Weinhardt F, Hoyer S: Disturbed oxidative metabolism in organic brain syndrome caused by bismuth in skin creams. Lancet 1976;1:485–487. 24. Lambert JR: compounds. Rev

Pharmacology of bismuth-containing Infect Dis 1991;13:S691–S695.

25. Liessens JL, Monstrey J, Vanden Eeckhout E, et al: Bismuth encephalopathy. Acta Neurol Belg 1978;78:301–309. 26. Martin-Bouyer G, Foulon G, Guerbois H, Barin C: Epidemiological study of encephalopathies following bismuth administration per os. Characteristics of intoxicated subjects: Comparison with a control group. Clin Toxicol 1981;18:1277–1283. 27. Martin-Bouyer G, Weller M: Neuropsychiatric symptoms following bismuth intoxication. Postgrad Med J 1988;64:308–310. 28. McClendon SJ: Toxic effects with anuria from a single injection of a bismuth preparation. Am J Dis Child 1941;61:339–341. 29. Mendelowitz PC, Hoffman RS, Weber S: Bismuth absorption and myoclonic encephalopathy during bismuth subsalicylate therapy. Ann Intern Med 1990;112:140–141.

30. Molina JA, Calandre L, Bermego F: Myoclonic encephalopathy due to bismuth salts: Treatment with dimercaprol and analysis of CSF transmitters. Acta Neurol Scand 1989;79:200–203. 31. Monseu G, Struelens M, Roland M: Bismuth encephalopathy. Acta Neurol Belg 1976;76:301–308. 32. Nwokolo CU, Pounder RE: D-Penicillamine does not increase urinary bismuth excretion in patients treated with tripotassium dicitratobismuthate. Br J Clin Pharmacol 1990;30:648–650. 33. O'Brien D: Anuria due to bismuth thioglycollate. Am J Dis Child 1959;97:384–386. 34. Pamphlett R, Stoltenberg M, Rungby J, Danscher G: Uptake of bismuth in motor neurons of mice after single oral doses of bismuth

compounds.

Neurotoxicol

Teratol

2000;22:559–563.

35. Phillips RH, Whitehead MW, Diog LA, et al: Is eradication of Helicobacter pylori with colloidal bismuth subcitrate quadruple therapy safe? Helicobacter 2001;6:151–156. 36. Pickering LK, Feldman S, Ericsson CD, Cleary TG: Absorption of salicylate and bismuth from a bismuth subsalicylate containing compound (Pepto-Bismol). J Pediatr 1981;99:654–656. 37. Pollet S, Albouz S, Le Saux F, et al: Bismuth intoxication: Bismuth level in pig brain lipids and in subcellular fractions. Toxicol Eur Res 1979;2:123–125.

38. Randall RE, Osheroff RJ, Bakerman S, Setter JG: Bismuth nephrotoxicity. Ann Intern Med 1972;77:481–482. 39. Rodilla V, Miles AT, Jenner W, Hawksworth GM: Exposure of human cultured proximal tubule cells to cadmium, mercury, zinc, and bismuth: Toxicity and metallothionein induction. Chem Biol Interact 1998;115:71–83. 40. Ross JF, Broadwell RD, Poston MR, Lawhorn GT: Highest brain bismuth levels and neuropathology are adjacent to fenestrated blood vessels in mouse brain after intraperitoneal dosing of bismuth subnitrate. Toxicol Appl Pharmacol 1994;124:191–200. P.1273 41. Sainsbury SJ: Fatal salicylate toxicity from bismuth subsalicylate. West J Med 1991;155:637–639. 42. Serfontein WJ, Mekel R: Bismuth toxicity in man II. Review of bismuth blood and urine levels in patients after administration of therapeutic bismuth formulations in relation to the problem of bismuth toxicity in man. Res Commun Chemical Pathol Pharmacol 1979;26: 391–411. 43. Serfontein WJ, Mekel R, Bank S, et al: Bismuth toxicity in man I: Bismuth blood and urine levels in patients after administration of a bismuth protein complex (Bicitropeptide). Res Commun Chem Pathol Pharmacol 1979;26:383–389. 44. Slikkerveer A, Jong HB, Helmich RB, de Wolff FA: Development of a therapeutic procedure for bismuth intoxication with chelating agents. J Lab Clin Med 1992;119:529–537.

45. Slikkerveer A, Noach LA, Tytgat GN, et al: Comparison of enhanced elimination of bismuth in humans after treatment with meso-2,3-dimercaptosuccinic acid and D,L-2,3dimercaptopropane-1-sulfonic acid. Analyst 1998;123:91–92. 46. Stevens PE, Bierer DW: Bismuth subsalicylate: History, chemistry, and safety. Rev Infect Dis 1990;12:S3–S8. 47. Stevens PE, Moore DF, House IM, et al: Significant elimination of bismuth by haemodialysis with a new heavy metal chelating agent. Nephrol Dial Transplant 1995;10:696–698. 48. Stoltenberg M, Schionning JD, Danscher G: Retrograde axonal transport of bismuth: An automettalographic study. Acta Neuropathol 2001; 101:123–128. 49. Suarez FL, Furne JK, Springfield J, Levitt MD: Bismuth subsalicylate markedly decreases hydrogen sulfide release in the human colon. Gastroenterology 1998;114:923–929. 50. Szymanska JA, Zelazowski AJ, Kawiorski S: Some aspects of bismuth metabolism. Clin Toxicol 1981;18:1291–1298. 51. Taylor EG, Klenerman P: Acute renal failure after bismuth subcitrate overdose. Lancet 1990;335:670–671. 52. Thompson HE, Steadman LT, Pommeranke WT: The transfer of bismuth into fetal circulation after maternal administration of sobisminol. Am J Syph 1941;25:725–730.

53. Tremaine WJ, Sandborn WJ, Wolff BG, et al: Bismuth carbomer foam enemas for chronic pouchitis: A randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther 1997;11:1041–1046. 54. Urizar R, Vernier RL: Bismuth nephropathy. JAMA 1966;198:207–209. 55. Walsh JH, Peterson WL: Drug therapy: The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med 1995;333:984–991. 56. Wilson APR: The dangers of BIPP. Lancet 1994;334:1313–1314. 57. Zala L, Hunziker T, Braathen LR: Pigmentation following long-term bismuth therapy for pneumatosis cystoides intestinalis. Dermatol 1993;187:288–289.

Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S. Title: Goldfrank's Toxicologic Emergencies, 8th Edition Copyright

©2006

McGraw-Hill

> Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > I - Metals > Chapter 87 Cadmium

Chapter

87

Cadmium Stephen J. Traub Robert S. Hoffman Cadmium

(Cd)

Atomic

number

=

48

Atomic

weight

=

112.40

Normal Whole Urine

concentrations blood

=

< 5µg/L(4 nmol/L)

=

Table of Contents > Part C - The Clinical Basis of Medical Toxicology > Section I - Case Studies > I - Metals > Chapter 89 Cobalt

Chapter

89

Cobalt Gar Ming Chan Cobalt (Co) Atomic

number

=

27

Atomic

weight

=

58.9

Normal

concentrations

Serum

=

0.1–1.2 µg/L

Urine

=

0.1–2.2 µg/L

A 13-month-old, 10-kg girl was brought to the emergency department (ED) for evaluation of lethargy and vomiting of 1 week's duration and decreased oral intake and urine output for 8 hours. She had a normal birth history, no significant past medical history, and was fully immunized. On presentation to the ED, her

vital signs were blood pressure, 98/53 mm Hg; pulse, 180 beats/min; respiratory rate, 60 breaths/min; temperature, 96.5°F (35.8°C); and oxygen saturation 98% on room air. Physical examination revealed dry mucous membranes, normal reactive pupils, a clear chest with intercostal retractions, decreased bowel sounds, mottled skin, an increased capillary refill time, and a depressed mental status with minimal withdrawal to pain. The patient was endotracheally intubated, resuscitated with 0.9% NaCl, and given ceftriaxone and ampicillin intravenously. Complete blood count revealed a white cell count of 12,000/mm3 , hemoglobin of 18.6 g/dL, an anion gap of 22 mEq/L, and a lactate concentration of 4 mmol/L. Analysis of the cerebral spinal fluid, including cell count and chemistry, was normal. The ED obtained cultures of the blood, urine, and cerebral spinal fluid (CSF) for testing. An electrocardiograph (ECG) showed a narrow complex tachycardia with low-voltage QRS complexes. Her chest radiograph revealed cardiomegaly and no infiltrates. An echocardiogram revealed a dilated cardiomyopathy with a moderate-size pericardial effusion. The patient was admitted to the pediatric intensive care unit. Over the next 24 hours, the parents were questioned regarding genetic counseling, malnutrition, and neglect. Eventually, the patient's 4-year-old brother admitted to feeding her, about 20 refrigerator magnets 1 week prior to presentation. An abdominal radiograph revealed 20 radiopaque densities scattered throughout the gastrointestinal (GI) tract, which on reevaluation were visible on the original chest radiograph. Whole-bowel irrigation (WBI) was initiated via a nasogastric tube with polyethylene glycol electrolyte solution at 150 mL/h and titrated up to 250 mL/h. WBI was tolerated well. After 6 hours of WBI, all 20 magnets [samarium cobalt (SmCo)] were retrieved from the effluent, and a repeat abdominal radiograph revealed no further magnets in the GI tract.

The child's clinical condition did not improve. While undergoing a 24-hour urine collection for cobalt, 1000 mg/m2 /d of CaNa2 EDTA (edetate calcium disodium) was administered by continuous intravenous infusion. Intravenous chelation with N-acetylcysteine (NAC) was also administered, using the standard 20-hour acetaminophen protocol (see Antidotes in Depth: NAcetylcysteine). Intravenous thiamine (25 mg/d) was also initiated. After 2 days of therapy, the patient's lethargy improved. Her leukocytosis, anion gap, and serum lactate concentration normalized. All of her cultures were sterile, and antibiotic therapy was discontinued. Additional laboratory results revealed hypothyroidism, evidenced by an elevated thyroid-stimulating hormone (TSH) concentration of 12 mIU/mL (normal: 1.7–9.1 mIU/L); a decreased total T4 of 4.7 µg/dL (normal: 7.8–16.5 µg/dL); increased erythropoiesis, evidenced by an increased reticulocytosis of 8.3% (normal: ≤7%); and an increased erythropoietin (EPO) concentration of 30 mIU/mL (normal: 1.0–21.0 mIU/mL). The patient was extubated on hospital day 3. Chelation therapy with CaNa2 EDTA and NAC were stopped on day 5, and initial urine cobalt level was reported as 1237 µg/L. Her repeat echocardiogram prior to discharge showed substantial resolution of both the cardiomegaly and the effusion. The patient was discharged on hospital day 7 after her family received thorough counseling on poison prevention. The patient's thyroid and hematologic abnormalities had resolved completely at 2-week followup.

History

and

Epidemiology

The name cobalt (Co) originates from “kobold,― the German word for “goblin,― and was given to the cobalt-containing ore, cobaltite (CoAsS), because it made exposed miners ill. Their

illness

was P.1288

most likely related to arsenic toxicity from the ore, rather than from the cobalt. Georg Brandt discovered cobalt in 1753, during an attempt to prove that an element other than bismuth gave glass a blue hue. The main industrial use of cobalt is the formation of hard, highspeed, high-temperature cutting tools. With an atomic number of 27 and a molecular weight of 58.93 daltons, Co is a light metal that has a melting point of 2723.1°F; (1495.1°C) and a boiling point of 5611.7°F (3099.9°C). These attributes make elemental cobalt a very useful industrial metal. When aluminum and nickel are blended with cobalt, an alloy (alnico) with magnetic properties is formed. Other uses for cobalt include electroplating, because of its resistance to oxidation, and as an artist's pigment because of its bright blue color. A Co3 + ion is at the center of cyanocobalamin (vitamin B12), which is synthesized only by microorganisms and is not found in plants. Common dietary sources include fish, eggs, chicken, pork and seafood; a diet deficient in cyanocobalamin results in pernicious anemia. Hydroxocobalamin, a Co3 +-containing precursor to cyanocobalamin, is a therapy for cyanide poisoning (see Antidotes in Depth: Hydroxocobalamin) . Medicinally, cobalt chloride was combined with iron salts and marketed in the 1950s as “Roncovite,― for the treatment of anemia. As recently as 1976, physicians still used cobalt in the treatment of anemias, thereby reducing transfusion requirements in spite of concomitant adverse effects. 34 The other common medical use of cobalt is as a radioactive isotope, cobalt-60 (60Co), in the radiotherapy of head and neck cancers, breast cancer, and some tissue sarcomas of the extremities. This form of radiotherapy has been largely replaced by linear accelerators in the Western world.

Historically, epidemics of cardiomyopathy and goiter termed “beer drinker's cardiomyopathy―10 and “cobalt-induced goiter―58 occurred between the 1960s and the 1970s. During this period, cobalt sulfate was added to beer as a foam stabilizer. In the 1970s, these epidemics were halted when the use of cobalt for this purely aesthetic purpose was discontinued. 91 Sources of cobalt include chemistry kits,63 weather indicators,63 antiquated anemia therapies,63 cement,70 fly ash,70 mineral wool,70 asbestos,70 molds for ceramic tiles,40 the production of Widia-steel (used in the wood industry),125 mining,64 porcelain paint,109 orthopedic implants,62 and dental hardware.5 The most clinically important source, however, arises through the formation of cemented tungsten carbide, a “hard metal.― In tungsten carbide factories, powdered cobalt and tungsten are combined by an intense sintering process that exposes the metals to hydrogen, heated to 1832°F (1000°C). The first published investigation of these factories reported a 10-fold increase in workspace cobalt concentrations, compared to atmospheric concentrations.37 These respiratory exposures have resulted in pulmonary toxicity, known as “hard-metal disease.― As a result of this report, occupational studies and preventive respiratory measures have greatly reduced the acceptable cobalt exposure level in the workplace.

Chemistry Like other metals, cobalt is available in elemental, inorganic, and organic forms. The clinical effects of each form are less-well defined than the effects of mercury or arsenic. Elemental cobalt (Co0 ) toxicity is reported by both inhalational138 and oral exposures.57,58 Inorganic cobalt salts most commonly occur in 1 of 2 oxidation states: cobaltous (Co2 +) or cobaltic (Co3 +). Inorganic cobalt salts, such as cobaltous chloride (CoCl2 ) and cobaltous sulfate (CoSO4 ), were historically used for the treatment of

anemias,11,47,53,108,147 and were associated with the “beer drinker's cardiomyopathy.―1,87,93 Organic cobalt exposure results from cyanocobalamin (vitamin B 12) ingestion, but because of its limited oral absorption and its rapid renal elimination, it is considered to be of low toxicity.105 Other organic forms of cobalt (eg. stearate) are toxic, following oral exposures in rodents.13 In comparison, the inorganic chloride, sulfate, and nitrate cobalt salts appear to have more acute toxicity in animal models, when compared to the organic forms, such as cobalt stearate.13

Toxicokinetics Based on animal studies, oral absorption of cobalt oxides, salts, and metals via the gastrointestinal tract is highly variable, with a reported bioavailability of 5–45%.71,81 In human studies, both iron deficiency and iron overload (hemochromatosis) enhance radiolabeled 57CoCl2 absorption in the small bowel.99 Inhaled cobalt oxide is approximately 30% bioavailable,81 but the volume of distribution and elimination half-life are not defined. Most (50–88%) absorbed cobalt (organic and inorganic) is eliminated renally, and the remainder is eliminated in the feces.123 Acutely, an increase in the inorganic cobalt burden will result in increased renal elimination.68 However, this initial increased elimination rapidly diminishes to a steady state, despite a large body burden.2,99 Thus, a significant percentage of elimination of a large cobalt exposure will be delayed. The characteristic elimination of cobalt correlates with the patterns of occupational exposure.138 For example, a worker with a standard workweek will have much higher urine cobalt levels on Friday morning when compared to Monday morning.138 However, Monday afternoon urine cobalt levels may be higher than Friday morning levels because of the rapid elimination that occurs

following an initial exposure.2,138 Based on these findings, the exposure over time must be considered when interpreting urinary cobalt concentrations.7

Pathophysiology Like most other metals, cobalt is a multiorgan toxin. CoSO4 inhibits several key enzyme systems and interferes with initiation of protein synthesis.8 Polynucleotide phosphorylase, an essential enzyme in RNA synthesis, requires Mg2 + to function normally. The enzyme functions at 50% that of normal in the presence of CoSO4 . 8 It is hypothesized that Co2 + is capable of displacing M g2 +, the normally required cofactor, from the enzyme cofactor site.8 CoCl2 increases the rate of glycolysis and at the same time decreases oxygen consumption,20 suggesting that cobalt may inhibit aerobic metabolism. In vitro studies demonstrate that divalent cations, Zn2 +, Cd2 +, Cu2 +, and Ni2 +, inhibit αketoglutarate dehydrogenase, a mitochondrial Krebs cycle enzyme (Chap. 13) .143 When compared to these divalent cations, Co2 +, is not as potent an inhibitor of this same enzyme.143 However, when NADH (the reduced form of nicotinamide adenine dinucleotide) is added to this in vitro model, Co2 + is capable of inhibiting up to 95–100% of the reaction.143 This model suggests that NADH abundance, such as in chronic ethanol use, may potentiate the inhibition of P.1289 α-ketoglutarate dehydrogenase.144 Cobalt may also complex with the reduced form of α-lipoic acid, thereby interfering with the Krebs cycle.145 Moreover, cobalt salts are capable of inhibiting dihydrolipoic acid by complexing with its sulfhydryl groups.23,143 These reactions result in the inability to convert both pyruvate into acetylcoenzyme A (acetyl-CoA) and α-ketoglutarate into succinylcoenzyme A (succinyl-CoA). These two enzymes are

integral in the efficient transition from anaerobic glycolysis to the Krebs cycle and for the Krebs cycle to produce reducing equivalents (Chap. 13 and Antidotes in Depth: Thiamine Hydrochloride). These toxic effects may help explain why the combination of chronic ethanol use and cobalt exposure results in cardiomyopathy (see “Beer Drinker's Cardiomyopathy below).143 In addition to enzyme inhibition, oxidant-mediated toxicity is supported by in vivo and in vitro studies of CoCl2 -induced pulmonary toxicity (see Chronic Exposure, Pulmonary below).97 Xenobiotics implicated in free radical-mediated pulmonary injury are capable of accepting an electron from a reductant and subsequently transferring the electron to oxygen, forming a superoxide free radical (Chap. 12). Cobalt is then capable of accepting another electron, which starts the cycle over again, a process known as redox cycling. This will result in an accumulation of free radicals in the lung as a result of the abundance of oxygen ready to receive electrons and result in injury (Chap. 12) . Cobalt chloride inhibits tyrosine iodinase (Chap. 49) .74 This enzyme is responsible for combining iodine (I2 ) with tyrosine to form monoiodotyrosine and serves as the first step in the synthesis of thyroid hormone. Inhibition of tyrosine iodinase results in a decrease in T3 and T4 , which may result in clinical hypothyroidism and goiter (see Clinical Effects, Endocrine below). Multiple animal models demonstrate that CoCl2 administration results in reticulocytosis, polycythemia, and erythropoesis.43,72,90,100,101,147 These events occur in both the bone marrow and extramedullary locations.11,45 Although the pathogenesis of these events remains largely unknown,23 one theory is that cobalt binds to iron-binding sites such as transferrin,65 resulting in impaired oxygen transport to renal cells, which, in turn, induces erythropoietin production. In an animal model of anemia, a greater degree of gastrointestinal iron uptake

occurs in cobalt-treated rats compared to rats with either hypoxia or nephrectomy.45 A similar study in mice suggested that the rise in iron uptake exceeded that following exogenous erythropoietin.3 Cobalt chloride inhibits neuromuscular transmission by competing with Ca2 +, another divalent ion. Cobalt ion is 20 times more potent than magnesium with regard to its ability to compete with calcium for a site on the motor nerve terminal.142 This may be the manner by which some of the neurological symptoms occur.

Clinical

Effects

and

Toxicity

The single, acute, minimal toxic dose of cobalt compounds is not well defined. In fact, varying effects have occurred at variable doses in different patients. Patients with “beer drinker's cardiomyopathy― received an average daily dose of 6–8 mg of CoSO4 (over weeks to months) and developed life-threatening illness,69,93 whereas infants being treated for anemia who received much higher daily cobalt doses of an iron-cobalt preparation (40 mg of CoCl2 and 75 mg of FeSO4 ) for 3 months did not develop similar toxic effects of acidemia, cardiomyopathy, or shock.114 The inconsistency of these findings suggests that multiple factors are responsible for the development of the clinical manifestations; in this case, the role of ethanol metabolism may be an important variable. Death also has been reported after acute cobalt exposure.63 Organ systems affected by acute cobalt poisoning are endocrine,57 gastrointestinal,34,47 hematologic,43,72,90,147 cardiovascular,58 metabolic,58 and the central47,122 and peripheral nervous systems.122 Chronic inhalational exposures affect the pulmonary16,21,37,76,77,111,130 and dermatologic systems.41,117,146 Radioactive 60Co used for radiation therapy is associated with radiation burns (Chap. 128). Unlike acute toxicity, chronic cobalt exposure is not associated with an increased mortality rate; a cohort study evaluating more than 1100 persons with pulmonary

exposures to cobalt salts and oxides over a 30-year period was unable to show an increased mortality rate.95

Clinical Acute

Manifestations Exposure

Cardiovascular “Beer

Drinker's

Cardiomyopathy.―

In 1966, a Veterans Affairs (VA) Hospital in Nebraska cared for 28 males with a history of beer drinking who presented with tachycardia, dyspnea, and lactic acidosis but without any finding of congestive heart failure.87 The mortality rate for these cases was 38% and occurred rapidly, within 72 hours of presentation, as a consequence of severe acute failure.87 The survivors were care and thiamine therapy.87 immediately to therapy and a

metabolic acidosis and cardiac successfully treated with supportive Of the survivors, most responded lack of response was found to be

secondary to complications; most commonly, symptomatic pericardial effusions or embolic events.87 Epidemiologic evaluation revealed that these men commonly drank large quantities of beer. Ultimately, 64 cases and 30 fatalities were reported from Nebraska.137 Autopsies were performed in 26 of the decedents. Common postmortem cardiac findings were dilated cardiomyopathy and cellular degeneration with vacuolization and edema and a lack of inflammation and fibrosis.87 When cobalt was later implicated in the pathogenesis of these deaths, preserved cardiac tissue of 8 decedents revealed cobalt concentrations 10 times greater than that of controls.137 Within a year of the Nebraska cases, similar reports began to emerge from Quebec.93 Forty-eight beer drinkers (only 2 of whom

were women) developed unexplained cardiomyopathy with a mortality rate of 46%.93 The only common association among all of these patients was the consumption of brand “XXX― beer.93 The producers of this beer had factories in Quebec City and Montreal. The only difference between the two breweries was that the one in Quebec added 10 times the amount of CoSO4 to the beer as a foam stabilizer.91 Clinical findings in these cases included tachycardia, tachypnea, polycythemia, and low-voltage ECGs.92 Reports began to appear 1 month after the Quebec City produced beer with the excessive cobalt was released on the market and no new patients were reported in Quebec after its beer with the excessive cobalt concentration was removed from the market.91 In 1972, 20 additional cases occurred in Minneapolis with similar findings of tachycardia, dyspnea, pericardial effusion, polycythemia, and lactic acidosis, and a mortality rate of 18% acutely, and 43% over a 3-year period.1 Thus, several outbreaks have been recorded in beer drinkers with cardiomyopathy, metabolic acidosis, and a high mortality, all of which have been associated with the addition of CoSO4 to the beer. P.1290 Because the clinical findings resemble the cardiomyopathy associated with chronic alcoholism39 and infantile malnutrition,106 a debate persists as to whether cobalt is the sole cause of this syndrome. The chronic alcoholism and infantile malnutrition cardiomyopathies are caused by poor protein intake and vitamin deficiency and both have histologic findings similar to those of cobalt cardiomyopathy. For example, myocardial biopsy of dogs with cobalt-induced cardiac failure revealed diffuse cytosolic vacuolization, loss of cross-striations, and interstitial edema,120 all of which are similar to findings of malnutrition.39,106 However, some other findings may be specific to cobalt-associated cardiomyopathy. For example, a small retrospective analysis revealed myocyte atrophy and myofibril loss to be present in

people with cobalt-associated cardiomyopathy significantly more often than in those with idiopathic dilated cardiomyopathy.14 Some animal models of cobalt cardiomyopathy were only able to reproduce pathologic and ECG findings if cobalt was combined with ethanol,139 while others required protein deficiency.115 Contrary to these studies, several rodent and canine models of cobalt poisoning and nutritional supplementation have demonstrated cardiac lesions,51,119,120 cardiac failure,54,119,120 and ECG abnormalities.52,119 Despite the implication that cobalt-induced cardiomyopathy requires malnutrition or alcoholism, a case of cardiac toxicity following acute cobalt poisoning has been reported.57,58 However, it is difficult to identify other cases reported outside of the aforementioned small epidemics in beer drinkers. In a controlled study of occupationally exposed subjects evaluated with echocardiograms, significantly more cobalt-exposed workers had diastolic dysfunction when compared to controls.79 However, none of these subjects under study developed congestive heart failure.79 There are rare reports of cardiomyopathy in chronically exposed workers,9,19,67 which suggests that the cardiomyopathy reported in the “beer drinkers― cohort is multifactorial and not solely caused by cobalt. Another source of doubt regarding of the role of cobalt in the development of cardiomyopathy is the relatively low dose of cobalt needed to induce heart failure in these patients.69 In patients receiving 20–75 mg/d of CoCl2 for various red cell dysplasias, there were no reports of heart failure, 69 whereas the “beer drinker's cardiomyopathy― group reportedly consumed only 6–8 mg of CoSO4 from drinking 24 pints of cobalt-containing beer.69,91 All patients who developed cardiomyopathies were malnourished, which supports the theory that a multifactorial nutritional deficiency in the presence of excessive cobalt may be necessary for the development of cardiomyopathy.69

Endocrine Both acute and chronic cobalt exposures are associated with thyroid hyperplasia and goiter. A series of patients with severe sickle cell anemia treated with cobalt therapy also developed goiter with varying degrees of thyroid dysfunction, 53,73 including clinical hypothyroidism.74 In one patient, the goiter was so severe that airway obstruction developed.73 More recent occupational data suggest that inhalational exposure to cobalt metals, salts, and oxides may result in abnormalities in thyroid function studies.138 When 82 workers in a cobalt refinery were compared to sex- and age-matched controls, exposed workers had significantly lower T3 levels.138 Within the previously mentioned beer drinker's cardiomyopathy cohort, 11 of 14 decedents had abnormal thyroid histology.116 Among them, the most common findings were follicular cell abnormalities and colloid depletion, which were not present on thyroid analysis from 11 randomly selected autopsies that served as controls.116

Hem atologic Anemias of the newborn, 17,66,108

erythrocyte

hypoplasia,124 red

cell aplasia,141 renal failure,47 and chronic infection113 have all been successfully treated with cobalt salts. Patients undergoing CoCl2 therapy for these diseases had increased hemoglobin,47,108 hematocrit,47,108 and red cells,47 but the benefits did not persist after cessation of therapy.47,108 In a published series, Peruvian cobalt miners working in an open pit at 4300 m (2.7 miles) elevation developed clinical effects, including headache, dizziness, weakness, mental fatigue, dyspnea, insomnia, tinnitus, anorexia, cyanosis, polycythemia, and conjunctival hyperemia, consistent with acute mountain sickness.64 When the study group was compared to age-, height-,

and weight-matched high-altitude controls, the study group was noted to have higher chronic mountain sickness scores.64 The only difference detected was elevated serum cobalt levels in the study group.64 In addition to effects on red cells, recent work demonstrates transient hemolysis, methemoglobinemia, and methemoglobinuria from subcutaneous CoCl2 exposure in mice.59 These findings may explain reports of dark urine following cobalt exposure in other animal models.49,132 Human cases have not been reported.

Other Gastrointestinal distress following the ingestion of “therapeutic― doses of cobalt salts,122 as well as of elemental cobalt, has been reported.63 Decreased proprioception, impaired cranial nerve VIII function, and nonspecific peripheral nerve findings are reported with acute oral CoCl2

Chronic

exposures.122

Exposure

Pulmonary Two pulmonary diseases are associated with cobalt exposure: asthma and “hard-metal disease.― Occupational asthma is reported in hard-metal workers with a prevalence of 2–5%16,76,77 at exposure levels as low as 50 µg/m3 . 77 As is the case with most causes of occupational asthma, cobalthypersensitivity-induced asthma is most likely immune-mediated rather than toxicologic.18,76,130 Most hard-metal workers are exposed to other metals, such as tungsten (W) and nickel (Ni), in addition to Co, and these other metals may account for some cases of occupational asthma that are attributed to cobalt.128,129 However, in a small but well-performed study of patients with cobalt-associated asthma, intradermal CoCl2 resulted in a positive

wheal response in all subjects, and 50% of patients had a positive radioallergosorbent test (RAST) score, which correlated to the wheal size.127 Cobalt-associated pulmonary toxicity was first noted in tungstencarbide workers,37,55 and was subsequently referred to as “hard-metal disease.― Exposures result from the process by which tungsten-carbide is sintered with cobalt. Signs and symptoms of hard-metal disease include upper respiratory tract irritation, exertional dyspnea, severe dry cough, wheezing, and interstitial lung disease ranging from alveolitis to progressive fibrosis. The prevalence of hard-metal disease is largely unknown. In one study, 11 of 290 (3.8%) exposed workers were diagnosed with interstitial infiltrates on chest radiographs, but only 2 (0.7%) had a decreased predicted total lung capacity.133 Certain individuals who are exposed to large doses of hard-metal for prolonged periods never develop disease, which suggests that a susceptible population exists. A glutamate substitution for lysine in position 69 of the β unit HLA-DP has a strong association with hard-metal disease, similar to the situation with chronic beryllium disease.107 Clinically, hard-metal disease is difficult to distinguish from berylliosis, although an occupational history should be helpful. P.1291 Common findings of hard-metal disease on histopathology are multinucleated giant cells and interstitial pneumonitis with bronchiolitis.6 Elevated levels of cobalt in lung tissue can be detected,112,131 even as long as 4 years after exposure.112 Bronchoalveolar lavage commonly reveals multinucleated giant cells, type II alveolar cells, and alveolar macrophages in patients with interstitial lung disease.21 The finding of multinucleated giant cells from bronchoalveolar lavage washing is characteristic of hard-metal disease.18,24,25,88,140 A cross-sectional study of more than 1000 tungsten-

carbide–exposed workers found an increased odds ratio [OR] of 2:1 for having a work-related wheeze when exposed to greater than 50 µg/m3 of Co.134 In the same study, workers with exposures recorded at greater than 100 µg/m3 had higher OR (5.0) of having a chest radiograph profusion score of ≥1/0.134 This profusion score, established by The International Labor Organization (ILO) and most recently updated in 2000, is a grading system for pneumoconioses. When used to grade radiographs of asbestosis, this score correlates strongly with mortality risk,86 reduced diffusing capacity, and decreased ventilatory capacity.56,96 A score of 0/1 is suggestive but not diagnostic (“negative―), and a score of 1/0 is presumptively diagnostic but not unequivocal (“positive―).26 Additional studies have similarly concluded that pulmonary disease occurs when individuals are exposed to doses of cobalt that approach 100 µg/m3 . 75 Thus, the current threshold limit value (TLV) is 500µg/m3 ) and unexposed workers with any objectively measured pulmonary tests.138 Neither group had any abnormality in chest radiography that would suggest pulmonary fibrosis.138 The only significant pulmonary differences detected were a higher reported rate of dyspnea, both on exertion and at rest, and the presence of wheezing in the exposed group.138 These authors concluded that cobalt contributes to the development of pulmonary disease but is not independently responsible for the development of pulmonary fibrosis.138 Despite the progressive and debilitating nature of hard-metal disease, most signs and symptoms improve with cessation of exposure.85,89,148 Moreover, the length and dose of exposure do not appear to correlate with the presence or severity of illness, suggesting that individual susceptibility is the most important risk factor for illness.85,118

Renal A single report associates reversible renal tubular necrosis with the chronic administration of CoCl2 as treatment for anemia.122 Some animal models of cobalt cardiomyopathy demonstrate cellular changes in renal tissue.50 However, when 26 cobaltexposed hard-metal workers were evaluated for urinary albumin, retinol-binding protein (RBP), β2 -microglobulin, and tubular brush border antigens, no detectable difference could be found between the study group and controls.44 Based on these few reports, it appears that acute and chronic exposure to cobalt has little effect on the kidneys.

Dermatologic In a study of 1782 construction workers, 23.6% developed dermatitis and 11.2% developed oil acne while using cobaltcontaining cement, fly ash, or asbestos.70 As in hard-metal

disease, it is difficult to isolate cobalt as the sole contributor to the development of dermatitis. Nickel, the classic toxicant causing dermatitis, is commonly found in some of these preparations and may be implicated in the development of cutaneous sensitivity.41,117

Reproductive A pregnant woman with hard-metal disease was able to bring her fetus to term and deliver without complication. 110 In pregnant rats, CoCl2 exposure results neither in teratogenicity nor fetotoxicity.103 Only doses that are toxic to the mother result in fetal toxicity.33 In mice, chronic exposure to cobalt results in impaired spermatogenesis and decreased fertility, without affecting follicular-stimulating hormone (FSH) or leuteinizing hormone

(LH),

whereas acute exposures did not demonstrate similar reproductive effects.104 Additional murine studies discuss the possible interactions between cobalt with iron and zinc, which are both essential elements for spermatogenesis.4 Despite these findings, there are no reported human cases that associate cobalt exposure with teratogenicity or impaired fertility.

Carcinogenesis Based solely on animal experiments leading to the development of soft-tissue sarcomas following the injection of CoCl2 into soft tissue, the International Agency for Research on Cancer (IARC) considers cobalt and cobalt-containing compounds possibly carcinogenic to humans.12,22,35,135 There are case reports and cohort studies that suggest that pulmonary exposure to Co2 + increases the risk for lung cancer. However, these studies were unable to control for other known carcinogens such as arsenic.22 The largest cohort study to date followed more than 1100 workers for more than 38 years and found no increase in the prevalence of

lung

cancer.94

Diagnostic

Testing

Body fluid cobalt concentrations are not readily available and therefore cannot be used to direct emergent clinical care. Some adjunctive testing that might support a clinical diagnosis of cobalt toxicity includes complete blood count (CBC), reticulocyte count, EPO concentration, and TSH concentration. The results of these tests might reflect the level of exposure or potential toxicity discussed above.

Cardiac

Studies

Electrocardiogram, echocardiogram, and radionuclide angiocardiography with 99Tc are useful screening tests for detecting abnormalities associated with cobalt cardiomyopathy and/or pulmonary hypertension caused by hard-metal disease. 19 It is important to remember that these cardiac tests are neither specific for, nor diagnostic of, cobalt-induced cardiomyopathy. Biopsy of myocardial P.1292 tissue may show multinucleated giant cells, but testing of this nature may be impractical.

Pulmonary

Testing

Patients with hard-metal lung disease may demonstrate bilateral upper lobe interstitial lung disease on chest radiograph. However, patients may have signs and symptoms of disease without specific radiographic findings.110 Pulmonary function testing in occupationally exposed workers may show decreased vital capacity110 and a decrease in transfer factor for carbon monoxide (TLCO), both of which might be useful in identifying patients at risk for developing pulmonary fibrosis.136 Some authors suggest

an inversion of the CD4/CD8 ratio in bronchoalveolar lavage washings as a useful tool for diagnosis and evaluation of progression of illness and that normalization is a marker for improvement.111 Despite these available tests, a definitive diagnosis of hard-metal disease requires a tissue sample with findings of multinucleated giant cells in the setting of interstitial pulmonary fibrosis.

Cobalt

Testing

Cobalt is primarily eliminated in the urine, and to a lesser extent in the feces, making urine cobalt evaluation most appropriate.81 The difficulty lies in the interpretation of the result. Cobalt is detectable in the urine after inhalational exposure and reflects elimination kinetics that are rapid during an initial exposure, but which slow after prolonged exposure.81,121 Because of this variable elimination pattern, it is difficult to interpret both urine and blood concentrations unless the dose and length of exposure are precisely known. Furthermore, the defined patterns may be applicable only to shift workers using soluble forms of cobalt.81 Further complicating the interpretation of urinary cobalt levels is the abundance of organic cobalt in the form of vitamin B12. A detailed vitamin supplementation history is required prior to the interpretation of a urine or blood cobalt level, as a diet regimen high in vitamin B12 might increase urine cobalt concentrations. For this reason, speciation of cobalt has been investigated. The ratio of inorganic to organic cobalt is higher in occupationally exposed workers (2.3) when compared to controls (1.01), independent of the wide variations of urinary cobalt concentrations.46 This is a promising area of study for the evaluation of a cobalt-exposed worker. Toxic concentrations of cobalt in serum and urine are poorly defined. Published literature on “normal concentrations― is fraught with variability that may reflect differences in the

population under study and the techniques used for measurement. Normal serum concentrations of cobalt are frequently reported as 0.1–1.2 µg/L.2,10,57,58,61,126 In comparison, a single, acutely poisoned patient had a reported serum concentration of 41 µg/L.57 Normal reference urine cobalt concentrations are between 0.1 and 2.2 µg/L.2,10,57,58,61,102,126 In contrast, patient with an acute elemental cobalt ingestion had a concentration of 1700 µg/L on a spot urinalysis several days after the exposure.58 Patients with chronic exposures should be evaluated differently as discussed above (see Toxicokinetics). Exposed workers, without clinical disease, have reported spot urine concentrations that range from 10 µg/L to several hundred µg/L.60

Treatment Acute

Management

Patients with acute cobalt poisoning require aggressive therapy. It is reasonable to conclude that the same decontamination principles used for other metals apply to cobalt. There have been no studies to date examining the benefit of gastric emptying, activated charcoal, or whole-bowel irrigation (WBI). An attempt at WBI for radiopaque solid forms of cobalt should be made prior to endoscopic or surgical removal. Regardless of the decontamination procedure used, chelation therapy should