2008 Kaplan USMLE Step 1 Home Study Program-Brand New Volume III: Organ Systems Book 1

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2008 Kaplan USMLE Step 1 Home Study Program-Brand New Volume III: Organ Systems Book 1

Contents I: Cardiovascular Section System Chapterl.Embryology. C h a p t e rH2i.s t o l o g y .....5 .......13 Chapter

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Contents I: Cardiovascular Section System Chapterl.Embryology. C h a p t e rH2i.s t o l o g y

.....5 .......13

Chapter5.Anatomy....

....19

Chapter4.Physiology,.

.,..51

C h a p t e rP5a. t h o l o g y . . .

....87

Chapter 6. Pharmacology

. .123

Section ll: Respiratory System C h a p t e rEl .m b r y o l o g y C h a p t e rHZi.s t o l o g y C h a p t e rASn.a t o m y . . . .

....141 ......143 ...147

C h a p t e rP4h. y s i o l o g y

.....157

C h a p t e rP5a. t h o l o g y . .

....185

6. Pharmacology Chapter

. . .217

lll: Rena/Urinary Section System l. Embryology . Chapter C h a p t e rH 2 i.s t o l o g y

...227 ......231

iliiitical

vii

Chapter5.Anatomy

......239

Chapter4.Physiology..

...241

Chapter 5. Pathology ...

. . .257

Chapter 6. Pharmacology

. . 281

Section lV:Hematologi{Lymphoreticular System C h a p t le. rH i s t o l o g y

......289

Chapter 2.Anatomy

. . . . . .297

ChapterS.Physiology..

...299

C h a p t e rP4a. t h o l o g y . . .

...303

Chapter 5. Pharmacology

. .327

Section V:Nervous System Chapterl.Embryology. Chapter2. Histology: NerveTissue

.....339

Chapter 5.Histology: Sensory Organs

. .345

Chapter4. Neuroanatomy: lntroduction ,..

...355

Chapter 5.Divisions oftheNervous Sy$em

. . . 559

Chapter 6.Meninges, Ventricular System, andCerebrospinal Fluid 7.Cross Chapter Anatomy oftheSpinal Cord.

viii

ilitstical

...335

. . . . . 561 . . . . . .367

Chapter 8.Spinal Regulation ofSkeletal Muscle Activity Cord

, , . .375

Chapter 9.Functional Anatomy andLesions oftheSpinal Cord.

. .379

Chapter 10.TheAutonomic Nervous Sy$em

. . 389

Chapter ll. ThePeripheral Nervous System

. . .395

B r a iSnt e m C h a p t le2r. T h e

.....401

i ael r v e s C h a p t lesr. C r a n N

......413

Nerves andCranial oftheBrain Stem 14.Lesions Chapter

. .431

Formation 15.Reticular Chapter

. .435

16.TheVestibular System Chapter 17.TheAuditory System Chapter

. . . . .439 . .443

Cerebellum C h a p t le8r. T h e

.....447

19.TheVisual System Chapter

. . .453

Chapter20.TheDiencephalon..

......459

21.TheThalamus Chapter

. . 461

22.TheHypothalamus Chapter

. . 465

.. andSubthalamus 25.TheEpithalamus Chapter

. . .471

24.TheLimbic System Chapter

. . .473

25.TheMotorSystem Chapter

. . .479

.. Hemispheres Anatomy oftheCerebral 25.Cross Chapter

. . . . .483

Cortex 27.TheCerebral Chapter

. .491

to theBrain 28.BloodSupply Chapter

. . 501

Chapter2g.Physiology.

...507

C h a p t e r 5P0a. t h o l o g y . .

...555

. . . 585 Nervous System theAutonomic Drugs Affecting 51.Pharmacology: Chapter Nervous System. . . . . 607 Affecting theCentral Drugs Chapter 52.Pharmacology: Drugs Psychoactive 53.Pharmacology: Chapter lndex

. . . . .643 ....653

ifitshical

ix

I SECTION

System Cardlovascular

Embryology Cardiovascular Allof these andlymphatic vessels. Thecardiovascular system consists of theheart, bloodvessels, isoutlined inthischapter. arederived frommesoderm;their development structures

PRIMITIVE VASCULAR SYSTEM A. Blood islands. During the third week of development, mesenchymal cells associatedwith the yolk sac,chorion, and connecting stalk form clusters called blood islands, which acquire lumina and fuse to form endothelium-lined capillary plexuses.Peripheral cells of the islands become angioblasts that give rise to the endothelial cells of the vessels,whereas centrally located cells become embryonic hemoblasts that give rise to primitive blood cells. 1. Certain capillaries enlargeto form the major blood vessels:vitellinevessels are formed in the yolk sacwall and umbilical vesselsare formed in the vascular chorion. 2. Extraembryonic blood vessels join with intraembryonic blood vesselsformed from splanchnic mesoderm and the primitive vascular systemis established. B. Hematopoiesis first occurs within the islands of the yolk sac.Later, blood cells are formed in the liver (1-7 months), spleen and lymphatic organs (2-4 months), and bone marrow (after 4 months).

Cardiovascular System

PRIMITIVE HEART TUBE FORMATION The pericardial cavity of the coelom lies cephalic to the buccopharyngeal membrane and neural plate in the embryonic disk Mesenchymeclusters in this region form a pair of endothelium-lined heart tubes on either side of the midline. With transversefolding of the embryonic disk, thesetubes fuse to form the single median primitive heart tube. A. Rotation. Cephalocaudal folding of the embryonic disk causesthe pericardial cavity and heart tube to rotate 180' along a transverseaxis and become located ventral to the foregut and caudal to the buccopharyngealmembrane. 1. The heart tube bulges into the pericardial cavity and becomestransiently suspendedfrom its dorsal wall by the dorsal mesocardium. 2.1\e mesoderm adjacent to the heart tube thickens to form the epimyocardial mantle; mantle cells differentiate into muscle cells of the myocardium and mesothelial cells of the epicardium. B. Early differentiation. The cephalic,or arterial, end of the heart tube is continuous with the aortic sac,while the caudal, or venous,end receivesthe vitelline veins from the yolk sac,the umbilical veins from the placenta,and the common cardinal veins from the body wall. The heart tube expands and differentiates to form, in a cephalocaudal direction, the bulbus cordis, primitive ventricle, primitive atrium, and sinus yenosus. 1. The aortic arches connect the truncus to the paired dorsal aortae, which arise from the aortic sacand lie dorsolateral to the foregut. 2. The distal portion of the bulbus, the truncus arteriosus, becomesthe proximal part of the aorta and pulmonary artery. 3. The sinus venosus eventually forms a major part of the wall of the right atrium and the coronary sinus. C. Loop formation. Becausethe bulbus cordis and the ventricular parts of the heart grow more rapidly than the pericardial caviry elongation of the heart tube is accomplishedby the formation of a dorsoventral cardiac loop, which has its convexity directed anteriorly and to the right. 1. In the resulting S-shapedheart, the expanding atrium lies cranial to the ventricle and bulbus cordis, on either side of the truncus arteriosus, and the passagebetween the atrium and ventricle narrows to form the atrioventricular canal. 2. Thesechangesin position are accompaniedby a caudal migration of the pericardium and heart tube from the level of the third and fourth somites to the level of the seventeenthto the rwentiethsomites(FigureI-1-1).

Embryology

Aorticsac ' Truncusarteriosus -----l. r'r r

I"

-' ' ,

l,

"l

Ventricle

Sinusvenosus

Homsof sinusvenosus

Umbilicalvein

Commoncardinalvein ( r. o-

Vitellinevein (1.o.,

.-

1't"

Aorticsac n,

',

.:

.p...

,

,\ i.

I I

Ventricle

;.i

I

Sinusvenosus

c

Hornsof sinusvenosus Aorticsac

Rightatrium

D

Leftatrium

Ventricle

Figure l-1-1.Bending of the endocardial heart tube in the pericardium.

SEPTUM FORMATION A. Primitive atrium 1. At the end of the fourth week, the septum primum grows from the roof of the primitive atrium towards two mesenchymal cushions, the endocardial (atrioventricular; AV) cushions, which appear in the ventral and dorsal walls of the AV canal. a. The transient opening between the septum primum and endocardial cushions is known as the interatrial foramen primum. b. The endocardial cushions gradually extend along the edge of the primum, thereby obliterating the foramen primum.

-a

o, 38

r\ "'

It

"

System Cardiovascular

c. Prior to its closure,the central portion of the septum primum perforatesto form the interatrial foramen secundum, which insures free blood flow from the right to left primitive atrium. 2. As the sinus venosusbecomesincorporated into the right atrium, the septum secundum grows from the ventral cranial wall of the atrium towards the endocardial cushions. a. The lower edgeof the septum secundumenclosesthe foramen secundum in the septum primum but does not extend firlly towards the endocardialcushions.The opening it leavesbetween the right and left primitive atria is known as the foramen ovale. b. The upper part of the septum primum disappears,but the lower part becomesthe valve of the foramen ovale, which allows blood from the vena cava to pass from the right to left atrium. B. Primitive ventricles

^,-{ rj

-,r1. .,.r r

1. The ventricle beginsto dilate by the end of the fourth week. 2. The expanding walls of the apposing ventricles approach each other medially and fu1e to form the muscular interventricular septum. 3. The interventricular foramen, which lies between the muscular interventricular septum and the endocardialcushionsand permits communication betweenthe two ventricles,is eventually closedby the membranous interventricular septum. C. Ttuncus arteriosus. During the fifth week, the right superior and left inferior bulbar ridges appearin the cephalicportion of ttre truncus arteriosus. 1. The right superiorbulbar ridge grows distally to the left, and the left inferior bulbar ridge grows distally to the right. 2. The bulbar ridges twist around each other and fuse to form the aorticopulmonary septum, which divides the truncus arteriosusinto aortic and pulmonary passages.

VALVES OFCARDIAC FORMATION A. Aortic and pulmonic valves 1. The semilunar valves of the aorta and pulmonary arteries develop following the formation of the aorticopulmonary septum. 2. Three swellingsof endothelium-coveredloose connectivetissue form at the orifices of both the aorta and pulmonary artery. These swellingsbecome hollowed at their uPper surfacesto form semilunar valves. B. Atrioventricular (AV) valves 1. The AVvalves form after the endocardialcushionsfuse. 2. Each atrioventricular orifice becomessurrounded by endocardium-coveredconnective tissueswellings,which hollow on their ventricular surfacesto form valves. a. Two valve leaflets, the bicuspid (mitral) valve, are formed in the left atrioventricular canal. b. Three valve leaflets, the tricuspid valve,are formed in the right atrioventricular canal. 3. The valvesremain connectedto papillary musclesin the wall of the ventricle by meansof chordae tendinae.

6

Embryology

ARTERIAT SYSTEM A. Formation of the aortic arch arteries 1. The aortic arch arteriesarise during the fourth week from the aortic sac,the most distal part of the truncus arteriosus. 2. Eachof the six pairs of arteriesis embeddedin the mesenchymeof its correspondingpharyngeal arch and terminatesin the paired dorsal aortae. 3. The dorsal aortae fuse by the fifth week to form the descendingthoracic aorta and the abdominal aorta with branchesto the embryo, yolk sac (vitelline arteries),and allantois (umbilical arteries).

Flashbackto GeneralPrinciples Nowmaybea goodtimeto review thepharyngeal arches andtheirderivatives inthe lastEmbryology chapter of Book2 Ceneral Principles ftolumell). a o(" ( o SAnode atrialmuscle AVnode+ Hisbundle and bundle branches + Purkinje fibers + ventricular muscle

B. Electrophysiologic categories of cardiac cells 1. Cardiac cellscan be divided into two electrophysiologiccategories: a. Fast fibers: atrial and ventricular muscle cells,Purkinje cellsof the His-Purkinje system b. Slow fibers: SA node, AV node 2. Fast fiber versus slow fiber terminology is based primarily on the velocity at which the electricalimpulse is conducted. C. Basic cellular electrophysiology 1. The phospholipid bilayer of the myocardial cell membrane, particularly its hydrophobic core' servesasan insulator that allows the cell to maintain a potential differencebetweenits interior and its exterior. This potential differenceis generatedby:

t2

Physiology

a. Net movement of ions (i.e., electrical current) across the cell membrane through transmembrane protein "openings" in the phospholipid bilayer, called channels. Channelsare usually selectivefor a specific ion (Na*, K*, Ca2*,or Cl-) and are controlled by protein gates,whose conformation (open or closed) may depend on the potential difference acrossthe cell membrane. b. Exchange of ions along their concentration gradients via protein transmembrane transport systems c. Active transport of ions against their electrochemical energy gradients by special transmembranepumps, which may be electrogenic(i.e., effect net chargemovement acrossthe membrane) 2. Adjacent myocardial cells are connectedend-to-end by a thickened portion of the cell membrane, called the intercalated disk. The nexus, or gap junction, is a region in the intercalated disk that provides a low-resistanceelectrical connection and allows movement of ions betweenadjacentcells. D. Resting membrane potential (RMP). The RMP is -90 mV in fast fibers (atrial and ventricular musclecells,Purkinje cells)and {0 to-7O mV in slowfibers (SA node,AV node), with the inside of the cell being negativewith respectto the outside. 1. Two characteristicsof resting cardiaccellsare important for establishingthe RMP: a. Differences in composition between the extracellular fluid (ECF; often abbreviated as o = outside) and intracellular fluid (ICF; often abbreviatedas i = inside): most importantly [K*], >> [Kn]. and [Na+]">> [Na*J,. b. The selectivepermeability of the cell membrane: most importantly, the K+ permeability (P") >> Na* permeability (P*"). 2. Given thesetwo characteristics,the RMP originatesas follows: a. Due to the high P*, K+ movesfrom ICF to ECF along its concentrationgradient,leaving an excessof anions (many of which are too large to diffirse out of the cell along with K+) in the ICF and creating a negative transmembrane potential (TMP). This negativeTMP tends to slow the further efflux of K+. b. If the cell were permeable only to K+, an equilibriurn would be establishedin which the negative TMP created by K* efflux would exactly balance the tendency of K+ to leavethe cell along its concentration gradient. The negativeTMP at equilibrium would then equal the K+ equilibrium potential (V*), as calculated by the Nernst equation for K+: V r = 6 1 .5l o g ([K+ ]./[K + ],)mV c. However, due to the small P*u,Na+ moves from ECF to ICF along its concentration and electrical gradients,making the actud RMP lessnegativethan V* and allowing for a continued small K+ efflux. Thus, at the RMR there is a small outward K+ current balancedby a small inward Na+ current. d. Slow fibers have a somewhat greater PN"/PKratio than fast fibers and therefore a less negativeRMP. 3. The RMP can be changedby: a. Changes in the K+ concentration gradient. For example, a decrease in the K+ concentration gradient decreasesthe tendency of K+ to leavethe cell along its concentration gradient, resulting in a less negative RMP. (1) Hyperkalemia (increased[K"].) reducesthe magnitude of the gradient.

,,

System Cardiovascular

(2) Myocardial injury or ischemia can result in a local decreasein the magnitude of the gradient. b. Changes in the ionic permeabilities. For example, an increase in K" permeability increasesthe tendencyof K* to leavethe cell along its concentration gradient, resulting in a more negative RMP. Acerylcholine hyperpolarizes cardiac cells by this mechanism. E. Cardiac action potentials (APs). When a resting cardiac cell is depolarized to a certain critical potential, the threshold potential, an AP is initiated. The APs in fast fibers (fast responseAPs) differ from the APs in slow fibers (slow responseAPs) (Fig:ureI-4-2, Thble

r_4_1):

20 0 o -20 = o -40 = -60 -80 -100

20 0 a -20 = o -40 = -60 -80 -100 0,1 0.2 Seconds

0.3

0.1 0.2 Seconds

0.3

Figurel-4-2.Fastresponseand slow responsecardiacactionpotentials.

Thble I-4-f . Comparison of fast and slow response cardiac action potentials. Parameter

Fast ResponseAP

Slow ResponseAP

Resting membrane potential (RMP)

-90 mV

-60 to -70 mV

Threshold potential

-60 to -70mv

-30 to -40mV

Rapid inward Na+ current 100-130mV 200-1,000mV/sec

Slow inward Ca2+ current 35-75 mY 1-10 mV/sec

0.3-3.0 m/sec

0.01-0.10m/sec

Phase0 Primary current Amplitude Slope Conduction velocity

1. Fast responseAPs. The fast responseAP can be divided into four phases(Figure l-4-3, Table I-4-2), which are causedby passiveion fluxes along their establishedchemical and electrical gradients,primarily through ion-specific channels. The rapid, spike-like depolarization (phase0) is followed by a gradual repolarization (phasesf to 3) back to the RMP (which is commonly referredto asphase4).

,4

Physiology

?able l-4-2. The phasesof the fast response action potential. Phase

Description

0

Rapid depolarization,which determinesconduction velocity of action potential

1

Early repolarization

2

Plateau

3

Late repolarization

4

Resting potential

Nrc'hcLcx

{< c[tex '*[trl,r Ca

K "llt'.^

g E

Figure l-4-3. Conductances of Na+,Ca2*,and K+ during the phases of the fast response action potential.

a. Phase 0 is causedby an increasein Na* permeability, or conductance,resulting in a Na* influx that depolarizes the cell to = +20 mV. This increasein Na* permeability can be attributed to the activation of the voltage-gatedNa* channels, which are rapidly activated when the fast fiber is suddenly depolarized to its threshold potential. The Na* influx is termed the rapid inward Na* current. (1) The Na* channelscan be blocked pharmacologicallyby the classI antiarrhythmic drugs, such as procainamide, quinidine, and lidocaine. (2) The Na* channelsare inactivated if the RMP becomesless negative (e.g.,due to hyperkalemia, myocardial injury or ischemia) or if the fast fiber is gradually (rather than suddenly) depolarized to its threshold potential. b. Phase l, the initial repolarization phase,is especiallyprominent in Purkinje fibers. It is causedby the termination of the rapid inward Na* current, due to inactivation of the Na* channels (thus, the phase0 depolarization approaches,but never reaches,the Na+ equilibrium potential of +40 mV), a transient efflux of K+, and possibly a transient influx of Cl-.

Bridgeto Pharmacology These drugsarereviewed in detailin theCardiovascular Pharmacology chapter.

55

Cardiovascular System

Note Inatrial andventricular phase muscle, 2 Caz* isresponsible fortriggering therelease of largeramounts of Ca2*from reticulum thesarcoplasmic (Ca2*-induced Ca2*release).

c. Phase2,the plateau, is the longest phaseof the AP and is characterizedby an increase in Ca2*permeability, resulting in a Caz+influx. This influx of Ca2ndoes not causethe transmembrane potential to become more positive becausethe K* permeability, which decreasedduring phase0, is sufficiently large to allow K* efflux. This increasein Ca2* permeability can be attributed to the activation of the voltage-gated L-type 662* channels, which are slowly activated when the fast fiber is depolarized to a transmembrane potential of = -60 to -70 mV (i.e., the activation of the Ca2+channels actually begins during phase 0, but since the activation is slow, the Ca2+influx is delayed).The Ca2*influx during phase2 is termed the slow inward Ca2*current. (1) The Ca2* channels can be blocked pharmacologically by the Ca2* channel blockers, such asverapamil and diltiazem. (2) Caz*influx through the Ca2*channels is increasedby sympathetic stimulation (B, receptors)and inhibited by parasympatheticstimulation (M, receptors). (3) The phase2 Caz*influx is responsiblefor triggering the releaseof larger amounts of Ca2*from the SR (Cah-induced Cah release). d. Phase3, the final repolarization phase,is causedby the termination of the slow inward Ca2*current, due to the inactivation of the Ca2*channels,and an increasedK* efflux, due to the return of K* permeability to its high resting value. At the end of phase 3, the potential returns to the RMP (i.e., the hyperpolarization seen at the end of the nerve AP is not observed). The phase 3 slope is an important determinant of the action potential duration (APD), i.e., the width of the AP (phases0 through 3). (1) The typical APD in cardiaccellsis 200 to 300 msec,markedly longer than the I to 2 msecAPD observedin nerve and skeletalmuscle. (2) Purkinie fibers havethe longestAPDs, while atrial muscle fibers havethe shortestAPDs. (3) The APD varies with the heart rate: the faster the rate, the shorter the APD. (a) The APD varies with the temperature hypothermia increasesthe APD. 2. Slow responseAPs. The major differencesbetween fast responseAPs and slow response APs are summarized in Thble I-4-1. The most significant differencesinvolve phase 0: a. The phase0 slope and amplitude are reduced in slow fibers. b. Phase0 depolarization is accomplishedby the slow inward Ca2*current (rather than the rapid inward Na* current) in slow fibers. In fact, slow response APs can be observedin fast fibers if the rapid inward Na* current is blocked by inactivating the Na* channels. Such inactivation can be achievedpharmacologically(procainamide, quinidine,lidocaine) or by making the RMP lessnegative(hyperkalemia,myocardial injury or ischemia). The conduction velocity refers to the speed of impulse propagation and is determined by various characteristics of the cell and also by the phase 0 slope and amplitude. 1. A decreasein fiber diameter increasesthe resistanceto current flow and slows conduction. The siow conduction observedin the AV node can be attributed in part to the small diameter of AV nodal cells. 2. A decreasein contractile protein content reduces the resistanceto current flow and speeds conduction. The rapid conduction observed in the Purkinje cells of the HisPurkinje systemcan be attributed in part to a reduced contractile protein content. 3. A decreasein electrical resistance of junctions between adjacent cells speedsconduction. The rapid conduction observedin the Purkinje cells of the His-Purkinje systemcan be attributed in part to their long,low resistancenexus (gap) junctions.

56

Physiology

4. Conduction velocity is directly proportional to the phase 0 slope and amplitude. Thus, conduction velocity in fast fibers is markedly greater than that in slow fibers (Table I-a-l); in fact,the fast fiber-slow fiber terminology wasoriginally developedto emphasize this difference in conduction velocity. G. Excitability refersto the ability of cardiac cellsto respond normally to electrical stimulation. During the AP, cardiaccellsare refractory to excitation,i.e.,they cannot be excitedby electrical stimulation in the normal way. The effective refractory period (ERP) is the interval during which a propagatedAP cannot be elicited, no matter how strong the depolarizing stimulus.The relative refractoryperiod (RRP) is the interval during which a propagatedAP may be elicited,but only if the depolarizingstimulus is strongerthan is neededto initiate an AP when the excitability is normal (Figure I-4-4).

In a Nubhell Conduction Velocities > Purkinje fibers> ventricles AVnode

1. In fast fibers, the ERP starts at the beginning of phase0 and typically lastsuntil repolarization reachesa transmembranepotential of = -50 mV. The RRP startsat the end of the ERP and typically lastsuntil the end of phase3. As repolarizationproceedsduring phase 3, increasingnumbers of Na* channelshaverecoveredand are readyto be reactivatedby the next stimulus. Thus, the later the cell is stimulated in the RRP,the greaterthe phase0 slope and amplitude, and hence conduction velocity, of the resulting AP. Conduction velocity is constantand maximal once the cell is completelyrepolarized.

Fast response

40

Slow response 2

0 I

E*o =

-80 -'120 ttl

0 A

100 200 300 Time(msec)

0 B

100 200 Time (msec)

Figure l-4-4. Refractory periods in fast and slow fibers. (ERP = effectiverefractoryperiod;RRP = relativerefractoryperiod.)

2. ln slowfibers, the ERPis much longer than in fast fibers and typically extendsbeyond phase 3, i.e.,evenwhen the slow fiber is completelyrepolarized,it may not be ableto respondnormally to electrical stimulation. Thus, the RRP extendsinto phase4. Theselong refractory periods account for the increasedlikelihood of conduction blocks in slow fibers (e.g.,the AV node). H. Automaticity refers to the ability of some cardiac cells to automatically depolarize toward thresholdduring phase4. Suchcellsdo not exhibit a constantRMR but insteaddisplaygradual phase4 depolarization (Figure I-4-5). 1. Automaticity normally occurs in the cells of the SA node, AV node, and His-Purkinje system. The mechanism for automaticity involvesa gradual increasein Na* influx during phasea (the pacemakercurrent), due to the activation of a specialpopulation of Na* channels;in the SA node and AV node, a gradual increasein Ca2*influx and a gradual decreasein K* eflux are important.

Note Automaticity isdefined asa gradual depolarization phase during 4.

17

Cardiovascular System

In a Nutshell Pacemaker Cells . SAnode . AVnode . Purkinje fibers > rate AV SA rate> Purkinje rate

2. If phase4 depolarization is not interrupted before the threshold is reached,an AP will be initiated spontaneously. Thus, cells that possessautomaticity can function as pacemakers, i.e.,sourcesof APs that can propagatethrough the remaining myocardialtissue. Normally, the SA node is the dominant pacemaker becauseit depolarizes more rapidly and becauseof what is known as overdrive suppression, the slowing of other pacemakers roughly in proportion to the duration and rate of stimulation of the dominant pacemaker (e.g.,the fasterthe SA node dischargerate, the slower the rate of the AV node and His-Purkinje system pacemakers).Clinically, the use of percutaneouspacemakersto terminate arrhythmias takesadvantageof overdrive suppression. 3. The pacemaker firing rate, and therefore the heart rate, is determined by: a. The rate of phase4 depolarization,i.e.,the phase4 slope. (1) Sympathetic stimulatiot (F, receptors) and fever increasethe phase 4 slope, thereby increasingthe heart rate (Figure I-4-5). (2) Parasympatheticstimulation (M, receptors)and hypothermia decreasethe phase 4 slope,there\ decreasingthe heart rate (Figure I-4-5). b. The threshold potential c. The transmembrane potential at the start of phase4 (maximum diastolic potential). Parasympatheticstimulation causeshyperpolarization of the cell membrane, i.e., a more negative maximum diastolic potential, which contributes to its abiliry to decreasethe heart rate (Figure I-4-5).

mV

t

Sympathetic stimulation

mV

Figure l-4-5. Automaticity in SA nodal cells, illustrating the effect of sympathetic and parasympatheticstimulation on heart rate.

MYOCARDIAL CONTRACTION Note T tubules facilitate action potential transmission intotheinterior ofthefiber. Theyarewelldeveloped intheventricles.

58

A. Mechanism of excitation-contraction coupling. As in skeletal muscle, Ca2+ions mediate myocardial excitation-contraction coupling. 1. During phase 2 of the action potential, Ca2nions enter the cell through voltage-gated L-type Ca2*channels (slow inward Ca2*current). At the Z line of each sarcomere,the sarcolemma invaginates to form the system of T tubules, thus ensuring that the action potential spreadsinto the interior of the myocardial fiber. 2. Although the Ca2*ions that enter the cell during phase2 are not sufficient to activatethe contractile mechanism of the myocardial cell, their entry causesthe releaseof a much

Physiology

larger number of Ca2*ions from the sarcoplasmic reticulum (SR), an intracellular Ca2* storage reservoir that consists of a network of anastomosingtubular structures surrounding each myofibril. This Ca2*-induced Ca2*release provides a sufficient amount of Ca2*to initiate contraction. a. Sac-like cisternae, or lateral sacs,of the SR are found adjacent to the T tubules and surfacesarcolemma. b. The Ca2*ions entering during phase2 releaseCa2*from the SR by binding to Ca2+ releasechannels (also known as ryanodine receptors) on the cisternaeof the SR. 3. The amount of Caznreleasedfrom the SR, and hence the number of activatedcontractile sites and the force generatedby the contraction, is determined by the amount of extracellular Ca2*entering the cell during phase2, the time that has elapsedsincethe previous action potential (which, in turn, determineswhether the Ca2*releasechannelshave recovered their ability to respond to Ca2*),and the sizeof the SR Ca2*stores. 4. The amount of extracellular Ca2nentering the cell during phase2 is directly proportional to the: a. ExtracellularCa2*concentration b. Number of open Ca2*channels c. Duration of the action potential d. Number of action potentials 5. Sympathetic stimulation (p, receptors) and p-receptor agonists increasethe force of myocardial contraction by increasingthe probability that a given Ca2*channel is open, thereby increasing Ca2*influx. B. Mechanism of myocardial contraction I. Caz*binds to troponin C, causing the troponin complex to undergo a conformational change,which in turn causestropomyosin to move deeperinto the groove betweenthe two actin strandsof the thin filament. 2. The movement of tropomyosin into the grooveuncoversthe myosin binding siteson the actin strands, allowing the myosin headsto bind to the thin filament. 3. The myosin headundergoesa changein shape,which causesthe myosin head to move the thin filament (power stroke),thereby shorteningthe sarcomere. C. Mechanism of myocardial relaxation 1. The influx of extracellularCa2*stopsat the end of phase2 of the action potential. reducing the intracellular Ca2*con2. The SR actively accumulatesCa2*via a Ca2*-ATPase, centration and removing Ca2*from troponin. 3. The regulatory proteins troponin and tropomyosin now assume their inhibitory conformation, preventing cross-bridging between actin and myosin and resulting in myocardial relaxation. D. Differences between cardiac and skeletal muscle contraction 1. Prolongedtetanic contraction, possiblein skeletalmuscle,cannot occur in the myocardium, becausethe efifectiverefractory period of the myocardial fiber extendsbeyond phase 2 of the action potential; thus, relaxation is part of the contractile rycle triggeredby each action potential.

T9

Cardiovascular System

In a Nutshell . Skeletal muscle: changes in contractile forcearedueto changes inthenumber of fibersactivated . Cardiac muscle: changes in forcearedueto contractile inconFactility changes offiben

2. Forceofcontraction a. In skeletalmuscle, each activated fiber generatesa maximum force and any variation in the total force generatedby the skeletalmuscle is therefore due to changesin the number of fibers activated. b. In cardiacmuscle,all fibers are activatedwith eachcontraction; any variation in the force of contraction is therefore due to changesin the contractile properties,or contractility, of the individual fibers rather than to changesin the number of fibers activated.

THECARDIAC CYCTE The concurrent electricaland mechanicaleventsoccurring during the cardiacrycle are shown in Figure l-4-6 (the Wiggers diagram). In the following description of the cardiac rycle, the eventson the left side of the heart will be emphasized. A. Atrial systole ( 150 milliseconds). The atria contract,accomplishingthe final = 20o/oof ventricular filling (atrial kick) (Figure l-4-7). 1. On the ECG, the P wave (atrial depolarization) startsjust before the beginning of atrial systole,triggering atrial muscle contraction. 2. Left atrial pressure increasesasthe left atrium contracts,causingthe a wave. 3. Left ventricular pressure increases,paralleling the a wave,but remains below left atrial pressure. Thus, the pressuregradient for ventricular filling is maintained. The left ventricular pressureat the end of atrial systolerepresentsthe left ventricular end-diastolic pressure. 4. Leftventricular volume increases= 20o/oto its maximum value during the cardiac rycle (= 120 ml), the end-fiastolic volume. Left atrial volume falls. 5. The fourth heart sound (Sn)occurs during atrial systole,but typically is audible only in pathologicalconditions that result in a more forceful atrial systole(e.9.,a reduction in left ventricular compliancedue to hypertrophy or infarction).

40

Physiology

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4l

Cardiovascular System

Figure l-4-7. Atrial systole. B. Ventricular systole(300 milliseconds). The contraction of the ventriclescanbe divided into threephases: 1. Isovolumetric contraction (50 milliseconds).The left ventricle contracts at a constant volume,sinceboth the mitral and aortic valvesare closed(FigureI-4-S).

Figure l-4-8. lsovolumetric contraction. On the ECG, the QRS complex (ventricular depolarization) starts just before the beginning of isovolumetric contraction, triggering ventricular muscle contraction. b. Left ventricular pressure rises above the left atrial pressure,closing the mitral valve; in fact, mitral valve closure defines the beginning of isovolumetric contraction. Left ventricular pressurecontinuesto rise at an increasinglyrapid rate until aortic pressure is reached. Note that mitral valve closure occurs very shortly before tricuspid valve closure. c . Left atrial pressure increasestransientlydue to the bulging of the mitral valveinto the

left atrium at the beginning of isovolumetric contraction, causingthe c wave.

42

Physiology

d. teft ventricular volume remains constant at its maximum value (end-diastolic volume); isovolumetric contraction causesonly a shape change and a rise in left ventricular pressure.

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Figure l-4-10. lsovolumetric relaxation.

a. Ieft ventricular pressure falls below aortic pressure,resulting in closure of the aortic valve; in fact, aortic valve closure defines the beginning of isovolumetric relaxation. Left ventricular pressurecontinues to fall, due to the continued relaxation of the left ventricular muscle. Note that aortic valve closure precedespulmonic valve closure; thus, ventricular ejection is longer in the right ventricle. b. I€ft ventricular volume remains constant at its minimum value (end-systolicvolume). c. Aortic pressure shows a dip, the incisura, when the aortic valve closes,followed by a small pressureincrease. This is due to a short period of backward flow of blood immediately prior to aortic valve closure that is interrupted by the closure. d. Left atrial pressure continues to increasedue to continued refilling of the left atrium, reaching its maximum value, the peak of the v wave, at the end of this phase. e. The secondheart sound (Sr) coincideswith semilunar valve closure.Two S, sounds can be heard: aortic valve closure(4) followed by pulmonic valve closure(Pr). f. On the ECG, the beginning of the isoelectricTP segment is recorded.

2. Rapid ventricular filling (100 milliseconds).The mitral valve is open and most (= 80o/o) of ventricular filling occurs (Figure I-4-11).

u

Physiology

Figure l-4-11. Rapid ventricularfilling.

a. I,eft ventricular pressure falls below left atrial pressure,opening the mitral valve; in fact, mitrd valve opening definesthe beginning of ventricular filling. Left ventricular pressurecontinues to fall in parallel with left atrial pressure. b. I^eft ventricular volume increasesrapidly as the left ventricle fills. c. Ieft atrial pressure starts at the peak of the v wave,then falls as blood flows into the left ventricle (the y descent). Left atrial pressureremains above left ventricular pressure,maintaining a pressuregradient for ventricular filling. d. Aortic pressure decreasesslowly due to the drainage of blood into the peripleural arteries. e. The third heart sound (Sr) coincideswith rapid ventricular fillitg. S, can be a normal finding in children and young adults,but in adults over 30 to 35 yearsof age,it usually is audible only in pathologic conditions. f. On the ECG, the isoelectricTP segment is recorded. 3. Diastasis (duration dependson heart rate) is the period of slow ventricular filling.

In a Nutshell

a. Left ventricular pressure and left ventricular volume slowly increase,due to the slow filling. b. Left atrial pressure slowly increases,due to continued left atrial filling from the pulmonary veins. c. Aortic pressure decreasesslowly, due to the continued drainage of blood into the peripheral arteries. d. On the ECG, the end of the isoelectricTP segment is recorded. 4. Atrial systole. The rycle begins again.

Left MiFal Aortic \ftnthhr Vahe Valve Volume bo,ofum€fic closed closed women). It is rare in infants.

r88

Pathology

1. Pathogens include aerobic and anaerobicStreptococcus, S. aureus,gram-negativerods, and mouth anaerobes,including Bacteroides, Fusobacterium,and Peptostreptococcus. 2. Routes of infection a. Aspiration of gastric contentsand mouth flora b. Bacterialpneumonia (inhalation) c. Septicemboli from the venous circulation or the right side of the heart d. Neoplasiawith postobstructivepneumonia e. Miscellaneoustrauma, extension of infection from other organs, hematogenous spread,or cryptogenic (no identifiable cause) 3. Clinical features include fever, paroxysmal cough with foul-smelling, purulent or sanguineous sputum, and weight loss. Clubbing can occur within weeksof abscessformation. Ten to fifteen percent of patients have underlying carcinoma. With appropriate resolvewithout sequelae.An air-fluid level is antibiotics,75o/oof pulmonary abscesses often seenon chestx-ray. 4. Pathology a. Grossly,lung gangrene(fetid, green-blackmultilocular cavities)is seen. b. Microscopically, there is suppurativedestruction of lung parenchymawithin the central area of cavitation. 5. Complications include respiratory failure, extensionof infection into the pleural space, and embolization to the brain and meninges. H. Pulmonary tuberculosis (TB) primarily affects the lungs and is caused by acid-fast Atypical mycobacmycobacteria.Almost all casesare causedby Mycobacteriumtuberculosls. teria can causeinfection, especiallyin the immunocompromised host. BecauseM. tubercu/oslsis a strict aerobe,reactivationtends to occur in the apex of the lung and renal cortex. There is an increasedincidencein areaswith poor sanitary conditions, poverty,overcrowding, malnutrition, and limited accessto medical care. The emergenceof AIDS and other immunosuppressedstateshas led to a resurgencein the incidenceof TB. Of concern now is the occurrence of multiple drug-resistant TB.

BridgeToMicrobiology in M.tuberculosis isdiscussed intheMicrobiology detail section t ofCeneral Principles Book (Volume l).

l. Primary pulmonary TB a. Pathology.The lung is the usual location of initial infection, typically the lower part of the upper lobe or the upper part of the lower lobe. Parenchymalor subpleural lesions occur associatedwith enlarged,ipsilateral caseouslymph nodes, which are "draining" the parenchyma.The "Ghon complex" refersto radiographicevidenceof a calcifiedperipheral lesion in conjunction with a calcifiedhilar lymph node. b. Clinical features. Most patients are asymptomatic,and the lesionsbecome fibrotic and calcified over time. It is the macrophagethat leads to phagocytosisof tubercle bacilli, epitheloid giant cell fusion, and granuloma formation with central caseous necrosis.The tuberclebacilli survive in granulomasfor years,only to reactivatewhen the patient's immune systemis depressed(e.g.,elderly or malnourished patients or patientswith HIV). 2. Secondarypulmonary TB. Most casesrepresentreactivation (rather than reinfection) of old TB that had disseminatedat the time of primary TB. Reactivationoccurs often in areasof high oxygentension,such asthe lung apices.Only 5-I0o/oof patientsexposedto TB developreactivation.ReactivationTB usually occursin debilitated elderly patients.

r89

RespiratorySystem

a. Pathology (1) Grossly, there is a small focus of consolidation,usually lessthan 3 cm, in the lung apex.Hilar ly-ph nodes are also involved, developingfoci of tuberculous activity. Parenchymallesionscan developsmall areasof caseousnecrosisthat may not cavitate. The usual course is fibrous encapsulation,leading to fibrocalcific scarsand pleural adhesions.A thick, collagenouswall may totally enclose caseousdebris. This may never resolveand can remain asa granular lesion. (2) Microscopically, characteristicgranulomas composedof epithelioid cells,with occasionalLanghans'giant cells,are seen.Granulomas are surrounded by fibroblastsand lymphocytesand exhibit a region of central caseation(Figure II-5-2). Tlrberclescoalesce,and large areasof the lung becomescarred. b. Complications include hemoptysis resulting from ulceration of the bronchial mucosa, pleuritis, tuberculouspneumonia,and bronchopleuralfistula with empyema. 3. Late progressive pulmonary TB shows progression of an early tuberculous apical lesion to a fibrocaseousareawith cavitation. Spreadis through erosion into an airway to other regionsof the lung, resulting in multiple lesionsthat may cavitate.Spreadmay also occur via the lymphatic systemor blood, leading to distant dissemination.The pleura is often involved and may lead to exudativepleural effusion,frank tuberculousempyema,or massive obliterative fibrous pleuritis. Bronchi are also involved as a result of seedingand can causemucosalulcers.Pathologyrevealscaseatinggranulomas (Figure II-5-3).

Figurell-5-2.Pulmonarygranuloma(microscopic).

t90

Pathology

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4. Miliary TB is due to spreadvia blood or lymphatics. Diseasemay remain confined to the lung but usually disseminateswidely. For example,erosion into a pulmonary artery leadsto lung lesions;erosion into a pulmonary vein leadsto systemiclesions.Extrapulmonary sites of involvement include the renal cortex,lymph nodes,genital tract, peritoneum, bone marrow, adrenalgland, pericardium, and meninges. a. Pathology (1) Grossly, there are small, distinct, firm, yellow and white areasof consolidation. (2) Microscopically, there are individual or multiple confluent regions, showing granulomaswith areasof central caseation. b. Diagnosis is made by skin test, chest x-ray, sputum smear,and culture. If indicated, lung biopsy,urine, gastric aspirate,and CSF need to be evaluated. 5. Isolated organ TB occurs when organismsare destroyedduring hematogenousor lymphatic spreadexcept in a particular organ, €.8.,lymph nodes (scrofula),vertebrae (Pott disease),meninges(tuberculousmeningitis), adrenals,kidneys,and genitals. I. Legionella infections. Legionellapneumophila (a gram-negativebacillus) is the etiologic agent of theseinfections.It is usually found in soil or water.Tiansmissionis via inhalation into the lungs. Major environmental sourcesinclude water reservoirs and cooling units of air conditioning systemsthat may contain blue-green algae and amoebae,among which Legionellacan survive for prolonged periods.

Correlate Clinical pneumophilo Legionello of infection isa result from inhalation oftheaerosol water, most contaminated foundinair commonly systems. conditioning

1. Clinical features. Community outbreakstraced to an infected water source reveal two patternsof illness. a. Pontiac fever is a mild, nonfatal, systemicfebrile illness. b. Legionnaires diseaseis a severepneumonia with l5-20o/omortality. After approximately 5 days of incubation, patients develop fever, dry cough, malaise,chest and abdominal discomfort, confusion, and, occasionally,diarrhea.Frequently,pulse-temperature dissociation exists (a high temperature with no increasein pulse). Severe

t9l

Respiratory System

caseshaveblood-tinged sputum, dyspnea,high fevers,and impressivesystemicsymptoms. Death may occur due to progressiveventilatory failure or from a shock-likesyndrome with disseminatedintravascularcoagulation(DIC) and renal failure. 2. Pathology. Bronchopneumoniawith fibropurulent exudatecan coalesceand occasionaily mimic lobar pneumonia. Microscopically, there is a mononuclear infiltration with macrophagessurrounding necrotic tissue. Surrounding the mononuclear infiltrate are proliferating pneumocytes,hyaline membranes,and edema. 3. Complications a. Inflammation of small pulmonary arteriesand veins can lead to thrombosis. b. Abscessformation is frequent,but the abscesses are small. c. Organization and scarring secondaryto destructive lesions can lead to ventilatory impairment. d. Fibrinous pleuritis is usually mild with serouseffi,rsion. e. Bacteremiais alwaysa risk. L Diphtheria (due to C. diphtheriae)and whooping cough (due to B. pertussis)both cause toxin-mediated upper respiratory tract infections that can be accompaniedby lower respiratory tract infection. The diphtheria toxin inducesnecrosisof the epithelium of the upper respiratory tract, resulting in the formation of a "diphtheric pseudomembrane."

Note

(COPD) GHRONTC OBSTRUCTTVE PUTMONARY DTSEASE

COPD isa groupof disorders thatincludes:

COPD is a group of disorders characterizedby increased resistanceto airflow during both inspiration and expiration due to airway obstruction. The obstruction can occur at any level from the trachea to terminal bronchioles.This group representsthe most common form of pulmonary diseaseand includesemphysema,chronic bronchitis, asthma,and bronchiectasis.

. Emphysema . Chronic bronchitis . Asthma . Bronchiectasis Note . cr,-Antitrypsin inhibits the destruction of elastin by elastase, a proteolytic enzyme carried by inflammatory cells. Elastase actsonalveolar walls. . a,-Antitrypsin deficiency isa hereditary disorder that results in defective secretion of a,-antitrypsin bytheliver. Inhomozygotes, this eventually results in panacinar emphysema and hepatic cirrhosis.

r92

A. Emphysemarefersto distention of air spacesdistal to the terminal bronchiole with destruction of alveolarseptae,probably secondaryto ischemia. 1. Incidence. Emphysemais associatedwith cigarette smoking, urban living, and pollution. Cigarettesmoke causesan increasein elastaseavailability (releasedby neutrophils and macrophages)and a decreasein antielastaseactivity (due to oxidant effects).Men are affectedmore frequently than women. 2. Types a. Centrilobular emphysema affects the central and proximal part of a lobule; distal alveoli are not involved. It is more common and usually more severein the upper lobes.Inflammation surroundingbronchi,bronchioles,and alveoliis common. b. Panacinar emphysema causesa uniform enlargementof lobules, including terminal and respiratory bronchioles as well as distal alveoli. It is more common and more severein the lower lobes. Alpha,-antitrnrsin deficiency is thought to lead to an imbalancebetween proteaseand antiproteaseactivity. This imbalance then leads to panacinaremphysemaby young adulthood, especiallyin the lower lungs. c. Paraseptalemphysema involvesthe distal region of the acinus, sparing terminal bronchiolesand respiratorybronchioles.It is most severealong the pleura, septae,and the lobule edge.It commonly occursadjacentto areasof fibrosis,scarring,or atelectasis and is more severein the upper lung. Paraseptalemphysemaforms multiple confluent distendedair spaces. It may be the causeof spontaneouspneumothorax(collapsedlung) in young adults.

Pathology

d. Irregular emphysema describesirregular acinus involvement. It is associatedwith scarring. e. Bullous emphysema refers to large, balloon-like distended air spacesin the lung periphery,which can lead to pneumothorax. f. In interstitial emphysema,an alveolartear allows air into the connectivetissuestroma of the lung, mediastinum,or subcutaneoustissue. 3. Pathology a. Centrilobular emphysema(Figure II-5-4) (1) Grossly, the lungs may not be particularly enlargedor pale unlessdiseaseis well advanced.The upper two thirds are more severelyinvolved. (2) Microscopically, central airspaces(respiratory bronchioles and alveolar ducts) are destroyedwith sparing of peripheral alveoli; inflammation around bronchi and bronchiolesis common. b. Panacinar emphysema (1) Grossly, panacinar emphysema causes hyperinflated lungs with increased crepitance.Involved areasare pale as a result of blood vesseldestruction and compression. (2) Microscopically, there is little inflammatory involvement of septae or alveoli associatedwith their destruction.

Figure ll-5-4.Gentrilobular emphysema (gross).

4 . Clinical features include dyspneawith or without cough,weight loss,barrel-chest due to hyperinflation, pursed-lip breathing, prolonged expiratory time, and cor pulmonale (right-sided heart failure).*Pinkpuffers" are patientswho overventilateto maintain oxygenation despitethe elevatedwork of breathing.x-Raysrevealhyperinflation with flattened diaphragms.

t95

Respiratory System

5. Pathogenesis.There are two theories. a. Protease-antiproteasetheory, as describedpreviously. b. Loss of bronchial cilia as a result of smoking leads to mucus plugging and alveolar overdistension.Alveolar overdistention,resulting from obstruction, can compromise the septalblood flow,leading to ischemiaand alveolardestruction.Inflammation and mucus plugging may exacerbatethe obstruction. 6. Complications include cor pulmonale as a result of increasedpulmonary vascularresistance,ventilatory failure, polycythemia,and pneumothorax. B. Chronic bronchitis is a common disorder that can lead to obstructive airway disease. Chronic bronchitis is a clinical diagnosis,that is, persistentcough with sputum production for at least3 months for 2 consecutiveyears.Sputum variesfrom uninfected mucus (simple chronic bronchitis)to purulent (mucopurulentchronic bronchitis). 1. Pathogenesis.There are two major factors. a. Chronic irritation from inhaled substances(e.9., nitrogen dioxide, sulfur dioxide) may causeinflammation.

In a Nutshell Chronic Bronchitis . lsa clinical diagnosis of persistent cough with production sputum forat for least 3 months 2 years consecutive . lsassociated with infections, cigarette airpollution, and smoking, genetic factors various . Canpresent withmucus plugging, inflammation, fibrosis, and edema, muscle atrophy smooth . lncreases = Reidindex thickness layer ofgland thickness ofbronchial wall Note ln contrast to delayed hypersensitivity skintestsin TB,where thereaction takes 2-3 daysto form,thelgEisreferred mediated reaction to asimmediate hypersensitivity andproduces a wheal andflarein a few minutes.

t94

b. Recurrent infections do not initiate bronchitis, but they do perpetuateit and result in acute exacerbations. Common organisms include Haemophilus influenzae, Streptococcus viridans, and S. pneumoniae.Smoking can lead to both irritation and infection. Smoke destroysthe lung's ciliary tree, damagesthe mucosa,and interferes with WBC function. It is believedthat changesin the small airwaysare important in the pathogenesisof bronchitis. Small airway obstruction representsthe earliestmanifestation of COPD. Inflammation and mucus plugging increaseresistanceto air flow in theseusually low-resistanceairways.Continued exposureto irritants and repeated infection eventuallylead to chronic bronchitis. 2. Pathology a. Grossly,lungs are boggy,hyperemic,and hyperinflatedwith copious mucus plugging the airways. b. Microscopically, there is hypertrophy of the submucosaiglands first in the large airways and then in smaller airways.Bronchial epithelium may exhibit squamousmetaplasia or dysplasia.Mucus plugging, inflammation, edema,smooth muscle hypertrophy, and fibrosis are all common. 3. Ctinical features. There is a productive cough with copious sputum production, dyspnea, barrel chest, ryanosis,hypercapnia,hypoxia, and frequent infection. Patients are classicallyknown as"blue bloaters" becausethey are constantlycyanotic. 4. Complications. Respiratory failure usuallyoccursduring a bout with an acuteinfection. Cor pulmonale may occur asa result of pulmonary hypertension(increasedresistanceof pulmonary vasculatureas a result of alveolardestruction and hypoxic vasoconstriction). Dysplasiaof bronchial epithelium may lead to cancer. C. Asthma is characterizedby enhancedairway reactiviry leading to intermittent episodesof reversible paroxysmal airway narrowing. 1. Types a. Extrinsic asthma (allergic, atopic). Attacks are triggered by environmental antigens (e.g.,dust, pollen, food). There is frequently a family history of atopy (e.g.,rhinitis, asthma,and eczema).Bronchospasmis mediatedby a tfpe I immunoglobulin E (IgE) hlpersensitivity responseto a particular antigen.Histamine,leukotrienes([Cn, LID4, and LTE'), prostaglandin D, (PGD2),chemotacticfactors, and platelet activation all

Pathology

lead to airway-constricting inflammation and increasedvascular permeability. Serum IgE levels are elevated,and a positive skin test may be demonstrated to the offending antigen. b. Intrinsic asthma (idiosyncratic). Exacerbations frequently follow a viral infection that causesinflammation and a lowering of the vagal threshhold for irritants. Other causesof increasedairway reactivity include stress,pollution, occupationalexposure, exercise,and cold weather. There is no family history, skin tests are negative,and IgE levelsare normal. c. Aspirin-induced asthma may be seen in adults. There is a classic triad of nasal polnrs, rhinitis, and bronchoconstriction. It may be causedby excessiveleukotriene production from inhibition of the cycloorygenasepathway,and it is not immunologically mediated.This syndromemaybe seenwith almost all NSAIDs and acetylsalirylic acid (aspirin) compounds. 2. Pathology Bronchi and a. Grossly,asthmacauseshyperinflatedlungs with small areasof atelectasis. bronchiolesare occludedby thick, tenaciousmucus plugs. b. Microscopically, mucus plugs contain shed epithelium in a spiral configuration ("Curschmann spirals"). Eosinophils and membrane protein form crystalloid collections (Charcot-Leyden crystals). Basementmembrane thickening, an inflammatory infiltrate with large numbers of eosinophils,edema,and submucosalgland hyryertrophy occur. Hypertrophy of bronchial wall muscle is probably caused by repeatedbronchospasm. 3. Clinical features include cough, dyspnea,and wheezing. x-Ray revealshlperinflation. If airway obstruction is severe,the patient may not be able to ventilate,leading to respiratory failure (increasedPco, and decreasedPor). Between attacks,patients are asymptomatic. Emphysemacan alsooccur becausehyperinflation leadsto local ischemiaasa result of capillury compression.

ln a Nutshell SomeMicroscopic Pathologic Findings in Asthma . Mucus plugs containing Curschmann spirals and Charcot-Leyden crystals . Eosinophilic infiltrate . Edema . Submucosal gland hypertrophy . Bronchial wallmuscle hypertrophy

D. Bronchiectasis is an abnormal, permanent dilatation of airways causedby chronic necrotizing infection and obstruction. 1. Pathogenesis a. Bronchial obstruction (e.g.,tumor, foreign body, COPD, mucus plug) leadsto atelectasisand airway smooth musclerelaxation. b. Infection further weakens the airway wall. Organisms include Staphylococcus, Streptococars,enteric anaerobes,and H. influenzae.Patients are susceptibleto recurrent infection due to impaired defenseagainstpathogenscausedby cough, injury to the mucociliary apparatus,and impaired phagocytosis. c. Examplesof disordersin which chronic infection leadsto bronchiectasisinclude: (1) Cystic fibrosis, which is characterizedby exocrinegland dysfunction,leading to viscoussputum (2) Kartagener syndrome, one of severalimmotile cilia syndromes,is characterized by a triad of sinusitis, bronchiectasis, and situs inversus. Absenceof pulmonary cilia interfereswith bacterialclearance. (3) Anomalous intralobar sequestration,which frequently becomesinfected,leading to airway dilatation

t95

System Respiratory

2. Patholog;y a. Grossly, bronchiectasispredominantly affectsthe lower lobes. Dilated airways may be cylindroid, fusiform, or saccular.The lumen is filled with a purulent exudate,and the mucosa is edematousand ulcerated. b. Microscopic findings vary with the chronicity and activity of disease.There may be an acute or chronic inflammatory exudate within bronchi and bronchioles associated with desquamation of the lining epithelium with extensiveareasof necrotizing ulceration. There may also be areasof "pseudostratification"or squamousmetaplasia.In some cases,necrosisleads to abscessformation. 3. Clinical features include cough, fever,and foul-smelling purulent sputum, which is most copious in the morning due to pooling. Clubbing and frequent pneumonia may also be seen. 4. Complications include lung abscess,pneumonia, empyema, and septic emboli.

RESTRICTIVE LUNG DISEASE This is a group of diseasescharacterizedby decreasedlung compliance, i.e., stiff lungs. The decreasedcompliance results in small lung volumes with augmented air flow rates. Varying pathologic processescan result in restriction, including extrinsic disease(neuromuscular,chest wall, myasthenia) and intrinsic lung disease.Intrinsic lung processesinclude interstitial and infiltrative disease,adult respiratorydistresssyndrome (ARDS),pneumoconiosis,and granulomatous disease. A. ARDS is the final common pathway of acute diffrrse alveolar damage (both physiologic and pancreatitis, histopathologic).It can be causedby a variety of insults,including sepsis/shock, burns, trauma, drug overdose,pneumonia,and toxins. 1. Clinical features include the rapid onset of severe respiratory insufficiency, resulting from alveolarflooding with impaired ventilation (decreasedPor; increasedPcor). ARDS frequently requires intubation for ventilatory support. There is a compensatory hyperdynamic state with hyperventilation and increasedcardiac output (increasedheart rate or stroke volume) to ensure oxygen delivery and avoid anaerobic metabolism. X-ray reveals a diffirse alveolar infiltrate. 2. Pathogenesis a. Alveolar membrane damage allows fluid, protein, and cellular debris to enter the interstitium and alveolar space.There is both endothelial and epithelial injury. This damageis due, in part, to neutrophils and macrophagesgenerating oxygen free radicals and degradativeenzfmes as part of an inflammatory reaction. b. Coagulation. Fibrin is found in many alveolar spacesasa component of hyaline membranes.Fibrin is also located within the pulmonary arteries and capillariesand can causethrombotic occlusion. c. The complement cascadeappearsto attract and sequesterneutrophils (C5a). In addition, the "attack complex" (C6C7C8C9) of complement can directly injure cells. d. Cpokines. Macrophages release interleukin-l (IL-l) and tumor necrosis factor (TNF), which attract neutrophils and stimulate them to releasetoxic metabolites. e. Arachidonic acid metabolites produce chemoattractants such as leukotrienes and products of the cycloorygenasepathway.

r96

Pathology

3. Pathology a. In early gross pathology, the lung shows heavy, firm, boggy congestion and is atelectatic.Interstitial edemaand alveolaredemacauseseptalwidening. In late gross pathology, chronic inflammation can lead to fibrosis. There can be focal areas of intraalveolarhemorrhageand patchy atelectasis. b. Microscopically, edematous alveolar septaewith proteinaceous fluid within alveolar spacesare found. Frequently, hyaline membranes of fibrin and cellular debris line injured alveoli. Inflammatory cells are present and can eventually lead to fibroblast proliferation and collagenformation. In more chronic cases,alveolarspacesbecome relined with cuboidal, type II pneumocftes.The interstitium is widened. B. Pneumoconiosis refers to the presenceof environmental "dust" in the lung and the lung's responseto this foreign entity. It appliesto any aerosol,whether in the form of fumes or particulate matter. Developmentof diseasedependsupon the amount of exposure,the sizeand shape of the particles, and the solubility and cytotoxicity of the offending material. AII can result in progressivemassivefibrosis with diffi.rsescarring and restrictive lung disease. 1. Coal workers'pneumoconiosis occurs after prolonged periods (>10 years)of exposure to coal dust containing both carbon and silica.

ln a Nubhell ARDS . Manycauses, including shock, trauma, sepsis, and aspiration . Diffuse alveolar damage, protein-rich fluid with leaking intoalveoli. . Hyaline membranes, made offibrinandcellular fragments, formin alveoli. . lmpairs gasexchange and in hypoxia results . Fatal in over500/o of cases

a. Clinical features. Most patients are asymptomatic or have a slight cough productive of blackened sputum. X-ray revealsdiffirse nodularities ("tattooirg").A small number of casesgo on to develop progressivediseasewith dyspnea,chronic cough with blackenedsputum, poorly localized chest pain, and frequent infections. If exposure continues, progressive massive fibrosis with large blackened scars (usually in the upper regions of various lobes) with cor pulmonale can develop,and the pleura can becomeretractedand thickenedif near fibrotic lesions. b. Pathology. Microscopically, "coal dust macules" are formed initially by the aggregation of macrophages,creating intensely pigmented areas.With continued exposure and inflammation, these macules become fibrotic nodules with new collagen and reticulin (i.e.,progressivemassivefibrosis). 2. Anthracosis is causedby the inevitableinhalation of some carbonaceousparticlesby city dwellers, cigarettesmokers,and miners. a. Clinical features. Deposition of carbon dust can be seen as black pigment in lung parenchyma,pleura, and lymph nodes.When isolated,it is not associatedwith symptomatic disease. b. Pathology. Macrophages aggregateinto small, peribronchiole regions in an attempt to phagocytosethe dust. 3. Silicosis. Chronic silicosisoccurs with prolonged exposureto silica dust (mining, glass production, sandblasting, farming, road construction), causingan insidious diseasethat can progressto respiratory failure and death. a. Clinical features. Patients with silicosis are at increasedrisk of developing TB. There is no associatedincreasedcancerrisk. b. Pathology. Collagenousfibrotic nodules form whereverthe silica is deposited,probably due to macrophage releaseof lysosomal enzymes and production of fibroblast growth factor (FGF). Initial involvement tends to be in the upper lobes and perihilar region. Pleural involvement creates dense fibrous plaques and adhesions that may obliteratethe pleural cavities.Similar nodulesappearin the lymph nodesand may calciff, resulting in an "eggshell"pattern on chestx-ray. Nodules can increasein size to such an extent that bronchioles,alveoli,pulmonary arteries,and subpleuraltissuecan all be compressed(i.e.,progressivemassivefibrosis).Uninvolved parenchymatends to be hyperinflated and emphysematous.

Note Silica dustinthelungs is ingested byalveolar macrophages, whichbecome damaged. There isthena release ofthemacrophages' lysosomal enzymes and production in of FCF,resulting fibrotic silicotic nodules.

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4. Asbestosisis a diseasecausedby a family of fibrous silicatescommonly found in shipyards,insulation, and roofing industries. a. Clinical features. Many years after exposure,patients complain of dyspnea,chronic dry cough, recurrent respiratory infections (especially viral), and weight loss. Respiratory failure can occur many years after exposure has ceased.Patients with asbestosexposure are at increased risk of developing bronchogenic cancer and mesothelioma (pleural and peritoneal). Smoking causesa multiplicative increasein the risk of developinglung cancer.Patientswith asbestosis are also at risk of developing renal and gastrointestinalcarcinoma. b. Pathology. Smaller asbestosfibers that reach smaller airways and alveoli are phagocytosed by macrophagesafter being covered with hemosiderin and glycoprotein (ferruginous body). This may incite an inflammatory responsedue to lysosomalrupture or oxygenfree radicals.Fibroblastsare abundant and createstriking interstitial fibrosis with septal wall widening, which is usually worse in the lower lobe and near the periphery. This processmay also involve the visceral pleura. In addition, patients developdensehyalinizedand possiblycalcifiedparietal pleural plaquesof varying size. Uninvolved parenchyma becomes hyperinflated, leading to "honeycombing." Secondarybronchiectasismay complicatethe picture. Extensivescarringmay narrow or obliterate alveoli,lymphatics, or pulmonary vessels,leading to pulmonary hypertension and cor pulmonale. 5. Berylliosis is causedby heavy exposureto airborne beryllium or its salts.Becauseof its high tensilestrength and resistanceto heat and fatigue,beryllium is still used in the electronic, ceramic, aerospace,and nuclear energy industries. Diseasecausedby beryllium probably representsa type IV hypersensitivityreaction, with noncaseatinggranuloma formation and eventualfibrosis.There is an increasedincidenceof bronchogeniccancer in patientswith berylliosis. C. Hypersensitivity pneumonitis (external allergic alveolitis) is an immunologically mediated interstitial lung diseasecausedby exposureto organic dustsand other occupationalantigens. 1. Clinical features. Patients tend to have a heightened responseto the offending agent, involving alveoli rather than the airways.Acute attacks are characterizedby fever, cough, dyspnea,and leukocytosis. Nodular and diffuse infiltrates appear on x-ray. Pulmonary function testsmay revealrestriction. Acute attacksare probably mediated via a type III immune complex reaction. If exposure is chronic, progressiverespiratory failure can occur with interstitial fibrosis and obliterativebronchiolitis. 2. Pathology. Microscopically, macrophages,plasma cells, and lymphocytes within the interstitium can be found. Peribronchiolargranuloma can be seen(chronic diseaseprobably representsa type IV delayedhypersensitivityreaction). 3. Types a. Farmer's lung is causedby thermophilic actinomycetesthat grow on hay. b. Byssinosis is causedby cotton, linen, or hemp exposure,leading to bronchospasm (possiblyhistamine related). D. Goodpasture syndrome is a necrotizing hemorrhagic interstitial pneumonia that can lead to hemoptysis (coughing up blood) and rapidly progressive glomerulonephritis (with crescentformation). The diseaseappearsto involve antibody recognition of a common pulmonary and renal basementmembrane antigen.

t98

Pathology

1. Clinicat features. Goodpasture syndrome usually occurs in individuals in their twenties and thirties and is more common in men. Death usually occurs as a result of complications of renal failure, but massivehemoptysiscan be responsible. 2. Pathology

In a Nutshell

a. GrosslR heavylungs with areasof red-brown consolidationare seen. b. Microscopically, there is focal necrosisof the alveolarwall, associatedwith intra-alveolar hemorrhage,fibrous thickening of the septa,hypertrophy of lining septal cells, and hemosiderin-containingmacrophages.Immunofluorescencestudiesreveallinear deposits of immunoglobulin along renal and pulmonary basementmembranes. 3. Prognosis hasbeen improved by using immunosuppression to inhibit antibody production and by plasma exchangethat can remove antibody and other immune response mediators. E. Idiopathic pulmonary hemosiderosisis an uncommon condition. 1. Clinical features.It is characterizedby the insidious onset of cough, hemoptysis,weight loss,and diffuse pulmonary infiltrates.It occursin young adults and children.Diseasecan vary from mild (occasionalhemoptysis) to severe(pulmonary fibrosis). Most patients have a chronic remittent course over years that eventually improves. The etiology is unknown.

Goodpasture Syndrome glomerular Antibodies against basement andpulmonary result in a membranes pneumonitis and hemorrhagic glomerulonephritis. reveals lmmunofluorescence linear deposits of lgCalong basement theglomerular you membrane. lf seea patient withbothhemoptysis think andhematuria, syndrome. Coodpasture

2. Pathology. There are focal areasof red to red-brown consolidation with degeneration, shedding, and hyperplasia of alveolar epithelial cells and alveolar capillary dilatation. Varying degreesof fibrosis may be seen.Hemorrhage occurs into alveolarspaces.Septae and free macrophageswithin alveolarspacescontain hemosiderin. F. Pulmonary alveolar proteinosis 1. Ctinical features. The diseaseis insidious in onset with cough productive of gelatinous material. The courseis variable,but patients can progressto pulmonary fibrosis (rarely) with dyspnea,cyanosis,and respiratory insufficiency. 2. Pathology. Pulmonary alveolarproteinosisis characterizedbythe accumulationof dense, homogeneous,granular, strongly PAS-positivematerial within the intra-alveolar space. This material contains abundant phospholipid and protein with lamellar bodies and refractile crystals. 3. Etiology. The causesremain obscureand are probably variable,including overproduction of surfactant-like material and a possiblemacrophagedeficiency that preventsalveolar scavenging. G. Diffuse idiopathic pulmonary fibrosis, or usual interstitial pneumonitis (UIP) is a syndrome of unknown etiology that resultsin chronic interstitial pneumonitis, which can lead to interstitial fibrosis and respiratory failure. 1. Clinical features. Men are affected more than women. The usual age for diagnosisis 30-50 years.Progressionis unpredictable;some individuals develop cor pulmonale and cardiac failure within severalyearsdue to lung disease,whereasothers experiencespontaneousremission.The rare, rapidly progressiveform of this diseaseis sometimesknown as the Hamman Rich syndrome. 2. Pathology. There is alveolar wall damage (possibly as a result of immune complex formation), especiallyto type I pneumocytes,that leadsto interstitial edemaand alveolitis. Hyperplasiaof type II pneumocftes occurs in an attempt to restorethe alveolar lining. Recruitment of fibroblastscan lead to fibrosis of both the interstitium and intra-alveolar exudate.The end stageof this processis the "honeycomb lung."

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Respiratory System

H. Desquamative interstitial pneumonitis (DIP) is a rare illness of unknown etiology that may be a precursor of interstitial fibrosis of the usual type. 1. Clinical features. Patients present with cough and dyspnea that can progressto ventilatory failure with ryanosis and clubbing. Radiographically, bilateral lower lobe groundglassinfiltrates are noted. Patients with DIP tend to respond more favorably to steroids than do patients with UIP. 2. Pathology. Mononuclear cells are found within alveoli, presumably desquamatedfrom alveolarwalls. Ninety percent of thesemononuclear cellsare macrophages,many of which contain lipid and PAS-positivevacuolesin addition to phagocytosedlamellar bodies. I. Pulmonary eosinophilia is a diverse group of illnessescharacterizedby eosinophilic pulmonary infiltrates. l. Simple pulmonary eosinophilia (Liiffler syndrome) a. Clinical features. Patients develop dyspnea with evidence of both restriction and obstruction on pulmonary function tests. b. Patholog;y.Tiansient pulmonary infiltrates of varying size and shapewith peripheral eosinophilia are seen.There is alveolar septal thickening as a result of eosinophils and occasionalgiant cellswith focal hyperplasiaof alveolarepithelial cells.This most likely representsa type I immune response. 2. Chronic eosinophilic pneumonia a. Clinical features. Patients develop high fevea night sweats,and dyspnea,all of which respondto steroids.This may representa primary immunologic processor a response to a number of parasitic, fungal, or bacterial infections, hypersensitivity pneumonitis, drug allergy,asthma, or allergic bronchopulmonary aspergillosis. b. PathologT. Peripheral and focal areasof cellular consolidation that represent alveolar and interstitial infiltration by lymphocftes and eosinophils iue seen. l. Sarcoidosis is a multisystem disorder of unknown etiology, characterizedby noncaseating granulomata. The diseaseusually involvesthe lung, followed by skin and eyemanifestations.

In a Nubhell Interstitial LungDiseases . Hypersensitivity pneumonitis . Coodpasture syndrome . ldiopathic pulmonary hemosiderosis . Pulmonary alveolar proteinosis . Diffuse idiopathic pulmonary fibrosis . Desquamative interstitial pneumonitis . Pulmonaryeosinophilia . Sarcoidosis 200

l. Epidemiology. SarcoidosisaffectsBlacks more than Caucasians,women more than men. Sarcoidosisis gener"lly. diseaseof young adults aged20-35 years. 2. Pathology. The granulomatous nature of the lesions suggests an immunologically mediated diseaseof the delayedhypersensitivity type. In fact, although patients have low peripheral T-cell counts (and are usually anergic), the number of T-helper cellswithin the lung is greatly increased,whereasT-suppressorcells are lacking. 3. Clinical features. Becausesarcoidosis is a multisystemic illness, presenting complaints vary markedly. a. Most patients seekmedical attention with the onset of respiratory symptoms, such as dyspnea,cough, chest pain, or hemoprysis. Others have systemic symptoms, such as fever,fatigue, weight loss, anorexia, and night sweats. b. Eighty percent presentwith hilar and mediastinal lymph adenopathywithout parenchymal involvement ("potato nodes") seenreadily on chestx-ray.Within the nodesare noncaseatinggranulomata that often contain Schaumann bodies (collection of calcium and protein) and asteroid bodies (star-shapedinclusions within giant cells). Occasionally, small nodules can be found in the lung parenchyma. c. Fifty percent present with a hypersensitivity reaction with fever, polyarthritis, erythema nodosum, and hilar adenopathy.

Pathology

d. Other involved organsinclude skin (nodules,plaques,macules),eyes(iritis, iridocyclitis), liver, spleen,and bone marrow. All involved organs display similar histopathology. 4. Diagnosis. Becauseof the variable presenting complaints, the diagnosis of sarcoidosisis frequently made clinically. Tissue demonstrating noncaseatinggranulomas confirms the clinical impression (Figure II-5-5). This distinguishessarcoid from TB, which shows caseatinggranulomas (central areasof caseousnecrosis).

* ':: ,'# g$

a'

Figure ll-5-5.Sarcoidosis: noncauseating granulomas (microscopic).

5. Prognosis. Sarcoidosis follows an unpredictable course characterized by alternating periods of remission and activity. Most patients recover with minimal or no residual effects.Twenty percent have permanant loss of pulmonary function or visual acuity. Ten percent develop chronic diseasewith pulmonary fibrosis and cor pulmonale. K. Pulmonary disease with collagen vascular disorders. Many collagen vascular disorders affect the lung and can lead to diffirse interstitial fibrosis. 1. Scleroderma classicallycausesinterstitial fibrosis. 2. Lupus erfthematosus causestransient pulmonary infiltrates and, occasionally, severe pneumonitis. 3. Rheumatoid arthritis may cause chronic pleuritis with or without an effirsion, diffi,rse interstitial pneumonitis with fibrosis, intrapulmonary nodules, rheumatoid nodules with pneumoconiosis( Caplan syndrome),or pulmonary hypertension. 4. Wegener granulomatosis is an acute necrotizing vasculitis with granuloma formation involving the lung in addition to the kidney and upper respiratory tract. It may consolidate and causescarring. 5. Lymphomatoid granulomatosis is a pleomorphic cell infiltration and destruction of lung tissue,which in some casesis a true monoclonal B-cell lymphoma.

20r

Respiratory System

In a Nutshell

VASCUTAR DISORDERS

Cardiogenic Pulmonary

A. Pulmonary congestion and edema result from an accumulation of fluid and protein within the pulmonary interstitium and alveolar spaceas a result of hemodynamic (Starling) derangementsor from increasedcapillary/alveolarpermeability.

Edema . Leftventricular failure . Mitral stenosis Noncardiogenic Pulmonary Edema . Septic shock . Pancreatitis . Burns . Toxin inhalation . 0,toxicity . Narcotic overdose . Pneumonia . Organic solvents

1. Most commonly, pulmonary edema developswhen there is an increasein pulmonary capillary pressure,as with left heart failure. Volume overload of the nephrotic syndrome and decreasedlymphatic drainagealso lead to transudation of fluid acrossthe alveolar membrane.As fluid accumulatesin the interstitium, interendothelialjunctions stretch, leading to increasedpermeability to both fluid and macromolecules.The lymphatic flow must be increasedlO-fold beforethe lung's drainagemechanismis overwhelmed,leading to edema.It is only after even higher capillary pressuresare achievedthat fluid moves from the interstitium into the alveolarspace. 2. Alveolocapillary permeability. Edema results after injury to both capillary endothelial and alveolarepithelial cells.Fluid and protein accumulateinitially in the interstitium and subsequentlyin the alveolar space.Noncardiogenic pulmonary edema can result from septic shock, pancreatitis,burns, toxin inhalation, oxygen toxicity, narcotic overdose, pneumonia, organic solvent hypersensitivity,and other causes.Pathologically,the lungs are heavy, wet, and subcrepitant, mostly involving the bases.Alveolar capillaries are engorged,and the alveolar spacecontains a granular pink precipitate.Alveolar microhemorrhageand hemosiderin-containing macrophages are present(FigureII-5-6). If the processbecomeschronic, macrophageswith hemosiderin are abundant,and alveolarwall fibrosis resultsin firm, brown lungs ("brown induration"). Thesepatientsare particularly susceptibleto bronchopneumonia(FigureII-5-7).

Figure ll-5-6.Ghronic passive congestion with hemosiderin-filled macrophages (microscopic).

202

Pathology

Figure ll-5-7.Chronic passive congestion with interstitial fibrosis (microscopic).

B. Pulmonaryhypertension. The pulmonary circulation is characterizedby low pressureand work. Pulmonary hypertenlow resistance,which protect the right ventricle from excessive sion usually occursas a result of elevatedpulmonary vascularresistance. 1. Primarypulmonaryhlpertension has an unclear etiology,although there are numerous theories.It generallyaffectsyoung women 2A40 yearsof age.Sometheoriesinclude: a. Multiple small pulmonary emboli, which becomeorganizedand incorporated within arterial walls b. Neurohormonal-induced vascular hyperreactivity, causing chronic vasoconstriction and pulmonary hypertension c. Immune complex-mediated disease d. Diet or medicinal products, such as appetite suppressants,which may causedirect endothelialdamage causingelevatedpul2. Secondarypulmonary hn>ertension resultsfrom known diseases, monary vascularresistanceand pulmonary pressures. a. Increasedpulmonary blood flow may be due to atrial septaldefect,ventricular septal defect,patent ductus arteriosis,or Eisenmengercomplex. b. Hypoxic vasoconstriction may be seenin COPD and interstitial lung disease. c. Elevatedleft heart pressures,transmitted back to the right sideof heart,may occur in congestiveheart failure, mitral stenosis,and left atrial myxoma. necrotizingvasculid. Destruction of pulmonaryvessels may occur in schistosomiasis, tis, multiple pulmonary emboli, sickle cell anemia,scleroderma,and COPD. 3. Pathology. A variety of vascularlesions with much overlap between primary and secondary hlpertension is seen.

20t

Respiratory System

In a Nubhell Pulmonary Embolism . Verycommon occurence . Occurs during timesof venous stasis, especially prolonged during bedrest orsittingCHF, andin primary venous disease . Mostoftenoriginates from a deepvenous thrombosis (DUDin thelower extremities or pelvic area . Risk factors include: obesity, pregnancy, cancer, oral contraceptives, hypercoagulabil ity,multiple fractures andpriorDVI . lf youaregiven a que$ion ontheexam where a patient (often bedridden post-surgical) develops sudden shortness of breath, thinkpulmonary embolism. Diagnosis wouldbe confirmed witha V/Q (ventilation/perfusion) scan.

204

a. In primary hypertension, medium-sized muscular arteries develop medial hlpertrophy, intimal thickening and fibrosis with adventitial fibrosis, and internal and external elastic membrane thickening and reduplication. Small arteries and arterioles are most affectedwith medial thickening. A "plexiform lesion" may form, consisting of cellular intraluminal angiomatous tufts. b. Secondarychanges are similar to those in the primary diseasebut may have organized thrombi and diffirse atheroscleroticchangeswithout calcification or ulceration. 4. Clinical course. Patients become symptomatic only after the diseaseis well advanced. They usually presentwith dyspneaand fatigue. Occasionally,syncopeor angina can be the initial manifestation. Respiratory failure or decompensatedcor pulmonale result in death within severalyears of presentation. C. Pulmonary thromboembolism and infarction is an underdiagnosedentity (500,000annually; 10olofatal) resulting in occlusion of a pulmonary artery by an embolic blood clot. Thrombosis on top of a nonocclusiveembolus may lead to complete arterial obstruction. The usual sourcesof emboli are the deep veins of the leg. However, a clot can also develop in the pelvic veins and right heart. 1. Risk factors include bed-bound conditions, obesiry cancer,pregnancy,oral contraceptives, hypercoagulabiliry and prior deep venous thrombosis. a. Large emboli may occludethe main pulmonary artery or its major branchesor lodge in the pulmonary arterybifurcation,leading to a "saddleembolus."Suddendeath can follow from blockageof blood flow out of the right ventricle or from acute right heart failure (acutecor pulmonale). b. Small emboli occlude smaller vessels.Fewerthan 10oloof pulmonary emboli causeinfarction asa result of bronchial artery collateralflow to the lung parenchyma.Under theseconditions, hemorrhage with parenchymal preservation rather than infaraion occurs. If the collateral circulation is compromised, even small emboli can causeinfarction. 2. Pathology. Characteristically,infarctions extend to the lung periph.ry forming a wedgeshaped,pleural-basedinfiltrate. Initially, the infarct is hemorrhagic with ischemicnecrosis ("red infarct") (Figure II-5-8). Fibrinous exudateforms on the apposedpleural surface.RBCslysewithin 48 hours, and eventually fibrous replacementbegins at the margins, leading to scarformation.

Pathology

Figure ll-5-8.Pulmonaryinfarct (gross).

3. Clinical features of a pulmonary embolus depend on its size. a. Small emboli causetransient cough, dyspnea,tachycardia,hyperventilation,and possibly chestpain. Infarction may producefever,worseningchestpain, and hemoptysis in addition to dyspneaand tachypnea. b. Large emboli can produce sudden death with a clinical syndrome similar to an acute myocardialinfarction (chestpain, severedyspnea,shock,fever). D. Fat embolism is characterizedbyprogressiverespiratoryinsufficiency,mental deterioration, and occasionallyrenal insufficiency.Theseemboli usuallydevelop 1-3 daysafter a longbone fracture. 1. Pathogenesisis controversialand probably multifactorial. a. Releaseof fat globules from the marrow may simply occlude vesselsin the lung and brain. Smallerglobulesmay fit through the pulmonary vasculatureand causesystemic emboli. b. Chylomicrons may coalescewith stress,leading to vesselocclusion. c. Disseminatedintravascularcoagulation (DIC) may cause obstructive symptoms, exacerbatedby fat emboli. d. Freefatty acidsmay causemicrovasculartoxic injury, leading to capillary block. 2. Prognosis.Mortaliry is high (10-i5%). E. Amniotic fluid embolism. Releaseof thrombogenic amniotic fluid into the maternal circulation during delivery causeswidespreadthrombosis and occlusion of pulmonary capillaries.DIC may follow. There is a high mortality rate.

205

System Respiratory

MISCELTANEOUS DISORDERS PUTMONARY A. Lipid pneumonia is causedby aspiration of a variety of oils, and it resultsin patchy or diffuse consolidation. The aspirated oil is emulsified upon reaching the alveolus, and oil droplets are phagocytosedby macrophages.In the early stage,the involved alveoli are partially or totally filled with distended,occasionallymultinucleated macrophagescontaining clear cftoplasmic granules.Progressionof diseaseinvolves fibroblast organization of the inflammatory reaction into granulomataand fibrous tissue.

ln a Nutshell Neonatal Respiratory (Hyaline Distress Syndrome Membrane Disease) . Mostcommon cause of deathin premature neonates . Deficiency of surfactant, mainly of composed lecithin dipalmitoyl . Atapproximately the33rd the weekofpregnancy, lecithin concentration increases. Thesphingomyelin remains $able. concentration A lecithin: sphingomyelin ratiogreater orequalto 2:l lunpinthe indicates mature newborn. . Risk factors forneonatal include respiratory distress prematu rean rity,caesa birth,mother with section diabetes mellitus.

B. Neonatal respiratory distress syndrome (hyaline membrane disease)occurs in premature infants asthe result of a deficiency in pulmonary surfactant becauseof inadequatelecithin synthesisby irnmature tnre II pneumocftes. Grossly, the lungs are normal sizedbut solid, airless,and reddish-purple.Alveoli are small and collapsed(atelectasis),whereasproximal alveolar ducts and bronchi are overdistended(emphysema).Necrotic material becomes incorporated into pink fibrin-rich hyaline membranesthat line alveolarducts and alveoli. C. Pneumonia in the immunocompromised host. Pulmonary infiltrates and signsof infection commonly occur in immunosuppressedpatientsundergoing chemotherapy,after transplantation, or with AIDS. A wide arrayof opportunistic infections can causethesepneumonias, many of which rarely causediseasein normal hosts. 1. Cytomegalovirus (CMV) infections acquired postnatally tend to be asymptomatic but can produce seriousillnessin the immunocompromised host, usually involving the lung and intestinal tract. Lung involvementtakesthe form of an interstitial pneumonitis with intracellular inclusions in the alveolarlining cellsand in endothelial cellsof septalcapillaries,as well as in macrophages.Intra-alveolar edema,proteinaceousexudate,and focal hyaline membranesmay appear,depending on the severity of infection. Cellular inclusions occur in enlarged cells (cytomegalo-) with pleomorphic nuclei containing acidophilic nuclear inclusions. The inclusion may be one half the diameter of the nucleus and is surrounded by a clear halo, separating it from the nuclear membrane. Acidophilic inclusions may alsobe seenin the cytoplasm. 2. Pneumocystiscarinii pneumonia (discussedearlier in this chapter) 3. Other infections are caused by fungal (Cryptococcus,Aspergillus) and bacterial (Pneumococcus, S. aureus)agents. D. Atelectasiscan be causedby either a failure of the lungs to expand at birth or by collapseof previously air-filled lungs by processesincluding air obstruction (followed by resorption of air), compression(by blood, fluid, tumor, or air in the pleural cavify), or contraction (by fibrosis). Microscopically, the alveolar spacesare compressedand contain little or no air. Atelectasisis typically a benign condition unless infection supervenesor so much lung tissueis involved as to compromise respiratory function.

LUNGTUMORS Most lung tumors representmetastaticlesions.Of the primary lung neoplasms,most are bronchogenic carcinomas. A. Benign neoplasms 1. Hamartomas are the most common benign pulmonary neoplasm.They affect men more frequentlythan women (3:1) with a peak incidencein the sixth decade.They are uncommon in patientsunder 30 yearsof age.Hamartomas :re mesenchymalneoplasms,composedof a mixture of tissuesusually found in the lung (cartilage,smooth muscle,collagen)in a disorganizedarray.They can becomeextremelylarge despitetheir benign nature and can remain

206

Pathology

clinically silent becauseof their peripheral location. Calcification resemblittg"popped popcorn" occurstn 5-20o/oof hamartomas. 2. Bronchial adenomasarisefrom bronchial mucous glands. 3. Leiomyomas arise from smooth muscle,usually in an endobronchial location. They are usually a diseaseof young women (averageage37)' 4. Hemangiomas are usually peripheral and often subpleural. 5. Lipomas are usually endobronchial and can occur on either side of the bronchial cartilage. 6. Chondromas are derived exclusivelyfrom formed bronchial cartilage. (e.g., 7. Teratomas are rarely found in the lung and may contain tissuefrom any germ layer teeth,hair). g. Endometriosis may be metastatic,or it may arisefrom pleuripotential pulmonary tissue. B. Bronchial carcinoids make up 5o/oof all primary lung tumors. They are a diseaseof young adults (3545 yearsof age).The frequencyis equal in men and women. Smoking does not appearto be an indepenJentrisk factor.The cellsare derivedfrom a precursorcell,are closely ielated to the Kulchitsky neuroendocrine argentaffin cell, and contain neurosecretory granules.The releaseof neuroendocrinesubstancesleadsto the carcinoid syndrome. l. Clinical features. Eighty percent of bronchial carcinoids are central lesions that are "radiographicallysilent" but can lead to bronchial obstruction, causingcough,fever,chest pain, and localizedwheeze.Hemoptysis is presentin approximately50o/o,reflecting ceniral origin and hypervascularity.Complete obstruction can lead to bronchiectasisand pu..rr.hy-al necrosisdistal to the obstruction. Twenty percentare peripheral lesionsthat ur. ,rr,rully clinically silent; they are detected fortuitously on routine chest x-ray as a slightly lobulated nodule. Calcificationis rare.Only 3.5o/odevelopthe carcinoid syndrome with diarrhea,cutaneousflushing, wheezing,heart disease(valvular fibrosis), abdominal pain, and.telangiectasia.Symptoms are due to releaseof such comPoundsas bradykinin' prostaglandins,serotonin,insulin, gastrin,ACTH, and melanocyte-stimulatinghormone' bevelopment of the carcinoid syndrome usually reflectsmetastaticdiseaseto the liver. 2. pathology. Becausethe appearance,both grossly (presenceof a capsule)and histologically (absenceof mitoses),correlatespoorly with the clinical behavior, all carcinoids should be regardedas potentially malignant. They grow as either polypoid lesions or as a predominantly infiltiative process with submucosal growth and minimal protrusion into the lly, they most commonly form clumps of small, uniformly bronchial lumen. Mi*or.opi. staining cells with round nuclei and infrequent mitoses with a rich vascular stroma. Carcinoidscan alsohavenestsor cordsof cellsseparatedby a delicateweb-like stroma.Some form acini and producemucin, whereasothersappearhighly malignant and resembleoat cell carcinoma.Local invasion is relativelycommon. Distant metastasisoccursin2-5o/o. 3. Tleatment is usually surgical removal of nonmetastaticdisease.If metastatic,5-yearsurvival is only 2}o/o,althoughsome havean indolent and protracted coursespanningmany years. C. Bronchogenic carcinoma is the leadingcauseof cancerdeath among both men and women. The female preponderancehas increased,most probably as a result of increasedsmoking among women in the past few decades.Bronchogeniccarcinomaoccurs most commonly in patients 40-70yearsoi"g.. Adenocarcinoma is the most frequent type of bronchogeniccarcinoma, surpassingsquamouscell carcinoma.Carcinoma of the lung begins as an area of cellular hyperplasi. u"a atypia that causesthickening of the bronchial mucosa.Eventually,

207

Respiratory System

an irregular elevationforms that can elevateor erodethe lining epithelium. Continued progression can follow one of three paths: intraluminal growth, infiltrative peribronchial growth, and intraparenchymal cauliflower-like gto*th that pushes normal tissue away. When bulky' hemorrhageor necrosiscan convertthe usual grey-whitefirm massto yellowa white mottled and softer mass.Spreadto hilar, mediastinal,bronchial, and tracheal lymph nodes is common (50olo).Metastasisvia lymphatics or blood occurs relatively early. Oniv approxim ately25o/oof lung cancersare operablewhen discovered. l. Types a. Adenocarcinoma (35o/o)usually forms peripheral tumors that arisefrom distal airways and alveoli, although occasionally they occur proximally, arising from submucosal glands or epithelium. Ttrmors form well circumscribed, gray-white massesthat rarely cavitate.They may alsodevelopin areasof parenchymal scarring (scarcarcinoma,Figure II-5-9). Microscopi."lly' thereis a spectrumof disease. Well differentiatedtumors have cuboidal or columnar cellswith microvilli that form gland-like structuresand produce mucin. Poorly differentiatedtumors form papillarylesionsor solid massesthat tend not to be mucin producing.Adenocarcinomaoccursequallyin men and women and is less closelyassociated with smoking than squamouscell.

Note Small cellcarcinoma cells secrete thehormones ACTH andADH.Thismaygiverise to a Cushing syndrome or syndrome of inappropriate ADH(SIADH), respectively. Squamous cellcarcinoma may secrete a parathyroid hormone-like substance that maycause hypercalcemia. (See Table ll-5-tonpage 211 formoreonparaneoplastic syndromes.)

b. Squamous cell (25o/o)arisesfrom bronchial epithelium after yearsof mucosal alterations, including metaplasia,dysplasia,and carcinoma in situ. The tumor starts as a small red granular plaque or as a focus of whitish leukoplakiaand progresses to a large intrabronchial mass. Cavitation may occur in the lung distal to the mass. Microscopi.ully' there are intercellular bridges connecting the abnormal neoplastic cellsand abundant keratin formation ("squamouspearls").Squamouscell carcinoma is most closely related to cigarette smoking. It tends to metasiasizelocally and somewhat later than the other lung tumors. It is more common in men and is usually centrally located. c. Small cell carcinoma (25o/o)forms proximal, large, soft, gray-white masses that can narrow bronchi circumferentiallysimply by extraluminal tumor bulk. There is rapid growth and early disseminationso that, if untreated,the median survival is lessthan 3 months. Microscopically, fusiform round or polygonal cellsin clustersexhibit neither glandular nor squamouscharacteristics.Cell, upp.oximately two times the "." size of lymphocyteswith inconspicuousnucleoli and modest amounts of cytoplasm (the classic"oat cell carcinoma" presentation).The cytoplasm holds derrse'granules and contains various peptides, suggestingthat small ceil carcinoma is part of the group of cancersderived from neuroendocrineApuD cells. d. Large cell carcinoma ( l5o/o) forms peripheral, anaplasticlesions that can become quite large and active.Microscopically, cells are large with abundant cytoplasm and distinct cytoplasmic membranes,prominent nucleoli, and large nuclei. There is no squamous or glandular differentiation, although large cell cancer may represent a poorly differentiatedform of adenocarcinomaor squamouscell carcinoma. -e[s may contain mucin. Some form multinucleated giant cells.Others have clear cytoplasm, whereasothers form spindles. e. Bronchioalveolar carcinoma (5o/o)is a subsetof adenocarcinomathat arises from terminal bronchioles or alveolar walls. These tumors form peripheral nodules with mucinous grey translucence. Fifty percent secrete mucin. Microscopically, tall, columnar-cuboidal cells grow along the walls of pre-existing alveoli and can project into alveolarspacesin papillary formations. However,most are well differentiated and preservealveolararchitecture.

208

Pathology

2. Major risk factors a. Cigarette smoking. The incidence of lung canceris related to the number of cigarettes smoked per day,the duration of cigaretteuse,the depth of inhalation, and the type of cigarette used. Histologic changes in the bronchial epithelium caused by smoking include: (1) Lossof bronchial cilia (2) Basalepithelial hyperplasia (3) Nuclear hlryerchromatism b. Occupational exposure, including uranium mining, metal work, painting, and exposure to radiation, may increasethe risk of cancer. c. Air pollution. Reducing agents (sulfur dioxide and carbonaceousparticulate matter) appear to be carcinogenic,whereasoxidants are not. d. Genetics. There maybe a familial predisposition to lung cancer,particularlywith deletions or mutations of p53 or the retinoblastomagene.

Figure ll-5-9.Adenocarcinoma of lung associated with scar (microscopic).

209

Respiratory System

3. Clinical features. There are two modes: early and late, depending upon cell type and site of origin. Stagingof diseaseis by the sizeof the tumor, number of affectednodes,and distant metastasis(TNM system).In the early stageof disease,intrabronchial lesionscause mild cough or a changein the characterof a chronic cough. Partial obstruction may produce focal emphysema.Total occlusionleadsto postobstructiveatelectasisor pneumonia with fever,chills,sputum production,localizedwheeze,hemoptysis,or abscess formation. In the late mode, there is a wide spectrum of presentations.

Note venacava(SVC) Superior syndrome maybea presentation of bronchogenic carcinoma. Inthissyndrome, ob$ruction oftheSVCby tumorresults in dilatation of headandneckveins, facial swelling, andcyanosis.

a. Nonspecific systemic symptoms include weight loss, anorexia, fatigue, weakness, and nausea. b. Intrathoracic spread can lead to Horner syndrome with secondarycervical sympathetic nerve involvement, superior vena cava syndrome, dysphagia with secondary esophagealobstruction, hoarseness with secondaryrecurrent laryngealnerve involvement, diaphragmatic paralysiswith secondaryphrenic nerve damage,and Pancoast tumor (causingulnar nerve pain and Horner syndrome). c. Extrathoracic extension may involve prescalenelymph nodes, brain, liver, adrenal, and, most commonly, bone metastases. d. The systemicsyndromes,or paraneoplastic syndromes, may occur before the lesion is visible on x-ray. (1) Endocrine/metabolicsyndromesare listedin ThbleII-5-1. (2) Neuromuscular syndromes include cerebral encephalopathyand cortical cerebellar degeneration(small cell), peripheral neuropathy with pain, paresthesias, myasthenia(Eaton-Lambertsyndrome),and proximal muscleneuromyopathy. (3) Hematologic/vascularsyndromes include anemia unrelatedto therapy or bone marrow infiltration, coagulopathy (Trousseausyndrome), migratory thrombophlebitis,DIC, noninfectious endocarditis,and arterial embolization. (4) Dermatologic signs are dermatomyositis,hyperpigmentation, and acanthosis nigricans. (5) Skeletal and connective tissue syndromes include hypertrophic pulmonary osteoarthropathy (periosteal new bone formation, clubbing, and arthritis), which is sometimescausedby squamouscell carcinoma.Vasomotor instability with blanching of hands and feet may alsobe seen.

2t0

Pathology

Thble II-s-f . Paraneoplastic syndromes. Hormone Secretedby Tirmor

Pathophysiologic Consequences

ACTH MSH PTH

Cushing syndrome (rare) Increasedskin pigmentation Hypercalcemia,often due to squamouscell carcinoma Hlponatremia Gynecomastia(large cell) Lactation in men or women Diarrhea, hypokalemia, achlorhydria (squamouscell) Hypocalcemia

ADH HCG Prolactin VIP Calcitonin

Definitions: ACTH - adrenocorticotropic hormone; MSH : melanocyte-stimulating hormone; PTH = parathyroid hormone; ADH = antidiuretic hormone; HCG : human chorionic gonadotropin; VIP = vasoactiveintestinal polypeptide.

4. Treatment. Surgical resection offers the only definitive means of therapy by which nonsmall cell lung cancer can be cured. Unfortunately, fewer than 30oloare "curable" upon presentation,so that the 5-year survival has not improved over the last four decades. Adjuvant therapy (chemotherapy and/or radiation) remains controversial. For most patients with non-small cell cancer,palliation of symptoms becomesmost important. A trial of chemotherapy in "healthy" patientsthat is continued only if a responseoccurscan be attempted. Radiation is highly effective palliation for superior vena cava (SVC) syndrome, hemopfysis,pain, and dyspnearesulting from airway obstruction. Lasertherapy can also improve airway obstruction.

MEDIASTINAT MASSES Mediastinal massesoften present as an unexpectedfinding on routine chest x-ray. Symptoms are due to either compressionor invasion of neighboring structures.Vascularlesionsmay present as"masses"in all parts of the mediastinum and include congenitalvascularrings; double superior venaecavae;aortic malformations,aneurysms,and dilatations;aneurysmor dilatation of major aortic branches;and dilated pulmonary arteries.Other massesinclude diaphragmatic herniations and pulmonary lobar sequestrations.The mediastinum can be divided into three compartments,eachwith characteristiclesions: A. The anterior mediastinum rangesfrom the root of the neck, extending down to include the region betweenthe sternum (anteriorly) and pericardialsurface(posteriorly). 1. Thymoma is the most common anterior mediastinal mass. There are four cell types: epithelial,lymphocytic, spindle, and mixed. Benign thymomas have a thick fibrous capsule and do not invade.Malignant thymomas lack a capsuleand do invade.

ClinicalCorrelate Sputum cytology, transbronchial biopsies, and openbiopsies areallusedto diagnose lungcancer. Pathologists to arealsoasked margins evaluate resection aftersurgery the andto detect presence of lymphnode metastases. Evaluation of liver andbonemarrow biopsies arerequired inthesetting of meta$atic disease forthe purpose of staging.

Bridgeto Cardiovascular Theanatomy ofthe mediastinum in isreviewed theCardiovascular Anatomy chapter.

2. Teratomasare tumors derived from pluripotential precursor cells. a. Mature teratomas (dermoid cysts) generally show ectodermal differentiation, although elementsfrom other germ layersmay be present.They are generallybenign, although approxim ately lo/oundergo malignant transformatio n. b. Immature teratomas havea fetal or embryonic appearancemicroscopically;primitive neuroepithelial cells are frequently encountered.Immature teratomas may behave aggressively; tumor behavior correlateswith histologic grade.

2tl

System Respiratory

3. Lymphorna. The most common lymphoma is nodular sclerosingHodgkin disease. Tiachealcompressionoccursin 2096. 4. Glsts of pericardial,bronchogenic,or tlymic origin are alsorarely seen. Bri{e to Hene/L,ymgt Lvmphoma isdiscussed in detailin the Hematologiq Lymphoreticular Pathology chapter ofthisbook.

5. Introthoracic goiter is an unusualfinding. B. The middle mediastinum includesthe pericardium and its contents,lower trachea,carina and mfi bronchi, and lymph nodes. 1 Ct/sts a- Pericardial cysts are usually located in the cardiophrenicangle.They occasionally communicatewith the pericardialspaceand are composedof one mesotheliallaye6 coveringa thin fibrous wall. b. Bronchogeniccystsarelined with ciliated columnarepithelium with mucousglands and cartilagein the wall. c. Enteric c1stsarelined by squamousepitheliumand smoothmusclewithout cartilage. 2. Lymphoma, both Hodgkin and non-Hodgkin types, may involve middle mediastinal nodes, 3. Primarymediastinal carcinoma may arise from cyst epithelium. 4. Granulomatous lesions. Histoplasmosis, sarcoidosis, and TB all may involve middle mediastinalnodes,usually becausethey drain primary lesionsin the lungs. C. The posterior mediastinum includes the posterior pericardium to the anterior vertebral column and posterior ribs, including the paravertebralgutters. 1. Neurogenic tumors are almost alwaysbenign in adults, although 10o/ohave an intraspinal component. Thesetumors are describedmore fully in the Neuropathologysection. a. Schwannomas (neurilemomas) are benign nerve sheath tumors of Schwann cells. b. Neurofibromas are benign nerve sheath tumors of fibroblasts. c. Ganglioneuromas are benign nerve cell tumors of sympathetic ganglion cells. They occur primarily in the second and third decades. d. Ganglioneuroblastomas are malignant tumors of sympathetic neurons; they are common in children and infants. e. Neuroblastoma is also common in children and infants and is highly malignant.

2r2

Pathology

DISEASES OFTHEPTEURA A. Effusions are abnormal accumulations of fluid within the pleural space; they are a common manifestation of both systemic and intrathoracic disease.The normal pleural space contains no more than 15 mL of serousfluid that lubricates the pleural surface.The factors that determine whether pleural fluid accumulates include oncotic pressure in the pleural microcirculation and surrounding tissue,permeability of the pleural microcirculation, pressure in the pleural microcirculation and surrounding tissue,intrathoracic negativepressure, and lymphatic drainage.Pleural effusions can be divided into transudates (low lactate dehydrogenase,lowprotein) and exudates(high lactatedehydrogenase; high protein). 1. Noninflammatory pleural eftrsions (transudates) a. HydrothorilL Noninflammatory serous fluid collects in the pleural cavity as a result of CHF (increasedpressure),renal failure (fluid overload,increasedpressure),cirrhosis (fluid overload, decreasedoncotic pressure), or nephrotic syndrome (fluid overload, decreasedoncotic pressure).The fluid is clear and straw colored, with a specific gravity of less than 1.012 (normal value). It does not loculate unless there are preexisting pleural adhesions. Meigs syndrome is the association of ovarian cancer, ascites,and pleural effusion; it is thought to be causedby lymphatic stasis.

Bridge tg -Cardio-v1Rula1 Nowmaybea goodtimeto review theStarling equation in theCardiovascular Physiology chapter inthisbook. Transudates result fromt P.,J rr",ot a combination of thetwo.

b. Hemothorax follows hemorrhage into the pleural space,often the result of a rupturing aortic aneurysmof iatrogeniccauses,such asbiopsies. 2. Inflammatory pleural effrrsions (exudates) a. Serofibrinous pleuritis is caused by inflammatory diseases within the lung such as TB, pneumonia,lung infarcts,lung abscess,and bronchiectasis.Systemicdisease,such as rheumatoid arthritis, systemiclupus erythematosus,uremia, and diffirse infections, can also causeserous or serofibrinous pleuritis. The fluid consistsof relatively clear, straw-colored fluid with small strands of yellow fibrin and few WBCs. Specific gravit'' is greater than 1.020.Minimal inflammation is present,and the fluid can be absorbed with either resolution or organization of the fibrinous component. b. Suppurative pleuritis (empyema) is a purulent exudate with bacterial or fungal seeding of the pleural space,usually by contiguous spread from the lung. Occasionally, infection can come from blood or lymphatics. It is characterizedby yellow-green pus with massesof polyps and other leukocytes.Empyema infrequently resolvesbut usually organizeswith the formation of tough fibrous adhesionsthat can obliterate the pleural spaceor form a pleural "peel," preventing pulmonary expansion.Calcification is typical of tuberculous empyema. c. Hemorrhagrc pleuritis is uncommon, but it is found in patients with bleeding tendencies,rickettsial disease,and pleural neoplastic disease. B. Pneumothorax is an accumulation of air or gas in the pleural cavit'', leading to collapse of the underlying lung as a result of increasedsurrounding pressure(pleural pressureis usually negative).Pneumothorax is frequently causedby spontaneousrupture of an alveolusor bleb or by a communication between an abscessand either the pleural spaceor interstitium. It is most common in patients with emphysema, asthma, srd TB. Tlaumatic pneumothorax results from puncture of the chest wall with communication between the pleural space and external environment. When air can enter the pleural spacebut not exit during expiration, pressurebuilds, leading to a tension pneumothorax with tracheal deviation, respiratory compromise, and hemodynamic instability.

InlN,11$,etf Transudate Exudate . Specific grmty lesstran 1.012

. Speciftganty grmtettnn 1.020

' l,loninflammatorylnflammatory edema fluid

ederna fluidwifr

rsultingfrom

rnsorhr increased

changcin

permeabilrty

trydro*atic or

.i

osrnotcpr6$re influid intravascuhrto/ J $ucose . J protein influid

t inflamnntory cellsinfluid

21'

Respiratory System

C. Tumors 1. Metastatic involvement of the pleura is most common, usually from the breast or lung. 2. Malignant mesothelioma is a rare tumor that arisesfrom parietal or visceral pleura. It is associatedwith asbestose4posureafter a prolonged latent period of 2545 years.In contrast to bronchogeniccarcinoma,in which smoking and asbestosexposureact synergistically, smoking does not increasethe risk of malignant mesothelioma.The malignant mesothelioma is a diffuse lesion that spreadsover the lung surface,causing a pleural effirsion and invasion of thoracic structures.The lung is encasedby a thick tayerof gray-pink tumor, composed of mesenchy-d stromal cells or even papillary, epithelial-like cells. Patientscomplain of chestpain and dyspnea.prognosisis poor.

IARYNGEAI DISEASES A. Inflammation. taryngitis is usually part of an inflammatory processof the lung and lower respiratory tract. It may also be involved with dififr.rseinfections, such as TB, ryphilir, diphtheria' and local diseaseof the mouth and throat. Although trivial in the adult, laryngeal inflammation can lead to upper airwayobstruction in children. B. Tumors 1. Benign neoplasms a. Pollps usually occur on the true vocal cords as smooth, round nodules that may be pedunculatedor sessile.Polyps are composedof loose connectivetissueand covered by squamous epithelium that can ulcerate when traumatized by the opposite vocal cord. They are associatedwith heavy smoking and vocal cord overuse. b. Papilloma is a true neoplasm,usually a soft, friable nodule on the true vocal cords. Papillomasfrequently ulcerateand bleed with manipulation. They are composedof multiple finger-like projections composed of fibrous tissue coveredwith squamous epithelium. Papillomasrarely undergo malignant transformation. 2. Malignant tumors are uncommon except for those arising from the surfaceepithelium. Most occur on the vocal cords, although they can occur anywhere.Ninety-five fercent are squamous cell carcinomas, which can cause hoarseness,difficulty swallowing, pain, hemoptysis,and, eventually,respiratory compromise.Ulceration can lead to suplrinfection. Complications arise due to direct extension,metastases, and infection. Risk factors include cigarettesmoking, alcohol,and frequent cord irritation. C. Congenital anomalies. Laryngeal stenosis and atresia require rapid diagnosis and tracheostomyat birth. They may be accompaniedby cardiacor renal difects.

214

Pathology

AIRSINUSES DISEASES OFIIIE NASAT CAVITIES ANDACCESSORY A Rhinitis is an inflammation of nasal cavitiescausedby viruses,bacteria,and allergens. Mucinousdischargeandcawrhal exudationarecommon.Thenasalmucosais thickened,edematous,and hyperernic.Nasalcavitiesare narrowed.Turbinatesare enlarged.Inflanmatory hypertrophicswellingof the mucosagivesris€ to nasalpolyps.Micoscopically, polypsshow edemaand infiltration with eosinophilsandplasmacells. B. Sinusitis is inflammation of the nasalaccessorysinuses;it is closelyrelatedto rhinitis. It is usually precededby acute inflammation of the nasal cavities,leading to infection and inflammation of the sinuses.

Note Nasl polyps,a$hma,and arepathognomic sinusitis manifestations of aspirin allergy'

C, Ttrnors. Various types of mesenchymalneoplasmscan occur, although most are poorly differentiatedsouamouscell carcinomas.

215

Respiratory Pharmacology "breathe There area number of classes of drugs thathelppeople easie/' by$imulating dilatation of passages thebronchial or reducing bronchopulmonary inflammation. Thischapter reviews the different classes of drugsthathavebeeneffective in thetreatment of respiratory disorders andtheir pharmacologic properties, specific mechanisms of action, andpertinent sideeffeG.

ADRENERGIC AGONISTS Adrenergic drugs causevasoconstriction by stimulating cr-adrenergicreceptors,cardiac stimulation by stimulating B,-adrenergic receptors,and bronchodilatation by stimulating Br-adrenergic receptors.Adrenergic drugs include the direct stimulants of c-adrenergic and p-adrenergic receptors,such as epinephrine; the indirect and direct stimulants, such as ephedrine; and the selectivep-adrenergic stimulants, such as isoproterenol. This last group of p-adrenergic receptor stimulants may be further subdivided into agents that have a preferential action on bronchial muscles (p, stimulants) and agentsthat preferentially effect the heart (B, stimulants). Various pr-selectivedrugs have been developed primarily for their value in treating bronchial asthma.Through their specificity for pr-adrenergic receptors,they relax smooth musclesof the bronchi but have much lessstimulatory action on the heart than does isoproterenol. A. Epinephrine 1. Pharmacologic properties

Bridgeto Neruous System Foranextensive review of the receptors oftheautonomic nervous system aswellas theiragonists andantagonists, seethePhysiology and Pharmacology chapters inthe Nervous System section.

Note B,arefoundonallsmooth particularly muscles, blood vessels; theirstimulation results invasodilation, a dropin bloodpressure with possible reflex tachycardia.

a. Epinephrine stimulatesboth u- and p-adrenergicreceptors.

Mnemonic

b. o-adrenergic receptorsmediate a potent vasopressoraction on the vasculatureof skin, mucosa,and kidneys.

. 9,4 2 lungs .9,Jlheart

c. A positive cardiacchronotropic and inotropic action is B, mediated. d. Bronchial smooth muscle is relaxedby activation of pr-adrenergic receptorsthat stimulate cAMP production. e. A decreasein mast cell secretions(p, mediated) may also help to alleviate asthma. f. Vital capacity is increasedsubsequentto relief of bronchial mucosal congestion. 2. Pharmacokinetics a. Epinephrine is rapidly absorbedafter intramuscular or subcutaneousinjection. It is not effective if taken orally but can be administered by inhalation of nebulized solution. b. Metabolism occurs by either hepatic oxidative deamination by monoamine oxidase (MAO) or methylation by catechol-O-methyltransferase (COMT). c. The primary excretion product is urinary vanillylmandelic acid.

Bridgeto Pathology Pheochromorytomas are uncommon tumors ofthe producing adrenal medulla catecholamines. Their presentation isidentical to sideeffects andtoxicity of epinephrine, andtheir diagnosis involves the measurement of elevated urinary VMA.

217

Respiratory System

3. Indications for use. Epinephrine is usefrrl for acute asthmatic attacks to provide rapid relief of respiratory distress,for hypersensitivity reactions to drugs and other allergens, for the prolongation of infiltration anestheticaction, and for its topical hemostatic effect. 4. Side effects and toxicity a. Excessivestimulation of adrenergic receptors causes anxiery tremoS palpitations, tachycardia,headache,diaphoresis,and pallor. b. Contraindications include hypertension, hlperthyroidism, ischemic heart disease, and cerebrovascularinsufficienry (not recommended over age 60 unless asthma is intractable).

ln a Nubhell Epinephrine stimulates crand adrenoreceptors and isused B foracute reactions, allergic especially anaphylactic shock. It isalsousedforacute asthma attacks andrespiratory distress. There areoften unwanted sideeffects associated withepinephrine's p, stimulation (e.g., tremor, palpitations, tachycard ia).

Note preparations Anumber ofOTC andherbal medicines contain ephedrine andanalogs and maybeabused fortheir psychostimula nt-likeeffect.

B. Ephedrine 1. Pharmacologic properties a. Ephedrine stimulates both o- and B-adrenergicreceptors;it also increasesthe release of norepinephrine (an indirect action). b. An increasein pulse pressureis causedby vasoconstrictionand cardiacstimulation. c. It is a CNS stimulant. 2. Pharmacokinetics a. Ephedrine is rapidly absorbedafter oral administration. b. Ephedrine is similar to epinephrine but has a longer duration of action, more pronounced central actions, and a much lower potenry. 3. Indications for use include chronic casesof asthma that require continued medication (used only occasionally now that Br-selectiveagentsare available) and as a mydriatic (in aqueoussolution). 4. Side effects and toxicity a. CNS stimulation may occur, manifesting as nervousness,excitabiliry or insomnia. b. Increasedperipheral vascularresistancemay result from its use. C. Isoproterenol 1. Pharmacologic properties a. Isoproterenolstimulatesp-adrenergicreceptors(9r and 0r) and hasvery little effecton o-adrenergicreceptors. b. Almost all smooth muscleis relaxed,especiallybronchialsmooth muscle,by stimulating the production of cAMP (p, mediated). c. Peripheral vascular resistanceis lowered in skeletal, renal, and mesenteric vascular beds. 2. Pharmacokinetics a. It is rapidly absorbed after inhalation. b. Metabolism occurs in the liver and elsewhereby COMT. 3. Indications for use. As a bronchodilator, isoproterenol relieves respiratory distress in severeasthmatic attacks.It is rarely used now that more selectiveagentsexist. It may prove useful in heart block.

2t8

Pharmacology

4. Side effects and toxicity. Acute toxicity is less than that seen with epinephrine. Thchycardia, headache,flushing, nausea, dizziness,and diaphoresis are common side effects.Anginal pain or cardiac arrhythmias may occur. Tolerance may occur with frequent administration.

ADREN ERGIC AGON |STS Fr-SELECTTVE

Note Headache andflushing are directsymptoms ofthe vasodilatory actionof p, agonists.

Br-Selectiveadrenergic agonists offer the advantageof minimal cardiac side effects. They also have greater bioavailability secondaryto less enzqatic degradation. Structural modifications make many of these drugs less susceptibleto COMT and MAO. They are most often used as inhalants, thus minimizing systemic side effects. A. Metaproterenol 1. Pharmacologic properties a. Relaxes smooth muscle of bronchi, uterus, and skeletal muscle vasculature and decreasesairway resistance. b. Causesmuch lesscardiacstimulant action than isoproterenol(ro F, stimulation). 2. Pharmacokinetics a. Metaproterenol is structurally similar to isoproterenol except for the positions of the hydroryl groups on the phenol ring; it is resistant to COMT methylation. b. It can be taken orally or inhaled and has a duration of action up to 4 hours. 3. Indications for use. It is effective as a bronchodilator in the treatment of bronchial asthma and reversiblebronchospasm.

ClinicalCorrelate agonists are B,-selective currently themainstay inthe treatment ofacute asthma. Theyhavetheadvantage of minimal cardiac sideeffects andgreater bioavailability.

4. Side effects and toxicity a. Sympathomimetic stimulation may cause tachycardia, hypertension, nervousness, tremor, palpitations,nausea,and vomiting. b. Must be usedwith caution in patients with severehypertension, severecoronary artery disease,congestiveheart failure, and hyperthyroidism. c. Tolerance is less likely to develop to inhaled metaproterenol than to inhaled isoproterenol. B. Terbutaline 1. Pharmacologic properties a. It is resistantto COMT methylation. b. A synthetic sympathomimetic, it is a relatively selective pr-receptor agonist when given orally. c. It causescardiovascular effects similar to isoproterenol when administered subcutaneously. 2. Indications for use. As a bronchodilator in asthma,terbutaline is the only F, agonist used parenterally for the treatment of status asthmaticus. 3. Side effects and toxicity a. Oral preparation causestremor. Dizziness,neryousness,fatigue, tinnitus, and palpitations are rare. b. With subcutaneous administration, adverse reactions resemble those seen with epinephrine.

Note Salmeterol isa newer, longerp, agoni$ acting usedfor prophylaxis. asthma

2t9

Respiratory System

C. Albuterol 1. Pharmacologic properties are similar to terbutaline. a. Albuterol is a relativelyselectiveBr-adrenergicreceptoragonist. b. It is availableas oral and aerosolpreparations. c. Its peak effectis in 30-40 minutes with a 3- to 4-hour duration of action after inhalation. 2. Indications for use.Albuterol is an effectivebronchodilator in reversibleobstructiveairway disease.

ln a Nutshell Allcr Epinephrine Ephedrine + a n d B receptors

B

3. Side effects and toxicity a. Nervousness,tremor, headache,insomnia, weakness,dizziness,tachycardia,and palpitations may occur.

lsopropterenol + receptors only

b. Albuterol should be used with caution in patientswith coronary artery insufficiency, hypertension,hyperthyroidism,and diabetesmellitus, and in patientsreceivingMAO inhibitors or tricyclic antidepressants.

Metaproterenol Terbutaline - F,, seleCtrve Albuterol

c. It has lessB, stimulation than isoproterenol,metaproterenol,and terbutaline.

(THEOPHYLUNE, METHYUXANTHINES AMtNOpHytHNE,CAFFEINE, THEOBROMTNE) Severalmechanismshavebeen proposedto explain methylxanthine-inducedbronchodilatation: /) accumulation of cAMP due to inhibition of cyclicnucleotidephosphodiesterases,2) increases in intracellular calcium, and 3) blockade of adenosine receptors (adenosinecausesbronchoconstrictionand increasesmast-celldegranulationof histamine). A. Theophylline 1. Pharmacologic properties. Theophylline relaxesbronchial smooth muscle, producing an increasedvital capacity; is a potent CNS stimulant; improves diaphragmatic contractility; has a positivecardiacinotropic action; and increaseswater and electrolyteexcretion. 2. Pharmacokinetics a. Theophylline can be administeredorally, rectallSor parenterally.It is distributed into all body compartments and is 600lobound to plasmaproteins. b. Subjectto hepatic metabolism,it has a half-life of 8 hours.

CilinicalCorrelate Theophylline isa second-line agent fortreating asthma. lts significant sideeffects include gastro nervousness, intesti nal irritation, andarrhythmias. Thearrythmias result from blockade ofadenosine (adenosine receptors decreases AVnodal conduction).

220

3. Indications for use. It is effectiveas a bronchodilator in asthmaand COPD, can improve diaphragmaticfunction in COPD, and can reduceprolonged apneain preterm infants. 4. Side effects and toxicity a. Oral administration may causeheadache,nervousness, dizziness,nausea,vomiting, and epigastricpain. b. Intravenous administration may resuit in cardiac arrhythmias, hypotension, cardiac arrest,and seizures. c. In children, CNS stimulation, diuresis,and feversare seen. d. Serum levels should be monitored becausetoxicity is seenat levelsgreaterthan 20 mglL; beneficialeffectsbegin around 7-10 mg/L.

Pharmacology

5. Drug interactions a. Barbiturates, phenytoin, and smoking increasetheophylline metabolism. b. Allopurinol, propranolol, cimetidine, erythromycin, and influenza vaccine decrease theophylline metabolism. B. Aminophylline is a widely used soluble theophylline salt (theophylline ethylenediamine), particularly in the treatment of status asthmatics.

CROMOTYN SODIUM ANDNEDOCROMIT A. Pharmacologic properties 1. It has no direct adrenergic,bronchodilator, antihistaminic, or anti-inflammatory actions. 2. It inhibits the degranulation of mast cells and releaseof histamine and other autacoids after immunologic and nonimmunologic (e.g.,exercise,hlryerventilation) stimulation. B. Pharmacokinetics 1. Cromolyn sodium is administered by inhalation. Oral absorption is very poor. The absorbed drug does not undergo metabolic degradation.Most is excretedunchanged within a few days. 2. Maximal plasmalevelsare reachedwithin minutes with a plasma half-life of I to 1.5hours. A pharmacologic responseis observedwithin weeks. C. Indications for use 1. Cromolyn sodium is used only to prevent asthmatic attacks (particularly in cold- and exercise-inducedasthma).It is ineffectivefor the treatment of acuteasthmaattacks. 2. Partialor completeprotection is experiencedin children with chronic unstableasthma.A smaller number of adults benefit from prophylactic use of this drug. 3. An inhaled nasalpreparation is used in allergic rhinitis. 4. Effects may not be seen for 4-6 weeks. D. Side effects and toxicity 1. Sideeffectsoccur in lessthan 5oloof patients. 2. Sorethroat, cough, and dry mouth are the most common problems. 3. Urticaria, maculopapulardermatitis, and gastroenteritismay also occur.

CORTICOSTEROIDS Corticosteroids are potent antiasthmatic drugs whose use is limited by the frequenry of adverse systemicreactions. Corticosteroids reduce inflammation and edema and potentiate the bronchodilating effectsof adrenergicagonists.The short-term administration of intravenouscorticosteroids is frequently necessaryin the treatment of status asthmaticus. Once the acute episode is controlled, oral therapy with a short-acting corticosteroid is established,and the dosageis reduced. Prednisone,prednisolone, and methylprednisolone are equally effective oral preparations.Beclomethasonedipropionate is an aerosolthat exertsa more localizedeffect.

221

Respiratory System

A. Prednisone and prednisolone

ClinicalCorrelate Corticosteroids mu$be tapered because theysuppress production endogenous by theadrenal gland, andacute withdrawal canprecipitate an addisonian crisis. Sideeffects of corticosteroids include: . Osteoporosis . Hyperglycemia . Dysphoria/psychosis . Potentialfor immune suppression

Clinical Correlate Lowdosage prevents the desensitization of B,receptors thatwouldoccur withchronic useof p,-agonists ClinicalCorrelate Aerosolized steroids suchas beclomethasone aredelivered directly to thelungs and produce fewersystemic side effects.

ClinicalCorrelate lpratropium bromide isoften usedin COPD because it produces bronchodilatation andreduces secretions.

1. Indications for use a. Theseagentsare useful in severechronic and acutebronchospasm. b. Optimally, oral steroidsare tapered,and the patient can be placed on inhaled preparations once the acuteepisodehas resolved. 2. Side effects and toxicity include suppressionof growth, osteoporosis,aggravation of diabetes,asepticbone necrosis,and adrenocorticalsuppression. B. Beclomethasone dipropionate 1. Pharmacologic properties a. Beclomethasonedipropionate is an esterifiedchlorinated analogof betamethasone. b. The aerosol preparation is inhaled in metered doses. c. A highly potent corticosteroid,it actslocally on respiratory mucosato reduceinflammation. d. It manifests only minor systemic absorption and rapid metabolism, and it has no effect on the hypothalamic-pituitary-adrenal axis. 2. Indications for use. Beclomethasonedipropionate servesas a substitutefor oral preparations in selectedindividuals with severesteroid-dependentasthma. 3. Side effects and toxicity a. Becauseit is inhaled, systemicside effects are greatlydiminished. b. Hoarseness,sore throat, and dry mouth are the most common side effects. c. Oropharyngealand laryngealcandidal infection may occur; to prevent infection, the mouth should be rinsed after eachdose.

ATROPINE ANDIPRATROPIUM BROMIDE A. Mechanism of action. These agentsact by blocking muscarinic receptors, thereby inhibiting acerylcholine-inducedbronchoconstriction ("anticholinergics,'). B. Indications for use 1. In the past, anticholinergicswere first-line drugs for asthma treatment; they have since been supplantedby adrenergicagonists. 2. They are usedin asthmapatientsunresponsiveto adrenergicagentsand methylxanthines. C. Side effects and toxicity l. Anticholinergic side effectsinclude drowsiness,sedation,dry mouth, blurred vision, urinary retention, and constipation. 2. CNS side effectsare not as pronounced with ipratropium becauseit does not crossthe blood-brain barrier.

222

Pharmacology

ANTITEUKOTRIENES This newer classof drugs usedin the treatment of asthmaworks by inhibiting the formation or action of the leukotrienes. A. Zileuton is a selective inhibitor of 5-liporygenase and thus blocks the synthesis of leukotrienes.It has a rapid onset and is used in combination with steroids.Its slow onset of activity forcesits use for prophylaxis.It can causediarrhea and headacheand can increase the risk of infection. B. Zafirlukast blocks the LTD* leukotriene receptors.

Bridgeto General Principles Toreview and thebiosynthesis see effects of theleukotrienes, within theAutacoid chapter thePharmacology section of z theCeneral Principles Book (Volume ll).

Bridgeto Pathology pulmonary 0bstructive ischaracterized by disease overproduction of mucus (chronic bronchitis, asthma, bronchiectasis) or lackof recoil ofthelungparenchyma (emphysema).

22',

SECTION III

RenaVurlnary System

RenallUrinaryEmbryology is andurethra), ducts(ureters andexcretory bladder, of thekidneys, consisting Theurinary system, the from contribution a smaller with derivatives andendodermal frommesodermal mainly formed isvestigial; themesonephros Thepronephros formsequentially. systems Threeseparate ectoderm. intothedefinitive develops disappears; themetanephros butthenmainly transiently, mayfunction provide to themalereproductive important contributions ducts Thepronephri(mesonephric kidney. sinus, ducts, theurogenital fromthemetanephric arederived excretory ducts system. Thepermanent ectoderm. andsurface

ANDURETERS KIDNEYS Renal development is characterizedby three successive,slightly overlapping kidney systems. A. Pronephros. Segmentednephrotomes appear in the cervical intermediate mesoderm of the embryo in the fourth week. These structures grow laterally and canalize to form nephric tubules. Successivetubules grow caudally and unite to form the pronephric duct, which emptiesinto the cloaca.The first tubules formed regressbefore the last ones are formed. By the end of the fourth week,the pronephros disappears. B. Mesonephros.In the fifth week,the mesonephrosappearsas"S-shaped"tubules in the intermediatemesodermof the thoracic and lumbar regionsof the embryo. l. The medial end of eachtubule enlargesto form a Bowman capsuleinto which a tuft of capillaries, or glomerulus, invaginates. 2. The lateral end of each tubule opens into the mesonephric (Wolffian) duct, an intermediate mesodermderivative. 3. Mesonephrictubules function temporarily and degenerateby the beginning of the third month. The mesonephricduct persistsin the male as the ductus epididymis, ductus deferens,and the ejaculatoryduct.

Bridgeto Reproductive derivatives Themesonephric inthe in detail arediscussed Embryology Reproductive of Organ Systems chapter (Volume lV). Book2

C. Metanephros. During the fifth week,the metanephros,or permanent kidney, developsfrom two sources:the ureteric bud, a diverticulum of the mesonephric duct, and the metanephric mass,from intermediatemesodermof the lumbar and sacralregions.

227

Rena/UrinarySystem

Stomach Midgut Cecum

Allantois Cloaca

Pronephros

Urogenital sinus Mesonephros

Metanephrogenic mass

Hindsut ffi3,|tr,' Figure lll-1-1.pronephros, mesonephros,and metanephros. l' The uretericbud penetratesthe metanephricmass,which condensesaround the diverticulum to form the metanephrogenic cap. The bud dilates to form the renal pelvis, which subsequentlysplits into the cranial and caudalmajor calyces.Each majo, .Jp buds into the metanephric tissueto form the minor calyces.One to three million collecting tubules develop from the minor calyces,thus forming the renal pyramids. 2' Penetrationof collectingtubulesinto the metanephricmassinducescellsof the tissuecap to form nephrons, or excretory units. a. The proximal nephron forms Bowman capsule, whereasthe distal nephron connects to a collectingtubule. b. Lengthening of the excretory tubule gives rise to the proximal convoluted tubule, loop of Henle, and the distal convoluted tubule. 3. The kidneys develop in the pelvis but appear to "ascend" into the abdomen as a result of fetal growth of the lumbar and sacralregions.With their ascent,the ureters elongate, and the kidneys become vascularized by lateral splanchnic arteries, which arise from the abdominal aorta.

ADRENAT GTANDS The adrenal glands lie above the kidneys and are of dual origin. The cortex develops from the mesoderm of the coelomic epithelium, and the medulla is derived from neural crest cells,which migrate to the areaand differentiateto form catecholamine-producingcells.

228

Embryology

BIADDER ANDURETHRA A. Urorectal septum dividesthe cloacainto the anorectalcanal and the urogenital sinusby the seventhweek. 1. The upper and largestpart of the urogenital sinusbecomesthe urinary bladder, which is initially continuous with the allantois.As the lumen of the allantoisbecomesobliterated, a fibrous cord, the urachus, connectsthe apex of the bladder to the umbilicus. In the adult, this structure becomesthe median umbilical ligament. 2. The mucosaof the trigone of the bladder is formed by the incorporation of the caudal mesonephric ducts into the dorsal bladder wall. This mesodermal tissue is eventually replacedby endodermal epithelium so that the entire lining of the bladder is of endodermal origin. 3. The smooth muscle of the bladder is derived from splanchnicmesoderm. B. Male urethra is anatomically divided into three portions: prostatic, membranous, and spongy (penile). l.

The prostatic urethra, membranous urethra, and proximal penile urethra developfrom the narrow portion of the urogenital sinus below the urinary bladder.

2. The distal spongy urethra is derived from the ectodermalcellsof the glanspenis. C. Femaleurethra. The upper two thirds developsfrom the mesonephricducts, and the lower portion is derived from the urogenital sinus.

ENITAIABNORMALITIES CONG A. Renal agenesis,failure of one or both kidneysto deveiop,is due to early degenerationof the uretericbud. Agenesisis fairly common in the unilateral form but leadsto deathshortly after birth in the bilateral form. B. Renal cysts are the formation of thin-walled, fluid-filled cystsfrom blind tubules, perhaps arising from improper linkage betweenthe collectingducts and distal convolutedtubules. C. Pelvic and horseshoe kidney. Pelvic kidney is due to a failure of one kidney to ascend. Horseshoekidney is a fusion of both kidneys at their ends and failure of the fusedkidney to ascend. D. Double ureter is due to the early splitting of the uretericbud or the developmentof two separatebuds. E. Extrophy of the bladder is a protrusion of the posterior urinary bladder wall through a weakenedanterior abdominal wall. The defectivewall is causedby deficient mesenchymal invasion of the areaand subsequentpoor closure. F. Patent urachus is a failure of the allantois to be obliterated. It causesurachal fistulas or sinuses.Remnantsof the allantoic stalk may give rise to urachal cysts.In male children with congenital valvular obstruction of the prostatic urethra or in older men with enlarged prostates,a patent urachusmay causedrainageof urine through the umbilicus.

229

RenaVUrinary Histology products Theurinary isthemajorsystem involved in theexcretion of metabolic waste system and a homeostatic balance excess water fromthebody. lt isalsoimportant in maintaining offluidsand Theurinary theurinary bladder, andthe electrolytes. system consists of twokidneys, twoureters, produced is via bladder urethra. Urine bythekidneys andisthentransmittedtheureters to the for Theurethra isthefinalpathway urineto theexterior. Thissystem temporary storage. thatconveys function intheproduction which alsohasanimportant endocrine of reninanderythropoietin, respectively. influence bloodpressure andredbloodcell(RBC) formation,

KIDNEYS A. Overview 1. The kidneys are retroperitoneal organs that remove urea and other waste products from the blood. In addition, they regulatethe chemical composition of plasma and the extracellular fluid of the body. 2. Eachkidney is composedof stroma and parenchyma. a. The stroma consistsof a tough fibrous connectivetissuecapsuleand a delicateinterstitial connective tissue composed of fibroblasts, wandering cells, collagen fibrils, and a hydrated proteogly.un extracellular matrix, which is collectively called the renal interstitium. b. The parenchyma consists of more than one million elaborate uriniferous tubules that representthe functional units of the kidney. 3. The kidney containsa hilum, a cortex, and a medulla. a. The hilum is located medially and servesasthe point of entrance and exit for the renal artery, renal vein, and ureter. (1) The renal pelvis, the expanded upper portion of the ureter, divides into two or three majorcalyces upon entranceinto the kidney.These,in turn, divide into eight minor calyces(FigureIII-2-1).

2rl

RenafUrinary System

Cortex

Me d u l l a

Minorcalyx

Renal pyramid

Majorcalyx H i l um

Renal c o l u mn (of Beftin)

Renal pelvis

Figure lll-2-1.Organizationof the kidney. (2) Branchesof the renal artery,vein, and nerve supply eachpart of the kidney. b. The cortex forms the outer zone of the kidney, aswell asseveralrenal columns, which penetratethe entire depth of the kidney (seeFigureIII-2-1). c. The medulla appearsas a seriesof medullary pyramids. The tips of the pyramids point toward the renal pelvislocatedat the hilus. The apexof eachpyramid directsthe urinary streaminto a minor calyx.TWoor three pyramids may unite to form a papilla. d. A renal lobe is defined as a medullary pyramid surrounded by its associatedcortex. 4. Uriniferous tubules consistof two functionally relatedportions calledthe nephron and the collecting tubule. B. Nephron consistsof a renal corpuscle,proximal convoluted tubule,loop of Henle, and distal convoluted tubule. The renal corpuscleconsistsof a tuft of capiliaries,the glomerulus, surrounded by a double-walledepithelial capsulecalledBowman capsule. 1. Glomerulus is madeup of severalanastomoticcapillaryloops interposedbetweenan afferent and an efferentarteriole.The endothelium of the glomerulusis thin and fenestrated. Plasma filtration (ultrafiltration) occursin the glomerulus. 2. Bowman capsule (Figure ll[-2-2) consistsof an inner viscerallayer and an outer parietal layer. The spacebetween these layers,the urinary space,is continuous with the renal tubule. a. Visceral layer is apposedto the glomerulus and closelyfollows the branchesof the glomerular capillaries.The viscerallayer is composedof a singlelayerof epithelialcells resting on a basal lamina, which is fused with the basal lamina of the capillary endothelium.

2t2

Histology

Afferent arteriole Efferent arteriole Viscerallayer (Podocytes) Area of detail

Parietal layer

Urinary space Fenestrated Basal lamina

Figure lll-2-2. Bowman capsule diagram.

(l)

The cells of the visceral layer, called podocytes, are elaborate and their nuclei bulge into the capsularspace.

(2) Cytoplasmicextensionsof podocytes,called pedicles, rest on the basal lamina. The pediclesof adjacentpodocytesinterdigitate along the basallamina. (3) Betweenadjacentpedicles,a thin slit diaphragm assistsin preventinglarge plasma proteins from escapingfrom the vascularsystem. b. Parietal layer is composedof a simple squamousepithelium that is continuous with the proximal convoluted tubule epithelial lining. 3. Proximal convoluted tubule is the longest and most convoluted segmentof the nephron. a. It is lined by a singlelayer of cuboidal to low columnar cellswith rounded nuclei and eosinophilicgranular cytoplasm.

ClinicalCorrelate processes Insomedisease (i.e.,diabetes mellitus, glomerulonephritis), the glomerulus becomes more permeable to proteins, leading to theappearance of protein intheurine(proteinuria).

b. Cell boundaries interdigitate with those of adjacent cells laterally and basally.

ztt

Rena/Urinary System

Note Nephrons nearthe junction corticomedullary are juxtomedullory called nephrons. These nephrons haveverylongHenle loops; therefore, theyarecritically important in establishing the gradient hypertonic inthe medullary interstitium.

c. The proximal convoluted tubule also possesses an apical brush border that provides the cell with a much greatersurfaceareafor reabsorptionfrom, and secretioninto, the fluid that becomesurine in the kidney tubules.In fact, most of the componentsof the glomerular filtrate are reabsorbedin the proximal tubule. 4. Loop of Henle is a hairpin-like loop of the nephron that extendsinto the medulla and consistsof thick and thin segments. a. The thick proximal portion of Henle's loop, or the descending thick segment, is a direct medullary continuation of the cortical proximal convolutedtubule. b. The descendingand ascendingthin segmentsof the loop of Henle are lined by a single layer of flat, squamous epithelial cells with nuclei that bulge into the lumen. c. The thick distal portion of the loop of Henle, the ascendingthick segment,ascendsto the cortex and is continuous with the distal convolutedtubule. It is lined by cuboidal cellsthat contain numerous invaginationsof cytoplasmand many mitochondria. 5. Distal convoluted tubule is lined by cuboidal cells that contain a granular cytoplasm. a. Cells of the distal convoluted tubule near the afferent arteriole are taller and more slenderthan elsewherein the distal tubule. They constitute the macula densa. (l ) Their nuclei are packed closely,so the region appearsdarker under the light microscope. (2) The macula densais thought to sensesodium concentrationin the tubular fluid. b. The major function of the distal tubule is to reabsorb sodium and chloride from the tubular filtrate.

Bridgeto Physiology In response to vasopressin (ADH)secreted bythe neurohypophysis, ng collecti permeable tubules become to waterand,thus,areimportant inthekidney's roleinwater conservation andurine concentration.

C. Collecting tubules consistof archedand straight segments. l. The arched collecting tubule segments,which arevariably present,arelocatedin the cortical labyrinths and empty into the straight collecting tubule segments,which pass through the medullary rays. 2. Epithelial cellsof the collectingducts range from cuboidal to columnar. 3. Identification of thesetubules is facilitatedby their distinct intercellularborders asa result of the lack of complex interdigitations seenin the proximal and distal tubules. D. Vascular supply beginswith the renal artery, entersthe kidney at the hilum, and immediately divides into interlobar arteries. These arteries supply the pelvis and capsulebefore passing directly betweenthe medullary pyramids to the corticomedullary junction. 1. The interlobar arteriesbend almost 90 degreesto form short, arching, arcuate arteries, which run along the corticomedullary junction. 2. The arcuatearteriessubdivideinto numerousfine interlobulararteries, which ascendperpendicularly to the arcuatearteriesthrough the cortical labyrinths to the surfaceof the kidney. Each interlobular artery passes approximately midway between two adjacent medullary rays.The location of interlobular arteriesrepresentsthe virtual boundariesof renal lobules. 3. The interlobular arteriesthen give off branchesthat becomethe afferent arterioles of the glomeruli. 4. As the afferent arteriole approachesthe glomerulus, some of its smooth muscle cellsare replacedby myoepithelioid cells,which are part of the juxtaglomerular apparatus.

214

Histology

5. The juxtaglomerular apparatusconsistsof juxtaglomerular cells,polkissencells,and the macula densa (Figure lll-2-3). a. The juxtaglomerular cells secretean enzyme called renin, which enters the bloodstream and converts the circulating polypeptide angiotensinogen into angiotensin I. Under the action of convertingenzyme,angiotensinI is convertedto angiotensinII, a potent vasoconstrictorthat stimulatesaldosteronesecretionfrom the adrenal cortex. Aldosterone increasessodium and water reabsorption in the distal portion of the nephron. b. Polkissen cells are located between the afferent and efferent arterioles at the vascular pole of the glomerulus,adjacentto the macula densa.Their function is unknown.

Proximal tubule 0

Efferent arterioles

1' o

G lo me ru l a r epi th e l i u m

Basementmembrane of Bowmancapsule Epitheliumof Bowmancapsule

Poikissencell Juxtaglomerular cells (Secrele rp-v.rln < i6-3s'aof€s Con1.r(aSiOr 4 *.qie (o^l?rF{ +d ,e-qU[^s;' I

Efferent arteriole

Afferent arteriole

gY[" A.qiolcn3in 11 1 g.t0,r.t faSO cay.S{r.) 1

Distal tubule

Renal artery J Interlobar arteries J Arcuate arteries J Interlobular arteries J Afferent arterioles J Clomerular capillaries

J

; Glomerular basement membrane

ln a Nubhell

Macula densa

In a Nutshell JCA(uxtaglomerular apparatus) consists of: . Juxtaglomerular cellsin (some afferent arteriole alsoin efferent arteriole) . Macula densa . Polkissen cells Juxtaglomerular cells secrete renin.

@ ntdos\Qrt*tL sgc t

v^ k w&,c- 7Wo

c. In the distal tubule, 5o/oof Na+ is reabsorbed (Na+-Cl- cotransport); the tubule is relatively impermeable to water.

. Ascending loop+ 200/o

d.In the collecting duct, 3 to 5o/oof Na+ is reabsorbed by electrogenic Na+ channel pumps that are aldosterone regulated; the duct is variably permeable to water with regulation by ADH, i.e., an increasein ADH will lead to an increasein H2O permeability and reabsorption.

. DCI+ 5olo . Collecting duct+ 3-50/o P.Sr PCf

i s pcrrw'ca-L\e

{ o rrla.{ L tc UCQli"tlt'tLu'\C wnd€.t }t-*.^f-tl

-r f+ D tsl

249

Rena/Urinary Sy$em

Clinical Correlate Hypoaldosteronism . t Na.loss + hypovolemia, J cardiac output, J renal blood flow . t K*retention -+ hyperkalemia, cardiac arrhythmias . t H*retention + acidosis Bridgeto Pharmacology Diuretis arediscussed in inthePharmacology detail section. Note ADHrelease isprimarily driven bychanges inosmolarity, although hugefluctuations in volume ADH canstimulate secretion aswell.

€linicalCorrelate (Dl) Indiabetes insipidus either doesnot anindividual havethecapability to synthesize ADH(central Dl)or theADHreceptors onthe collecting ductareresistant (nephrogenic Dl).ln either case, a functional deficit of ADHleads to theinability to reabsorb H,0,leading to massive diuresis andurine output.

250

e. GFR. Largeblood pressurevariations causechangesin glomerular capillary pressure despiteautoregulation,and the filtered load of Na+ can changealong with GFR and excretionif Na+ reabsorptionis unchanged. f. The renin-angiotensin-aldosterone system is a volume-dependent system. High blood pressuredecreasesrenin secretion,decreasingangiotensin II, reducing aldosterone,leadingto decreasedNa+ reabsorptionin the collectingduct and increasedNa+ excretion. 6. Diuretics generallyincreaseurine volume. In most cases,they inhibit Na+ reabsorption, thereby increasing Na+ excretion. IncreasedNa+ excretion lowers plasma osmolaliry which lowers ADH and increaseswater excretion.Different agentsact on different parts of the nephron (seeFigure III-6-1 in the RenaliUrinary Pharmacologychapter). 7. Water. The volume of water filtered is the GFR (lS0 l/day), and the volume of urine produced is approximately 1.5 Uday.Therefore,over 99o/oof the filtered water is passively reabsorbedby the nephron. a. The rate of reabsorptiondependsupon the plasmaconcentrationof ADH. Stimuli for the releaseof ADH include: (1) An increasein plasma osmolality, detectedby osmoreceptorsin the hypothalamus. (2) A drop in blood volume detectedby baroreceptorsin the carotid sinus, aortic arch, and atria. b. ADH actson the collecting duct, increasingpermeability to water. c. An osmolality gradient in the renal medulla ranges from an isotonic 300 mOsm/l near the cortical boundry up to 1200 mOsmil deep in the medulla (Figure III-4-4). This gradient is the result of action by the countercurrent multiplier, a complex mechanismused to concentratethe urine prior to excretion. (1) The ascendinglimb of the loop of Henle activelypumps NaCl into the cortical interstitium. However,becauseit is not permeableto water,the osmolality of the tubular fluid falls to approximately 100 mOsm/I. (2) If ADH concentrationis high, the cortical collecting duct becomespermeableto water,and water diffusesout until the contentsreach300 mOsm/l (isotonic with the cortical interstitial fluid). (3) The collecting duct passesback through the increasinglyhypertonic medulla, and water flows down its osmotic gradient through the epithelium. The resulting urine will have an osmolality of 1200 mOsm/l and a volume as low as 0.3 ml/min (approximately500 ml/day). d. The volume of urine excreteddependsupon fluid intake. In the absenceof ADH (due to diabetesinsipidus or water diuresis),urine flow may be 30 llday with an osmolality of only 50 mOsm/l. If an individual drinks largevolumes of fluid, plasmaosmoiality falls,and ADH releaseis inhibited, resulting in a largevolume of hypotonic urine. In the absenceof ADH, the collecting duct becomesimpermeableto water, resulting in an accumulation of water in the tubule despitethe osmotic gradient betweenthe tubular fluid and its adjacentinterstitium.

Physiology

;lJft5PqftT

.^^^ iTf.*j"id+ffi|

:.'wilK Loopot I I Interstitial Henle lluid

I lcollecting lnterstitialduct lluid

Figure lll-4-4. The countercurrent mechanism for concentrating the urine. per liter.(Reprintedwith permission Numericalvaluesare in milliosmoles from GuytonAC:Textbookof MedicalPhysiology, 8th ed. Philadelphia, PA, W.B.SaundersCompany,1991,p 310.)

8. Potassium. The daily intake of K+ is approximately 70 mmol. Becausethe plasma concentration of K+ is significantly lessthan that of Na+, very little K+ is filtered. a. Passivereabsorption of 70o/oof frltered K+ occurs in the proximal tubule, active reabsorption of 20o/oof filtered K+ occurs in the ascendingthick loop, and active reabsorption of l0o/oof fi.lteredK+ is accomplishedby the collecting duct intercalated cell. b. A variable amount of K+ is passivelysecretedby principal cellsof the collecting duct. c. The amount of K+ excretedby the nephron dependson passiveK+ secretion,the rate of which varies with intracellular K+ concentration and the electrochemicalgradient of K+ between the tubular cells and lumen. The major factors that increasethe rate of K+ secretion and excretion are increasedingestion of K+, alkalosis,and increased aldosterone(aldosteronecausesan increasein Na+ reabsorptionand an increasein K+ secretion). d. Diuretics can increaseor decreaseK+ excretion, depending on their site of action. Most diuretics increaseK* excretionand hypokalemiais a significant side effect.

251

RenafUrinary System

ACID.BASE REGUTATION A. Bufferiog. Ao excessof acid will result in most of the hydrogen ions (H+) binding to other compounds to counteract their acidic properties, a processknown as buffering.A small amount remains as free H+ in solution; its concentration (pH) is a valuable clinical indicator. The body buffers carbonic acid, a volatile acid, differently from other acids,called fixed acids. 1. Fixed acids are buffered by approximately half of the H+ reacting with extracellular bicarbonate (HCO:-): HzCOr 3.5 g/day), hypoalbuminemia (5lobes are called hypersegmented. They typically represent oldcells. In somepathological states, immature neutrophils can appear with5 or morelobes. ClinicalCorrelate Eosinophilia (anincrease in theabsolute number of eosinophils) isassociated with parasitic infection, allergy, asthma, andsomeneoplasms.

Note . Basophils maysupplement thefunctioning of mastcells in typeI (immediate hypersensitivity) immune resp0nse. . Remember thatmastcells donotcirculate in bloodtheyarefoundin connective tissuetusually inassociation withbloodvessels.

290

granulocytes (neutrophils' eosinophils,basophils) and agranulocrtes (lymphocytes, monocftes). 1' Granulocrtes are named accordingto the staining properties of their specificgranules. a. Neutrophils are 10-16 pm in diameter. (l) They have 3-5 nuclear lobes and contain azurophilic granules (lysosomes), which contain hydrolytic enrymesfor bacterial deitruction, in their cytoplasm. specific granulescontain bactericidalenzymes(e.g.,rysozyme). (2) Neutrophils are phagocytesthat are drawn (chemotaxis) to bacterial chemoattractants. They are the primary cells involved in the acute inflammatorv responseand represent54_620/o of leukocytes. b. Eosinophils (1) They have a bilobed nucleusand possessacidophilic granulationsin their cytoplasm.Thesegranulescontain hydrolytic enzymesand peroxidase, which are dischargedinto phagocyticvacuoles. (2) Eosinophils are more numerous in the blood during parasitic infections and allergicdiseases; they normally representonly !-3o/ooi l.,rkoryr.r. c. Basophils ( 1) They possesslarge spheroid granules,which are basophilic and metachromatic, due to their content of proteoglycansand to heparin, a glycosuminoglycan. Their granulesalso contain histamine. (2) Basophilsdegranulatein certain immune reactions, releasingheparin and histamine into their surroundings. They also releaseadditional vasoactive amines and slow-reactingsubstanceof anaphylaxis(SRS-A) consistingof leukotrienes LTC4'LTD4,and LTE*.They representlessthan lo/o ofleukocytes. 2. Agranulocytes are named accordingto their lack of specificgranules. a' Lymphocytes are generallysmall cellsmeasuring7-10 pm in diameter and constitute 25-33o/oof leukocytes.They contain circular dark-stained nuclei and scantyclear blue cytoplasm. Circulating lymphocytes enter the blood from the lymphatic tissues.Two principal types of immunocompetent lymphocytescan be identified using immunologic and biochemicaltechniques:T lymphocytesand B lymphocFtes. (1) T cells differentiate in the thymus and then circulate in the peripheral blood, where they are the principal effectors of cell-med.iated immunity. They also function as helper and suppressor cells by modulating the immune response through their effect on B cells,plasma cells,macrophage-s, and other T cells. (2) B cells differentiatein bone marrow and possiblyin the gut-associatedlymphatic tissues-(GAIT). They are the principal mediators Lf h,r-oral immunity through their production of antibodies. bnce activatedby contact with an antigen, they differentiate into plasma cells, which synthesizeantibodies that are secretedinto the blood, intercellular fluid, and lymph. B lymphocytes also give rise to memory cells, which differentiateinto plasma cells'oniy after the ,ecJrd exposureto the antigen. They are responsiblefor the secondary, or amnestic resPonsethat occurswhen the body is exposedto an antigen for a secondtime. b' Monocytes vary in diameter from 15-18 pm and are the largest of the periphera1 blood cells.They constitute 3-7o/oof leukocytes.

Histology

(1) Monocytespossessan eccentricU-shapedor kidney-shaped nucleus. The cytoplasm has a ground-glassappearanceand fine azurophilic granules. (2) Their nuclei stain lighter than lymphocyte nuclei because of their loosely arrangedchromatin. (3) Monocytes are the precursors for members of the mononuclear phagocyte system, including tissue macrophages (histiocytes), osteoclasts, alveolar macrophages,and Kupffer cells of the liver. C. Platelets (thromboplastids) are 2-3 pm in diameter. 1. They are anuclear,membrane-bound cellular fragments derived by cytoplasmic fragmentation of giant cells,called megakaryocytes, in the bone marrow.

In a Nutshell T cells+ cell-mediated immunity: . Differentiate in thymus . Helper T cell(CDa) . Cytotoxic T cell(CDB) . Suppressor T cell

3. There are normally 150,000-400,000plateletsper mm3 of blood.

B cells-+ humoral immunity: . Differentiate in bone marrow

4. Ultrastructurally, plateletscontain two portions: a peripheral,light-staining hyalomere that sendsout fine cytoplasmic processes,and a central, dark-staining granulomere that contains mitochondria, vacuoles,glycogengranules,and granules.

. Onceactivated byantigen + plasma cells(make + memory antibodies) cells

5. Plateletssealminute breaksin blood vesselsand maintain endothelial integrity by adhering to the damagedvesselin a processknown asplatelet aggregation. Plateletsare able to form a plug at the rupture site of a vesselbecausetheir membranepermits them to agglutinateand adhereto surfaces.

. Memory cells+ plasma cells aftersecond exposure to antigen

6. Plateletsaggregateto set up the cascadeof enrymatic reactions that convert fibrinogen into the fibrin fibers that make up the clot.

Bridgeto Physiology

2. They have a short life span of approximately 10 days.

PLASMA Plasmais the extracellularcomponent of blood. It is an aqueoussolution containing proteins, inorganic salts,and organic compounds. A. Albumin is the major plasma protein that maintains the osmotic pressureof blood. Other plasma proteins include the globulins (alpha, beta, gamma) and fibrinogen, which is necessary for the formation of fibrin in the final step of blood coagulation. B. Plasmais in equilibrium with tissueinterstitial fluid through capillary walls; therefore,the composition of plasmamay be used to judge the mean composition of the extracellularfluids. Large blood proteins remain in the intravascularcompartment and do not equilibrate with the interstitial fluid. C. Serum is a clearyellow fluid that is separatedfrom the coagulumduring the processof blood clot formation. It has the samecomposition as plasma,but lacks the clotting factors (especially fibrinogen).

TheStepsof Hemostasis . Primary aggregation plug) (formation of platelet . Secondary aggregation (platelets release crand6 granules thatpropagate the plug.ADPisa potent inducer) . Blood (clotting coagulation cascade) . Clotretraction . Clotremoval (viaplasmin) isdiscussed in Thisprocess intheHematologic/ detail phoreticu larPhysiology Lym chapter.

291

Hematologic/tymphoreticular System

ln a Nutshell Lymph capillaries

J Thinlymph vessels ,/\ Thoracic RLymphatic duct duct

JJ Junction of Junction of L internal Rinternal jugular and jugular and L subclavian Rsubclavian

Note = -20/oplasma Lymph fluidtheamount extruded through thecapillaries isgreater than theamount theveins reabsorb. Therefore, thefluid (no remains intheinterstitium RBCs, lymphocyte$. Lymph flowsthrough lymphnodesimmune system surveillance forantigens.

Note Theprocess oferythropoiesis ischaracterized by3 trends: a progressive J incellsize, a progressive lossof organelles, andaprogressivetin cytoplasmic concentration of hemoglobin.

TYMPHATIC VESSETS Lymphatic vesselsconsist of a fine network of thin-walled vesselsthat drain into progressively larger and progressivelythicker-walled collecting trunks. These ultimately drain, via the thoracic duct and right lymphatic duct, into the left and right subclavian veins at their anglesof junction with the internal jugular veins,respectively.The lymphatics serveas a one-way (i.e., toward the heart) drainagesystemfor the return of tissuefluid and other diffirsible substances, including plasma proteins, which constantly escapefrom the blood through capillaries.They are alsoimportant in servingasa conduit for channelinglymphocytesand antibodiesproduced in lymph nodes into the blood circulation. A. Lymphatic capillaries consist of vesselslined with endothelial cells, which begin as blindended tubules or sacculesin most tissuesof the body. Endothelium is attenuatedand usually lacksa continuous basallamina. B. Lymphatic vesselsof large diameter resembleveins in their structure but lack a clear-cut separation between layers.Valves are more numerous in lymphatic vessels.Smooth muscle cells in the media layer engagein rhythmic contraction, pumping ly-ph toward the venous system.Smooth muscleis well-developedin large lymphatic ducts. C. Circulation of lymph is slower than that of blood, but it is nonethelessan essentialprocess. It hasbeen estimatedthat in a single day,50o/oor more of the total circulating protein leaves the blood circulation at the capillary level and is recapturedby the lymphatics. D. Distribution of lymphatics is ubiquitous with some notable exceptions,including epithelium, cartilage,bone, central nervous system,and thymus.

HEMATOPOIETIC TISSUE Hematopoietic tissue is composed of reticular fibers and cells,blood vessels,and sinusoids (thin-walled blood channels).Myeloid, or blood cell-forming tissue,is found in the bone marrow and provides the stem cells that develop into erythrocytes, granulocytes, agranulocFtes, and platelets.Redmarrow is characterizedbyactivehematopoiesis;yellow bone marrow is inactive and containsmostly fat cells.In the human adult, hematopoiesistakesplacein the marrow of the flat bones of the skull, ribs and sternum, the vertebral column, the pelvis, and the proximal ends of somelong bones. A. Erythropoiesis is the processof RBC formation. Bone marrow stem cells (colony-forming units, CFUS) differentiate into proerythroblasts under the influence of the glycoprotein erythropoietin, which is produced by the kidney. l. Proerythroblast is a largebasophilic cell containing a large sphericaleuchromaticnucleus with prominent nucleoli. 2. Basophilic erythroblast is a strongly basophilic celi with a nucleus that comprisesapproximately 75o/oof its mass.Numerous cytoplasmic polyribosomes,condensedchromatin, no visible nucleoli, and continued hemoglobin synthesisare characteristicsof this cell. 3. Polychromatophilic erythroblast is the last cell in this line that undergoesmitotic divisions.Its nucleuscomprisesapproximately50o/oof its massand containscondensedchromatin, which appearsin a "checkerboard"pattern. The polychromasiaof the cytoplasmis due to the increasedquantity of acidophilic hemoglobin combined with the basophiliaof the cytoplasmicpolyribosomes. 4. Normoblast (orthochromatophilic erythroblast) is a cell with a small heterochromatic nucleusthat comprisesapproximately25o/oof its mass.It contains acidophilic cytoplasm

292

Histology

becauseof the large amount of hemoglobin and degeneratingorganelles.The pyknotic nucleus,which is no longer capableof division, is extruded from the cell. 5. ReticulocFte (polychromatophilic erythrocyte) is an immature acidophilic denucleated RBC, which still contains some ribosomes involved in the synthesisof a small quantity of hemoglobin. Approximately |o/o ofthe circulating RBCsare reticulocytes. 6. Erythrocyte is the mature acidophilic and denucleatedRBC. Erythrocytes remain in the circulation approximately 120 days and are then recycledby the spleen,liver, and bone marrow. B. Granulopoiesis is the processof granulocyteformation. Bone marrow stem cellsdifferentiate into all three tfpes of granulocytes(Figure IV-1-1). l. Myeloblast is a cell that has a largesphericalnucleuscontaining delicateeuchromatin and severalnucleoli. It has a basophilic cytoplasm and no granules.Myeloblastsdivide and differentiate to form smaller promyelocftes.

Clinical Correlate of blood Thenumber isa sensitive reticulocytes activity indexof bonemarrow with butmustbeinterpreted The respect to thehematocrit. countwillbe reticuloryte dueto in anemias decreased (e.g., marrow underproduction butwillbe irondeficiency), secondary in anemias elevated (e.g., to RBC destruction hemolytic anemias).

2. Promyelocyte is a cell that contains a large spherical indented nucleus with coarse' condensedchromatin. The cytoplasm is basophilic and contains peripheral azurophilic granules. 3. Myelocyte is the last cell in this seriescapableof division. The nucleusbecomesincreasingly heterochromaticwith subsequentdivisions. Specificgranulesarise from the Golgi apparatus,resulting in neutrophilic, eosinophilic,and basophilic myelocytes. 4. Metamyelocyte is a cell whose indented nucleus exhibits lobe formation that is characteristic of the neutrophil, eosinophil, or basophil. The cytoplasm contains azurophilic granulesand increasingnumbers of specificgranules.This cell doesnot divide. 5. Granulocytes are the definitive cells that enter the blood. Neutrophilic granulocytes exhibit an intermediatestagecalledthe band neutrophil. This is the first cell of this series to appearin the PeriPheralblood. a. It has a nucleusshapedlike a curved rod or band.

Clinical Correlate percentage of Anelevated is an bandneutrophils ofa indicator important suchas systemic stress, to infection. Thisisreferred or described asbandemia asa "left-shift."

b. Bands normally constitute 0.5-2o/oof peripheral WBCs; they subsequentlymature into definitive neutrophils.

29'

Hematologic/Lymphoreticular System

Early basophilic

My eloblas t

Promyelocyte

Late basophi l i c myelocyte

E osi nophi l i c myelocyte

Early neutrophilic myelocyte

N eutrophi l i c metamyelocyte

E osi nophi l i c metamyelocyte

Neutrophil with band-shaped nucl eus

B asophil

E osi nophil

N eutrop hil

Figure lv-l-1. Granulopoiesis.

Note Themainfeature of lymphopoiesis isa progressive decrease in cellsize. Monopoiesis ischaracterized bya reduction in cellsizeand progressive indentation of thenucleus.

C. Agranulopoiesis is the processof lymphocyte and monocyte formation. 1. tymphocytes developfrom bone marrow stem cells(lymphoblasts). a. B cells developin bone marrow and seedthe secondarylymphoid organs(e.g.,tonsils, lymph nodes,spleen). b. Stem cells for T cells come from bone marrow develop in the thymus and, subsequently,seedthe secondarylymphoid organs. 2. Promonocytes differentiatefrom bone marrow stem cells (monoblasts)and multiply to give rise to monocftes. a. Monocytesspendonly a short period of time in the marrow beforebeing releasedinto the bloodstream. b. Monocytesare transportedin the blood but are also found in connectivetissues,body cavities,and organs. c. Outsidethe blood vesselwall, they are transformed into macrophagesof the mononuclear phagocytesystem. D. Thrombopoiesis, or the formation of platelets,occursin the red bone marrow. 1. Megakaryoblastis a large basophiliccell that containsa U-shapedor ovoid nucleuswith prominent nucleoli. It is the last cell that undergoesmitosis.

294

Histology

2. Megakaryocytes are the largest of bone marrow cells,with diameters of 50 pm or greater. They undergo 4-5 nuclear divisions without concomitant cftoplasmic division. As a result, the megakaryocyteis a cell with polylobulated, polyploid nucleus and abundant granules in its cytoplasm. a. As megakaryocfte maturation proceeds,"curtains" of platelet demarcation vesicles form in the cytoplasm. Thesevesiclescoalesce,become tubular, and eventually form platelet demarcation membranes. b. Thesemembranesfuse to give rise to the membranesof the platelets. c. A single megakaryocytecan shed (i.e.,produce) up to 3,500platelets.

295

Hemato IogiclWmphoreticular Anatomy Thisverybriefchapter highlights theanatomy ofthespleen andthelymphatia thatdrainthe posterior wall.Lymphatic iscovered intheanatomy abdominal drainage of individual organs oftheirrespective organsystems sections

SPTEEN A. The spleen lies in the left hypochondriac region, where it is protectedby the rib cage.It is coveredby peritoneum. B. The gastrolienal ligament connectsthe hilus of the spleento the stomach,and the lienorenal ligament attachesthe hilus to the region of the left kidney. The splenic vesselspass through the lienorenal ligament.

TYMPHATICS Drainagefor eachparticular structure is discussedin relation to the structure in other sections of the notes. A. Lymphatics of posterior abdominal wall 1. Lumbar nodes drain the posterior wall, kidneys, ureters,gonads in both sexes,and the uterus and oviduct in women. Thesenodes alsodrain the hindgut, pelvis,and lower limb structuresby way of inferior mesentericand common iliac nodes.Efferentsfrom the lumbar nodes form the lumbar trunks, which drain to the cisternachyli. 2. Cisterna chyli is the dilated initial portion of the thoracic duct, which lies near vertebrae Ll and Lz.It may be rudimentary or altogetherabsent.The cisternachyli receiveslymph from the lumbar trunks and the intestinal trunk. 3. Thoracic duct receivesall the lymph from below the diaphragm from the left upper limb, left side of the head and neck,and left-sidedthoracic structures,exceptfor the lower lobe of the left lung. It begins at the cisternachyli and passesto the thorax through the aortic orifice of the diaphragm.The thoracic duct terminatesat the junction of the left internal jugular and left subclavian veins. The right lymphatic duct receiveslymphatic drainage from the right upper limb, the right side of head and neck, the right side of the thorax, and the lower lobe of the left lung. It terminates at the junction of the right internal jugular and right subclavianveins.

297

phoreticular Hematol ogiclLym Physiology Hemostasis istheprevention of bloodflow.Thehemostatic of bloodlossandthemaintenance include vascular spasm, formation mechanisms involved whena bloodvessel isruptured orsevered plug,bloodcoagulation, intotheclotto close andgrowth offibrous tissue thehole of a platelet permanently. inthelmmunology Thefunctioning ofthelymphoreticular system isreviewed section Bookt (Volume l). of Ceneral Principles Bridge To Histology

VASCUTAR SPASM When a vesselis severed,the loss of pressureresulting from the decreasingblood flow causesa reflex contraction of both circular and axial smooth muscle.This resultsin constriction of the vesselto limit blood loss,plus retraction of the vesselinto the surrounding tissue,protectingthe severedend from exposureto foreign materials. A. The more the vesselis traumatized,the more vascularspasmoccurs;thus, a sharply cut vessel often bleedsmore than a vesselruptured by crushing. B. In capillaries,flow is controlled by a precapillary sphincter that closesif the capillary pressure drops below a critical level. C. Vascularspasmis influenced by neural and humoral factors. 1. Injury stimulatesthe sympatheticnervous systemto produce vasoconstrictionover and abovethat resulting from myogenicreflexes. 2. lnjury leadsto a local releaseof vasoactiveagents,which leadsto further constriction. 3. Blood loss into a tissue (hematoma formation) can causethe local tissue pressureto increase,thereby slowing further blood loss.

PTATETET PIUGFORMATION Plateletsare cellular fragments derived from megakaryocytesin the bone marrow. Under normal conditions, they play an important role in the maintenanceof the endothelial lining of blood vesselsby rapidly repairing small breaks.Upon injury to a vessel,they quickly form a temporary platelet plug in the vesselwall to stem the flow of blood until a more permanent repair can be made.Plateletplug formation occurs in severalsteps: A. Adhesion.A breakin the vesselwall exposescollagenfibersin the endothelialbasementmembrane and underlying connectivetissue.The positively chargedamino acid residues(lysine and hydroxylysine)in the fibers attract nearby platelets,which adhere strongly to the cut surfaces.Plateletadhesionrequiresvon Willebrand factor (vWF), a plasmaprotein that circulatesin a complexwith factor VIII and binds to the plateletmembraneglycoproteinGPlb.

RedCellShape Theredbloodcell,the biconcave disk, hasa unique property. functional lt can change volume considerably without itssurface changing area. Thecellshape, commonly referred to asthe biconcave disk,hasthe geometric formoftheOvalof Cassini. Thisshape canevolve fromtheLemniscate of (actually Bernoulli a torus) where surfaces thebiconcave all actually on the inside touch thewayto theshape of a its changing sphere without the surface Thispermits area. redcellto wellwithosmotic pressure above its to 500/o normal without volume (lysis). the bursting Because surface areadoesnotchange appreciably thereisnostress leading onthecellmembrane to a rupture.

299

Hematologic/tymphoreticular System

B. Aggregation. The increasedturbulence in the areaof injury, along with secretionsreleased by the initially adhering platelets,leadsto the attraction of more platelets,which aggregate with those attachedto the injury site. 1. ADP is releasedfrom plateletsand promotes aggregation. 2. ThromboxaneA, (TxAr) is synthesizedbythe plateletsand promotesplateletaggregation. 3. Prostacyclin(PGIr) is synthesizedby blood vesselendothelial cells and inhibits platelet aggregation. C. Platelet swelling and release reaction. As soon as they adhere to the cut surface,platelets undergo a dramatic changein their morphology, which includes swelling and the assumption of an irregular shape,with numerous spiny processesprotruding from their surfaces. Thesechangesseemto make them sticky so that they adheremore readily to the injury site and to eachother. The result of this large accumulationof plateletsis to form a plateletplug over the injury site.As the plateletsundergo thesechangesthey releaseseveralproducts. 1. Adenosine diphosphate (ADP), a powerful inducer of platelet aggregation,which strengthensthe platelet plug by the addition of more activatedplatelets. 2. Calcium, an essentialfactor to increasethe degreeof aggregationand to strengthenthe plateletplug. 3 Vasoactiveamines, including serotonin, epinephrine, and kinins, all of which promote local vasoconstriction. 4. Thromboplastin, which initiates a seriesof reactionsresulting in the formation of a permanentclot. 5. Platelet factor 3 (PF3), which is involved in plasmacoagulation. D. Summary. The looseplateletplug is usually strong enough to stop the lossof blood. A more permanent sealis formed when the processof blood coagulation further altersthe platelets to bind them tightly together with fibrin and to anchor them firmly to the vesselwalls. The final stepin the processis clot retraction, which is due to a contraction of contractile (actin) proteins within the platelets.If the damageto a vesselis small, the platelet plug alone can stop the blood loss completely.With a larger hole, blood coagulation is also essential.The plateletplugging processis extremelyimportant in closingthe minute ruptures in small vesselsthat occur hundreds of times daily.A deficienry of plateletscan lead to many small hemorrhagic areasunder the skin.

PTASMA COAGUTATION The third mechanismin hemostasisis blood clot formation, which beginswithin 15-20 secondsin a severeirj.try and within 1-2 minutesin a minor one.Coagulationmaybe divided into threestages: A. Initiation by formation of prothrombin activator. Tiauma to the tissuesor to the blood vesselsor contact of the blood with collagenleadsto the formation of prothrombin activator. Either of two basicpathways,both involving a seriesof plasmaproteins known asclotting factors, may be involved: the intrinsic pathway, in which coagulation begins in the blood, and the extrinsic pathway, which begins with trauma to tissuesoutside the blood vessel. B. The coagulation cascadeshowing both intrinsic and extrinsic pathwaysis outlined in Figure IV-3 -1 . C. Extrinsic mechanism of clotting. When a liquid extract of any tissue is added to plasma, rapid clotting occurs.

500

Physiology

1. Damagedcclls releasetwo initiators of clotting, tissue thromboplastin (factor III) and tissuephospholipids. 2. Tisue thromboplastin,alongwith calcium,forms a complexwith factorVII, which, in the presenceof tissuephospholipids,actson factor X to form activatedfactor )C 3. Activatedfactor X, alongwith tisue phospholipidsand factorY form the complexprothrombin aAivator. D. Intrinsic mechanismof clotting This mechanismbeginswith trauma to the blood itself, usuallywhen it comesin contactwith the damagedvessel.The following eventsthen occur: l. PlateletsreleasePF3 (platel€tphospholipids)and calcium.Factor XII (Hagemanfactor) is activatedon contactwith the collagenat the sit€of injury. 2. Activatedfuctor xII actson factor xr to activat€it. 3. Activatedfactor XI actson factor IX (Christmasfactor) to activateit. 4. Activatedfactor Ix, actingtogetherwith factorvlII andwith plateletphospholipids,acti* vatesfactorx.

GiniOl GOffelah Clinically, theintrinsic system canbeassessed bymeasurinS ne pamar mromDopras[n time(PTD;theextrinsic systern is monitored usingthe prothrombin time(pD.

5. ActivatedfactorX combineswith factorV andplatel* phospholipidsto form the complex prothrombin activator.This stepis the samein both intrinsic andextrinsicmechanisms.

Intrinsic Pathway

Extrinsic Pathway

I

Contact of blood with collagen I

+ xilv Xlla

n

Traumato tissues

I

Xla

.(,._to e, tXa llla (plustissuephospholipids) v|1n G,, v t ll a l V l l a ,-cA\ xPFs+ Xa /6a\

V*

Va

Prothrombim

Thrombin(lla)

riorinogefi Fibrinmonomer(la) Figure lV-3-1.Goagulation cascade.

501

System Hematologic/Lymphoreticular

Note Vll, ll (prothrombin), Factors protein protein and lX,X, C, S areallvitamin K dependent.

E. Activation of prothrombin to thrombin. Prothrombin is a plasmaprotein producedby the liver. 1. Prothrombin activator,produced by either the intrinsic or extrinsic pathway,plus Ca2+, convertsprothrombin to thrombin by partial proteolysisof prothrombin. Vitamin K is necessaryfor adequateprothrombin production. 2. Thrombin is a proteolytic enzyme that splits a limited number of proteins at bonds involving arginine and glycine.Thrombin is ableto catalyzeits own activation.It alsoacts on the plateletplug to increaseaggregationand can activatefactor XIII and potentiatethe binding of factorsV and VIII to phospholipid-Ca2+. F. Conversion of fibrinogen to fibrin. Fibrinogen is a large protein (MW approx. 340,000) circulatingin the plasmaat concentrationsof 100-700mg/100ml. Thrombin splitstwo low molecularweight peptides(fibrinopeptidesA and B) from eachfibrinogen moleculeto form a fibrin monomer that has the capacityto automaticallypolymerize with other monomers into long fibrin threads.In the early stagesof this process,the monomers attachto eachother by loosehydrogenand hydrophobic bonds, forming only weak chains.However,factor XIII (fibrin stabilizingfactor) which is also activatedby thrombin, acts on the fibrin monomers Lo catalyzethe formation of covalentbonds beftveenthe monomers and between adjacent fibrin chainsto produce a strong three-dimensionalfiber network. This mesh surrounds the plateletsplug tcl form a permanent clot at the injury site.

Bridge To Pharmacology andstreptokinase Urokinase sources of areexogenous plasminogen activation. Tissue plasminogen (tPA)is activator produced, but endogenously canalsobeadministered asa of acute druginthesetting myocardial infarction.

G. Clot retraction and dissolution. The completed blood clot is a network of tangled fibrin threads,blood cells,and platelets. 1. Shortly after the clot hasformed, it beginsto shrink or retract.Most of the fluid oozesout of the clot in the form of serum, which contains no fibrinogen or other clotting factors. During clot retraction, the edgesof small wounds are pulled together.The retraction is the result of contraction of platelet actinomyosin, which is present in concentrations comparableto those found in muscle. 2. The final step in hemostasisis the dissolution of the clot. This occurs gradually as new fibroblastsarrive at the injury site and begin the processof repair. Fibrinolysis requires activation of the plasmaprotein plasminogen, which occurswhen the clot itself induces the releaseof plasminogen activator. Plasminogen activator converts plasminogen to plasmin, which in turn proteolyzesfibrinogen and fibrin. H. Prevention of coagulation in normal vessels.Under normal conditions,blood flow is iaminar (nonturbulent) and flows over the negativelychargedendothelial cell layer.Sincethe plasma proteins, including clotting factors, are negatively charged themselves,they are repelledfrom contact with the vesselwall. In addition, a number of anticoagulants circulate in normal plasma.Theseinclude: l. Fibrin, which adsorbsmost of the thrombin that is formed, keepingit from spreading. 2. Antithrombin III, an a-globulin that binds to and inactivatesthrombin. 3. Heparin, a polysaccharideproduced by many cell types,promotes antithrombin inhibition of thrombin. 4. Protein C and protein S are vitamin K-dependent plasmaproteins that serveasendogenous anticoagulants.Protein C is activatedby thrombin bound to the endothelial cell membrane protein thrombomodulin.In the presenceof protein S,activatedprotein C promotesanticoagulationby inactivating factorsV and MII. Activatedprotein C alsopromotesfibrinolysis by inactivatingt-PA inhibitor, therebypromoting t-PA fibrinolytic activity.

,02

Hematol ogiclLymphoreticu lar Pathology Disorders oftheheme/lymph system canresult fromunderproduction or overproduction ofthe formed elements oftheblood, hematologic malignancies, orautoimmune disorders. Thischapter will discuss thedifferent presentations, types of disorders, theirclinical andtheirdistinguishing features. Disorders involving thespleen andthymus willalsobereviewed.

ANEMIAS Anemias are a group of disorders characterizedby a decreasein the number of circulating erythrocytes.This decreaseis reflectedin the laboratory valuesof hemoglobin and hematocrit (the percentageof blood volume composedof RBCs). A. Signs and symptoms 1. Anemia causespalpitations, systoliccardiac murmurs, high-output heart failure, pallor, orthostatic hypotension (in casesof decreasedblood volume), fatigue,dizziness,syncope, and angina (due to impaired oxygentransport). 2. Anemia can alsobe causedby an underlying disease.Examplesare infection, bleeding as a result of leukemia,or tissueinfarction due to sicklecell crisis. B. Classification 1. RBC morphology. RBCs may be normal in size (normocytic), large (macrocytic), or small (microcytic). RBC size is measuredin terms of the mean corpuscular volume (MCV). Hgb content may be normal (normochromic) or decreased(hypochromic). 2. Pathogenesis.Anemia may result from blood loss,increaseddestruction of RBCs (hemo lysis), or decreasedproduction of RBCs.The reticulocyte count measuresthe percent of circulating RBCsthat are newly synthesizedreticulocytes.

Note Usethereticulocyte countto production: evaluate RBC = t reticuloryte count t production

a. Patientssuffering from a hypoproliferativeanemiahavelow reticulocytecounts. b. Patientswith blood loss or hemolysis should have a compensatoryincreasein the reticulocytecount, assumingthe marrow is normal. C. Anemia secondary to loss or destruction of RBCs 1. Blood loss

When chronic blood loss leads toirondeficiency, the reticulocyte countwillbelow because ironisnecessary to make reticulocytes.

a. Clinical features. There are variable presentations,depending on rate and severity of blood loss.Chronic blood loss is generallybetter tolerated,as the bone marrow is ableto regeneratelost RBCs by increasingerythropoiesis.Acute blood loss is dangerous;hypo volemiamay leadto shockand deathunlessintravascularfluid deficitsarerapidly restored.

505

Hematologic/tymphoreticular System

Clinical Correlate isnota good Hematocrit indicator of anemia inthe setting of acutebloodlosswon'tfalluntil thehematocrit fluidhashad theextravascular with timeto re-equilibrate intravascular bloodto restore volume.

Note Theeffects ofcompensatory mechanisms depend on whether RBCdestruction is Forexample, acute or chronic. gallstones arise bilepigment in hereditary spherocytosis episode butnotin anacute of hemolysis dueto C6PD deficiency.

{+bad( b Biodtemisty Nowisa goodtimeto review monophosphate thehexose lt isdiscussed inthe shunt. chapter in the Carbohydrates Biochemi$ry section of Principles Bookt Ceneral (Volume l).

b. Pathology. The peripheral blood smear initially shows normocytic normochromic RBCs.As the marrow begins to produce more RBCs,the reticulocfte count increases; these cells are macrocytic and polychromatophilic. Mobilization of platelets and leukocytesmay lead to thrombocytosis and leukocytosis. 2. Hemolytic anemias are a group of disorders characterizedby premature RBC destruction, hemoglobin (Hb) breakdown, and a compensatory increase in erythropoiesis. Hemolysis can be intravascular with elevated serum and urinary Hb, jaundice, urinary hemosiderin, and decreasedcirculating haptoglobin. Extravascular hemolysis generally occurs within organsof the reticuloendothelial system.Somehemolytic anemiasoccur on the basisof a defectinherent to the RBC (intracorpuscularmechanism);others are due to factorsextrinsic to the RBC, such asantibodies(extracorpuscularmechanism).The compensatory accelerationin erythropoiesis may lead to intramedullary erythroid hyperplasia, extramedullary erythropoiesis, skeletal deformities, bile pigment gallstones,and the presenceof nucleated RBCs in the peripheral blood. a. Hereditary spherocytosis (1) Clinical features. There is an autosomal dominant, intrinsic defect in erythrocyte membrane spectrin molecules,leading to a lesspliable, spherical RBC vulnerableto destruction in the spleen.The diseasemay presentwith anemia,jaundice, splenomegaly,cholelithiasis,or all four. (2) Pathology. The peripheral blood smear shows spherical RBCs lacking central pallor and reticulocytosis. The red blood cells also exhibit characteristic increased osmotic fr "Stlit''. (3) Treatment. Splenectomyis the treatment of choice.The postsplenectomyblood smearcontainsmore spherocytesand Howell-Iolly bodies. b. G6PD deficiency (1) Clinical features. The diseaseis due to an X-linked deficiency of the first enzyme in the hexosemonophosphate shunt. RBCs defend themselvesagainst oxidative injuryvia glutathione,which is maintained in a reducedform byNADPH. G6PD is necessaryto generateNADPH. In the absenceof G6PD, oxidative stresson the maybe induced by drugs (e.g.,sulfa, erythrocyteleadsto hemolysis;such stresses quinine, nitrofurantoin), infections (particularly viral), or certain foods (fava beans). (2) Pathology. The peripheral smear shows reticulocytosis and Heinzbodies, which are clumps of Hb degradation products seen after staining RBCs with new methylene blue. c. Sickle cell disease (1) Clinical features. A hereditary hemoglobinopathy is present in 2o/o of the African-American population of the U.S. (approximately 8o/ocarry the trait). HbS has a substitution of valine for glutamic acid at position 6 of the beta chain of Hb. The HbS molecules aggregateand polymerize when deorygenated; this leads to a change in RBC shape called "sickling," with resultant microvascular occlusion and hemolyrir.Although initially reversible,the sickling processeventually leads to irreversible RBC membrane changes.The tendency of RBCs to sickle dependson the concentration of HbS: heterozygoteswho have approximately 600loHbA and 40o/oHbS ("sickle trait") sickle only in extreme conditions; homozygotesfor HgbS ("sickle cell anemia") sickleunder lessextreme conditions. Factorsthat predisposeto sickling include hypoxia, dehydration, and low pH.

504

Pathology

(2) Diagnosis. A "sickle prep" is a blood sampletreatedwith a reducing agent such asmetabisulfite.Sickledcellsmay be seen.The definitive diagnosisis made by Hb electrophoresis. (3) Pathology. There is congestivesplenomegalyin young children. Erythrosrasisin the spleenmay lead to splenicthrombosis and infarction; the resultant scarring may lead to shrinkage of the spleenwith loss of function (autosplenectomy), usuallyby agefive. Microvascularocclusionmay lead to anoxiaand infarction in other tissues,including the liver, brain, kidney, and bones.Vaso-occlusionin the penis may lead to painful prolonged erection (priapism). In the lower extremities,vaso-occlusionmay lead to leg ulcers.Hemoglobinemiamay lead to pigment gallstoneformation.

Note Microvascular occlusion inthe lungwiththeresultant infarction andchest x-rayis verydifficult to distinguish frompneumonia.

(4) Course. This is a chronic diseasepunctuatedby acuteexacerbations. Vaso-occlusive crises ("painfrrl crises")are episodesof hypoxic infarction in bones,lungs, liver, spleen,and other tissuesthat may be triggeredby infection, dehydration,acidosis, or may occur sPontaneously. Aplastic crisesareepisodesof inadequatebone marrow activity that may be triggered by infection or folate deficiency.Parvovirus is a common etiologic agent.Sequestrationcrises occur in children or adults who havenot yet undergoneautosplenectomy, resulting in massivesequestrationand splenomegalywith resultanthypo-volemia that may lead to shock.In addition to crises, the functional asplenia leaves the patients vulnerable to Salmonella osteomyelitis and to infections with encapsulated organisms, such as Pneumococcrzs. Most patientsdie prior to age30. d. Thalassemias.The thalassemiasare an inherited group of disorderscharacterizedby absentor decreasedsynthesisof either the alpha or the beta chain of Hb. (i) Alpha-thalassemia (cr-thal) is due to decreasedor absentsynthesisof the alpha chains of Hb. It is of variable clinical severitysincethe normal person has four alpha genes.In the absenceof alpha chains,T+maydevelopin the fetus or may 0, developin children and adults.Generally,the nonalpha-chainaggregates are less toxic than those of the alpha chains;therefore,the hemolysisand anemiatend to be milder in a- than in p-thalassemia.The patients may have a silent carrier state (deletion of one alpha gene), a-thal trait (deletion of two alpha genes), HbH disease (deletion of three alpha geneswith resultant HbH), or hydrops fetalis (deletion of all four alpha genes),leadingto Hb Bart'sin the neonatewith resultant anoxia and intrauterine death. (2) Beta-thalassemia(F-thal major and B-thal minor) is due to decreasedor absent synthesisof the beta chain, usually asa result of defectivemRNA processing.It is most common in the Mediterranean countries,Africa, and SoutheastAsia. The result of the defect is a hypochromic cell with a relative excessof alpha chains. These alpha chains aggregateand become insoluble, leading to intra- and extramedullary hemolysis. Severeanemia stimulates erythropoietin secretion, leading to enhancederythropoiesisin bone, liver, and spleen.Frequenttransfusion may lead to iron overload.Patientswho are homozygous are said to have B-thalassemiamajor and heterozygotesare said to have B-ihalassemiaminor or B-thalassemiatrait.

In a Nutshell cr-Thalassemia isdueto gene deletion. isdue Bthalassemia to defects processing. in mRNA s -Thalassemia #of Genes Deleted 1 2

Type Silent carrier g,thaltrait

3

HbH disease inadults

4

Hydrops fetalis

(3) Pathology. In B-thal minor, the peripheral blood smear showsvarying degrees of anisocytosis(variation in size),hypochromia, microcytosis,target cells,and stippled or fragmentedRBCs.There is mild reticulocytosis.In more severecases, occasionalnucleatedred ceilsin the periphery are seen.In mild B-thal trait, the RBC count is often elevated.In cr-thal, the peripheral blood smear is variable, dependingon the specificsyndrome,but may show hypochromia, microcytosis,

505

Hematologic/tymphoreticular System

Note Animportant differential feature between the thalassemia traits andiron deficiency isthatthaltraits result in anelevated number of microrytes, whereas iron deficiency results in a decreased number of microcytes. Serum iron,total iron-binding capacity OlBC), andferritin confirm the diagnosis.

target cells, and stippled inclusion bodies (in HbH disease).Splenectomized patients may have Heinz bodies. (4) Course. Alpha-thal may range from asymptomatic (o-thal trait) to lethaliry in utero (hydrops fetalis).Patientswith HbH diseasegenerallyhave a mild anemia requiring transfusion only at times of acceleratedhemolysis or impaired erythropoiesis.Beta-thal major is a severediseasewith growth retardation,skeletal deformities, and hepatosplenomegaly. Multiple transfusions may lead to iron overload with resultant systemiceffects.Most patients die by the third decade. Beta-thal minor is clinically milder and may be discoveredincidentally as a hypochromic, microcytic anemia. e. Autoimmune hemolytic anemia

Todistinguish between u{hal andB-thal traits, anHb electrophoresis should be performed. Alphathal traithas normal HbA, andHbF. Betathaltraithaselevated HbA, andHbF.

(1) Clinical features. Extracorpuscularhemolysis is due to anti-RBC antibodies, which may be primary or secondaryto malignancy,infection, or drug use.The direct Coombs test measuresthe presenceof antibody on RBCs; the indirect Coombs test measuresthe presenceof anti-RBC antibody in the serum. These anemiasare often classifiedon the basis of properties of the antibody. Warm antibody, which functions at body temperature,is generallyIgG and causesmost hemolytic anemiasdue to drugs, as well as malignancy and SLE.Cold antibody functions below body temperature,is usually lgM, and includes hemolytic anemias associatedwith mononucleosis and Mycoplasmainfection, as well as idiopathic hemolytic anemia and hemolytic anemia associatedwith lymphoma.

Note

(2) Pathology. The peripheral smear may show spherocytesdue to injury of antibody-coatedRBCsby the reticuloendothelialsystem.

Thereticuloendothelial system recognizes damaged RBCs and phagocytoses thedamaged or antibody portions coated of themembrane.

In a Nutshell Anemias Caused by Lossor Destruction of RedBlood Cells . Bloodloss . Hereditary spherocytosis . CCPD deficiency . Sickle celldisease . Thalassemias . Autoimmune hemolytic anemia . Trauma to RBCs . Paroxysmal nocturnal hemoglobinuria

506

f. Trauma to RBCs (1) Clinical features.Varied situations,including prostheticvalvesand microvascu* lar fibrin deposition,may injure RBCs. (2) Pathology.The peripheralblood smearmay show RBC fragments(schistocytes), burr cells,helmet cells,and triangle cells. g. Parorysmal nocturnal hemoglobinuria is an acquired deficiency of a membrane glycoprotein that leads to chronic intravascularhemolysis,fypically without dramatic hemoglobinuria (despitethe name). Patientsmay eventuallydevelopother stem cell disorders(e.g.,aplasticanemia,acuteleukemia),but most frequently die of infection or venousthrombosis.

D. Anemias secondary to decreasederythropoiesis 1. Megaloblastic anemias a. Characteristics. A group of anemias characterizedby macro-ovalocytesand large, hypersegmented neutrophils (having greater than five lobes per nucleus) in the peripheral blood. Important causesare vitamh 8,, and folate deficiency. b. Pathogenesis.Vitamin B,, and folate deficienciesresult in impaired DNA synthesis without affecting RNA or protein synthesis;hence, they selectivelyimpair nuclear development.This resultsin destruction of immature RBCswithin the bone marrow (ineffectiveerythropoiesis),as well as extramedullaryhemolysis. c. Classification ( 1) Vitamh B,, deficiency hasprofound neurologicaswell ashematologicsequelae. It may result from multiple causes,including dietary deficiency,malabsorption,

Pathology

competitivetapeworm uptake,bacterialovergrowth,pregnancy,hyperthyroidism, and cancer.A deficienry of intrinsic factor leads to vitamin 8,, deficiency and pernicious anemia. (2) Folate deficiency produces megaloblasticanemia without neurologic changes. Folatedeficiencymay result from deficient intake (poor diet, alcoholism,malabsorption), increasedneed (pregnancy,malignancy,increasedhematopoiesis), or impaired use (antimetabolitedrugs). d. Pathology (1) In pernicious anemia, the peripheral smearshowsmacro-ovalocytesand hypersegmentedpolymorphonuclear leukocytes.The bone marrow is hypercellular with megaloblasticcells showing nuclearlcytoplasmicdissynchrony.The gastrointestinal tract showsatrophic gastritis,absentparietal ceils,and intestinalization of the gastric mucosa.The CNS shows myelin degenerationof dorsal and lateraltracts (i.e.,subacutecombineddegeneration).Perniciousanemiamay be due to antibodiesagainstintrinsic factor or intrinsic f-actorreceptors.

Note Thebody's 8,,stores vitamin aresolarge thatit usually years takes a to develop vitamin B,,deficienry after absorption Folate stops. deficiency develops much morequickly, ontheorderof months, in states ofvigorous production. RBC

(2) Folate deficiency showsa variablepicture, dependingon the underlying disease. Megaloblasticchangesappearin the peripheral blood and marrow without CNS disease. 2. Iron deficiency anemia a. Clinical features.Iron deficiencyis among the most common nutritional deficiencies worldwide.There are many causes, including poor diet, malabsorption,and pregnanmost By far, the common cause of iron deficiency anemia is blood loss, usually ry. from the gastrointestinal,genitourinary, or female genital tract. The finding of iron deficiencyanemia in an elderly patient should alert the clinician to the possibility of an occult sourceof blood loss,often a malignancy. b. Pathology. The peripheral smear shows hypochromic, microcytic changes.The Plummer-Vinson syndrome is a triad of microcytic anemia, atrophic glossitis,and esophagealwebs. 3. Aplastic anemia a. Clinical features. This is a stem cell defect, leading to pancytopenia (i.e., anemia, neutropenia,thrombocytopenia).Therearemultiple etiologies:idiopathic,drugs (i.e., alkylating agents,chloramphenicol), radiation, infections, and congenital anomalies (i.e.,Fanconianemia).

Note Thediagnosis of iron deficiency made iscommonly bydemonstrating lowserum iron,highTIBC, andlow serum ferritin. isno There stainable ironinthebone marrow Theanemia of chronic disease, alsoa microcytic anemia, exhibits lowserumiron,normal-to-low TIBC, andhighferritin.

b. Pathology. The peripheral smear shows markedly decreasednumbers of circulating RBCs,WBCs, and platelets.RBCsare normochromic and normocytic. The bone marrow is hypocellular with a few foci of lymphocytesand plasma cells.Other changes depend on the specific etiology or therapy; multiple transfusions,for example,may leadto hemosiderosis. c. Course.Prognosisis poor. Bone marrow transplant may be curative. 4. Bone marrow failure may result from many etiologies, including space-occupying metastaticmalignanry or granulomas(myelophthisis),liverdisease,chronic renal failure, endocrine disorders,and other infections or inflammations. Myeloid metaplasia with myelofibrosis is a chronic myeloproliferativedisorderin which the myeloid stem cellsare neoplastic,but are produced in reiativelysmall numbersbecausefibrosis of the bone marrow has causedpancytopenia.

Note Incontrast to CML,patients withmyeloid with metaplasia myelof ibrosishavenormal-toelevated leukocyte alkaline phosphatase.

t07

Hematologic/tymphoreticular System

5. Chronic renal diseasecan result in anemia due to an underproduction of erythropoietin by the kidney.

Table IV-4-f .Anemias.

In a Nutshell Anemias secondary to decreased erythropoiesis: . Megaloblastic anemias (8,,,folatedeficiencies)

Type

Peripheral Smear

Hereditary spherocytosis

. SphericalRBCslack central pallor ' Reticulocytosis . RBCswith Heinz bodies . Reticulocytosis

G6PD deficiency Sickle cell disease

. lrondeficiency anemia . Aplastic anemia

cr-Thalassemia

. Bonemarrow failure . Chronic renaldisease

Bone Marrow

. Sickled cells (especially with sickleprep) . Reticulocytosis . Variable but hypochromic RBCs . Microsftosis . Target cells . Stippled inclusion bodies (HbH) . Heinz bodies (if splenectomized)

p-Thalassemia

. . ' .

Megaloblastic

. Macro-ovalocytes . Hypersegmentedneutrophils

Fe deficiency Aplastic

. Hypochromia, microcftosis . J RBC, wBC, platelets RBCsnormochromic, normocytic

Anisocytosis Hypochromia, microcytosis Thrget cells Stippled/fragmentsand RBCs ' Hypercellular ' Nuclear/cytoplasmic dissynchrony . No stainableFe . Hypocellular

POTYCYTHEMIA Polycythemia is an increasein concentration of circulating erythrocytes. This increasemay be primary or secondary absolute or relative. A. Relativepolycythernia occurs due to loss or sequestrationof intravascularvolume without loss of RBCs.Volume loss may be due to decreasedfluid intake, vomiting, diarrhea,burns, or adrenal insufficiency.

Note Progression to myelofibrosis is progression common; to acute myelogenous leukemia islesscommon, butmoreso whenpatients aretreated with radioactive phosphorous (,,P).

508

B. Polycythemia vera 1. Clinical features. Polycythemia vera is a myeloproliferative syndrome characterizedby a marked increasein erythrocfte mass.It is most common in malesage40-60. The etiology is unknown but is probably due to a neoplastic hematopoietic stem cell. There are symptoms of increasedblood volume, vascularstasis/thrombosis,or bleeding tendenry. Patientsmay later develop anemia or acute leukemia due to "bone marrow burn out." Folate deficienry may develop due to the hyperproliferative state.

Pathology

2. Pathology. The peripheral smear shows a markedly increasednumber of RBCs,WBCs, and platelets. Erythropoietin levels are low. The bone marrow shows erythroid hyperplasia with excessnormoblasts.The marrow cavity may expand to cancellousbone and shafts.Later in the disease,fibrosis, aplasia,or leukemic infiltration may be seen.Other problems include vesselsdistendedwith viscousblood, congestivehepatosplenomegaly, and diffr,rsehemorrhages. 3. Management is generallywith therapeuticphlebotomy. C. Secondary polycythemia 1. Clinical features. An increasedRBC mass as a result of increased erythropoietin levels is seen.There are multiple etiologies,including high altitude with low Or, cigarettesmoking with high carbon monoxide levels,respiratory disease,cardiacdisease(e.g.,right-toleft shunts,cardiacfailure), hemoglobinopathies,renal disease(e.g.,cysts,hydronephrosis), and malignancies(e.g.,renal cell carcinoma,hepatoma,leiomyoma, adrenal adenoma, cerebellarhemangioblastoma). 2. Pathology.An isolatederythrocythemia without an increasein WBCs or plateletsis noted.

THROMBOCYTOPENIA Thrombocytopenia is a decreasein the platelet count (normal platelet count = 150,000400,000/mm3). A. Clinical features. There may be bleeding from small vessels,often skin, gastrointestinaltract, and genitourinary tract. The most common sign is the developmentof petechiae (minute pin-sizedhemorrhagesin the skin) and purpura (largered, nonblanchinglesions).Petechiae developbefore purpura, which are more often seenwith combined deficienciesof platelets and plasmaclotting factors. B. Classification 1. Decreasedproduction due to drugs, radiation, myelopthisis,aplasticanemia,or platelet maturation defect (due to vitamin B,, or folate deficienry) 2. Abnormal sequestrationof plateletsin the spleenin congestivesplenomegaly 3. Dilutional (e.g.,massiveblood transfusion) 4. Increaseddestruction,e.g.,DIC, TTR ITR drugs, or malignanry C. Idiopathic thrombocytopenic purpura (ITP) 1. Clinical features. ITP is characterizedby an increasedperipheral platelet destruction in the spleen,often immune mediated. The course may be acute and self-limited (most common form in children), often following a viral infection, or it may be chronic (most common form in adults). ITP may be primary or secondaryto another disorder such as SLE,HIV infection, or hemolytic anemia.The diseasemay presentwith a long history of easybruisabiliry mucous membranebleeding,gastrointestinalor genitourinary bleeding, and petechiae.CNS bleeding may occur. 2. Pathology. The peripheral smear shows a few, large young platelets;other cell lines are normal. The bone marrow shows increasedmegakaryocFtes,some of which may be immature. The skin showspetechiaeand, in severecases,diffrrsehemorrhages.

509

System Hematologic/tymphoreticular

D. Thrombotic thrombocytopenic purpura (TTP) 1. Clinical features. This is a rare diseasecharacterizedby thrombocytopenic purpura, fever, renal failure, neurological changes,and microangiopathic,hemolytic anemia.It appears most frequently in young women. The etiology is unknown; hypotheses include an immunologic reaction to endothelial cells,a primary platelet defect,or a prostaryclin deficiency. Platelet aggregation leads to the development of microthrombi throughout the vasculature,which causesmicroangiopathic, hemolytic anemia. 2. Pathology. The peripheral smearshowsfew platelets,fragmented RBC (schistocytes),and helmet cells.

PLATETET FUNCTION DEFECTS A. Clinical features. Thesedisorders are characterizedby prolongation of the bleeding time in the presenceof a normal platelet count. B. Classification. Qualitative platelet defectsmay be congenital or acquired. They may be classified as follows:

ToPhysiology Flashback Thestepsintheformation of plugarediscussed theplatelet in detail intheHematologi{ Lymphoreticular Physiology chapter.

1. Defectsof adhesion (e.g.,von Willebrand disease,Bernard-Soulierdisease) 2. Defects of primaryaggregation (e.g.,thrombasthenia) 3. Defects of secondary aggregation and release (e.g.,aspirin, storagepool disease) C. von Willebrand disease 1. Clinical features. There is an autosomal dominant defect in von Willebrand factor. This factor is necessaryfor adhesion of platelets to collagen.This results in impaired platelet adhesion, although the plateletsthemselvesare intrinsically normal. It is characterizedby spontaneoushemorrhage from mucous membranes,wounds, and excessivemenstrual bleeding. 2. Pathology. Patients with von Willebrand diseasehave a range of clinical syndromes but are usually diagnosedwhen they bleed after surgery or dental extraction. Von Willebrand factor (v'vYF)is also the carrier molecule for factor VIII, so patients with v\MF deficienry have low factor VIII levels and activiry.As a result, they have a prolonged partial thromboplastion time (PTT) in addition to an elevatedbleedingtime.

DISORDERS PLATETETS OFEXCESS These disorders are defined by the elevation of the platelet count above the normal range. A. Classification 1. Thrombocytosis is a reactive disorder resulting from bleeding, hemolysis,inflammation, malignanry, iron deficienry, stress,or postsplenectomy.

Note platelets Excess donot necessarily cause thrombosis because in myeloproliferative disorders theymaynot function normally.

5t0

2. Essential thrombocythemia is a primary myeloproliferative disorder. Thrombocythemia is also a prominent feature of chronic myelogenousleukemia (CML). B. Pathology 1. In reactive thrombocytosis the peripheral smear shows an elevated platelet count and may demonstrateother signsof an underlying disorder,such as anemia,leukocytosis,or Howell-Jollybodies. 2. Thrombocythemia may lead to dififrrsethrombosis. The peripheral smear often shows very large, abnormal platelets, or hypogranular platelets. In CML, there is an elevated number of immature white blood cells (WBCs) aswell as numerous platelets.

Pathology

FACTOR CLOTTING DISORDERS Clotting factor disordersare characterizedbydeficitsof secondaryhemostasis,due to alteration of the plasma protein factors of the clotting system. A. Clinical features. Bleeding in disorders of secondaryhemostasistends to be from small arteries or into deep structures such as joint spacesor the retroperitoneum. Tiauma may precedethe bleedingbut hemorrhageis often delayed. B. Laboratory values. The most common blood tests to assayfor the presenceof an intact clotting system are the prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time (TT). 1. PT measuresfactors(fibrinogen)I,II,VVII,

and X.

2. PTT measuresXII, prekallikrein, high-molecular weight, kininogen, and factors I, II, V VIII,IX, X, and XI. 3. TT measuresfactor I (fibrinogen). C. Hereditary deficiencies 1. Factor VIII:C deficiency (hemophilia A) is an X-linked recessivedisorder with an incidenceof 1/10,000.It resultsfrom defectivefactor VIII:C or impaired conversionof precursor to factor VIII:C. Severecasesbleed in infancy at circumcision or may have multiple hemarthroses.Moderate caseshave occasional hemarthroses.Mild casesmay be missed until the patients bleed following a dental or surgical procedure.Bleeding may require treatment with cryoprecipitateor lyophilized factor VIII. 2. Factor IX deficiency (Christmas disease,hemophilia B) occurs approximately one-sixth as often as factor VIII deficiency. It is due to inactive or inadequate Factor IX and is also an X-linked recessive. The signsand symptoms are the sameas hemophilia A. Sinceboth hemophilia A and B have a prolonged PTT, thesediseasesmust be distinguishedby specific factor assays. 3. Other inherited clotting factor deficiencies are quite rare and are usually autosomal recessivedisorders.Factor XII deficiencFcausesa very long PTT, but no bleeding disorder. Factor XI deficiency is seen mostly in Ashkenazic fews (German and Eastern Europeandescent);factor XIII deficienry is diagnosedby rapid clot lysis in 5N urea. D. Acquired disorders 1. Vitamin K deficiency. Vitamin K is a fat-soluble vitamin produced by bacterial metabolism of ingestednutrients within the large intestine. It is essentialin the posttranslational modification of factors II, VlI, IX, and X, as well as proteins C and S. Vitamin K deficiency may result from fat malabsorption, diarrhea, dietary deficienry (i.e., usually patients on parenteral feedings who are not receiving vitamin K supplements), antibiotics (which may kill gut flora), and some anticoagulantdrugs (e.g.,warfarin). 2. Liver disease.FactorsII, V VII, IX, X, XI, and XII are synthesizedin the liver; liver disease can result in failure to synthesizetheseclotting factors,with a resultant bleeding diathesis. 3. Disseminated intravascular coagulation (DIC) a. Clinical features. This is an acquired consumption deficiency of clotting factors and platelets, often resulting in fatal thrombosis and hemorrhage. Coagulation system activation leadsto microthrombus formation with consumption of platelets,fibrin, and clotting factors in the vasculature;this leadsto activation of the fibrinolytic system. Hence,morbidity from DIC may be relatedto either thrombosis (tissuehypoxia and infarction) or hemorrhage (coagulation factor consumption and fibrinolysis).

Clinical Correlate Proteins CandSareinvolved in normal People clotlysis. withdeficiencies ofthese proteins maydevelop frequent deepvenous thrombosis. Inaddition, factorV resistant to proteinC hasbeenrecognized asan inherited cause of deep venous thrombosis.

5tl

Hematologic/lymphoreticular System

BridgeTo Pharmacology withvitamin lnterference K-dependent factors isthe basis of oralanticoagulation. Theoralanticoagulant Warfarin isdiscussed in detail inthePharmacology chapter. ClinicalCorrelate A lowfactor Vllllevelmaybe usedto distinguish DICfrom thecoagulopathy of liver failure, hassimilar which fora normalfeatures except to-elevated factor Vllllevel. Notethatfactor Vlllin synthesized inthe endothelium of vessels; the otherclotting factors are synthesized intheliver, Bridge to Pharmacology Chloramphenicol a causes dose-related marrow suppression in allpatients, andaplastic anemia Inrare individuals. Neutropenia dueto alkylating agents ispartof a pancytopenia. Bridge to Pharmacology Cranulorytemacrophage gfactor(CMcolony-$imulatin CSF) andgranulocyte $imulating factor(CSF) arenow usedclinically totreatsome particularly neutropenias, those induced bychemotherapy. Patients recover fromtheir nadirs afewdaysearlier andare spared significant morbidity andmortality. Thefactors arediscussed in thePharmacology chapter.

tl2

There are many etiologies:amniotic fluid embolism, infections (particularly Gramnegativesepsis),malignanry, and major traumas, particularly head injury. The final common pathway is either endothelial injury or the releaseof thromboplastic substancesinto the circulation. The brain is a rich sourceof tissuefactor,which activates factor VII. b. Pathology. There is diffrrsethrombus formation, especiallyin the brain, heart, lung, kidneys, adrenals,spleen, and liver. There may be diffrrse bleeding as well. The lung may show pulmonary edemaand hyaline membraneformation. The CNS showshemorrhagic microinfarcts. The peripheral smear may show signs of microangiopathic hemolytic anemia (schistocytes). c. Diagnosis. DIC is diagnosedin the laboratory by demonstrating low platelets, low fibrinogen, and the presenceof fibrin degradation products. d. Tieatment must be directedto the underlying disease.The courseis variablebut often poor. The use of heparin is controversialbut often helps to slow the consumption of clotting factors. Fresh frozen plasma and platelet concentratemay then be used to replacethe deficits.

NON-NEOPTASTIC WHITE BTOOD CEttDISORDERS A. Leukopenia is a decreasein the circulating WBC count. It may selectivelyinvolve one WBC line, such as lymphocytes (lymphopenia), or more commonly, neutrophils (neutropenia or granulocytopenia). 1. Classification of neutropenias a. Decreasedneutrophil production is seenin megaloblasticanemias,aplasticanemia, some leukemiasand lymphomas, drug suppressionof myeloid stem cell differentiation, or autoimmune attack on stem cells. b. Increaseddestruction of neutrophils is usually due to splenicsequestration,which is often immune-mediated(e.g.,Felty syndrome). c. Drug-induced neutropenia may be seen in patients treated with alkylating agents, chloramphenicol, sulfonamides,chlorpromazine, and phenylbutazone.Mechanisms may include both decreasedproduction and increaseddestruction. The problem is usually reversibleif the drug is stopped. 2. Clinical features usually result from lack of immune defenseprovided by neutrophils. a. Constitutional symptoms include fever, chills, malaise,fatigability, and a high susceptibility to infection, particularly Gram-negativesepticemia. b. Prognosis is often poor with death resultingfrom overwhelminginfection; early diagnosis and antibiotic therapy for infections is required to avoid a fatal outcome. 3. Pathology a. Bone marrow findings depend on the etiology of the neutropenia.The neutropenia may be hypercellular due to increased destruction or megaloblastic anemia, or hypocellular,due to decreasedproduction. RBC and platelet lines may be affected. There may be increasednumbers of lymphocytes and plasma cells that result from relativepreservation. b. Infection. Infected,necrotic ulcersmay occur in the oral caviry skin,vagina,anus,gastrointestinal tract, or, less commonly, in the lungs and urinary tract. Lymphadenopathydraining infected sites may be seen.Uninhibited by neutrophils, bacteriamay form colonies.

Pathology

B. Leukocytosis is an increasein WBC count. 1. Classification. Leukocytosismay occur in a variety of WBC lines. a. Monocytosis may be seen in tuberculosis,endocarditis, malaria, brucellosis,rickettsiosis,and monocytic leukemia. b. Lymphocytosis may be seen in tuberculosis,brucellosis,pertussis,viral hepatitis, cFtomegalovirusinfections,infectious mononucleosis,chronic lymphocytic leukemia (CLL), and some lymphomas. c. Eosinophilic leukocytosis may be seenin neoplasms,allergy,asthma,collagen vascular diseases, and parasiticinfections.Any skin rash may produce eosinophilia. d. Polymorphonuclearleukocytosis (mostcommon) maybe seenin acuteinfection, tissue necrosis,and "stress,"and may be accompaniedby immature forms in the peripheral blood (leukemoid reaction or "left shift"). Chronic myelogenousleukemia (CML) producesextremeleukocytosiswith immature forms and eosinophilsaswell asbasophfia.

Note Leukocyte alkaline phosphatase iselevated in inflammatory Ieukocytosis. It isdepressed in chronic myelogenous leukemia.

2. Pathology. The peripheral blood shows elevation in granulocyte lines. In severeinfections, polymorphonuclear leukocytosismay be accompaniedby morphologic changesin the neutrophil. Dohle bodies are round, pale blue, cytoplasmicinclusions,the product of aggregatedrough endoplasmic reticulum. Toxic granulations are coarse, dark, neutrophilic granules(lysosomeson electron microscopy). C. Nonspecific lymphadenitis 1. Clinical features.Nonspecificlymphadenitismay be causedby drugs,toxins,or infection. It is common in the neck following dental or tonsillar infection, and in the axillae or the inguinal regionsfollowing infectionsof the extremities.Enlargedabdominal lymph nodes (mesenteric adenitis) may cause abdominal pain resembling acute appendicitis. Lymphadeno-pathy may be generalizedin systemicviral or bacterial infections.A syndrome of generalizedlymphadenopathymay be a precursorto AIDS. It is associatedwith hyperglobulinemiaand normal CD4 lymphocyte counts. 2. Pathology a. Acute lymphadenopathy producesswollen,red-graynodeswith prominent lymphoid follicles and large germinal centerswith numerous mitoses.Older patients tend to havelessgerminal centersthan do children. b. Chronic lymphadenopathy (1) Grossfindings are rnost common in axillary and inguinal nodes,which are characteristicallylarge and nontender. (2) Microscopic findings show three basic patterns, though combinations may occur. Follicular hyaerplasia is seen in primary antibody production. It produceslarge germinal centers,containing mostly B lymphoblasts,helper T cells, and histiocFtes.Paracortical hyperplasia is causedby a primary T-cell reaction. It produces reactive changesin the diffuse cortex, encroaching on germinal centers.Paracorticalhyperplasiamay be seenwith use of phenytoin. In sinus histiocytosis, lymphatic sinusoids become prominent and distended with macrophages.It may be seen in nodes draining carcinomas or any chronic inflammation.

Bridgeto lmmunology Follicular isoften hyperplasia seen inbacterial infections or withexposure to new antigens. Paracortical hyperplasia isoften seen in viralinfections orinsecondary immune responses.

5t5

System Hematologic/tymphoreticular

TYMPHOMAS A. Hodgkin disease(Hodgkin lymphoma) l. Overview. Hodgkin diseaseis classicallyconsideredseparatelyfrom other lymphomas (non-Hodgkin lymphomas) becauseits spread is almost alwaysin contiguity (i.e', from one setof lymph nodesto the next). The spleenis involved beforethe liver. It almost never has a leukemic component. It has a high cure rate, and, histologically,it is characterized by the presenceof the Reed-sternberggiant cell (RS cell). The RS cell is large (15-45 tt)' often with two or more nuclei, containing large"owl-eyed"nucleoli surroundedby a clear but halo; cytoplasmis abundant(FigureIV-4-l). The presenceof the RS ceii is necessary disease. of Hodgkin the diagnosis make to not sufficient 2. Incidence. The incidence is 2/100,000.There is a bimodal age distribution (high peak, ages15-35;low peak,after age50) in both men and women. 3. Clinical features. Hodgkin diseasemay presentwith painlesscervical adenopathyor with constitutional(hypermetabolic)symptoms:fevers,chills,night sweats,and weight loss. 4. Pathology.There are four variantsrecognized.In order of bestprognosisto worst: a. Lymphocyte predominance showsa seaof lymphocyteswith few RS cells,a variable number of histiocytes,little fibrosis,and no necrosis. b. Nodular sclerosis is more comlnon in wonren and tends to involve mediastinal, supraclavicular,and lower cervical nodes. There is a mixed infiltrate composed of lymphocytes,histiocytes,a few eosinophils,plasnracells,attclRScells.Birefringentcollagen bands createa nodular pattern. RS cellsare calledlacunar cells. The cytoplasm retractsas a result of fixation and de\dration, giving rise to the appearanceof a nucleussurroundedby a "lacuna"or clearspace. c. Mixed cellularity shows a mixture of neutrophils, lyrnphocytes,eosinophils,plasma cells,and histiocytes.Many classicRS cellsmay be identified. d. Lymphocyte depletion shows rare lymphocytes and many RS cells with variable eosinophils,plasmacells,and histiocytes.Diffuse fibrosis may be seen.

& -#w

F;* '"'* & a€

"4tu

wo

"

Figure lV-4-1.Reed'sternbergcell (microscopic).

tl4

*

Pathology

5. Diagnosis a. Physical examination. All lymph node groups,liver, and spleenmust be evaluated. b. Bipedal lymphangiogram, in which a radio-opaque dye is injected into the lymphatics of the feet to visualizeiliac and para-aortic nodes,may be usefi.rlin stagingsome patients. c. Computerizedaxial tomography (CAT) scan is very useful in visualizing thoracic and upper abdominal nodes. d. Laparoscopy may be used to inspect the liver and spleenand to biopsy the liver. e. Staginglaparotomy may be performed.The abdomenis surgicallyopened,suspicious lymph nodesare removed,splenectomyis performed, and the liver and bone marrow are biopsied. 6. Staging and classification a. StageI is involvement of a single lymph node group or extralymphatic site by direct extensionfrom an involved lymph node (stageIE). b. StageII is involvement of two or more lymph node regions on the sameside of the diaphragm or with direct involvement of contiguousextralymphatic organs (IIE). c. StageIII is involvement of ly-ph node regions on both sides of the diaphragm and may include the spleenor extralymphaticorgan by direct extension(IIIE). d. StageIV is disseminateddiseasein nonlymphatic organs,such as the lung, liver, or bone marrow. e. Classification. "r{'means there are no constitutional symptoms such as fever,chills, or night sweats."B" indicatesconstitutional symptoms (e.g.,stageIIA or IIIB). "E" indicatesdirect extension. 7. Course and prognosis dependson multiple factors,including age (younger do better), the presenceor absenceof constitutionalsymptoms(",{'patients do better),histology(patients with lymphocyte predominance and nodular sclerosisdo better than patients with mixed cellularity or lymphocyte depletion), and stage(the lower the stage,the better). 8. Therapy is usuallya combination of chemotherapyand radiation. One long-term problem encounteredin patients who have undergone therapy for Hodgkin diseaseseemsto be an increasedincidenceof secondarymalignancy,usuallyleukemia,approximately7-10 yearsafter primary treatment. B. Non-Hodgkin lymphomas (NHL) 1. Overview. This is a varied group of lymphoreticular neoplasmsusually characterizedby lymphadenopathy and hepatosplenomegaly. In most casesthe diseaseis first discovered in only one chain of nodes-usually cervical,axillary, inguinal, femoral, iliac, or mediastinal.In approximately30o/oof.cases,initial involvementis extranodal.Unlike Hodgkin disease,NHL do not produce RS cells,they generallydo not spreadin contiguity,and they frequently havea leukemic or blood-borne phase. in chil2. Incidence.The peakincidenceis in the late 50s.NHLs arerareand more aggressive dren and young adults. They may involve lymph nodes or lymphoid tissue in the gut, oropharynx, liver, spleen, and thymus. Presentationsinclude local or generalized lymphadenopathy,abdominal or pharyngeal mass,abdominal pain, or gastrointestinalbleeding. Weight loss is common and is a sign of disseminateddisease.NHLs are common in immunosuppressedpatients,whether iatrogenic,congenital,or aquired as in AIDS.

It5

Hematologic/tymphoreticular System

3. Classification a. NHLs can be divided into two main categoriesof nodular and diffirse and can be classifiedby cell tfpe (lymphocytic, mixed, histiocytic) and degree of differentiation (well-differentiated,poorly differentiated,undifferentiated).Lymphocytic,well-differentiatedhas the best prognosis(untreated). (1) Nodular lymphomas are characterized histologicully by aggregatesof lymphomatous cells arrangedin units resemblinggerminal centers.They are more common in the elderly and have a better prognosis(untreated). (2) Diffuse lymphomas have a sheet of malignant cells destroying lymph node architecture. There is evidencethat some diffirse lymphomas may develop from pre-existingnodular lymphomas.This portends a worse prognosis. b. An alternate classification of NHLS separateslymphomas on the basisof cell of origin: T cell,B cell,histiocyte (macrophages),and unclassifiable.Most ly-phorfttc lymphomas are B-cell neoplasms,exceptfor somelymphoblasticlymphomas and the cutaneouslymphomas (i.e.,mycosisfungoides,Sdzarysyndrome),which are T-cell neoplasms. 4. Types of non-Hodgkin lymphomas (NHL) a. Well-differentiated lymphocytic lymphoma (WDLL) (1) Clinical features. WDLL comprises approximately 5o/oof NHLs and is usually dif;frrse.It usually affects older patients who present with generalized lymphadenopathyand mild hepatosplenomegdy. (2) Pathology. Lymph nodes are replaced by small round lymphocytes with scant cytoplasm,dark nuclei, and rare mitoses.WDLL often seedsthe blood late in the disease,resemblingCLL. The bone marrow is almost alwaysinvolved. (3) Prognosis. Survival is approximately 5-7 years. This diseaseresponds rather poorly to cytotoxic drugs but is often sensitiveto apoptosis inducers, such as fludarabine. b. Poorly differentiated lymphocytic lymphoma (PDIL) (1) Clinical features. PDLL comprises approximately 30o/oof NHLs. It may be nodular or diffrrse.Patientsare usually middle-aged or older. ln 75o/oof cases, they present with lymphadenopathy and infiltration of bone marrow, liver, and spleenat the time of diagnosis. (2) Pathology shows afypical lymphocytes, often larger than in WDLL. Nuclei are irregular, angular, and indented with coarse chromatin. Mitoses are rare. A leukemic phaseis lesscommon than in WDLL. (3) Prognosis is fair; nodular PDLL has a better prognosisthan does diffi,rsePDLL. c. Histiocytic lymphoma

Note Theterm"histiocytic" is actually a misnomer: the tumors arecomposed of monoclonal B cells, notcells of macrophage lineage.

( 1) Ctinical features.This is one of the most common NHLs. It is usuallydiffusebut may be nodular. Diffirse histiocytic lymphoma (DHL) may presentwith nodal involvement (usually on one side of diaphragm), extranodal involvement (gastrointestinal tract, skin, brain, bone), or, rarely,liver and spleeninvolvement. (2) Pathology showslargetumor cellswith vesicularnuclei and prominent nucleoli. The cells may be pleomorphic. A leukemic phase is rare. The bone marrow is involved lessoften than in small cell lymphomas. (3) Prognosis is poor if untreated, but combination chemotherapy may induce remissionand occasionallya cure in lymphomas with a high mitotic rate.

5t6

Pathology

d. Mixed lymphocpic-histiocytic

lymphoma (MLHI)

(1) The diseaseis usually nodular. (2) Pathology shows cells with atypical lymphocytes (as in PDLL) and large cells (histiocytes).Thesecellsare merely cell cyclevariants of the malignant clone. (3) Prognosis is fair and remissionmay be achievedwith combination chemotherapy. e. Lymphoblastic lymphoma (1) Incidence. This is a diffi,rselymphoma that is most common in adolescentsand young adults,but there is a bimodal agedistribution with a secondpeak in the 70s.The male:femaleratio is 2.5:1. (2) Clinical features. MLHL is often associatedwith a mediastinal mass,particularly in boys, suggestinga thymic origin for the neoplastic cells. These cells often expressT-cell markers. (3) Pathology. The cells resemble the tymphoblasts of AtL. They have a uniform size,scantcytoplasm,delicatechromatin, and absentnucleoli. The nuclearmembrane may be loculated or convoluted.There are frequent mitoses. (4) Prognosis is uniformly poor but is improving with recent chemotherapy regimens.T-cell lymphomas usually do worse than B-cell lymphomas. f. Undifferentiated lymphoma: Burkitt (1) Clinical features. This diseaseis endemic in Africa and sporadic in the United States.It usually affectschildren or young adults. Lymphadenopathy is a rare initial presentation. In Africa it often arises in the mandible or maxilla; in the United States,it often arises in the abdomen (gastrointestinaltract, ovaries, retroperitoneum). The etioloW of Burkitt lymphoma is thought to be relatedto Epstein Barrvirus (EBV). EBV may act asa mitogen, initiating a sustainedpolyclonal activation of B cells.This eventually results in a neoplastic proliferation of a singleB-cell clone after a chromosomal translocationoccurs.

Note African Burkitt lymphoma essentially always hasa translocation of B:14,2:8, or 8:22.These translocations bringthec-mycgenenextto enhancers of immunoglobulin heavy or lightchain synthesis.

(2) Pathology. There is a uniform sea of moderately large cells with round nuclei, multiple nucleoli, moderate basophilic cytoplasm with lipid-containing vacuoles,frequent mitoses,and many macrophageswith ingesteddebris,producing the so-called "starry s\y''pattern. A leukemic phaseis rare. (3) Prognosis is fair. Somecuresmay be achievedwith vigorous chemotherapy. g. Undifferentiated non-Burkitt lymphoma (1) Clinical features.This is arare tumor usually affectingadults,and is not associated with EBV. (2) Pathology. The cell type is more variable than in Burkitq it may be multinucleate,havea singlenucleolus,and pale scantcytoplasm.Cell markersshow both Bcell and T-cell neoplasms.They behave aggressivelpas do all diffi,rse,large-cell lymphomas. h. Cutaneous T-cell lymphomas ( 1) Mycosisfungoides. There are three phasesof skin lesions:inflammation, plaque, and tumor. Nodal and visceral dissemination may occur. There are epidermal and dermal infiltrates by neoplastic T cellswith cerebriform nuclei. Nodules and fungating tumors may develop later in the disease.These tumors are usually composedof CD4 type cells.

tl7

Hematologic/lymphoreticular System

(2) sczarysyndrome' This is a rare chronic diseaseassociated erythroderma' exfoliation, and lymphade.rop",rry.;adrrry with progressive,pruritic cells,,,T cellswith cerebri, form nuclei' similar to those seen in fungoides, infiltrate the peripheral lycgsig blood' This may be considereda preterminal phaseof mycosisfungoides. 5' staging of non-Hodgkin lymphomas is simila-rto Hodgkin disease.Staging is lessclinically significant in NHL asprognosis is more affectedby histology, and the disease is often disseminatedat the time oi di"grrorir. 6' Prognosis dependson the extent and.histologyof disease.Treatment is usuallycombined radiation and chemotherapy. Survival is iowly implwing.-Tu-o., with very high offerthebestchance

of curebecause or rn.li.nsitiviry ,"l.ai",irn

ilHtff:fi;*

and

TEUKEMIAS The leukemiasare of malignant neoplasmsof wBC precursors ] Erouq characterizedby abnormal leukocrres in the peripheral b]ood, lr*r, and bone marrow. Most of the ;J.; morbidiry

ffi*:ti[Jfil""ionai

impairment of wB^c,RBC,andplatetets, leading to infectrr,,r,.-

A. Classification

In a Nutsheff Acuteleukemias haveblasts in peripheral bloodand decreased mature cells, while chronic leukemias havean increased number of mature WBCs intheperipheral blood.

1' Acute leukemias are charactetized,,bythe presenceof blasts in the peripheral blood and lack of mature cells'They are usuallyrapidiy fatal if reft ,rntr".t.J (2-4 months). The rwo most common types are acute lymphocytic leukemia (eril und acute myelogenous leukemia (Aur)' Acute monocytic leukemia (AMoL) and acute undifferentiated leukemia (AUt) occur lessfrequently. 2' chronic leukemias are characteri zedbyelevated numbers of more mature reukocytesin the peripheral_blood. They haye a ronger course (if untreated, 3_10+ years). chronic myelogenous leukemia (itvtl) and *;;t^thocytic leukemia (c61 are the rwo most common forms' chronic monocytic leukemia (cMot) is much less common. B' Incidence' There are approximately 7 new cases/100,[[V/year.of all leukemias, 600/o are acute and 40o/oare chronic; of the chronic l.ut -i.r, half are cMf and half cLL. Men have a higher incidence than women (especially cLL). Leukemia is the -or, common cancerdeath in children' The most causeof common leukemiasfor specific age-groupsare listed in ThbleIV-4-2.

Tablerv-4-z.The most commonleukemias for specificagegroups. Age Most common Ieukemia

Under 15 AtL

15-39 AML

40-59 AML and CML

Over60 CLL

Definitions: ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; cML = chronic myelogenous leukemia; cLL = chronic lymphocytic leukemia.

C. Acutelymphocyticleukemia(Att)

518

l' clinical features'ArL accounts for 60-70o/oof at age4; it is rareoverage50.ArL preserrt, childhoodleukemia.Thepeakincidenceis *ith.futigue,f.".; a;;;ondaryto neutropenia andinfection)'bleedingL theform of .pi;,.-;, gi"gi"a pa..rri.,-...hy-ores (secondary to thrombocrtopenia); subarachnoid o. ..r.u.? [.--rn"g. patients -", occur. havelymphadenopathy, may hepatosplenom.gd;o, iorr. pain from infiltration of theseareas.

Pathology

2. Pathology a. Almost all patients presentwith anemia and thrombocytopenia on peripheral smear. The initial WBC count is variable and may be high, normal, or low, dependingon the courseof the disease.Lymphoblasts are prominent and mature WBCs are rare. b. Bone marrow is packed with lymphoblasts-cells with round-oval nuclei, clumped chromatin, l-2 nucleoli, and scantbasophilic cytoplasmwithout granules. c. ALL is the leukemia most likely to involve the nervous system. Neoplastic cells may infiltrate meninges,compressingand destroyingadjacentcerebralstructures. 3. Prognosis a. Death often resultsfrom infection or bleeding.Chemotherapy may induce remission, a state in which leukemic cells are no longer present in bone marrow (although extramedullaryfoci of cancermay persist).Bone marrowtransplantation may rescue as many as 40o/oof children who relapse after chemotherapy. With radiation and intrathecal chemotherapyto prevent CNS involvement,approximatelyhalf the children

Note of preMostALLis composed isthe CDl0(CALLA) B cells. marker. surface diagnostic usually occur, variants T-cell a boysandcausing affecting mass thatmay thymic thetrachea. compress deoxynucleotidyl Terminal in transferase flDT)ispositive bothB-cellandT-cellALLand inAML. isnegative

are cured. b. Prognosisfor adults remains very poor and deciinessteadilywith age,especially10 yearsor more after treatment. D. Acute myelogenous leukemia (AML) l. Clinical features. AML representsapproximately 20o/oof acute leukemia in children and is the most common acuteleukemia in adults.Signsand symptoms resembleALL, except that AML usually presentswith lymphadenopathy or splenomegaly. 2. Pathology. One may seetissueinfiltrates of neoplasticcellscalledchloromas.The primary cell type is variable. a. Myeloblasts have a round-oval nucleus,loose chromatin, two or more nucleoli, and pale blue cytoplasm.They may contain Auer rods (finely granular cytoplasmicbodies),which are abnormal fusedlysosomalstructures' b. Neoplasticcellshave featuresof both myelocytesand monocftes. c. In promyelocytic leukemia, Auer rods are present,and neoplastic cells are filled with gt*.tl.r containing procoagulantmaterial; releaseof this material may lead to DIC. DIC, togetherwith thrombocytopenia due to bone marrow infiltration with leukemic cells,may lead to fatal bleeding. d. Erythroleukemia (De Guglielmo disease)featuresarypical multinucleated RBC precursors.It usually convertsto AML. e. Eosinophilic or basophilic leukemias are rare disorders in which the eosinophil or basophil precursor is the predominant neoplasticcell trpe. 3. prognosis is uniformly poor and patientsusually die within 3 years.Bone marrow transplantation is under investigationand has alreadycured some patients.

519

Hematologic/tymphoreticular System

Thble IV-4-3. The French, American, and British (FAB) classification of myelogenous leukemias. Classification

Description

MO MI

Undifferentiated; no consistentALL markers Myeloblastswithout maturation; cells express HLA, DR, CD34, CDl3, CD15, and CD33 Granulocyte maturation is recognizable Promyelocytic Mixed myeloid and monocytic differentiation Monoblastic or monocytic Erythroid differentiation Megakaryocytic differentiation

M2 M3 M4 M5 M6 M7

E. Chronic myelogenous leukemia (CML) 1. Clinical features. This is primarily a diseaseof middle agebut may occur in children and young adults. Initial symptoms are often fatigue, fever, night sweats,and weight loss. Splenomegaly is common and often massive enough to cause abdominal discomfort. Laboratory studiesmay show marked leukocytosis(50,00G-500,000),low-to-absent leukocyte alkaline phosphatase, elevatedserum vitamin B,, and vitamin B,r-binding proteins, and high uric acid as a result of rapid cell turnover. After a variable remission period, patients may develop blast crisis, which is an acute resistantform of leukemia, leading to death.Approximately two-thirds of patients convert to AML and one-third to B-cell ALL. 2. Pathology

Note ThePhchromosome wasthe firstchromosomal translocation foundto be specific fora disease. lt creates a bcr:abl fusion protein whichphosphorylates tyrosines inappropriately. STl57l isa drugwhich specifically targets thefusion protein (again thefirst)and hasproduced durable remissions.

Note Theclassical CLLcellisthe B CDs cell.CLLcellsdivide veryslowly butdonot undergo apoptosis andso accumulate endlessly.

t20

a. The peripheral smear shows a very high WBC count. Segmented neutrophils, metamyelocftes, and myelocftes are predominant, but promyelocytes and blasts are also present. Eosinophils and basophils are present and often prominent. Lymphocytesare few. There is a moderate anemia with some anisocFtosis.Plateletsare usually increased,often markedly. b. The bone marrow is packed,often 100o/ocellular with hyperplasiaof the granulocytic cell line. c. The spleen may be massively enlarged (up to 5 kg). Leukemic cells may obstruct vessels,leadingto multiple splenicinfarcts. d. Over 95o/oof patients with CML have the Philadelphia chromosome (Pht), the result of translocationfrom the long arm of chromosome22 to chromosome9 in all dividing progeny of pluripotent stem cells.This translocation is pathognomonic and confirms the diagnosis.Prognosisin CML is worse in Phr-negativepatients. 3. Prognosis. Control may be achievedwith hydroxyurea, but blast crisis and death usually ensuewithin 2-3 years.B-cell blast AIL crisis is more treatablethan AML. Bone marrow transplantationhas produced some cures. F. Chronic lymphocftic leukemia (CLL) 1. Clinical features.This is a diseaseof patients usually over 60 yearsof age.It is common in the West and rare in Asians.There is usually an insidious onset,often discoveredincidentally during routine blood testing.The patient may be asymptomaticor presentwith fatigue and weight loss; lymphadenopathy and hepatosplenomegalyare later findings. Patients may develop low levels of gamma globulins with resultant susceptibility to infection. Patients with CLL are also thought to have a higher incidence of visceral

Pathology

malignanry (e.g.,gastrointestinaltract, lung, skin), and develop autoimmune hemolytic anemia more frequently than the normal population. 2. Pathology a. The peripheral smear showsmarked lymphocytosis (50,000-250,000).Normochromic, normocytic anemiais common and autoimmune hemolysismay occur.Plateletsare initiully normal, then decreaseas the bone marrow is replacedby neoplasticcells. b. In the lyrrrph nodes,marked lymphadenopathy may develop late in the disease.Nodes are soft and rubbery. The cut surfaceis homogeneous.On microscopic examination,the infiltrate is indistinguishablefrom diffirse well-differentiatedlymphocytic lymphoma. c. The liver may be enlarged.Infiltrates are usually localized to portal areas. 3. Prognosis. Median survival with treatment is approximately 5 years but varies widely. TWenty-yearsurvivals are reported. Patientsoften die of other diseasesafflicting the elderly. The most important prognostic factor is extent of disease.When the WBC is 0z) (or = crz= Fr= Fz) Epinephrine

>> o) Dopamine(Dt = D2 > *Ephedrine(at = uz = Fr = Fr 0z)

9z Terbutaline Albuterol Metaproterenol Ritodrine

Adrenergic Receptors (major effects) cr,1Vasoconstriction,increasesblood pressure,stimulatesglycogenolysis,and mydriasis stimulatesplateletaggregation, cr2 Decreasesnorepinephrinerelease(presynaptic), vasoconstriction, inhibitslipolysis,and inhibitsinsulinsecretion 9r Increasesheart rate and force of contraction,stimulatesrenin release p2 Vasodilatation, relaxationof uterinesmoothmuscle,increased bronchodilatation, glucagon,and increasedglycogenolysis p3 Stimulateslipolysis D1 Relaxationof renaland splanchnicvasculature * Have both direct and indirecteffects

Figure V-31-3. Adrenergic agonists.

In a Nutshell . cr,-Agonists areoftenused aslocalvasoconstrictors. . q-Agoni$s areusedto lower bloodpressure. . p,-Agonists areusedto increase cardiac output. . B,-Agonists areusedfor broncochodilatation and uterine relaxation . Indirect acting agents are usedfornarcolepsy. . Ephedrine isusedasa bronchodilator.

600

4. Betar-agonists(e.g.,terbutaline) are used to produce bronchodilatation in patients with bronchial asthmaand (e.g.,ritodrine) to relax uterine smooth musclein pregnantwomen near term. 5. Indirect-actingagents (e.g.,amphetamineand analogs)are usedin narcolepsy,attentiondeficit disordet and in diet therapy to suppressappetite (amphetamineis no longer used for this). 6. Mixed-acting drugs (ephedrine) are used for vasoconstrictionand bronchodilation.

ADREN ERGIC ANTAGON ISTS(SYMPATHOTYTICS) A. Mechanism of action. Adrenergicantagonistscan be classifiedbasedon their mechanismof action: ct-adrenoceptorantagonists,B-adrenoceptorantagonists,and adrenergic neuron blockers,as describedin FigureV-31-4 and TableV-3I-7. B. Alpha-adrenergic receptor antagonists are subdivided based on their selectivity and reversibility. 1. Nonselective, irreversible (long-acthg) agents. Phenoxybenzamine irreversibly blocks o,- and or-adrenergicreceptorsby forming a covalentbond with the receptor.

Pharmacology: DrugsAffectingthe ANS

Table V-3f -6. Selectedproperties of adrenergic agonists.

Drug

Pharmacolog. Properties

ClinicalUses

Toxicity

Ineffective orally; does not enter CNS; usually given intravenously; and inactivated by COMT and MAO

Hemodynamic shock (not drug of choice)

Ischemiaand necrosis at injection site may causehlpertension in patient with hyperthyroidism

Epinephrine

Ineffective orally and does not enter CNS

Bronchial asthma,allergic anaphylaxis,cardiac arrest;to produce hemostasis;and to enhancelocal anesthetics

Anxiety,tremot irritabiliry headache, dizziness,tachycardia, hypertension,angina, and palpitations

Dopamine

Does not enter CNS

Shock;oligouria due to decreasedrenal bloodflow; to increaserenal bloodflow (low doses);to increasemyocardial contractility and heart rate (moderatedoses);to increase systemicblood pressure,heart rate,and forced contraction; and to reducerenal bloodflow (high doses)

Decreasedrenal perfusion,ischemia, local necrosis,tachycardia,angina,and hypertension

Nasaldecongestant, hlpotension mydriatic; to prolong local anesthetic; and to terminate PATs

Hlpertension, headache, and tissuenecrosis

Endogenous catecholamines Norepinephrine

o-Adrenergic agonists Phenylephrine(o,) Increasesblood pressureand TPR, reflex bradycardia,and resistantto COMT Methoxamine (4,)

Vasoconstriction and reflex bradycardia

Hypotension (especiallyduring Similar to phenylephrine anesthesia);and to terminate PAIs

Clonidine (ar)

Hypotension,sedation,reduced sympathetic oudow; rapidly entersbrain; and is administered orally and transdermally

Hypertension,opiatewithdrawal, andbenzodiazepinewithdrawal

p-Adrenergic agonists Isoproterenol(B,, B2) Increasesheart rate and contractiliry relaxesbronchial and gastrointestinalsmooth muscle, and is administered intravenourly ot inhaled. Metabolized by COMT, metabolized poorly by MAO.

Sedation,dry mouth, orthostatichpoten-

ffi'i.'#1"*'tunction' Bronchial asthmaand bradycardia Thchycardia,palpitations, headache, anginalpain, and cardiac arrhythmias

Dsfnitiorri CNS : c€ntra.l nervous syst€m; COMT = cat€chol O-methyltra$ferasej PATS= parcxtsmal atdal tachycardias.

MAO = monoamin€ onda!€; TPR = total peripheral resistancei and

(Continued)

601

Neruous System

Note Phenoxybenzamine isanirreversible used cr-antagonist inthetreatment of pheochromocytoma.

a. Pharmacologic effects. Catecholamine-inducedvasoconstriction is blocked, thus decreasingblood pressure.Phenorybenzamineproducestachycardiaby two mechanisms: through cardiovascularreflex, and by inhibiting negativefeedbackby blocking presynapticautoregulatorycrr-receptors,thus stimulating norepinephrine release. b. Indications for use include pheochromocFtoma, hlpertensive crises secondary to adrenergicagonist or MAO inhibitor overdose,in presurgicalmanagement,autonomic hyperreflexia,and prophylaxis of Raynaudphenomenon.

ThbleV-3f -6. Selectedproperties of adrenergic agonists (cont'd).

Drug

Pharmacologic properties

Clinical uses

Toxicity

Dobutamine (B,)

Positiveinotropy but less increasein heart rate

CHF; promotes increased output with little change in myocardial orygen demand

Thchyarrhythmias angina,hypertensln

Metaproterenol (M), (Fr), terbutaline(T), albuterol (A), and ritodrine (R)

Active orally and inhalation; resistantto COMT

Bronchospasm/asthma (M, T, A); delaysdelivery in premature labor (T and R)

Nauseaand vomiting, tachycardia,palpitations, hypertension, and tremors

Stimulatesreleaseof norepinephrine,dopamine, and serotonin increasesblood pressure, reflexly decreases heart rate, readily entersCNS, D-isomer has greaterCNS effects

Narcolepsyand appetite suppression(short-term)

Restlessness, dizziness, insomnia, impotence, headache,tremor delirium, paranoia, cardiacarrhythmias, hypertensivecrises, and arrhythmias (with MAO inhibitors)

Indirect-acting adrenergic agonists Amphetamine

Tyramine

Mixed-acting adrenergic agonists Ephedrine

Metaraminol

Presentin red wines,beer,cheese, None and chocolate;stimulatesrelease of norepinephrine and dopamine

In combination with MAO inhibitors, it can lead to a sympathetic crisis,which is potentially fatal.

Stimulatesreleaseof norepinephrine and dopamine; some direct receptor stimulation; stimulatesCNS; resistantto COMT and MAO

Bronchospasm/asthma, hypotension

Hypertension,insomnia, and tachyphylaxis

Stimulatesnorepinephrine release;cr-agonist;increases blood pressure;reflexly decreasesheart rate; doesnot enter CNS

Hypotension and associated PATs

Similar to norepinephrine

Definitions:CNS : central neryous system;COMT = catecholO-methyl-transferase;MAO = monoamine oxidase;TPR = total peripheral resistance; and PATs= paroxysmal atrial tachycardias.

602

Pharmacology: DrugsAffectingthe ANS

c. Side efifectsand toxicity. Adverse reactions include sedation, orthostatic hypotension, tachycardia,nasalcongestion,nausea,abdominal pain, and inhibition of ejaculation. 2. Nonselective reversible (short-acting) agents. Phentolamine competitively and reversiblyblocks cr,- and crr-adrenergicreceptors.Phentolamineis shorter acting than phenoxybenzamine.

Adrenergic neuron blockers Reserpine I Decrease GuanethidineJ norepinephrine release Nonspecific Phenoxybenzamine Phentolamine

Selective crr blockers Prazosin Terazosin Doxazosin

Selective az blockers Y o h i mb i n e ldazoxan

Selective Br blockers Acebutolol Atenolol Metoprolol Esmolol

Figure V-31-4. Adrenergic blockers. Table V-31-7. Comparison of B-adrenergic receptor antagonists.

Drug

Receptors blocked

Sympathomimetic activity

Local anesthetic activity

Therapeutic uses

Acebutolol Atenolol

F, F,

-r

+

Arrhythmias

None

None

Hypertension and angina pectoris

Esmolol Labetalol Metoprolol

p,

None

Arrhythmias

cr,,B,,B, I,

None

None + +

Nadolol

F,,F,

None

None

Hypertension and angina pectoris

Pindolol

F,,9,

+

-1-

Hypertension

Propranolol F,,F,

None

+

Hypertension,angina pectoris, and arrhythmias after myocardial infarction

Timolol

None

None

Hypertension, arrhythmias after myocardial infarction, and glaucoma

0,,9,

f

Hlpertension Hypertension,angina pectoris,and arrhythmias after myocardial infarction

605

NeruousSystem

Note Phentolamine isa reversible nonselective ntagonist cr-a usedinthetreatment of pheochromocytoma. ClinicalCorrelate (e.g., Selective cr,-antagonists prazosin) areusedinthe treatment of hypertension withminimal increase in heart rate. Terazosin isalsousedfor prostatic benign hyperplasia.

a. Indications for use include hypertensive crises associatedwith pheochromocFtoma and prevention of dermal necrosisfollowing extravasationof an o-adrenergicagonist. b. Side effects and toxicity. Adverse reactions include tachycardia,arrhythmias, angina, orthostatic hypotension, gastrointestinalstimulation (aggravatespeptic ulceration), nausea,vomiting, abdominal pain, and diarrhea. 3. Selectivecr,-antagonists.Prazosin,terazosin,and doxazosinare competitive, reversible blockersof cx,-adrenoceptors. a. Pharmacologic properties include vasodilatation in both arterial and venous beds, thus reducing both afterload and preload. The major advantageover nonselectivecrblockers is that they produce less tachycardiaand renin releasedue to lack of crrpresynapticreceptorblockade.Sometolerancedevelopswith chronic use. b. Indications for use include hypertension, congestiveheart failure (CHF), Raynaud phenomenon,and preventionof urinary retention in men with prostaticenlargement. c. Side effectsand toxicity. Adversereactionsinclude a "first-dose effect" (marked postural hypotension 30-90 minutes following the initial dose,which may lead to fainting), palpitations,dizziness,headache,and nasalcongestion. 4. Selective cr2-antagonists.Yohimbine and idazoxan are used primarily in research.They increasethe releaseof norepinephrine. C. Beta-adrenergrcreceptor antagonists (ThbleY-3I-7; FigureV-31-4).

Note names endin B-blocker "olol."Notethatlabetalol is alsoancr,-blocker.

1. Classification. Beta-adrenergicreceptor antagonistsare classifiedaccordingto three properties(TableY-31-7;FigureV-31-4). a. Selectivity. Some of the B-antagonists(e.g., propranolol) act on both B,- and Brreceptors.Other antagonists(e.g.,atenolol, metoprolol) are selectiveB,-antagonists. This selectivityhas two advantages:to treat patients who also havebronchial asthma (no blockade of B, in bronchial smooth muscle) and to prevent peripheral vasoconstriction (no blockade of B, in vasculature).Labetalolis a nonselectiveB-blocker,but it alsoblocks cr,-receptors,thereforehaving lesseffect on the vasculature. b. Intrinsic sympathomimetic activity. Pindolol and acebuodol,besidesblocking Breceptors,havepartial agonistactivity.They causelessslowing of the heart, lessbronchoconstriction,and lessalteration of serum lipids than other B-blockers.

ClinicalCorrelate Therapeutic Useof B-Blockers . Treatment ofglaucoma . Treatment of hypertension . Treatment ofarrhythmias . Reduction ofpostMl mortality . Migraine prophylaxis . Stage phobias fright/social

604

c. Local anesthetic activity (membrane-stabilizingactivity). This property is useful in the treatment of cardiac arrhythmias and is partially responsiblefor their effectiveness.It is a disadvantagewhen used topically in the eye. 2. Pharmacokinetics. The B-adrenergicblockersvary in their bioavailability,lipid solubility, and duration of action. Propranolol has low bioavailability due to first-pass metabolism.It is also lipid soluble,producing CNS effects.Some agents(e.g.,pindolol) havehigher oral bioavailability.Newer drugs (atenolol and nadolol) with lower lipid solubiliry havelessCNS side effects.Nadolol is the longest acting blocker (half-life up to 24 hours), while esmolol has a half-life of only 10 minutes. 3. Indications for use a. Aqueoushumor formation in the eyeis reducedin patients with glaucoma. b. Cardiac output and renin secretionare reducedin patientswith hypertension. c. Atrioventricular (AV) nodal conduction and automaticity of cardiactissuearereducedin patientswith tachyarrhythmias.

Pharmacology: DrugsAffectingtheANS

d. A depressanteffect on the heart reducesoxygen deficit and thus pain in patients with angina pectoris. e. Beta-antagonistsare used prophylacticallyfor migraine headache. f. Their CNS effectsreduce tremor and anxiety. g. This classof drugs is used as adjunctive therapy in hyperthyroidism becauseof their cardiac depressantand antianxiety effects. 4. Side effects and toxicity a. Bradycardia,A-V nodal block, CHF, and exacerbatedperipheral vasculardiseasemay occur. b. Bronchial asthmais exacerbatedin susceptiblepatients. c. Sedation,fatigue,and insomnia may occur. d. Symptoms of hypoglycemia in a diabetic patient (tachycardia, anxiety, and tremor) may be masked. D. Adrenergic neuron blockers are drugs that act presynapticallyto block the storageor release of catecholamines. 1. Reserpineblocks the reuptake of catecholamines(e.g.,norepinephrine, dopamine) and serotonin into the storagevesiclesin adrenergic neurons. This leads to neurotransmitter depletion. It is still available,though it is little used in the treatment of hypertension. In addition to peripheral sympatholytic effects,reserpine produces CNS depressanteffects. 2. Guanethidine enters the presynaptic adrenergic termin"l by the catecholamine uptake process.Once in the nerve,guanethidinedisplacesnorepinephrine from the storagevesicles.The norepinephrine is then metabolized to inactive products by MAO, and thus, the nerve terminal is depleted of neurotransmitter. Guanethidine also prevents the releaseof norepinephrine.The drug works only in peripheral neurons.It doesnot crossthe bloodbrain barrier. Guanethidine is used in patients with severehypertension and has a prolonged action.

ClinicalCorrelate (evenB,AllB-blockers selective be ones) should patients usedwithcarein with (e.9., lungdisease asthma, (blocks COPD) anddiabetes premonitory symptoms of hypoglycemia).

In a Nutshell thenerve Cuanethidine enters terminal bytheNEreuptake NEfrom carrier anddisplaces synaptic vesicles, leading to NEdepletion. lt alsoprevents release of NEintothesynapse. It therefore lowers blood pressure. blockers Uptake (e.g.,tricycl nts) icantidepressa prevent guanethidine's actions.

605

the DrugsAffecting System CentralNervous nervous inthecentral neurotransmission drugs thatactbyaltering There aremanytherapeutic forsurgery setting general (CNS). agents usedin a hospital anesthetic include These drugs system of in the treatment drugs used procedures, agents, antiepileptic sedative-hypnotics, or medical (e.g., psychiatric anxlety, disorders (e.g., parkinsonism), usedin anddrugs motordisorders thereisa better psychosig. hasexpanded, of brainfunction Asknowledge depression, moreeffective of newer, andthedevelopment agents ofthese ofthemechanisms understanding pharmacology of these drugs. basic reviews the Thissection agents.

ANESTHETICS GENERAT Generalanesthesiais a statecharacterizedbydrug-induced perceptualabsenceof all sensation. All generalanestheticsare administeredby inhalation or intravenousinjection and are classified by the route of administration (TableV-32-l). A. Overview 1. Characteristicsof the ideal anestheticagent are listed below. It is important to note that no single anestheticcan achieveall of the characteristicslisted; therefore,a combination of severaldrugs is used to achievethis goal (balancedanesthesia).Drug combinations may include a primary anestheticagent (e.g.,isoflurane) with a preanestheticagent for sedation(e.g.,a benzodiazepine),a rapidly acting agentfor induction (e.9.,nitrous oxide, thiopental), a skeletalmuscle relaxant (e.g., succinylcholine),and an analgesicfor pain (e.g.,morphine). a. Rapid, pleasantinduction and recoveryof anesthesia b. Rapid changesin the depth of anesthesia c. Adequateskeletalmuscle relaxationto perform surgery d. Production of amnesia e. Ability to provide analgesia f. A wide safetymargin g. Nontoxic

607

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Thble V-32-1. General anesthetic agents. InhalationalAnesthetics

IntravenousAnesthetics

Nitrous oxide Halothane Enflurane Isoflurane Desflurane Methoryflurane Sevoflurane

Barbiturates(thiopental) Benzodiazepines(diazepam,midazolam) Ketamine Propofol Etomidate

2 . Depth of anesthesiais directly proportional to the partial pressure(inhalation agents)or the drug concentration (intravenous agents)that is in the CNS. The rates of induction and recovery area function of how quickly the anestheticlevelschange.Factorsthat determine the CNS partial pressureof inhalational agentsinclude: a. Concentration of anesthetic agent in the inspired mixture b. Alveolar ventilation rate (increasing the rate of ventilation increasesthe rate of induction, particularly with high solubility anesthetics)

Note (blood-gas Blood solubility partition coefficient) is proportional inversely to the rateof induction.

In a Nutshell (when Atequilibrium the partial pressures of thegasin differentbodycompa rtments areequal), = Solubility

[Anesthetic]o,ooo [Anesthetic]ru,

c. Solubilig of anesthetic agent in the blood. The lesssoluble an agent is in the blood, the quicker the rise in partial pressureand the more rapid the induction. A soluble agent usesthe blood as a reservoirby dissolvingin the blood and does not reach the brain asrapidly as an insoluble agentbecauseit takeslonger for the partial pressureto rise. The blood-gas partition coefficient reflects the relative solubility of an agent for blood versusair. The lower the blood-gaspartition coefficient,the more insoluble an agentis in blood and, thus, the fasterthe induction of anesthesia. (l) Desflurane:0.42 (2) Nitrous oxide:0.47 (3) Sevoflurane:0.67 (4) Isoflurane:1.4 (5) Enflurane:1.8 (6) Halothane:2.3 (7) Methoxyflurane 12.0 d. Alveolar to blood transfer, which is affected by the ventilation-perfusion ratio e. Loss of anesthetic from arterial blood to tissue, which is a function of the partial pressuregradient,perfusion, and partition coefficient 3 . Stagesof anesthesia.The stagesof anesthesiaprovide signs noted with increasingCNS depression,based on the effects of the classicanesthetic,diethyl ether. Though most newer anestheticsact more rapidly and are combined with other agentsthat may mask these stages,these signs of anestheticdepth are usefirl in understanding the effects of generalanesthetics.

608

DrugsAffectingthe CNS Pharmacology:

a. Stage I (analgesia) starts from the point of induction and lasts until loss of conthere is also a loss of pain sensation. sciousness; b. Stage2 (excitement,disinhibition) startsfrom the end of stage1 to surgicalanesthesia. This stagemay be associatedwith autonomic instabiliry airway irritation, excessivemuscle activity, rapid eyemovement, and vomiting. c. Stage3 (surgical anesthesia)consistsof four planes. (1) Plane I is from the onset of the return to regular breathing until the loss of eye movement.

( ) \ Plane 2 is from the cessationof eye movement until the initiation of intercostal muscleparalysis.

( 3 ) Plane 3 is from the initiation of intercostalmuscleparalysisuntil completion. ( 4 ) Plane 4 starts with complete intercostalparalysisand ends with diaphragmatic paralysis. d. Stage4 (respiratory collapse) lastsfrom diaphragmaticparalysisuntil cardiacarrest. 4 . Elimination of inhalational anesthetics a. Ideally,gaseousanestheticsareentirely eliminated by exhalation.In actuality,th.y may be metabolizedin part by the liver, leading to the formation of toxic metabolites.The less metabolism there is, the safer the anesthetic.The percent of each agent metabolizedis enflurane:2olo;isoflurane: methoxFflurane:70o/o;halothane:l5-20o/o;sevoflurane:2-5o/oi and nitrous oxide:0.004o/o. desflurane:0.02o/o; 0.2a/o; b. The rate of recoveryis partly dependenton the partition coefficient of the gas.The partition coefficient (which is approximately 1 for lean tissue) may be quite high for fat, leading to sequestrationin the fat and delayingrecovery. 1

Potency of inhalational anestheticsis inverselyproportional to the minimum alveolar concentration (MAC), the amount of anestheticneededto induce immobility in 50% of individuals following a noxious stimulus. MAC is dependentonly on the specific agent used.Increasedpotenry correlateswith increasedlipid solubility (or hydrophobic properties). Be awarethat MACs are additive when combining agents.MACs of inhalational anesthetics (from the least potent) are: nitrous oxide: >100o/o;desflurane: 6-70/o; and methoxyflurane:0.l6oio. enflurane:l.7o/o;isoflurane:l.4o/o;halothane:0.75o/o;

6 . Mechanism of action. The exactmechanismof action for the effectsof inhalational general anestheticsis not understood. a. Since the potency of the agent correlatesto the lipid solubility, these agents are thought to disrupt neuronal transmissionby intercalatinginto the lipid bilayer,leading to ion channeldysfunction.Nternation in various receptorfuntion is another possible mechanism. b. Analgesia,producedby someof theseagents,is due to a decreasein the activity of neurons in the substantiagelatinosain the dorsal horn of the spinal cord. c. Other stagesof anesthesiaare due to complex effectson higher brain regions.

Note Atequilibrium, Partition [Anesthetic],'rrr. coefficient [Anesthetic]o,ooo

ln a Nutshell r0lencY *

I MAC

Because theMACfornitrous l00o/0, thisdrug exceeds oxide intothe bringa patient cannot stage when surgical alone. administered ln a Nutshell are anesthetis Ceneral into thought to intercalate cell neuronal andexpand thusdisrupting membranes, transm ission. synaptic

609

Nervous System

B. Inhalational anesthetic agents 1. Halothane a. Pharmacologic properties (1) Halothane is a halogenatedgasand a potent anesthetic.

Note

(2) Cardiovasculareffectsinclude myocardial depressionwith reducedcardiacoutput and reduced renal and splanchnic blood flow. Halothane sensitizesthe myocardium to catecholamines,which can lead to tachyarrhythmias. (3) Respiratorydepressanteffectswith reducedtidal volume are dose-dependent.

produces Halothane cardiovascular depression and sensitizes theheartto the arrythmogenic effects of catecholamines.

(4) Cerebralblood flow increases,leadingto possibleincreasesin intracranial pressure. (5) In skeletalmuscle,halothaneproducesminimal relaxationvia CNS effects,but it increasessensitivityto neuromuscularblockers. (6) In the kidneys, halothane decreasesthe glomerular filtration rate (GFR) and renal blood flow. (7) In the liver, halothane decreasessplanchnicand hepatic blood flow. It can produce postoperativehepatitis. b. Pharmacokinetics. About 80o/oof halothane is eliminated via the lungs in 24 hours; approximately 15-20% is metabolizedby hepatic cytochrome P-450 over 2-3 weeks; bromine, chloride, and trifluoracetic acid appearin the urine as metabolites. c. Indications for use. Halothane is a potent anesthetic.Its use is precluded in neurosurgical casesbecauseit increasesintracranial pressureand in obstetric casesbecauseit inhibits activelabor by relaxing uterine smooth muscle.It is usefrrlfor pediatric surgery.

€linical Correlate

d. Side effects and toxicity

Halothane isassociated with posta nesthesia hepatitis ("halothane hepatitis").

(1) Halothaneis associated with hepatitis,2-5 dayspostanesthesia. It is characterizedby tissue necrosis,abnormal liver function tests,and eosinophilia.This is most often seenafter multiple exposures.Incidenceis low (1:10,000)but it is fatal in approximately50o/oof thesepatients.

In a Nutshell

(2) Malignant hnterthermia occurs with halothane and other halogenatedinhalational anesthetics.It is characterizedby a rapid rise in body temperature with massiveincreasesin oxygen consumption and metabolic acidosis.This is a rare but fatal condition unless it is aggressivelytreated with cooling measuresand dantrolene,which reducescalcium releasefrom the sarcoplasmicreticulum, thus blocking thermogenic skeletalmuscle activity.

Malignant hyperthermia may occur withgaseous anesthetics, especially when usedin conjunction with succinylcholine. lt istreated withdantrolene.

In a Nutshell Enflurane causes less cardiovascular sideeffects thanhalothane, butit can produce seizures.

2. Enflurane a. Pharmacologic properties are similar to but lesspotent than halothane. ( I ) Cardiovasculareffectsinclude dose-dependentmyocardialdepression(lessthan halothane) and lesssensitizationto catecholamines.Therefore,it is lessarrhythmogenic. (2) In the CNS, enflurane has been associatedwith the production of seizuresand elevatedintracranial pressure. (3) Enflurane producesmore respiratory depressionthan halothane. (a) Skeletalmuscle relaxation is greater than with halothane. Enflurane potentiates neuromuscularblockers. (5) In the kidney, enflurane reducesthe GFR and renal blood flow.

6t0

Pharmacology: DrugsAffectingthe CNS

b. Pharmacokinetics. About 80o/oof enflurane is excretedunchanged by the lungs, and 2o/ois metabolized in the liver. c. Indications for use. Enflurane is considereda good general anestheticagent,although it is not administered to patients with seizureconditions or renal dysfunction. d. Side effects and toxicity. Adverse reactions include postoperative hepatitis, seizures, renal toxicity, and malignant hyperthermia. 3 . Isoflurane. Isoflurane is an isomer of enflurane and is, thus, a potent anestheticagent. Pharmacologicproperties are similar to enflurane. a. Pharmacologic properties (1) In the cardiovascularsystem,it producessome myocardial depression,but it is not arrhythmogenic. (2) It producesa dose-dependentrespiratory depressionand respiratory irritation on induction. (3) In the CNS, isoflurane does not produce seizure activity and it decreases intracranial pressure,making this a preferredagentfor neurosurgery. b. Side effects and toxicity. Adverse reactions are similar to but less severethan with halothane;malignant hyperthermia is possible. 4. Desflurane. This is a new agentthat is similar in pharmacologicpropertiesto isoflurane, but it has a more rapid rate of induction. 5 . Methoxyflurane. This agent is not commonly used because of nephrotoxicity. Pharmacologicpropertiesare similar to halothane.Cardiacarrhythmias arelesscommon, but the drug may produce nephrotoxicity from the releaseof fluoride and oxalate. Induction and recovery areslow becauseof its high solubility. 6. Sevoflurane. This is the newest inhaled anesthetic.Induction and recovery is rapid. It is potentially nephrotoxic; hepatic metabolism produces fluoride ions and exposureto carbon dioxide absorbantsin anesthesiamachinesproducescompound A, which causesrenal damage in rats. However, sevoflurane has not been reported to cause renal damage in humans. 7. Nitrous oxide (laughing gas) a. Pharmacokinetics. This drug is quickly eliminated by the lungs; it has little or no metabolism.

Note Metabolites of methoxyflurane renal failure. maycause

Note isoflurane, Nitrous oxide, desflurane, andsevoflurane arethemostcommonly anesthetis usedinhalational intheUnited States.

b. Pharmacologic properties (1) Nitrous oxide decreasesmyocardial contractility and increasescirculating catecholaminelevelsand the myocardialresponseto them. The net result is increased cardiacoutput and mean arterial pressure.

ln a Nutshell

(2) Only mild depressionof respiration is produced.

. Coodinducing uq:T

(3) In the CNS, nitrous oxide preservesautoregulationof blood flow, thereforeproducing no increasein intracranial pressure.It doesnot relax skeletalmuscle.

. Coodanalgesic

c. Indications for use. Nitrous oxide is used alone for dental and obstetric procedures. It is a rapid-acting agent,providing good analgesia.However,surgicalanesthesiacannot be achievedwith nitrous oxide alone becauseof its low efficacy.It must be usedin combination with other inhalational agents.

Nitrous oxide(Nr0):

. Mustbeusedin withother combination anesthetics to produce surgical anesthesia

6ll

Neruous System

d. Side effects and toxicity. Nitrous oxide can causediffusional hypoxia, particularly at the end of administration. Supplementalorygen can be given to avoid tissuedamage. Long-term abuse by health care professionalshas led to toxicity, including parethesias, tolerance,and addiction.

Clinical Correlate Thiopental isuseful for induction ormaintenance forshortprocedures. Note Barbiturates actattheirown binding siteonCABA^ receptors to potentiate CABAs activity. At highdoses, they canstimulate thereceptor directly, causing severe CNS depression. Note

C. Intravenous anesthetic agents. Severalchemical classeshavebeen used as intravenous anesthetics:barbiturates,benzodiazepines, opioids, ketamine,and propofol. 1. Barbiturates include thiopental, thiamylal, and methohexital. Thiopental is an ultrashort-acting barbiturate, which is the prototype of this group. Loss of consciousness occurswithin 30 secondsof intravenousadministration. Recoveryoccurswithin 30 minutes following a single intravenousdose. a. Mechanism of action. Barbituratesact by enhancingthe effectsof y-aminobutyric acid (GABA), an inhibitory neurotransmitter. GABA binds to the GABAAreceptor,which is a ligand-gated chloride channel, to increasechloride influx, which hyperpolarizes the cell. Barbiturates also bind to the GABAA receptor and increasethe duration of Clchannelopening. b. Pharmacologic properties of the ultra-short-acting barbiturates are listed below. (1) CNS effectsinclude suppressionof the brain stem reticular activating system,a hyperalgesiceffect,and decreasedcerebralblood flow and metabolism. (2) Barbituratesproduce myocardial depressionand increasedvenouscompliance. (3) Theseagentsdepressthe respiratory center.

Whereas N,0isa good analgesic, barbiturates are gesic (intensify hyperal pain).

c. Pharmacokinetics. Thiopental's action is terminated by redistribution from the brain to adipose and lean tissues.The drug is ultimately metabolized in the liver. d. Indications for use. Theseagentsmay be usedto induce anesthesiaor maintain anesthesiafor short proceduresby continuous intravenousinfusion. They produce a rapid and pleasantinduction and recovery,with minimal arrhythmogenicity.

ClinicalCorrelate Benzodiazepines areuseful in shortdental andmedical procedures. Theyenhance CABA activity atCABA^ receptors. Overdose is reversed byflumazenil, a benzodiazepine receptor antagonist. ln a Nutshell Neuroleptic Analgesia . Fentanyl anddroperidol . Dissociated, butconscious

e. Side effects and toxicity. Adverse reactions include cough, respiratory depression, laryngospasm,bronchospasm,and precipitation of porphyria. 2. Benzodiazepines include midazolam, diazepam,and lorazepam. (The pharmacology of theseagentsis discussedlater in this chapter.)Theseagentsare used in high dosesintravenously in conjunction with inhalational agentsor opioids. They produce anxiolysis, sedation,hypnosis,unconsciousness, and amnesia. 3. Opioids include morphine and fentanyl.Theseagentshavebeen used as analgesicsboth preoperativelyand postoperatively.They havealsobeen usedin combination with nitrous oxide and droperidol, a neuroleptic agent,to produce neuroleptic anesthesia.Opioids are good adjuncts to anesthesiain cardiac surgery becausecardiac output is maintained. Fentanyl is more potent and shorter acting than morphine. Effects of overdose are reversedby naloxone, an opioid receptor antagonist. (Complete pharmacology of the opioids is discussedlater in this chapter.) 4. Ketamine a. Pharmacologic properties

Neuroleptic Anesthesia . Fentanyl,droperidol, andNrO

(1) Ketamine is a dissociative anesthetic characterized by sedation, analgesia, amnesia, and immobility associatedwith feelings of dissociation from the environment. It increases CNS blood flow and intracranial pressure and preserveslaryngeal reflexes.

. Leads to unconsciousness

(2) It blocks NMDA glutamatereceptorsin the cortex and limbic system.

612

DrugsAffectingthe CNS Pharmacology:

(3) CNS sympatheticstimulation producesincreasedheart rate, cardiacoutput, and increasedblood pressure. (4) Ketamine may increaseintraocular pressure. b. Pharmacokinetics. Ketamine is lipophilic and rapidly distributes to vascular organs. c. Indications for use. Ketamine is used for anesthesiain children, young adults, and outpatients. d. Side effects and toxicity. Ketamine has a high incidence of postoperativebehavioral phenomena (e.g., delirium), especiallyafter the age of 25. It is contraindicated in patientswith hypertension,psychiatricdisorders,or glaucoma.

ln a Nutshell isa dissociative Ketamine to anesthetic andisrelated phencyclidine (PCP, angel NMDA dust). lt blocks glutamate Ketamine receptors. causes anemerSence upon excitement-delirium awakening.

5. Propofol. Though the two drugs are not structurally related,the pharmacologyof propofol is similar to thiopental. It producesa rapid induction and even more rapid recovery than thiopental. It is commonly usedas an anestheticin outpatient surgeryand as a comIt is usedin ambulatory patientsand for sedationin intenponent of balancedanesthesia. sive care units. The drug can causemarked hypotensionduring induction and can cause apneaand bradycardia. 6. Etomidate. This is used for rapid induction and as a part of balanced anesthesiafor shorter procedures. It produces minimal cardiovascular and respiratory depressant effects.It is associatedwith a high incidenceof nauseaand vomiting, myoclonus,and pain on injection.

ANESTHETICS LOCAL A. Overview 1. Characteristics of ideal local anesthetics a. They should reversiblyblock nerve conduction, producing no permanent damageto the nerve. b. They should not irritate the tissueat the site of application. c. They should have minimal toxicity when absorbedinto the systemiccirculation. d. They should have a rapid onset of action. e. They should have a duration long enough to allow treatment to occur. 2. Chemistry a. Local anestheticsconsist of an aromatic ring (lipophilic group), a hydrophfic group (usuallya tertiary amine),and a linking intermediatechain (esteror amide) (TableV-32-2). Thble V-32-2. Local anesthetic agents. Ester-TypeAnesthetics

emide-TypeAnesthetics

. . . .

. . . . . .

Cocaine Procaine Tetracaine Benzocaine

Lidocaine Bupivacaine Mepivacaine Etidocaine Prilocaine Ropivacaine

Note . Lidocaine isalsoan antiarrythmic. . Cocaine canalsoproduce CNSeffeGandincrease bloodpressure.

Mnemonic have an"i" Amides before the"caine."

6t5

NervousSystem

b. The type of linkage altersthe pharmacologiccharacteristicsand metabolic pathway. c. The more lipophilic the drug, the longer its duration of action, the more potent, and the more toxic.

ClinicalCorrelate

d. Local anestheticsare weak baseswith a pK" of 8-9. They are usually marketed in watersoluble hydrochloride salts.Local anestheticspenetrate nerve cell membranes in their uncharged form. Once inside, they become protonated and block the voltage-gated Na* channel.

3 . Pharmacokinetics Vasoconstrictors are coadministered withlocal anesthetia to increase the duration ofaction andto limit systemic absorption.

a. Routes of administration. Local anestheticsmay be administered topically, through local injection into the skin or specific nerve plexes,through epidural or subdural injection (in spinal anesthesia),or intravenously (lidocaine) when used as a cardiac antiarrhythmic agent. b. Systemic absorption depends on the site of administration and degree of drug-tissue binding. Vasoconstrictors, suchasepinephrineand phenylephrine,may be addedto a local anestheticsolution to decreaseregionalblood flow and, thus, reducesystemicabsorption. This increasesthe duration of action and minimizes systemicadversereactions. c. Elimination ( I ) Ester-type anestheticsare degraded by plasma cholinesterasesand hepatic esterases. (2) Amide-type anestheticsare primarily metabolized by liver amidases.Caution must be usedwith patients in renal failure.

ln a Nutshell Local anesthetia stopnerve conduction byblocking voltage-gated Na.channels. In a Nutshell Thesmaller thediameter and thelessmyelinated anaxon is,themoresusceptible it isto localanesthetics. Fortunately, painfibers aresmall and either unmyelinated orlightly myelinated. In a Nutshell LocalAnesthetic SideEffects . Cardiovascular depression . CNSexcitability, then depression . Hypersensitivity reactions

6t4

(3) Metabolitesare excretedin the urine. 4. Mechanism of action. Local anestheticsinhibit both the generation and conduction of action potentials.Local anestheticsblock voltage-gatedNa* channelsby binding to the intracellular side of the channel. These drugs are frequenry (or use) dependent-they stop conduction fasterif the nerve is rapidly firing becausethey bind to open or recently inactivatedchannelsbetter than they bind to resting channels. 5 . Pharmacologic properties a. Small,unmyelinatedfibers areblocked first; rapidly firing fibers areblocked more easily than nerveswith a slower firing rate. (l) Neurons are blocked in the following order: autonomic, sensory,then motor. (2) Sensorymodalitiesareblocked in the following order: pain, cold, warmth, touch, then deep pressure. b. Local anestheticagentsdepressmyocardial irritability, prolonging the effective refractory period and conduction time. Lidocainehasbeen used asan antiarrhythmic agent basedon theseeffects.Myocardial depressioncan alsobe an adverseeffectof overdose. Local anestheticsalso produce vasodilatation. c. In general,local anestheticscauseCNS stimulation by initially depressinginhibitory neurons. Central stimulatory effects may be followed by CNS depression.Effects include dizziness,restlessness, sedation,or seizures.SevereCNS depressioncan lead to cardiovascularand respiratory collapse. d. Local anestheticscan produce hlpersensitivity reactions.In general,if patients are allergic to ester-tFpeagents,they are not allergic to amide-type agents,and vice versa. Patientsare more commonly allergic to the ester-t)?e agents.

Pharmacology: DrugsAffectingthe CNS

B. Specific agents 1. Ester-type local anesthetics a. Cocaine (1) Pharmacologic properties include vasoconstriction, slow absorption, and a half-life of t hour following oral or nasal administration. Moderate doses increaseheart rate and blood pressure. (2) Indications for use. Cocainehas been used as a topical anesthetic,especiallyin the nose and throat.

In a Nutshell Cocaine actsasa local anesthetic andalsoblocks thereuptake of catecholamines into presynaptic nerve (producing terminals vasoconstriction).

(3) Side effectsand toxicity. With increasingdoses,cocaineproducesCNS stimulation (i.e., irritabiliry psychosis,seizures)followed by respiratory depression. There is strong abusepotential. Cocainehas been associatedwith corneal ulceration when used topicaliy in the eye. b. Procaine (1) Pharmacokinetics. Procaineis rapidly absorbedfrom the injection site unlessa vasoconstrictor is used. It is hydrolyzed to para-aminobenzoic acid (PABA), which competitivelyinhibits sulfonamides. (2) Indications for use. Procaineis used for local injection, nerve blocks,and spinal anesthesia;it is ineffectiveby the topical route. (3) Side effects and toxicity. Procaine has low systemic toxicity due to short duration and rapid degradation. c. Chloroprocaine is a derivativeof procaine;it is more potent but lesstoxic than procaine.It is used for infiltration, nerve blocks,and epidural anesthesia. d. Tetracaine (1) Pharmacokinetics.Tetracaineis an esterof PABA,which is 10times more potent than procaine and has a longer duration of action. (2) Indications for use.It is used for spinal anesthesiaand as a topical anestheticin the eye and nasopharynx. (3) Side effects and toxicity. Adversereactions are similar to procaine. e. Benzocaine is an ester-typeanestheticthat is used only for topical anesthesia.It is availableover the counter. 2. Amide-tfpe local anesthetics a. Lidocaine (1) Pharmacokinetics. Lidocaine is twice as potent and toxic as procaine and is metabolizedby liver enzymes. (2) Pharmacologic properties. Lidocaine produceslocal vasodilatation. (3) Indications for use.Lidocaineis usedby topical and local injection and for spinal anesthesia.It is also administered intravenously for cardiac tachyarrhythmias. (a) Side effects and toxicity. Adverse reactions include sedation, amnesia, and convulsions. b. Bupivacaine has a prolonged duration of action. It is used for local infiltration, nerve blocks,and spinal anesthesia.Its side effectsare similar to lidocaine.

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NeruousSystem

ClinicalCorrelate

c. Mepivacaine has a pharmacologic profile similar to lidocaine, except it produces less vasodilatation.Indications include local infiltration, nerve block, and spinal anesthesia.

. Nondepolarizingblockers d. Etidocaine and prilocaine are amide-type agentssimilar to lidocaine. (e.g., tubocurarine) e. Ropivacaineis a newer amide-typelocal anesthetic. competitively blocknicotine AChreceptors intheNMJ. Patients immediately SKELETAT MUSCTE RETAXANTS paralysis. develop flaccid . Depolarizing (e.9., blockers succinylcholine) cause skeletal muscle relaxation bydepolarizing themuscle excessively, making it unresponsive. Patients have fasciculations before flaccid paralysis.

Note Acetylchol inesterase inhibitors reverse theeffects of a blocker competitive but prolong theeffects of a depolarizing blocker during phase I block. Phase ll block bysuccinylcholine isreversed byacetylcholinesterase inhibitors. ln a Nutshell Benzodiazepines actatthe CABA^ receptor. Baclofen acts attheCABA' receptor. Baclofen iscommonlv used forspasticity. In a Nutshell

A. Neuromuscular blocking drugs. Neuromuscular blockers are used to produce skeletalmuscle relaxation,as adjuncts in surgicalanesthesia,and in patientswith severerespiratoryfailure on mechanicalventilators. Theseagentsare subdivided into two groups: 1. Nondepolarizing (competitive) blockers are agents that compete with acetylcholine (ACh) for the nicotinic receptor at the neuromuscularjunction and prevent depolarization. These drugs include tubocurarine, pancuronium, atracurium, cisatracurium, mivacurium, vecuronium, pipecuronium, rocuronium, doxacurium, and rapacuronium. 2. Depolarizing blockers bind to the nicotinic receptor,initially causing depolarization. Prolongedbinding to the receptorproducespersistentdepolarization,making the membrane unresponsiveto new impulses (depolarization block); phase I block. The muscle repolarizesin phase II, but is resistant to depolarization (similar to nondepolarizing blockers).The only drug clinically availablein this classis succinylcholine. B. Spasmolytic drugs. Theseagentsare used to reduceskeletalmuscle tone and control muscle spasmsand involuntary movementsdue to such conditions asmultiple sclerosis,cerebral palsy,spinal cord injury, and stroke. 1. Diazepam. Diazepam is a benzodiazepine,which actsby enhancingthe effectsof GABA at the GABAAreceptor.It is alsoused as a sedative-hypnotic,an antianxiety agent,and an antiseizuredrug. 2. Baclofen. This is an agonist at the GABA' receptor.It may decreasethe releaseof excitatory neurotransmittersvia presynapticinhibition. Baclofenis rapidly absorbedfollowing oral administration. It is used in the treatment of spasticitydue to multiple sclerosisor other spinal cord disorders,particularly lesions due to trauma. Baclofen produces less sedationthan the benzodiazepines. It can,however,lowerseizurethreshold.Suddenwithdrawal following chronic use may causeauditory and visual hallucinations,anxiety,and tachycardia. 3. Dantrolene. Dantrolene is a direct-acting skeletalmusclerelaxant.It decreases the releaseof calcium from the sarcoplasmic reticulum, thus blocking the contractile mechanism. Dantrolene is used in the treatment of muscle spasmand malignant hyperthermia.Adverse reactionsinclude muscleweakness,sedation,and diarrhea.Prolonged usecan lead to hepatotoxicity. 4. Tizanidine. Tizanidine is a congener of clonidine that reinforces presynaptic and post-

prevents Dantrolene Car. synaptic inhibition in the spinal cord. It is usefi.rlin patients with many different types of release fromthesarcoplasmic spasticity. reticulum. lt isusedinthe C. Drugs used for acute local muscle spasm. treatment of malignant l. Cyclobenzaprine. Cyclobenzaprine is the prototype of this group. The mechanism of hyperthermia.

action is nuclear,though it appearsto act at the level of the brain stem. It has significant sedativeand antimuscarinic effects,and can causeconfusion and visual hallucinations in some patients.Cyclobenzaprineis ineffectivein muscle spasmsdue to spinal cord injury or cerebralpalsy.

6t6

Pharmacology: DrugsAffectingthe CNS

ANDANTAGONISTS OPIOIDANATGESICS Opioid analgesicsconsistof morphine and related drugs, which reducethe perception of and the emotional responseto pain. Opiatesare drugs derivedfrom the opium poppy,Papaversomniferum. Opioids is the classof drugs, natural and synthetic,that mimic the actions of the opiates.Theseagentsare widely used clinically for analgesic,antidiarrheal,and antitussive(cough suppression)effects.Some,like heroin, are abusedfor their euphoric effects.Opioid analgesics and antagonistsare classifiedbasedon their action at opioid receptors(TableV-32-3).

Clinical Correlate Clinically, opioids areusedas analgesics, antitussives, and antidiarrheals.

Table V-32-3. Opioid analgesicsand antagonists.

ReceptorAgonists

Receptor Antagonists

Morphine Hydromorphone Heroin Codeine Oxycodone Hydrocodone Methadone r-Alpha acetylmethadol (LAAM) Propoxyphene Meperidine Fentanyl Diphenoxylate Loperamide

Naloxone Naltrexone Nalmefene

Mixed AgonistAntagonists and Partial Agonists Pentazocine Nalbuphine Butorphanol Buprenorphine

(pAe)

A. Mechanism of action. Opioid analgesicsact by stimulating the same receptors as the endogenousopioid peptides (endorphins,enkephalins,and dynorphins). 1. Receptor tn>es a. Mu (p) receptors. Stimulation of p receptorsis involved primarily in supraspinalbut also in spinal analgesia,respiratory depression,euphoria, and physicaldependence. b. Kappa (r) receptors. The K receptors are primarily involved in spinal analgesia.They

Note Endorphins bindp receptors. Enkephalins bind6 receptors. Dynorphins bindrcreceptors.

ln a Nutshell . p: Supraspinal analgesia Euphoria Respiratory depression . K: Spinal analgesia Sedation

alsoproduce sedationand some dysphoric and psychotomimeticeffect. c. Delta (6) receptors. Stimulation of 6 receptorsis involved in spinal and supraspinal analgesia. d. Subtypes of F, K, and 6 receptors exist and havebeen cloned. Identification of these may lead to the developmentof more specificdrugs with lessadversereactions. 2. Secondmessengersystems a. The F, K, and 6 receptorsrespond by inhibiting adenylatecyclasevia a G protein, resulting in alterationsin ion flux and inhibition of calcium entry into neurons. b. Potassiumchannelsare openedby p receptors. c. Calcium channelsare closedby r receptors.

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Neruous System

Note Fir$-pass metabolism alters theeffectiveness of some opioidanalgesia (e.g., hydromorphone).

B. Pharmacokinetics 1. Absorption. Most opioid analgesicsare well absorbedfrom the gastrointestinaltract following oral administration. However, some undergo significant first-pass metabolism (e.g.,hydromorphone, oxymorphone). 2. Distribution. Although variable degreesof plasma protein binding occur, compounds rapidly leavethe blood and accumulatein tissues.With repeatedadministration of slowly metabolizedlipophilic agents,fat accumulation becomessignificant. Most opioids crossthe placenta,producing effectsin the fetus (e.g.,respiratory depression,physicaldependence). 3. Elimination. Many of the drugs undergo hepatic metabolism, including glucuronidation. Morphine-6-glucuronide is an active metabolite of morphine with analgesicproperties. The major route of excretionis through the kidney.

ln a Nubhell OpioidEffects on CNS . Analgesia

C. Pharmacologic properties 1. Acute effects a. Central neryous system

. Euphoria

( 1) Opioids are potent analgesiaagentsthat reducethe perceptionand reactionto pain.

. Antitussive

(2) Evenat low doses,theseagentsproduce euphoria,a pleasant,cloudy mental state. Dysphoria may also occur,particularly on first administration.

- useful . Miosis fordetecting suneptitious use

In a Nutshell MajorPeripheral Effects of Opioids . Con$ipation . Hypotension . Urinary retention

(3) Opioids inhibit the brain stem respiratory centers.The degreeof depressionis dose-related.Theseagentsdecreasethe responsiveness to increasedplasma carbon dioxide levels. (4) Low dosescan produce sedativeeffects.Elderly patients are most susceptible. High dosescan further depressthe CNS to the point of sleepor narcosis. (5) Opioids depressthe cough reflex (antitussiveaction). (6) Opioids stimulate the chemoreceptortrigger zone (CTZ), resulting in nausea and vomiting, particularly in the naive and ambulatory individual. (7) Opioids (especiallyfentanyl) increasemuscular tone (truncal rigidity) and can compromiseventilation. (8) Pupillary constriction (pinpoint pupils, miosis) is characteristicof opioids except meperidine,which has antimuscarinic actions.This is useful to diagnoseopioid abuse. (9) Increasedintracranial pressuresecondaryto dilatation of cerebralvasculature resulting from CO, retention. b. Cardiovascular system. Hypotension may occur via venous dilatation, but there is minimal effect on cardiacoutput at analgesicdoses. c. Gastrointestinal system.Constipation occursbecauseopioids produce an increasein resting tone and the amplitude of contractions and motility are reduced. Biliary smooth muscleis constricted,particularly sphincters,which may exacerbatepain from biliary colic. d. Urogenital system. Opioids increase urethral and bladder sphincter tone and may causeurinary retention. e. Uterus. Relaxeduterine smooth muscle as a result of opioids may prolong labor.

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Pharmacology: DrugsAffectingthe CNS

f. Endocrine system. Opioids increase release of prolactin, antidiuretic hormone (ADH), and somatotropin, and reducethe releaseof luteinizinghormone (LH). g. Opioids stimulate the releaseof histamine. 2. Chronic effects a. Tolerance.Chronic use of theseagentsresults in toleranceto their acute pharmacologic effects.Tolerancedevelopsto a lesserdegreeto miosis and constipation than to other effects.Cross-toleranceexistsamong the drugs. b. Dependence.Psychologicaland physicaldependenceto theseagentsdevelops.Abrupt withdrawal leadsto an abstinencesvndrome. D. Indications for use

Note Tolerance develops to a greater degree to the analgesic andeuphoric effects of opiates thanto miosis or constipation.

1. Analgesia.Opioids are indicated for use in moderateto severepain. 2. Treatment of diarrhea. Opioids relieve diarrhea. Agents specific for this use are loperamide and diphenoxylate.Theseagentsdo not crossthe blood-brain barrier. 3. Pulmonary edema. Opioids are usefrrl in decreasing cardiac preload and afterload secondaryto vasodilatory effects.Morphine is now consideredsecondaryto furosemide for this use. Agentsmost used are codeineand 4. Antitussive. Opioids are useful as cough suppressants. dextromethorphan. 5. Anesthesia.Opioids are used as pre- and postoperativemedicationsbecauseof sedative, analgesic,and antianxiety effects.High dosesof morphine and fentanyl are used as anesthetics in cardiovascularsurgerybecausethey produce minimal cardiacdepression. 6. Opioid dependence.Methadoneis usedto minimize withdrawal symptomsand in maintenanceprogramsfor opioid addicts. E. Side effects and toxicity 1. Respiratory depressionis the major acute toxicity of these drugs. The drugs are contraindicated in patients with emphysema and chronic obstructive pulmonary disease

(coPD). 2. Opioid analgesicsproduce constipation,nausea,and vomiting.

Clinical €orrelate Acute overdose of opioids mayleadto respiratory depression, anddeath. coma, iswithnaloxone, Treatment anopioid antagonist.

3 . Opioids can produce dysphoria, restlessness,tremors, hyperactivity, and increased intracranial pressure. 4. Hypotension resultsfrom histamine releaseand depressionof compensatoryvasomotor reflexes. 5. Opioids can produceurinary retention.They should be usedwith caution in patientswith prostatic hypertrophy. 6. Theseagentscausepruritus due to histamine release. 7. Toleranceand physicaldependence.

Clinical Correlate leads useof opioids Chronic For to physical dependence. withdrawal or controlled replacement maintenance iswith therapy, treatment methadone.

F. Drug interactions. Use of opioids with sedative-hypnoticsincreasesCNS and respiratory depression.Opioids increasesedation,antimuscarinic effects,and alpha-blocking effectswhen combined with antipsychotic medications.Use with monamine oxidase (MAO) inhibitors is contraindicatedbecauseof the production of hypertension and hyperpyrexic coma.

619

Neruous System

G. Specific agents 1. Opioid agonists.Thesedrugs haveprimary activity at p receptors,someat r and 5 receptors. a. Morphine is availablefor oral or parenteraladministration. It has high abusepotential. Morphine-6-glucuronide, a major metabolite,has potent analgesiceffects. b. Hydromorphone. This drug is more potent than morphine and is used for the treatment of severepain. c. Heroin is not used clinically in this country. It is metabolized to morphine. It is more lipid solublethan morphine and more readily entersthe CNS. It has high abuse potential. d. Codeine is usedorally in combination with NSAIDs to relievemoderatepain and as a cough suppressant. e. Oxycodoneand hydrocodone are analogsof codeineusedin the relief of moderatepain. f. Methadone is used for severechronic pain and in the treatment of opioid addiction. It has a longer half-life than morphine,less sedativeeffects,and lessseverewithdrawal symptoms.

ln a Nutshell Codeine andpropoxyphene areusedformild-to-moderate pain.

In a Nutshell Fentanyl andsufentanil are primarily usedin anesthesia.

ln a Nutshell Diphenoxylate and loperamide arecommonly usedantidiarrheals. Theydo notcross theblood-brain barrier well,andhavelittle euphoriant oranalgesic activity.

g. LAAM is a longer-aaingmethadoneanalogusedin maintenancetherapyof opioid addicts. h. Propoxyphene is a weak agonistusedin the relief of moderatepain. It is usedin combination with NSAIDs.Meperidine is availablefor oral and parenteraladministration. It has one-tenth the potency of morphine. It produceslessconstipation and lessurinary retention than morphine. Intravenous administration can cause tachycardia becauseof its antimuscarinicaction. CNS excitatoryeffectsare high. Normeperidine, a metabolite,can produce dysphoriaand seizures.It has high abusepotential i. Fentanyl, sufentanil, and alfentanil are congenersof meperidine and act primarily at the p receptor.They are used more frequently for anesthesiaand are short acting. Fentanylis availablein transdermalpatchesto treat cancerpain. j. Diphenoxylate. This drug is used as an antidiarrheal agent. When administered orally, it is minimally absorbed from the gastrointestinaltract. It is often given in combination with atropine to prevent potential abuse. k. Loperamide. Loperamide is an over-the-counterantidiarrheal agentwith no significant analgesiceffects. 2. Mixed agonist-antagonistsare drugs that are antagonistsat the p receptor,but agonists at the r and o receptors. a. Pentazocineis a weak antagonistat p receptorsbut a potent agonist at K receptors, which is responsiblefor its analgesicproperties. It can precipitate withdrawal in opioid-dependent patients. Addiction can develop. Pentazocine may cause psychomimeticeffectsthat are thought to result from o receptorstimulation. It is the only agonist-antagonistavailablefor oral administration. b. Nalbuphine. This is a more potent antagonistat p receptorsthan pentazocineand can precipitatewithdrawal in patientsdependenton opioid agonists. c. Butorphanol is similar to pentazocine.

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Pharmacology: DrugsAffectingthe CNS

3. Partial agonist. Buprenorphine. This drug is a partial agonist at p receptors.It is more potent as an analgesicthan morphine. 4. Opioid Antagonists. These agentsare analogs of morphine, which have affinity for, but no efficary,at opioid receptors;therefore,they block the actions of opioids. a. Naloxone (1) Pharmacologic properties. Naloxone is effective only by injection (intravenous or subcutaneous).It is rapidly metabolizedby hepaticenzymes,hasa rapid onset ( 1-5 minutes), and has a half-life of 60-100 minutes. (2) Mechanisms of action. Naloxone is a competitive antagonist at opioid receptors. (3) Indications for use. Naloxone is the drug of choice in the treatment of acute opioid overdose.Severaldosesmay be necessarydue to its short duration of action. This drug precipitateswithdrawal syndrome in individuals dependenton opioids.

Clinical Correlate Naxolone isanopiate receptor antagonist used inthetreatment of opiate overdose.

b. Naltrexone. Naltrexone has similar actions to naloxone; however,it is effective orally and has a longer duration of action. It is useful for long-term treatment of opioid and alcohol dependence. c. Nalmefene is similar to the other antagonists,but has a longer half-life. 5. Miscellaneous. Tramadol is a newer analgesic with weak mu agonist effects. It also inhibits norepinephrine and serotonin reuptake, and is only partially antagonizedby naloxone.Adverseeffectsinclude dependence,withdrawal, and seizures.

SEDATIVE.HYPNOTI CDRUGS Sedative-hypnotic and antianxiety drugs are prescribed worldwide with increasing frequenry. Many of the drugs in this classhave all three actions,with effectsbeing dose-dependent,such asmild sedation,sleep,anesthesia, respiratoryand cardiovasculardepression,coma,and death. The drugs are divided into three subclasses: barbiturates,and miscellaneous benzodiazepines, agents. A. Benzodiazepines. Benzodiazepinesare the most commonly prescribed antianxiety and sedative-hypnoticagents.Thesedrugs are saferthan the barbiturates. 1. Mechanism of action. Benzodiazepinesact by potentiating the effects of GABA, an inhibitory neurotransmitter.

Note potentiate Benzodiazepines CABAs activityattheCABA^ receptor.

a. GABA binds to the GABAA receptor, which is a chloride channel, thus causing chloride influx and hlperpolarization of the cell, making it more difficult to depolarize. b. Benzodiazepinesbind to an allosteric site on the GABA receptor and enhancethe effectsof GABA. They require the releaseof GABA to produce their effect. increasethe frequencyof opening of the chloride channel,increasing c. Benzodiazepines the amplitude of the inhibitory postsynapticpotential (IPSP). 2. Pharmacologic properties have anxiolytic effectsand sedative-hypnoticproperties. a. Benzodiazepines b. They produce skeletalmuscle relaxation and have anticonvulsant properties.

ln a Nutshell Benzodiazepines areusedas anxiolytics, sedative-hypn otics, skeletal muscle relaxants, and anticonvulsants.

c. Their effect on respiration is slight with hypnotic doseshaving no effect.

621

Nervous System

3. Pharmacokinetics. Most of the benzodiazepinesare readily absorbed from the gastrointestinal tract and crossthe blood-brain barrier. Benzodiazepinesare metabolizedin the liver, many initially to active products. 4. Indications for use a. Anxiety and insomnia b. Alcohol withdrawal symptoms (usually chlordiazepoxide,diazepam) c. Spasticityand skeletalmusclespasm(diazepam) d. Statusepilepticus(diazepamIV lorazepamIV) e. Epilepsy(clonazepsrrr,clorazepate) f. Anesthesia(midazolam,diazepam,lorazepam) 5 . Side effects and toxicity

In a Nutshell Theeffects of benzodiazepines areall additive withotherCNS depressants. Thecombination ispotentially lethal

a. Benzodiazepines can produce drowsiness,ataxia,confusion (especiallyin the elderly), increasedreaction time, impaired short-term memory, and impaired performanceof complex tasks(e.g.,driving), blurred vision, vertigo, and headache. b. Dependencymay occur.Temporaryenhancementof the symptomsthat prompted the use of thesedrugs (e.g.,anxiety,insomnia) can occur upon withdrawal. Seizuresand psychosismay occur with suddenwithdrawal after prolonged use at high doses. c. Benzodiazepinesproduce little respiratory depressionfrom oral administration. In combination with alcohol or other CNS depressants, they can produce significant respiratory depression. d. Tolerance(pharmacodynamictolerance)occurs at a cellular level. 6 . Drug interactions a. Drugs that increasebenzodiazepinelevelsinclude: (1) Acetaminophen(by decreasingdiazepamexcretion) (2) Cimetidine, disulfiram, ethanol, isoniazid, and valproic acid (by decreasing metabolism) (3) Valproic acid (by displacingthem from binding sites) b. Drugs that decreasebenzodiazepinelevelsinclude: (1) Antacids(by decreasingabsorption) (2) Oral contraceptives(by increasingmetabolism) c. Benzodiazepines enhancethe CNS depressanteffectsof alcohol and other depressants. d. There is cross-tolerancebetweenbenzodiazepinesand other CNS depressants. 7 . Specific agents. Most benzodiazepinescan be used interchangeably.The therapeutic uses are often dependent on the half-life of the drug rather than for what they are marketed. a. Oxazepam is used for the treatment of anxiety. b. Triazolam is used for the treatment of insomnia. c. Npraznlam is used for the treatment of panic disorders. d. Lorazepam is used for the treatment of anxiety,preanestheticmedication, and status epilepticus.

622

Pharmacology: DrugsAffectingthe CNS

e. Temazepamis used for the treatment of insomnia. f. Midazolam is usedfor anesthesiaand medical procedures.It is administeredonly parenterally. g. Clorazepate is used for the treatment of epilepsy and anxiety. h. Diazepam is the most commonly used benzodiazepine.It is used for anxiety, skeletal muscle relaxation,preanestheticmedication, and statusepilepticus. i. Flurazepam is used for the treatment of insomnia.

Note Flumazenil isa benzodiazepi neantagonist usedto reverse theCNS depressant effects of benzodiazepines andto hasten recovery after procedures. medical

j. Chlordiazepoxide is used for ethanol withdrawal symptoms, anxiety, and preanesthetic medication.

B. Barbiturates 1. Structure-function relationship a. The CNS depressantaction of barbituratesis relatedto their lipid solubility.Increased lipid solubility is associatedwith shorter latencyto onsetof action, decreasedduration of action, increasedmetabolic degradation,and often greaterhypnotic effect. b. Thiobarbiturates such as thiopental have increasedlipid solubility and ultra-short duration of action. c. Phenobarbital, having a phenyl group at C5, has relatively selectiveanticonvulsant activity. 2. Pharmacokinetics a. The barbiturates are well absorbedafter oral administration. Thiopental is administered intravenously. b. There are three mechanismsby which the action of barbituratesare terminated: ( 1) Physicalredistribution for very short-actingbarbituratesto adiposetissue(most important with short-acting agents,e.g.,thiopental) (2) Hepatic metabolism (3) Urinary excretion c. Barbiturates induce hepatic microsomal enzymes and, to a lesserextent, cytoplasmic and mitochondrial enzymes. d. Tolerancemay result from decreasedeffect at the target site (pharmacodynamictolerance) and increasedmetabolism (pharmacokinetic tolerance). Anticonvulsant and lethal effectsshow little tolerance. 3. Mechanism of action. Barbiturates depressneuronal activity by enhancing the effects of GABA, an inhibitory neurotransmitter. Barbiturates bind to the GABAAreceptor,increasing the duration of the GABA-mediated opening of the chloride channel. 4. Specific agents include a. Phenobarbital (longest-acting) b. Mephobarbital c. Pentobarbital (short-acting) d. Secobarbital (short-acting) e. Amobarbital (short-acting)

ln a Nutshell Barbiturates induce hepatic (P*o), microsomal enzymes leading increased to metabolism ofthemselves andother drugs. ln a Nutshell Barbiturates enhance CABAtr receptor activity byincreasing theduration oftheClchannel opening. In a Nutshell Phenobarbitol isused asan anticonvulsant. Thiopental is anexcellent inducing agent forgeneral anesthetics.

62t

Neruous System

f. Thiopental (ultra-short-acting) g. Methohexital (ultra-short-acting) 5. Indications for use

ln a ftuBhell Acute toxicity of barbiturates canleadto respiratory depression, coma, anddeath. Chronic usecancause tolerance andphysical dependence.

a. Barbiturateshavebeen used as sedative-hypnoticagents.The benzodiazepinesare now most commonly used becauseof their relative safetyand minimal adversereactions. b. Phenobarbitalis used as an antiepileptic agent. c. Thiopental and methohexital are used intravenously in anesthesiafor induction or maintenanceof anesthesiafor short procedures. d. Phenobarbital has been used for treatment of kernicterus and hyperbilirubinemia in neonates.It works by increasing the elimination of bilirubin. 6. Side effects and toxicity a. CNS effectsinclude sedation,confusion,ataxia,respiratory depression,coma, and death. b. Barbiturates can produce tolerance and psychological and physical dependence. Abrupt discontinuation may produce life-threatening withdrawal symptoms, which include anxiety, tremors, nausea,and vomiting, orthostatic hypotension, convulsions, and cardiovascularcollapse. c. Mild overdose casesare similar to ethanol intoxication. Severeoverdose may cause coma, shock, and hypothermia. Osmotic diuresis with alkalinization of the urine enhancesexcretionof phenobarbital. d. Barbiturates may produce rash, angioedema,and rarely, exfoliative dermatitis. e. Barbiturates may rarely produce folate-responsivemegaloblastic anemia and osteomalacia. f. Effects on porphyrin metabolism may precipitate acute intermittent porphyria. 7. Drug interactions a. Barbiturates increase the metabolism of other drugs by induction of microsomal enzfmes. Thesedrugs include phenytoin, steroid hormones, triryclic antidepressants, oral anticoagulants,digitoxin, quinidine, theophylline, and p-adrenergic blockers. b. Barbituratesmay displacedrugs (e.g.,thyroxine) from albumin-binding sites.

ln a Nubhell

c. There is cross-tolerancebetweenbarbituatesand other CNS depressants. C. Other sedative-hlpnotic drugs

Buspirone isa anxiolytic. serotonergic

1. Buspirone is a nonbenzodiazepineanxiolytic agent,which appearsto work by binding to specificserotonin S-hydrory-tryptamine 1A (5-HT,^) receptors,acting as a partial agonist. It can alsobind to some dopaminergic receptors.Unlike the benzodiazepines, buspirone has no muscle relaxant or anticonvulsant activity and does not increasethe CNS depressant effect of ethanol.Adversereactionsof buspirone include dizzinessand headaches. 2. Zolpidem tartrate is a nonbenzodiazepinehypnotic agent. The proposed mechanism is modulation of the GABAAreceptor.It is usedfor short-term treatment of insomnia.It has minimal anxiolytic, anticonvulsant, and muscle relaxant properties when compared to benzodiazepines. This is likely becausezopidem is BZ, selective,whereas,traditional benzodiazepinesinteract with both BZrandBZ, receptors. 3. Meprobamate is an older sedative-hypnotic and antianxiety agent. Its use has generally been replacedby the benzodiazepines.

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Pharmacology: DrugsAffectingthe CNS

a. Pharmacokinetics. Meprobamate is well absorbed after oral administration. It is metabolizedin the liver, where it can induce some of the microsomal enzymes. b. Side effects and toxicity. Adversereactions include sedation and ataxia, hypotension, abusepotential, and rash.It is contraindicatedin pregnancy. 4. Chloral hydrate is a chlorinated derivative of acetaldehyde,which is used as a hypnotic, inducing sleepin about 30 minutes. a. Pharmacokinetics. Following oral administration, chloral hydrate is rapidly converted to trichloroethanol, which is largely responsiblefor its hlpnotic action. b. Mechanism of action is unknown. c. Side effects and toxicity. Adverse reactions include epigastric distress,nausea,vomiting, and flatulencedue to irritation of mucous membranes.Chloral hydrate potentiatesthe effectsof ethanol; it inhibits ethanol metabolism,while ethanol increasesthe generation of trichloroethanol. Chronic use may lead to tolerance,physical dependence,and addiction. 5. Glutethimide is a sedative-hypnoticwith pharmacologicproperties similar to the barbiturates. a. Pharmacologic properties. Glutethimide is a CNS depressant.It has pronounced anticholinergicactiviry and it inducesliver microsomal enzymes. b. Side effects and toxicity. Adversereactionsinclude constipation,mydriasis,xerostomia, sedation,ataxia,epigastricpain, rash, and blood dyscrasias.

ALCOHOT ANDRETATED COMPOUNDS Ethanol (ethyl alcohol) is a drug with sedative,hypnotic, and antianxiety actions.Its useis not regulated,and abuse(alcoholism) representsa complex sociomedicaldisorder with devastating effects(dysfunctional families,violent crimes, child and spousalabuse,work-related and automobile accidents,and medical disorders).Methanol (methyl alcohol) is consumed accidentally or as a substitute for ethanol and has significant toxicity. Ethylene glycol is sometimes consumedby children becauseof its sweettasteor is inhaled or absorbedthrough the skin and has considerabletoxicity. A. Ethanol. The structure of ethanol is CH.CH"OH. 1. Pharmacokinetics

ln a Nubhell Ethanol ismetabolized to acetaldehyde byalcohol dehydrogenase; acetaldehyde ismetabolized to acetic acid byaldehyde dehydrogenase.

a. Ethanol is water soluble.It is rapidly and completelyabsorbedfollowing oral administration; approximately30o/ois absorbedfrom the stomach and 70o/ofrom the small intestine.Absorption is delayedwith food intake. b. The rate of metabolism is independentof serum concentration (zero-orderkinetics). Over 90olois oxidized in the liver. (1) Alcohol dehydrogenaseis a cytosolic zinc-containing enzyme,which is largely responsiblefor hepatic metabolism and probably the only systemactive at low serum ethanol concentrations. It catalyzesthe following reaction: CH.CH2OH + NAD* + CHTCHO (acetaldehyde)+ NADH (2) Acetaldehyde (CH.CHO) is further oxidized by the mitochondrial enzyme, acetaldehyde dehydrogenase,to acetic acid, which can be metabolized to carbon dioxide and water. Acetaldehydedehydrogenaseis inhibited by disulfiram.

625

Neruous System

(3) Microsomal enzymescontribute to ethanol metabolism at high serum concentrations. This system is called the microsomal ethanol oxidizing system (MEOS).Induction of theseenzymesaccountsfor enhancedethanol metabolism with chronic use and in drug interactions. c. TWopercent of ethanol is excretedunchangedthrough the lungs; this is the basisfor the Breathalyzertest for intoxication. Eight percent is excretedunchangedin the urine. 2. Pharmacologic properties a. Moderate use is associatedwith a decreasedincidenceof coronary artery disease.

Note There isa strong relationship withBACandlevelof intoxication. A BACof 25 mg/dlproduces impaired fine motorcontrol anddelayed reaction time;a BACof toO mg/dlisthelegallimitfor driving under theinfluence in moststates, Somestates have lowered thislimitto 80mg/dl.

ln a Nutshell Withdrawal following chronic produces useof alcohol symptoms similar to other CNSdepressants: anxiety, anorexia, insomnia, confusion, delirium, tremor, lifethreatening seizures, agitation, andhyperthermia. Seizures canbecontrolled with diazepam.

Bridgeto Gastrointestinal Thehepatic and gastrointestinal effects of ethanol arediscussed in greater detail inthe ntestinal Pathol Castroi ogy chapter of Organ Systems Bookz ft/olume lV).

626

b. The exactmechanismof action of ethanol is not known; it has been shown to affect many cellularcomponentsincluding neurotransmitterreceptors,various enzymes,the electron transport chain, and ion channels.TWo of the better studied mechanisms include the potentiation of GABA at GABA^ receptorsand inhibition of the NMDA glutamate receptor. 3. Indications for use a. Ethanol is used for the treatment of poisoning by methanol and ethyleneglycol. b. Dehydratedethanol hasbeen injected closeto nervesin patientswith trigeminal neuralgia, inoperablecancer,and other conditions for the relief of pain. It is not the first line of therapy. c. Topical ethanol, which has a vasodilatoryeffect,has been used to reducefever and as a skin disinfectant. 4. Side effects and toxicity a. CNS effects (1) Acute effects. Low dosesof ethanol can impair judgment and performance of fine motor tasks and delay reaction time. Acute intoxication is associatedwith cold clammy skin, tachycardia,hypothermia, stupor, or coma.Initial "stimulant" efifectsobservedwith ethanol use are due to depressionof inhibitory neurons. High dosesmay causeataxia,vertigo, diplopia, respiratorydepression,coma,and death.A blood alcohol concentration (BAC) of greater than 400 mg/dl can be lethal. (2) Chronic effects include psychiatric disorders; sleep disorders; Wernicke encephalopathy(a clinical triad of encephalopathSopthalmoplegia,and ataxia), resulting from thiamine deficiency; Korsakoff psychosis with memory loss; cerebellardegenerationsyndrome; lowering of the seizurethreshold; tolerance; and physicaldependence. b. Cardiovascular effects (1) Ethanol can depressthe myocardium with moderateor large consumption.This may be precededby transient hypertension and tachycardia. (2) Ethanol causesvasodilatation,resulting in loss of body heat. (3) Ethanol can produce atrial fibrillation and supraventriculartachycardia. (4) Chronic use can produce cardiomyopathy,which may be related to nutritional deficiencyoften seenin alcoholics. c. Hepatic effects include fatty liver changes,aicoholic hepatitis (often seen in binge drinkers),and cirrhosis(in chronic users).

Pharmacology: DrugsAffecting he CNS

d. G.strointestinal €ffects include irritation of the gastrointestinalmucosa,gastritis, pq>tic ulcer disease,esophageal varices,and acuteand chronic pancreatitis.Fatalgastrointestinal hemorrhagemay occur.Ethanol exacerbates aspirin-inducedprolonged bleedingtime. e. Musculoskeletaleffects (1) Ethanol usehasbeen relatedto skeletalmusclemyopathy. (2) Chronic useof ethanol may lead to peripheral neuropathy. f. Hemstopoietic€ff€cts ( I ) Inhibition of leukocfte migration to inflammatory foci may contribute to infections in alcoholics. (2) Anemia occursftom bone marrow depression,nutritional deficiences,and gastrointestinalblood loss. (3) Thrombocytopeniais associatedwith ethanolabuse. g. Body temp€rature.Vasodilatationmay produce a transient feeling of warmth, but togetherwith increasedsweating,body heat is lost. Largeamountsof ethanoldepress : CNStemperatureregulatorycenters,which producea markedd€crease in body temPerature' h. Endocrine effects include inhibition of ADH, causingdiuresisand increasedreleas of adrenocorticotropichormone (ACTH), cortisol,and circulating catecholamines. i. Carcinogenesis.Chronic alcoholuseis associated with an increasedincidenceof carcinomasofthe head,neck,lung,esophagus(especiallywhencombinedwith tobacco), and stomach. j. Teratogericeff€ctsinclude t}le fetal alcohol syndrome (FAS).This syndromeis associatedwith dronic ethanolabuseduring pregnancy.Clinical featuresinclude growth retardation, developmentaldelay,low IQ, microcephaly,poor coordination, facial anomalies(short palpebralfissuies,short nose),joi"t *J;;;"od "no-ai"r, septaldefects.Hypertelorism(wide-spacedeyes)is also seen. 5. Drug interaction" a. Chronic useinduceshepaticmicrosomalenzymesand may enhancemetabolismof other drugs (e.g.,phenytoin,oral hypoglycemics) b. Acute ingestion may inhibit metabolismof other drugs competing for microsomal " enz).mes. c. Ethanol potentiatesthe activity of other CNS depressants(e.g.,sedative-hypnotics, anticonvulsants,antidepresants,anxiolytics,opioid analgesics). 5. Disulfiram (antabuse).Disulfuam is usedasa deterrentto ethanoluse.It is an adjunct in the treatmentof alcoholism. a. Mechanisn of action Disulfiram inhibits aldebde dehydrogenase,the second enzymein the metabolismof ethanol. Thus, patientson disulfiram who consume ethanolwill haveelevatedserumacetaldehyde levels,whidl resultsin the acetatdeh'yde . syndrome.The levelsof acetaldehyde in blood are5-I0 timesthat found in untreated individuals.

h a trubherl FetalAlcoholSyndrome ' GroMhretardation . Hypertelorism ' LowlQ . Developmental delay ' Grdiacmalformations

U* Ethanol induceshepatic microsomal enrymes. lt also $e effu{B acutelypotentiates of otherCNSdepressants.

Noh

'*-'-

Manvantibiotics have disulfimmlike effecSe.g., metronidazole, moxalactam, cefoperazone, etc.

627

Neruous System

b. Side effects and toxicity (1) Symptoms of the acetaldehydesyndromebegin within 5-10 minutes of ethanol consumption and last between30 minutes and severalhours. Symptomsinclude systemicvasodilatation,pulsating headache,hypotension, orthostatic syncope, weakness,vertigo, blurred vision, nausea,vomiting, sweating,and respiratory difficulties. Fatalitieshavebeen reported.

ln a Nutshell Methanol toxicityresults from anaccumulation of its meta bolites, forma ldehyde, andformic acid. Treatment is withethanol.

(2) Adverse reactions of disulfiram (alone) include acneform eruption, urticaria, headache,dizziness,garlic-like and dermatitis;lassitude,fatigue,and restlessness; taste, and mild gastrointestinal disturbances; hepatotoxicity, enhanced by ethanol consumption; enhancedabsorption of lead;and teratogenicity(not to be used in pregnant women). B. Methanol (methyl alcohol) 1. Pharmacokinetics a. Absorption from the gastrointestinaltract and distribution are similar to ethanol. b. Methanol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase to formaldehyde and formic acid, respectively. 2. Indications for use.There is no clinical usage. 3. Toxicity a. Ingestion of methanol may be accidentalor for inebriation in those who consume methanol or denaturedethanol (to which methanol is as adulterant).A latency period of 8-40 hours may precedesymptoms. b. Metabolitesof methanol are responsiblefor most of the toxicity. (1) Metabolic acidosis is causedby formic acid. (2) Blindness is causedby formaldehyde damageof retinal cells. (3) Other symptoms include headache,nausea,vomiting, agitation, vertigo, and dyspnea.

Note Ethanol isalsousedto treat glycol poisoning. ethylene Note Fomepizole, analcohol dehydrogenase inhibitor, is alsousedasanantidote for gylcol methanol andethylene poisoning.

c. Acute methanol toxicity is often treatedwith ethanol, which has a higher affinity than methanol for alcohol dehydrogenase,thus reducing the production of the toxic metabolites. C. Ethylene glycol 1. Pharmacokinetics. Exposureis usuallyby inhalation, skin absorption, or ingestion (e.g., by drinking antifreeze).Ethylene glycol is metabolized by alcohol and aldehydedehydrogenaseto glycolic acid. Metabolic products are responsiblefor renal damage. 2. Toxicity a. Ethyleneglycol is a CNS depressantwith large quantities leading to narcosis,coma, and death. The chemical causessevereacidosisand renal damage,resulting in acute renal failure. b. Acute ethylene glycol poisoning is similar to methanol; ethanol is used as a substrate for alcohol dehydrogenase, thus decreasingthe rate of formation of toxic metabolites.

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Pharmacology: DrugsAffectingthe CNS

DRUG DEPENDENCE, TOTERANCE, ANDABUSE A. Characteristics 1. Dependence a. Drug dependenceis a state in which an individual either psychologicallyor physically requiresa drug to feel well in the absenceof medical indications. (For a scheduleof controlled substances,seeTableV-32-$. ?able V - 32-4. Abbreviated schedule of controlled substances.* Schedule

Description

Examples

I

High abusepotential; no medical use High abusepotential; medical use Moderate abusepotential; medical use Low abusepotential; medical use Lowest abusepotential; medical use

Heroin, LSD, and methaqualone marijuana Morphine, cocaine,and amphetamines Codeine,thiopental, tetrahydrocannibinol Benzodiazepines

II III ry V

Diphenoxylatewith atropine

*A controlled substanceis a drug that has been determined to have abusepotential. LSD - lysergic acid diethylamide.

b. Psychologicaldependenceis defined as compulsivedrug-using behavior or craving. c. Physical dependence is a state in which withdrawal of the drug from chronic use or administration of an antagonistleadsto physicalsymptoms,usually oppositethose of acuteadministration of the drug.

Note Withdrawal symptoms areusually opposite ofthe effects ofthedrug.

d. Abstinence syndrome is the description of the symptoms observed after withdrawal of a drug to which an individual is physically dependent. 2. Tolerance a. Drug tolerance is the phenomenon in which individuals progressivelyrequire larger dosesof a drug to achievethe sameeffect. b. Three tfpes of pharmacologic tolerance are: (1) Dispositional (pharmacokinetic) tolerance develops when changesin pharmacokineticscauselessdrug to be presentat the site of action. The major mechanism is an increaseddrug metabolism with continued administration. (2) Pharmacodynamic tolerance developswhen adaptive changesin the target tissue occur, causingdecreasedresponsesto a given drug concentration.This may involve modification of neurotransmitter systems,such as changesin neurotransmitter release,or alterationsin the number or sensitiviryof receptors.

Tolerance Tolerance maybecaused by changes inthemetabolism of a drug(pharmacokinetic tolerance) orinthecellular response to thedrug (pharmacodynam ictolera nce).

(3) Behavioral tolerance developswhen there is adaptation to behavior-altering effectsof a drug. c. Thchyphylaxis is a rapidly developing tolerance to the effects of a drug, even after a few doses.An exampleis tachyphylaxisto amphetamineas a result of the depletion of catecholaminestores.

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Neruous System

3. Measurement of a drug of abuse or its metabolite in the urine is an indication that the drug was used,but it does not indicate when the drug was used, or if there is a current performancedecrement.Plasmalevelsare a much better indication. B. Opioids 1. Dependence

In a Nutshell OpiateWithdrawal . Chills . Mydriasis

a. Patientswithdrawing from opioids experiencethe opiate withdrawal syndrome (especially with heroin and morphine), which begins 6-10 hours after the last dose; the time courseof effectsvarieswith the individual agent. b. Symptoms,which are most severe36_48hours after the last dose,include rhinorrhea, chills, piloerection, mydriasis, hyperventilation, hyperthermia, myalgias, diarrhea, vomiting, and irritability. Thesesymptoms subsidewithin I to 2 weeks,dependingon the drug.

. Diarrhea

c. Methadone withdrawal is not as severe;the onset of symptoms is delayed and more gradual and may last up to 2 weeks.

. Vomiting

d. Treatment

. Piloerection "going (hence, coldturkey") . Hyperventilation . Dysphoria . Anxiety . Muscle aches

(1) Methadone is used for controlled withdrawal or maintenance.This therapy is effectiveas a result of good oral availabiliry longer duration, and lesssedation and euphoria produced by methadonethan by heroin or morphine. (2) LAAM is a longer acting methadone-likecompound. (3) Naltrexone,a pure opioid receptor antagonist,is useful as an adjunct to therapy to block the effectsof any opioid agonist (e.g.,heroin) that may be taken. 2. Tolerance a. Tolerance develops rapidly when large doses are given frequently. Tolerance is minimized by giving small dosesat lengthy intervals. b. Patients and opioid addicts can experienceup to a 30-fold increasein the dose required to produce a given effect. c. Tolerance develops to all effects but to different degrees.Tolerance to the euphoria, analgesia,respiratory depression,hlryotension,emesisand urinary retention develops rapidly; toleranceto the miotic and constipatingactions developsmore slowly. C. Sedative-hypnotics: barbiturates, benzodiazepines, and alcohol 1. Dependence

Clinical Correlate Diazepam isusedto treat withdrawal fromCNS depressants to prevent or reduce seizure activity.

a. Acute effects of these drugs are due to CNS depressionand may include respiratory depression,coma, and death.Benzodiazepines are the safestof thesedrugs and rarely, if ever,causecoma when taken alone. b. Short-acting barbiturates causea severeand rapid withdrawal syndrome, similar to alcohol,whereasagentswith longer half-livescausesa more prolonged,lessseveresyndrome (symptoms may not appearfor 2-3 days). c. With short-acting agents (duration of action of 8-24 hours), symptoms include tremors, twitches, nausea,and vomiting. Seizurescan occur 1il8 hours into withdrawal. If severe,hallucinations and delirium may occur. d. Tieatment of withdrawal includes replacementwith a long-acting sedative-hlpnotic (diazepam).Clonidine and propranolol are used as adjuncts.

650

Pharmacology: DrugsAffectingthe CNS

2. Tolerance a. Both metabolicand pharmacodynamicmechanismsare involvedin tle development produceonly pharmacodyof toleranc€to barbituratesand alcohol.Benzodiaznpines namic tolerance. b. Thoughpatientsrequireprogressivelylargerdosesover time to achievea giveneffect, the level ofwhat constitutesa lethal doseofbarbiturates and alcoholrisesonlv modestly.This is in contrastto the dramaticrise seenwith opioids. D. CNSstinulants: amphetanines rnd cocaine

1.Dq'€nd€trcc

' !!:J!Si:!!

Amphetamines stimulate $e a. Anphetamines and cocaineare CNS stimulants that increasemental alertnessand of catecholamines and self-confidenceandproduceeuphoria"This is becauseofincreaseddopaminelevelsin : release the brain. Sympathomimeticeffectsinclude tachycardiaand hnrrtension asa result cocaine blodstheirreuptake. of their effecton peripheralnorepinephrinereleaseor reuptake,respectively.Seizure : with its local anestheticeffect. activity with cocaineis associated I h a l{Ubhell (1) Amphetaminederivativ€swith potent CNS effectsare dextroamphetamineand : : ThecentralefeG of methamphetamine(alsoknown asspeedor ice). : stimulanbarelargelydueto (2) crack is the ftee baseform of cocaine;it is smoked. i increases The in dopamine. b. Chronic use or excessivedosescan produce a psychoticstate witl delusionsand : ordiovascular efecbof Paranoia. stimulanb aredueh in norepinephrine. c. Psychologicaland phpical dependencecan oc{ur. Abstinenceproduceslethargy, : increases sleqriness,increasedappaite, prolongeddeep,and mentaldepression. Sfimulant withdrawal: 2. Tolerance . tncreased sleeping a. Toleranceoccursto the euphoria,anorexia,and the lethal dosewith regularuse. . lnceasedappetlte b. Litde or no toleranceoccursto the CNStoxicity. . DeDression E. Nicotine 1. Dcpendence a. Chronic nicotine use,asin cigarettesmoking,producesboth psychologicaland phpwith cardiovascular and respiratorydisical dependence. Smokinghasbeenassociated and deaths, ease cancer

:

b. Withdrawalryndromevariesin intensityamongindividuals.Symptoms,which usually beginwithin 24 hours becauseof nicotinet short biologichdf-life, indude irritability, : anxiety,headaches, increasedappetite,insomnia,and difficulty irnpatience,resdessness, in heart rate,blood pressure,and circulating in concentrating.Thereis alsoa decrease andskin temperatureincreases. epinephrine.Blood flow to the skin increases, 2. Tolerance a. With repeateduse,tolerancedevelopsto the dizziness,nausea,andvomiting associat- i ed with nicotineb. l:ss tolerancedevelopsto the increasein blood pressureand hand tremor and to the in skin temperatur€. decrease c. Chronic useleadsto an increascin nicotine metabolismbv the liver.

i

6rl

Neruous System

3. Trcatment of d?€ndence. Nicotine is availablein gum and transdermalpatchesto aid individualstrying to quit smoking. '

F. Caffeine 1..Dqrcndence a. Caffeineproducesboth prychologicaland physicaldependence.Symptomsof withdrawalappearwithin 12-24hours. b. The most common symptom of withdrawal is headache.Other symptomsinclude fatigue,lethargy,anxiety,and irritability. c. Chronic ingesion of more than 250 mg of caffeinedaily can be associatedwith nervousness, resdessness, insomnia,muscletwitching, and cardiacand gastrointestinal disturbanc€s. 2. Tolerancedwelops to the dysphoriaand anxiety. G. Cannabinoids 1. Generalclaracteristics

Cli{!a! ,C9m-Fte GnnibinoidshaveDotential theraDeutic usesas

a. Tetrahydrocannabinol is the activeingredientofnarijuana. Hashishis partially purified and more potent.

o||UE|||EUL), O> OPPEUTE

b' cannabinolsact by binding to specificreceptorsin the cNS to producetheir effects'

stimulants, andin thetherapy of giaucoma. Dronabinol, or oralTHC,hasbeenapproved forusein nausea and vommn8 a550oale0 wm chemotherapy andf'r AIDS wasting syndrome.

c. Acuteeffectsinclude euphoria,distortionsin perceptionof time and space,disinhibition, increasedappetite,and reddeningof the conjunctiva. d. Cannabinoidsreduceintraocularpresure (usefirlin somepatientswith glaucoma)and havean antiemeticeffect(usefi.rlin somecancerpatientsundergoingchemotherapy). e. The increasein app€titeis the basisfor their usein the AIDS wastingsyndrome. 2. Dqrendence

llS

a. Withdrawal symptoms,following chronic heavyuse,begin within a few hours.

A putative endo8enous liSand forthe cannabinoid receptor, anandamide, haSbeen identified.

b. Symptomsof with&awal include restlessness, irritability, insomnia, neryousness, decreasedappetiteand weight loss,rebound increasein REM sle€p,increasedbody temperature,chills, and tremors. 3. Tolerance a. Tolerancedevelopsto changesin mood and in impairment of performanceof psychomotor skills. b. Tolerancealsodevelopsto the tachycardia,increasein body temperature,and decrease in skin temperature. H. Inhalants. Only a few of the many compoundsusedasinhalantshavebeensystematically studied.Abuseis due largd to ready availability,low cost, quick intoxicating effect, and short duration of action (Fl5 minutes).Toxicityvarieswith the individual agents. .

1. Chlorinated solventsdecrease cardiaccontractility,leadingto a reflexincreasein sympathetic activity. 2. Fluorinat€d hydrocarbonsfound in aerosolpropellantsmayleadto cardiacarrhythmias.

6t2

Pharmacology: DrugsAffectingthe CNS

3. Ketones havebeen reported to causepulmonary hlpertension. 4. Lacquer thinner may causefatal neurologic deterioration and peripheral neuropathy. 5. Toluene has been associatedwith renal damageand diffuse CNS atrophy. 6. A-yl nitrite may result in profound vasodilatationand a suppressionof immune function.

ANTIEPITEPTIC AGENTS Seizuresare due to abnormal electrical dischargesof cerebralneurons. Epilepsy is the state of recurrent seizures.Seizuremanifestationsvary with the site of the focus and pathwayof discharge spread;they include changesin motor activiry loss of consciousnessor confusion with subsequent amnesia,hallucinations and illusions in any sensorymodaliry and behavioral changes. A. Overview. Types of epilepsy are classifiedaccording to the clinical features of the seizures, many of which have characteristicabnormalitieson the electroencephalogram(EEG). l. Generalized seizures are bilateral symmetrical manifestations. a. Petit mal (absence)seizures (1) Clinical features include brief (5-20-second) episodes of loss of awareness. Occasionally,the seizuresare associatedwith minor motor activity (e.g.,blinking), an onset usually between ages4-8, and a usually favorable prognosis with spontaneousresolution in most cases;however,in some cases,another seizure type develops. (2) The EEG showsgeneralized3-secondspike and a slow wavepattern. (3) Ethosuximide is the drug of choice for treatment; valproic acid is equally effective but has greater toxiciry (especially hepatic). Clonazepam is available, but causessedationand tolerance.Lamotrigine is a newer agentused in children. b. Tonic-clonic (gt*d

In a Nutshell . Seizures: abnormal electric discharge of cerebral cortex . Epilepsy: recurrent spontaneous seizures ClinicalCorrelate Petitmalseizures seenin children arecharacterized by briefepisodes of lossof awareness. Ethosuximide is thedrugof choice. Valproic acidisuseful forpetitmaland allotherseizure types.

mal) seizures

( 1) Clinical featuresinclude loss of consciousness associatedwith the tonic phaseof extensorrigidiry followed by clonic movements; incontinence of urine and feces or tongue biting may occur during the clonic phase.Seizuresare intermittent, though repetitive tonic-clonic seizureswithout recovery of a normal attentive state may occur. (2) The EEG shows symmetrical electrical dischargesduring the seizure;between seizures,the EEG may or may not be normal. (3) Intermittent seizures are principally treated with carbamazepine and phenytoin. Valproic acid is also useful. Phenobarbital (in children) and primidone are lesslikely to provide complete control of seizureswhen used alone as initial treatment. More than one drug may be required. Status epilepticus is usually treated with intravenous diazepam or lorazepam.Intravenous phenytoin or phenobarbital is given for longer control. Continuous infusion with diazepamor lidocaine,or generalanestheticswith neuromuscular-blockingagentsmaybe required.

ClinicalCorrelate Tonic-clonic seizures arethe characteristic seizures of severe epilepsy. Carbamazepine andphenytoin are thedrugs ofchoice. ClinicalCorrelate Diazepam isthedrugof choice forstatus epilepticus.

c. Myoclonic epilepsy. TWo forms of symmetric myoclonus are associatedwith EEG abnormalities: infantile spasmsand childhood myoclonic epilepsy.Myoclonus refers to a group of involuntary movements characterizedby jerking movements, many of which are not epileptic. ( 1) Infantile spasmsaretreatedwith adrenocorticosteroidsor corticotropin. Valproic acid or clonazepammay alsobe used.Prognosisis poor.

6tT

NeruousSystem

(2) Childhood myoclonus epilepsyis treated with valproic acid, diazepam,and clonazepam.Lamotrigine is effectivein children with myoclonus status.Phenytoin is not used due to lack of efficacy,and it may produce hlperactivity in children. d. Febrile seizures (1) Theseare brief generalizedseizuresassociatedwith fever in the absenceof CNS infection, and usually occur between the agesof 6 months and 5 years. (2) Tieatment includes antipyretics.A single dose of phenobarbital may be required; prophylactic phenobarbital is administered when seizuresare recurrent.

Note Focal seizures beginata "focus" andmayspread (become secondarily generalized). In a Nutshell . Complex partial seizures alterconsciousness. . Simple partial seizures do notalterconsciousness.

2. Focal (partial) seizures are characterized by abnormal dischargesarising from a focal area of the brain; these dischargesmay remain localized,spreadto adjacentregions,or become generalized. a. Simple focal seizures involve no loss or alteration of consciousness. b. Complex seizuresare associatedwith impairment of consciousness, motor automatisms (lip smacking),confusion,and amnesia. c. Tieatment includes carbamazepine,phenytoin, primidone, and phenobarbital, listed in order of effectiveness. Valproic acid may be used.Felbamate,gabapentin,lamotrigine, and vigabatrin are effective in the treatment of partial seizures.Many patients require more than one anticonvulsant. 3. Neonatal seizures occur during the first 30 daysof life. a. Neonatal seizuresare characterizedby: ( 1) Tonic deviation of the eyes,repetitive blinking, or rapid eye movements (2) Clonic movementsof posturing of one or more extremities (3) Grimacing (4) Apnea (5) Generalizedtonic-clonic seizures(rare) b. The causesof these seizuresmay include perinatal hypoxia or trauma, metabolic abnormalities,drug withdrawal from addicted mothers, aminoacidurias,CNS infection, or developmentalanomalies. c. Tieatment includes correction of any metabolic abnormality, phenobarbital (the drug of choice),and phenytoin.

B. Antiepileptic drugs. There are two principal mechanisms of anticonvulsant action: inhibi-

ln a Nutshell Antiepilectis actto either: . Inhibit a focus . Inhibit spread ofa discharge

tion of seizure focus (i.e., the neurons generating the abnormal discharge) and inhibition of spread of the discharge. Most of the drugs act by reducing the excessivedischarge of neurons.ThbleV-32-5lists the drugs used in eachseizuretype. 1. Phenytoin (diphenylhydantoin) a. Mechanism of action. Phenytoin acts by inhibiting voltage-gated sodium channels, thus suppressingepisodesof repetitive neuronal firing. b. Pharmacokinetics (1) Phenytoin is slowly absorbedfollowing oral administration. (2) Ninety percent of the drug is bound to plasmaproteins.

6t4

DrugsAffectingthe CNS Pharmacology:

(3) The concentration reaching the cerebrospinalfluid is equal to that of the free drug level in the blood. ( ) The drug is metabolizedby hepatic microsomal enzymes;the major metabolite is inactive. (5) Plasmahalf-life is 6-24 hours. c. Indications for use. Phenytoin is effective in many forms of epilepsy except absence seizures.It is also usefrrl in the treatment of trigeminal neuralgia and has limited use as an antiarrhythmic agent.

Clinical Correlate forall iseffective Phenytoin absence. typesexcept seizure

Thble V-32-5.Antiepileptic drugs. Seizure Type Generalized Absence (petit mal) Tonic-clonic (grand mal) Myoclonic Febrile Partial

Status epilepticus*

Preferred Drugs

Alternatives

Ethosuximide and valproate Carbamazepineand phenytoin Valproate Antipyretics and phenobarbital Carbamazepine, phenytoin, and valproate

Clonazepam

Diazepamand lorazepam

Phenobarbital Clonazepam

Gabapentin,lamotrigine, phenobarbital,primidone, and felbamate Phenobarbital and phenytoin

*Status epilepticus is a seriesof rapidly repeated convulsions that can be life-threatening if untreated.

d. Side effects and toxicity ( 1) Phenytoin exertsits therapeuticeffectwithout causinggeneraldepressionof the CNS as do the other drugs. (2) CNS symptoms may include irritabiliry nausea,depression,nystagmus,ataxia, diplopia, confusion, and coma.

In a Nubhell sideeffemof Unique phenytoin includegingival andhirsutism. hyperplasia

(3) Gastrointestinalsymptoms include nauseaand vomiting. (a) Phenytoin causesgrngival hyperplasia. (5) Hirsutism is a common effect. (6) Other adversereactions include osteomalacia,folate-responsivemegaloblastic anemia, hypersensitivity reactions, blood dyscrasias(aplastic anemia), and peripheral neuropathy. e. Drug interactions (1) Drugs that increaseserum phenytoin levelsvia interferencewith its metabolism include warfarin, chloramphenicol, cimetidine, disulfiram, doxycycline, isoniazid, and sulfonamides. (2) Drugs that reduce serum phenytoin levelsinclude ethanol, carbamazepine,pyridoxine, theophylline, and folate.

Note phenytoin Atlowbloodlevels, metabolism. first-order exhibits levels, Atmoderateto-high phenytoi n exhibitszero-order kinetia.

655

Neruous System

(3) Phenytoin-induced decreasedserum levels of other drugs via increased metabolism include warfarin, carbamazepine, chloramphenicol,corticosteroids, haloperidol, and oral contraceptives. 2. Phenobarbital a. Mechanism of action. Phenobarbital enhancesthe effects of GABA by increasingthe duration of opening of the chloride channel of the GABAAreceptor.It may also reduce the calcium-dependentreleaseof neurotransmitters.

In a Nutshell Phenobarbita I potentiates CABA-ergic transmission at theCABA^ receptors. lt is effective withallseizure types except absence.

b. Pharmacokinetics. Phenobarbital is 50olobound to plasma proteins. Seventy-five percentis metabolizedby hepatic microsomal enzymesand conjugated;2|o/ois excreted unchangedin the urine. The plasmahalf-life is 50-120 hours. c. Indications for use ( I ) Phenobarbitalis effectivein tonic-clonic and partial seizures. (2) It is the drug of choicein febrile seizureswhen an anticonvulsantis necessary. (3) It is useful in statusepilepticus,especiallyin children. d. Side effects and toxicity (1) CNS symptoms include sedation,irritabiliry confusion, respiratory depression, nystagmus,ataxia,and coma. (2) Other adversereactions include rash, folate-responsivemegaloblasticanemia, and osteomalacia. (3) Abrupt withdrawal may precipitatestatusepilepticus.

Note Phenobarbital increases its ownmetabolism aswellas themetabolism of manyother drugs byinducing P450.

e. Drug interactions (1) Drugs that increase phenobarbital levels via interference with metabolism include ethanol (short-term), chloramphenicol,and valproic acid. (2) Drugs that reduce phenobarbital levels by increasing its metabolism include ethanol (chronic use) and pyridoxine. (3) Barbiturates decreaseserum levels of a variety of drugs via increasedhepatic microsomal metabolism. 3. Primidone a. Mechanism of action is similar to phenobarbital. b. Pharmacokinetics. Primidone is rapidly and completely absorbed following oral administration. It is metabolized to phenobarbital and phenylethylmalonamide, both active products. The half-life of primidone is 5-15 hours; the half-life of phenylethylmalonamideis 16 hours. c. Indications for use. Primidone is generallya second-linedrug effectiveagainstgeneralizedtonic-clonicseizuresand simple and complex partial seizures.It is usedin combination with phenytoin or carbamazepine.It is sometimes used to treat myoclonic seizuresin young children. d. Side effects and toxicity. Adverse reactions occur from the parent drug and its metabolites.Sideeffectsinclude sedation,respiratorydepression,vertigo,ataxia,dizziness, nystagmus, diplopia, nausea, and rarely, a lupus-like syndrome and blood dyscrasias.

656

DrugsAffectingthe CNS Pharmacology:

e. Drug interactions (1) Carbamazepineand phenytoin alter its metabolism, reducing plasma levels of primidone but increasinglevelsof phenobarbital. (2) Primidone causesincreasedmetabolism of oral contraceptivesand quinidine. 4. Carbamaznpine a. Mechanism of action. Carbamazepine inhibits voltage-gated sodium channels, resulting in decreasingepisodesof repetitive neuronal firing. b. Pharmacokinetics. Carbamazepineis slowly and erratically absorbed following oral administration. The drug is metabolized to an active product, which reaches50o/oof levelsof the parent compound in plasmaand brain. Half-life is 10-20 hours. The drug inducesits own metabolism. c. Indications for use. Carbamazepineis effectivein generalizedtonic-clonic seizuresand in simple and complex partial seizures.It is usefi.rlin the treatment of trigeminal neuralgia.

In a NuBhell canbeused Carbamazepine typesexcept forallseizure absence. lt isalsousedfor neuralgia. trigeminal

d. Side effects and toxicity (1) CNS symptoms include ataxia,sedation,nystagmus,diplopia, and convulsions. (2) Other adverseeffectsinclude nauseaand vomiting, oliguria, hepatocellularand cholestaticjaundice, bradycardia and cardiovascularcollapse,water retention and hyponatremia,and hypersensitivityreactions. e. Drug interactions (l) Drugs that increase carbamazepinelevels via interference with metabolism include cimetidine, erythromycin, and isoniazid. (2) Drugs that reduce carbamazepinelevels by increasing metabolism include phenytoin and valproate. (3) Lithium enhancescarbamazepinetoxicity. 5. Valproic acid a. Mechanism of action. Various mechanismsof action havebeen proposedfor valproic acid, including the inhibition of GABA transaminase(reducing GABA metabolism) and enhancingpotassiumconductance(causinghyperpolarization).

Clinical Conelate Lithium enhances ne'ssideeffects; carbamazepi areusedin bipolar bothdrugs has lithium although disorder, noantiepileptic effects.

b. Pharmacokinetics. Valproic acid is rapidly and completely absorbed following oral administration. It is metabolized to two active metabolites. The drug is 90oloprotein bound. It appearsto be transported into the cerebrospinalfluid (CSF)by a carrier. c. Indications for use. Valproic acid is one of the preferred drugs in the treatment of absenceseizures.It is usefi.rlin myoclonic, akinetic, and atonic seizuresin young children. It has been shown to be effective in a variety of partial and generalizedseizures. d. Side effects and toxicity (1) CNS symptoms include sedation,tremor, and ataxia.

In a Nubhell

(2) The most serious side effectsare hepatotoxicity and hemorrhagic pancreatitis.

Valproic acidisuniquely types, in allseizure effective absence. including

(3) Other adverseeffectsinclude nauseaand vomiting, mild alopecia,and weight gain. e. Drug interactions (1) Carbamazepinereducesplasmalevelsby increasingmetabolism.

6t7

l{ervousSystem

(2) Antacids increaseabsorption, and salidates displacevalproic acid from binding sites,thereby increasing free drug levels. (3) Valproic acid reducesthe metabolism of phenobarbital. 6. Ethosuximide a. Mechanism of action. The exact mechanism is not known. Ethosuximide may inhibit cdcium channels.It does not alter sodium channels,nor GABA-mediated effects.

ln a Nutshell Ethosuximide canbeused onlyforabsence seizures.

b. Pharmacokinetics. The drug is completely absorbedfrom the gastrointestinal tract. It is well-distributed with little protein binding. Ethosuximide is metabolized by hepatic microsomal enzfmes to inactive products. Plasmahalf-life is 40-50 hours in adults, less(30 hours) in children. c. Indications for use. It is the drug of choice in absenceseizures. d. Side effects and toxicity (1) CNS symptoms include sedation and headache.It may exacerbatetonic-clonic seizures. (2) Other adverseeffects include nausea,vomiting, anorexia, rash, blood dyscrasias (leukopeniaand aplasticanemia),lupus-like syndrome,and Stevens-Johnson syndrome. 7. Benzodiazepines

ln a Nutshell Benzodiazepines areusedfor status-epilepticus anddruginduced seizures.

a. Mechanism of action. Benzodiazepinesact by enhancing the inhibitory effects of GABA at the GABAA receptor to increasechloride influx, thus causing hyperp olarization of neural cells. b. Pharmacokinetics. The drugs are well absorbed from the gastrointestinal tract. Eighty-five to ninety-nine percent are bound to plasma proteins. Some are metabolized to active products, which account for their prolonged duration. c. Indications for use (1) Diazepam and lorazepam are given intravenously in the treatment of status epilepticus. They are also useful in the treatment of drug-induced seizures.

ClinicalCorrelate Flumazenil, a benzodiazepine antagonist, isusedfor benzodiazepine overdose.

(2) Clonazepam is a long-acting analog, effective in the therapy of absenceseizures and myoclonic seizuresin children. (3) Clorazepate,which is hydrolyzed in the stomach to desmethyldiazepam,is effective in combination with other drugs in the treatment of partial seizures. d. Side effects and toxicity, Intravenous diazepam may causerespiratory depressionand hypotension. Other less severeeffects are sedation, irritabiliry ataxia, diplopia, and dysarthria. Sedation is the most common effect with clonazepam and clorazepate. 8. Newer agents

ln a Nutshell Newer Antiepileptics . Cabapentin . Lamotrigine . Felbamate . Topiramate

658

a. Gabapentin is a GABA analog useful in the treatment of partial seizures.Adversereactions include dizziness,fatigue, somnolence,and ataxia. It is usually well-tolerated. b. Lamotrigine is useful as an adjunct in partial seizures.It prolongs inactivation of neuronal sodium channels.Adverse reactions include a potentially life-threatening rash, dizziness,headache,and minimal sedation. c. Felbamate is an agent found usefrrl in the treatment of partial seizuresand LennoxGastautsyndrome in children.In late l994,use of felbamatewas associatedwith aplastic anemia; accordingly,the drug use was suspended.Later it was recommended only

Pharmacology: DrugsAffectingthe CNS

asa second-lineagentin patientsthat do not respondto other antiepileptics.The drug may act through NMDA receptors. d. Topiramate is effective against partial and tonic-clonic seizures.Adverse reactions include sedation,renal stones,and weight loss.

DRUGS ANTIPARKINSONIAN Parkinson'sdiseaseis an idiopathic movement disorder characterizedbybradykinesia,resting tremor, rigidity, and postural instability. The diseaseusually appears after the age of 50 and afflicts lo/o of the population over the age of 65. People exposed to the toxin N-methyl-4-phenyl-1,2,3,6-retrahydropyridine(MPTP) develop Parkinson-like symptoms. Other causes of parkinsonism include drug toxicity (antipsychotics, reserpine), carbon monoxide, manganesepoisoning, viral encephalitis,head trauma, and stroke. Pathologically, degeneration of the substantia trigt" and the dopaminergic nigrostriatal pathway (from substantianigra to caudateand putamen) is found. Dopamine depletion in the striatum causes a relative cholinergic overactiviry which may contribute to the symptoms (especially tremor). Therapy for parkinsonism includes dopaminergic agonistsand muscarinic cholinergic blocking drugs.A list of effectivedrugs is presentedin TableV-32-6. A. Dopaminergic agonists

ln a NuBhell

1. kvodopa (r-dopa) a. Mechanism of action. Levodopa is a precursor of dopamine. It is converted to dopamine by aromatic r-amino acid decarboxylase(dopa decarboxylase)to restore dopamine levels. b. Pharmacokinetics. Levodopa is absorbed from the gastrointestinal tract. More than 95olois metabolized to dopamine by peripheral dopa decarborylase; less than 2o/o reachesthe brain. Therefore,when used alone,largedosesare required,and peripheral side effectsare common.

L-dopa replaces lost lt is endogenous dopamine. with coadministered (which carbidopa doesnot barrier) cross theblood-brain peripheral to inhibit metabolism of L-dopa.

TableV-32-6.Agentsusedin the treatmentof Parkinsonism. TherapeuticAgent

MechanismofAction

Note

Levodopa Carbidopa

Precursorto dopamine Inhibitor of peripheral dopa decarboxylase; of levodopa enhanceseffectiveness Dopaminergic receptoragonist Dopaminergic receptoragonist Stimulator of dopamine release Inhibitor of monoamine oxidasetfpe B Muscarinic receptor antagonist Muscarinic receptorantagonist Muscarinic receptorantagonist Muscarinic receptorantagonist

Pramipexole isa recently approved drugfor Parkinson lt isa dopamine disease. agonist andanantioxidant.

Bromocriptine Pergolide Amantadine Selegiline Benztropine Tiihexyphenidyl Proryclidine Biperiden

Indications for use. Levodopa is usually given with carbidopa, a peripheral dopa decarborylaseinhibitor for the treatment of Parkinson disease.It may be given alone to patients who are sensitiveto the development of involuntary movements causedby the combined preparation.

659

Nervous System

Clinical Correlate L-dopa administration can resultin toxicside-effects related to excessive dopamine levels, suchaspsychotic behavior andhyperkinetic movement disorders,

d. Side effects and toxicity (1) CNS effects include dyskinesiasand other involuntary movements and behavioral changessuch as paranoia and hallucinations. (2) Nauseaand vomiting may occur due to direct stimulation of the chemoreceptor trigger zone. (3) Cardiovascular effectsinclude postural hypotension and, rarely, tachycardia and other arrhythmias. (4) Levodopa may elevateliver function tests. (5) Most patientsexperiencesome adversereactions,which are dose-dependent.An on-off syndrome may occur in which the drug suddenly loses its effectiveness. Peripheral sympathomimetic effects are reduced by use of carbidopa. e. Drug interactions

Bridgeto Biochemistry (vitamin Pyridoxine Bu)isa cofactor forall decarboxylation reactions.

(1) Pyridoxine increasesperipheral metabolism of levodopa,thus reducing its effectiveness. (2) Reserpine,which depletesdopamine stores, and antipsychotics,which block dopamine receptors,exacerbateparkinsonism. (3) Combination with MAO inhibitors may causehypertensivecrises. (a) Anticholinergicsmay reducegastrointestinalabsorption.

2 . Carbidopa a. Mechanism of action. Carbidopa is an inhibitor of dopa decarboxylase, which does not crossthe blood-brain barrier. Therefore,it inhibits the peripheral metabolism of levodopa,increasingthe percentageof the drug that reachesthe brain. b. Indications for use. Carbidopa is given in combination with levodopa in the treatment of parkinsonism.It reducesthe amount of levodopa neededby the patient and minimizes peripheral side effectsof levodopa. c. Side effects and toxicity (1) When administeredalone,this agentis without toxic effectsat therapeuticdoses. (2) When administeredwith levodopa,it enhancesthe CNS effectsand toxicities of levodopa.

3 . Bromocriptine

Note Bromocriptine isa dopamine agonist usedin end-stage Parkinson disease, whenLdopalosesitseffectiveness because of progressive degeneration of nigrostriatal neur0ns.

a. Mechanism of action. Bromocriptine is an ergot derivative, which is an agonist at dopaminergic receptors. b. Pharmacokinetics. The drug has a half-life of 8-12 hours. It is 30oloabsorbedfrom the gastrointestinaltract and undergoesextensivefirst-passmetabolism. c. Indications for use (1) Bromocriptine is usually usedin combination with levodopain the treatment of parkinsonism to allow a reduced dosageof levodopa.It is also used when levodopa is associatedwith the on-off phenomena. (2) Bromocriptine is used in the treatment of hyperprolactinemia endocrine abnormalities.

640

and other

Pharmacology: DrugsAffectingthe CNS

d. Sideeffectsand toxicity (1) CNS symptomsinclude involuntary movement(lesscommon than levodopa), behavioralchanges,hallucinations,delirium, and conf.rsion. (2) Other side effects include nauseaand vomiting, arrhythmias, and postural hn>otension. (3) The drug is contraindicatedin patientswith recentmyocardialinfarction or prydriatric illness. (4) It maygiverise to a first-doseph€nomenacharacterizedby suddencardiovascular collapse. 4. Pergolide.Pergolideis a dopaminergic(Dl and D2) r€ceptoragonisLIts therapeuticuse with longand pharmacologyare similar to bromocriptine.It tendsto lose effectiveness t€rm use.

s.Amantadine a. Mechanismof action. Amantadinestimulates the releaseof dopamine from presynaptic vesicles.It may alsodelayreuptake. b. Pharrnacokinetics.Amantadineis well-absorbedfollowing oral administration.It is excretedunchangedin the urine and hasa plasmahalf-life of24 hours. c. Indications for use (1) Amantadineis usedin t}te treatm€nt of Parkinsondisease-Effcacy is reduced after 2 months of therapy;it is thereforeoften usedintermittently asan adjunct. (2) Amantadineis alsousedin prophylaxisand treatmentof influenzaA infections.

!ti!-s9!9!l-q-9-li9l9.!y Amantadine wasdeveloped as ananti-viral agentandwas discovered to havea beneficial effecin Parkinson diseaselt stimulates dopamine release. lts usein A is thetreatment of influenza discusedin theAntimicrobial Agenb,chapter of ceneral PrinciDles BookI 0olumel).

d. Sideeffectsand toxicity (1) Amantadineis r€lativd fue of sideeffecrc;most are reversible.Mverse reactions aremostcommonin patientswith impairedrenalfunction. (2) CNSeffectsinclude insomnia,arxiety, andbehavioralchanges. (3) Amantadinemay induce congestiveheart failure (CHF) in patientswith preexistingcardiacinsufficiency. 6' selegiline (r-deprenyl) a. Mechanisn of action. Selegilineis a selectiveinhibitor of MAO tylte B (MAO-B), which metabolizesdopamine. b. Indications for use. Selegilineis used as an adjunct in the treatm€nt of Parkinson diseasein patients who are being managedwith levodopa-carbidopaand exhibit reducedresponseto therapy.The addition of this drug reducesthe requireddoseof levodopa,and the interval betweendosescanbe increased.The drug appearsto have limited valuein patientswith advanceddisease.

!r! 9..!-rtF..!-e!! seregirine is a I!iAO-B inhibitor,andisanadjundin thetreatment of parkinson disease

c. Sideeffecrsand toxicity (1) The drug increaseslevodopa-associated adversereactions;thus, the dose of levodopamay haveto be reduced. (2) At higher doses,the drug becomeslessselectivefor MAO-B and may potentiate when tyramine-likesubstances arepresent. the effectsof catecholamines (3) Other adversereactionsincludenausea,dizziness,lightheadedness, and fainting.

641

Neruous System

In a Nubhell (-)

(+)

striatum

B. Anticholinergic drugs. Normally, dopaminergic neurons have an inhibitory effect on cholinergic neurons in the striatum. Due to a decreasein dopaminergic activiry there is a decreaseof this inhibitory control of the excitatory cholinergic neurons. Anticholinergic agentsare sometimesgiven as adjuncts to reduce the relative increasein cholinergic activity. 1. Mechanism of action. These drugs compete with acetylcholine for the muscarinic receptors. They have affinity but no efficacy and, thus, block the effectsof acetylcholine.

v

2. Pharmacokinetics. Thesedrugs are given by the oral route. They are well-absorbed from the gastrointestinal tract and distribute to the CNS.

(to substantia Substantia niora pars . "6^pi""t"

ntgra pars reticulata and intemalglobal pallidus)

. ToolittleDAleads to excessive striatal ACh. . So,anticholinergia area useful adjunct.

3. Indications for use. These drugs are used as adjuncts with dopaminergic agents in the treatment of parkinsonism. They appear to improve tremor and rigidity but have little effect on bradykinesia. a. Benztropine has an antimuscarinic potency 25o/othat of atropine and has antihistaminic properties. b. Trihoqrphenidyl has weak antimuscarinic and antispasmodicproperties. c. Procyclidine is mostly used as a substitute for trihexyphenidyl. d. Biperiden is a congener of trihexyphenidyl.

l{o{e

4. Side effects and toxicity

Anticholinergics suchas benztropine and trihexyphenidyl helpto restore theDA/ACh balance inthestriatum.

a. These drugs produce classic antimuscarinic side effects including: (1) Sedation,confusion,hallucinations (2) Dry mouth, constipation,and urinary retention (3) Blurred vision and precipitation of acuteclosed-angleglaucoma (4) Tachyarrhythmias b. Antimuscarinic drugs should be avoided in patients with closed-angleglaucoma,prostatic hypertrophy, or obstructive gastrointestinal disease.

In a Nutshell Disease

Drug

Essential tremor

Propanolol

Huntingon disease

Neuroleptia

Tourette syndrome

Neuroleptia

5. Drug interactions include tricyclic antidepressantsor antihistamines since these drugs have antimuscarinic properties and, thus, may be additive.

DRUG THERAPY FOROTHER MOVEMENT DISORDERS A. Tremor. Propranolol has proven usefi,rlin the treatment of physiologic and essentialtremor. B. Huntington disease.Huntington diseaseis an inherited disorder causedby a degeneration of striatal GABA-ergic and cholinergic neurons and a deficiency of cholinergic function. Haloperidol and the phenothiazines,both of which block dopaminergic receptors,are useful in therapy. Therapy to enhanceGABA or acetylcholine brain aaivity is not currently successful. C. Tourette syndrome. This disorder is currently treated with dopaminergic (Dr-receptor) blockers (e.g.,haloperidol).

ilz

Psychoactive Drugs

physiology, Pathologic changes in theanatomy, of thebraincontribute andbiochemistry substantially to mental illness. ln addition to psychological useof drugs isa major therapies, patients. component in thetreatment However, forpharmacotherapy it is of mental to succeed, crucial to makethecorrect to choose theappropriate drugs, andto befamiliar withthe diagnosis, pharmacology of theseagents. Thischapter reviews thedrugsusedinthetreatment of depression andpsychosis.

ANTIDEPRESSANTS Depresion,a mood disorder,is manifestedby feelingsofterrible sadness andhopelesness;mental slowness;agitation;insomnia;psychoses; lossof energy,sexdrive,and hunger;and a signifi(bipolar) disordersaremanifestedby mood swingsbetween cantrisk ofsuicide.Manic-depressive mania(manifestedby euphoria,elation,restlessnes, hyperactivity,urd insomnia)anddepression.

ilote ---''

Depresionisthoughtto be ousedbya deficiency of norepinephrine and/or is believedto be causedprimarilyby a defciencyofthe ,{ Ilicyclicsandheterogrclic.s.Depression Antidepressant drug catecholamines andindoleamines: norepinephrine,serotonin,and,to a less€rodent,dopamin€ . serotonin. therapyinffeases (i.e.,the biogenicaminedeficiencytheory).This deficiencyis hypothesized thesynaptic to secondarilylead to up-regulationof the correspondingreceptors,causingthe clinicalmanifestations descibed. larelsof oneor bothof these The irnmediateeffectsof these drugs include a bloclade of the cateclolamine and/or : neurotransmitters anda indoleaminere-uptakesystemsat pre.synapticnerre terminels.However,therapeuticeffects I receptor down+egulation of thesedrugs do not app€arwrtil after 2-4 weels. The inhibition of the re-uptakeis now (delayed action). thought to increasethe levelsof synapticneuotransmittersand to producea compe ntory down+egulationof correspondingreceptorsto the normal status(FigureV-33-1).Convers€ly, maniamight be associated with an excess of theseamines.

645

Nervous System

Postsynaptic terminal

Presynaptic terminal

,-

NT )

3-/

Normalstatus

ro

@ .--'@ @ J

R

NT

R

R I,l R\\

s/

Rff

\='ry

(NT) (e.9.,NE, s-HT) levelslead Reducedneurotransmitter eventuallyto up-regulationand an increasein receptors(R) with clinicalmanifestations of depression.

.--

R R DNT F R R

n(

ft -\

Rll \-ff

Drug (D) inhibitsthe uptakeof NT, immediately leadingto increasedsynapticlevels,which,over the next few weeks,down-regulatesreceptorsto "normal"levelsand restoreshealth. Figure V-33-1.Status of "normal" neurons, of "abnormal" neurons leading to depression, and action of drugs to correct the "abnormality."

1. Pharmacologic properties a. Except those with strong anticholinergic properties, tricyclics are usually well absorbed after oral administration, and they show good central nervous system(CNS) penetration. b. They are mostly oxidized by hepatic microsomal enzymes and conjugated with glucuronic acid. c. Oxidation and demethylationof some parent drugs resultsin the production of active metabolites,some of which are also available as separatedrugs. d. Most tricyclics are strongly bound to plasmaproteins. 2. Specific agents a. Tricyclic antidepressants. Tertiary amines include amitriptyline, imipramine, doxepin, and trimipramine. Secondaryamines include desipramine, nortriptyline, and protriptyline.

644

Pharmacology: Psychoactive Drugs

Thble V-33-f . Side effects of some antidepressant drugs. Drug

AntiOrthostatic Cholinergic Sedation Hnrotension

Amitripryline Imipramine Doxepin Desipramine Fluoxetine Trazodone

+++ ++ ++ + 0 0

+++ ++ +++ + + +++

+++ +++ +++ ++ 0 ++

Insomnia

Sexual Dysfunction

0 0 0 0 +++ 0

++ ++ ++ + +++ ++

(+) Indicates extent of side effects

b. Heterocyclics include amoxapine, maprotiline, trazodone, and bupropion (secondgeneration antidepressants)and mirtazapine, nefazodone, and venlafaxine (thirdgeneration antidepressants).Tiazodone, nefazodone,and mirtazapine block 5-HT? receptors. 3. Choice of agent. Theseagentsare therapeutically similar. The choice of drug dependson the previous experienceof the patient, side effects,and the intended duration of action. A comparison of the side effectsof some of the major antidepressantsis provided in Thble

v-33-1. 4. Indications for use include depression(unipolar, bipolar), certain pain syndromes (neuralgias),prophylaxis of migraine, enuresis(bed wetting) in children (imipramine is usedin children over 6 yearsas a last resort), bulimia, diabetic neuropathy, and phobias. 5. Side effects and toxicity a. Blockade of muscarinic receptors by some drugs leads to anticholinergic effects (more common with tertiary amines),including constipation,urinary retention, dry mouth, and blurred vision. b. Blockade of cr-adrenergic receptors by some drugs leads to postural hypotension, especiallyin the elderly. c. CNS effects include sedation (especiallytertiary amines,trazodone, ofld mirtazapine), lowering of the seizurethreshold, dizziness,manic episodes,and psychosis.Maprotiline lowers the seizurethreshold significantly. d. Cardiotoxicity of some drugs includes first-degree heart block and other cardiac arrhythmias.

In a Nubhell lmportantSideEffects of Tricyclic Antidepressanb . Anticholinergic sideeffects . Postural hypotension . Sedation . Cardiac (especially toxicities uponoverdose)

e. Other side effectsinclude weight gain, obstructive jaundice, and tremor. f. Overdose is a common problem in depressedpatients and may result in convulsions, severearrhythmias, and respiratory depression.Treatment consists of gastric lavage, Noc HCO' lidocaine,and/or diazepam.With acutedepression,only small amounts of medication (e.g.,1-weeksupply) should be dispensed. g. Amoxapine is also a dopamine receptor antagonist and can causeside effects similar to antipsychotics.

645

Neruous System

6. Drug interactions

Note Tricyclis blockre-uptake, and interfere withother therefore drugs thatusethere-uptake carrier fortheirmechanism of (e.9., guanethidine). action

a. These drugs can be displaced from their binding on plasma proteins by aspirin, aminopyrine, phenothiazines,phenylbutazone,and scopolamine.This enhancesthe effectsof antidepressantsby increasingthe amount of free drug in the plasma. b. The metabolism of these agents can be decreasedby oral contraceptives, antipsychotics, and methylphenidate, thus enhancing the effectsof the antidepressants. c. The metabolism of antidepressantscan be increasedby barbiturates,some sedatives, and cigarettesmoking, thus leading to a reduction in their therapeutic effects. d. The CNS effectsof alcohol are potentiated by tricyclics. e. Becausethe tricyclics can have notable antimuscarinic activity, their effects should be monitored when used with other agentspossessingantimuscarinic activity. f. Agents that block the uptake of neurotransmitters can have a potentially dangerous interaction with biogenic amines. g. Concomitant use of MAO-inhibitors causessigns of atropine poisoning. h. Nefazodone inhibits CYP3A4, and therefore should not be used in combination with drugs such as cisaprideor astemizole. 7. Pharmacokinetics. Becauseapproximately 40o/oof patients receiving psychotherapeutic medications are noncompliant, it is important to determine plasma drug levelsto distingurshbetweenpatients who are noncompliant and those who exhibit individual differences in pharmacokinetics.Monitoring these levels also potentiully reducesthe toxic effects of antidepressantsand lithium becausetheir therapeutic indices are low. However,evenwhen an antidepressantis within its therapeutic range,not all patients respond favorably. B. Buproprion (second generation) 1. Pharmacologicproperties blockade of norepinephrine and dopamine uptake mechanisms. 2. Indications include depressionand cessationof smoking. C. Selectiveserotonin re-uptake inhibitors (SSRIs)

ln a Nutshell block SSRIs selectively 5-HTreuptake.

1. Pharmacologic properties. Unlike the tricyclics that inhibit the uptake of norepinephrine and serotonin, SSRIsselectivelyinhibit serotonin uptake. These agentsshow fewer anticholinergic and antiadrenergic side effects,less cardiotoxiciry no weight gain but loss, and a lower risk of overdosethan the triryclics. Some are metabolized to active metabolites(e.g.,fluoxetine + norfluoxetine). 2. Specific agents include fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine. 3. Indications for use. SSRIs are indicated for depression,panic disorders, obsessivecompulsivedisorder,post-traumatic stresssyndrome,and bulimia. 4. Side effects can include behavioral changes,sexual dysfunction, nervousness,nausea, diarrhea,dyspepsia,insomnia, and headache. 5. Drug interactions. SSRIsinhibit cytochrome P450 isozymes, increasing the activity of other drugs (e.g.,tricyclic antidepressants, warfarin). SSRIscombined with MAOIs can cause a potentially fatal serotonin syndrome characterized by hyperthermia, muscle rigidiry myoclonus,and rapid changesin vital signsand mental status.

646

Pharmacology: Psychoactive Drugs

D. Monoamine oxidase (MAO) inhibitors. The enzymeMAO is present on the outer membrane of mitochondria in most tissues.In neurons,it degradesbiogenicamines,including catecholamines,serotonin,and relatedamines.Hepatic MAO inactivatesdietary and circulating monoamines(e.g.,tyramine,epinephrine).Therearetwo typesof MAO: MAO-A and MAO-B. Equal amounts of both types are found in the brain and liver. 1. Pharmacologic properties a. MAO inhibitors reducebiogenic amine metabolism and, in the brain, increaseintraneuronal levels.Increasedsynaptic concentrationsof these amines are thought to result in down-regulationof the pathologicallyincreasednumber of receptorsand accountfor their antidepressant action. b. They are absorbedreadilyfollowing oral administration. c. Up to 2 weeksmay be required beforeamine metabolismreturns to normal after withdrawal of the inhibitor. 2. Agents include phenelzine and tranylcypromine. These drugs inhibit the enzyme. Phenelzineis inactivated by acetylation (50oloof the population are either slow or fast metabolizers),which can lead to increasedlevels in the slow metabolizers,causing increaseddrug toxicity. 3. Indications for use include depression(when tricyclics are ineffective),phobias, narcolepsy,and panic attacks. 4. Side effects and toxicity a. Tyramine is not degradedin the presenceof a MAO inhibitor and causesthe releaseof stored norepinephrine,leading to an increasein blood pressure(hypertensivecrisis!). Newer MAO inhibitors are currentlybeing developedwith a shorterduration of action, which allowsfyramine metabolism.

In a Nutshell MAOinhibitors increase intraneuronal levels of norepinephrine andserotonin byinhibiting theirmetabolism anddecrease theirreleases. ClinicalCorrelate Patients taking MAOinhibitors mustavoid tyraminecontaining foods(e.g., cheese, redwine). Normally, tyramine undergoes first-pass elimination uponingeston. However, withMAOinhibitors, tyramine issystemically absorbed, andenters norepinephrine nerve terminals viare-uptake. Massive amounts of norepinephrine aredisplaced bemetabolized andcannot because MAOinthenerve isalsoinhibited. This terminal fatal canleadto a potentially hypertensive crisis.

b. Restlessness, insomnia,and dizzinessarerelativelycommon. c. Orthostatic hypotensionis mostly at start of therapy.

ClinicalCorrelate

d. Constipation,urinary retention (lessthan with the tricyclics),tremors, peripheral neuropathy,nausea,weight gain, and edemaoccur occasionally.

g interactions Life-threatenin withMAOinhibitors include:

e. The useof any irreversibleMAO inhibitor in patientsover 60, in patientswith cardiac disordersor hypertension,or in patients at risk for stroke is questionable.

. Drugs thatincrease synaptic (e.g., NElevels tyramine, tricyclic antidepressants, Ldopa, alpha agonists)

f. Hepatotoxicity is very rare. 5. Drug interactions a. Precursorsof biogenic amines (e.9., t--dopa), sympathomimetic drugs (e.9., amphetamine),and tricyclics should not be given with MAO inhibitors since severe hypertensionmay result. b. Detoxificationof certain drugs is impaired, and toxicity may developwith general anesthetics, alcohol,antihistamines,and sedatives. c. Patientstaking opiatesand MAO inhibitors may develop rigidity, hypertension,and irritability. d. A hypoglycemiceffectwith drugs used for diabetescan be expected.

. Drugs thatincrease 5HT, causing a serotonin (e.9., syndrome SSRI) . Opiates (e.g., meperidine)

Correlate Clinical Co-administration ofeither (e.g., or opiates demerol), tricyclic antidepressants with MAOinhibitors canbefatal andiscontraindicated.

647

NervousSystem

E. Lithium. The mechanismof action of lithium in depressionis uncertain but seemsto block development of dopamine-receptorsupersensitivity,increaseacetyicholinesynthesis,and enhanceserotonergicactivity. Lithium is thought to prevent the recyclingof phosphoinosi(PIP2),which is the tides,leadingto the depletionof phosphatidylinositol-4,5-biphosphate precursor to the second messengersinositol 1,4,5-triphosphate(IP.) and diacylglyceroi (DAG). This may diminish the effectsof excesscatecholaminesor serotonin,which are thoughtto causemania. l. Pharmacologic properties a. Given orally aslithium carbonate,lithium ions (Li*) are absorbedreadilyand almost tract. completelyfrom the gastrointestinal condithrough the blood-brain barrier is slow. Under piasma steady-state b. Passage (CSF) found 40-50o/o of that fluid is about in the cerebrospinal the level of Li* tions, plasma. in

ln a Nutshell second Lithium seems to affect messenger system, andNa.loss leads to Li.increase.

c. Lithium doesnot bind to plasmaproteins. d. Lithium is excretedsolelyby the kidneys.An inverserelationship existswith sodium if ions (Nat); that is, a Na* loss increasesLi* levels.A reduction in doseis necessary creatinineclearanceis impaired. e. Lithium hasa low therapeuticindex. initially to optimize f. Measurementof serum concentrationsof lithium are necessary effects. to minimize the toxic effects and the therapeutic 2. Indications for use include acute mild-to-moderatemania, prevention of manic and depressive episodesin patientswith bipolar illness,and asan alternativeor supplementto antidepressant treatment. 3. Side effectsand toxicity a. Acute intoxication includes nausea,vomiting, and tremors, and late toxicity includes convulsions,coma,and death. b. Lithium is contraindicatedin pregnanryand may causecardiacand other birth defects. Becauselithium is secretedin breastmi1k,it should not be usedby nursing mothers. c. Lithium is excretedby the kidneys.With impairedrenalfunction,levelsmust be monitored carefully.It rarely causeschronic interstitial nephritis. d. Other side effectsinclude thyroid enlargement,polydipsia,polyuria, and fatigue. 4. Drug interactions a. Diureticsand other conditionsthat promote Na' lossincreaselithium reabsorption. and phenytoin. b. IncreasedCNS toxicity resultswith methyldopa, carbamazepine, c. Indomethacin and phenylbutazonecan increasetubular resorption of lithium and renal lithium clearance. decrease

648

Drugs Psychoactive Pharmacology:

ANTIPSYCHOTICS Schizophreniais manifestedmainly asa thought disorderwith delusions(often paranoid),halsocialwithdrawal, and blunted affect.It is believedto lucinations,looseningof associations, result from a coexistenceof hyperdopaminergicactivity in the mesolimbic system (positive signs)and hypodopaminergicactivity in the mesocorticalsystem(negativesigns).There are severaldopaminereceptorsubtypesincluding Dl,D2,D3,D4, and D5. SubtypesD2 andD4 seemparticularly involved.In addition, serotonin receptorsin the cortical structuresplay a role Anatomic abnormalitieshavebeenfound in the temporallobe and the amygin schizophrenia. dalaof schizophrenicpatients. A. Pharmacologic properties 1. Mechanism of action a. Antipsychotic drugs are thought to be effectivebecausethey block dopamine receptors (particularly D2 and Da) in mesocorticaland mesolimbic areas.However,they alsoblock dopaminereceptors(CD2) in the following areas: (1) In the basalgangiia(nigrostriatalpathways),causingmovementdisorders (2) In the hypothalamusand pituitary gland (tuberoinfundibularpathway),leading to increasedprolactin secretion (3) In the chemoreceptortrigger zone,inhibiting emesis b. Antipsychoticsalsoblock cholinergicreceptors(leadingto anticholinergicsigns)and u-receptors(leadingto posturalhypotension).Other receptors,suchashistamineand serotonin receptors,are also blocked.Newer "atypical" antipsychoticsblock mostly 5HT2 receptors.

ln a Nutshell Allantipsychotics (neuroleptics) aredopamine Thegoalisto antagonists. in receptors block dopamine andmesocortical mesolimbic theyare areas. Unfortunately, inthebasal alsoblocked (leading ganglia to sideeffects) extrapyramidal (leading to andinthepituitary hyperprolactinemia).

2. Routesof administration include oral, intravenous,or intramuscularinjection. Depot injectionsare available(e.g.,fluphenazine,haloperidol)for psychiatricpatientswho are noncompliant.One dosemay last 2-6 weeks. mediatedby hepaticmicrosomalor other 3. Metabolism is mainly by oxidativeprocesses drug-metabolizing enzymes.These drugs are highly lipophilic and protein-bound (92-99o/o).They are sequestered in the lipid compartmentsof the body and have long durations of action, resulting in elimination half-lives of 20-40 hours. After cessationof therapy,they can be detectedfor months in body fat. 4. Efficacyis similar for all antipsychoticdrugs but they vary in their potency.They are often classifiedashigh-potency(i.e.,lowdose)or low-potency(i.e.,high dose)drugs.For example, chlorpromazineis a low-potencydrug, and haloperidol is a high-potencydrug.

ln a Nutshell Drugs Low-potency Chlorpromazine Thioridazine Drugs High-potency Fluphenazine, Haloperidol

B. Indications for use l. Antipsychotic drugs are used for psychoticsymptomatologyor schizophrenia.The onset of antipsychoticaction is delayed2-6 weeks,but sedationoccursquickly.Therapy is often necessaryfor life. 2. Thesedrugs are also usefulfor severemanic or agitatedepisodes,for certaindrug overdoses(e.g.,amphetamines). 3. Somedrugs in this classare usedto treat nauseaand vomiting (e.g.,prochlorperazine), intractablehiccups,and Tourettesyndrome(e.g.,haloperidol). C. Side effectsand toxicity. The following side effectsare common to almost all antipsychotic drugs,but they may vary in intensity.This classof drug showsa high therapeuticindex with only rare fatal overdoses.

649

NervousSystem

In a Nutshell Extrapyramidal sideeffects (EPS) arethought to result froma dopamine/ACh imbalance inthestriatum. Balance canberestored with anticholinergics.

ln a Nutshell Extrapyramidal SideEffects Acute: . Parkinsonism . Akathisia . Dystonia Late: . Tardive dyskinesia Miscellaneous SideEffects . Sedation . Anticholinergic . Postural hypotension . Hyperprolactinemia . Lowers seizure threshold

l. Extrapyramidal side effects (EPS) are causedby a disturbance of the balancebetween dopamine and acetycholine(ACh) in the basalganglia.Cholinergic overactivityis caused by dopamineblockade.Balancecanbe restoredby administeringan anticholinergicagent (e.g.,benztropin). a. Parkinsonian syndrome is observed,including rigidiry restingtremor, and bradykinesia. b. Akathisia occurswith restlessness and increasedmotor activity. c. Acute dystonic reactions are observed,including oculogyric crisis. d. Thrdive dyskinesi4 a condition characteruedby stereotypicalinvoluntary movements such aslip-smackingand grimacing,ffiny develop,especiallyin the elderlyand after longterm therapy.It is thought to be causedby dopamine receptorup-regulation asa result of long-term receptorblockade.No satisfactorytreatment for tardive dyskinesiais available. 2. Other side effectsinclude sedation,galactorrhea,postural hypotension (most severewith intramuscular injections of chlorpromazine),anticholinergicside effects,lowered seizure threshold,difficultiesin regulatingbody temperature,and menstrualchanges. 3. Neuroleptic malignant syndrome with muscular rigidity, fever,diaphoresis,myoglobinuria, and metabolic acidosisoccurs in some patients.Tieatment is with dantroleneor dopamineagonists. 4. Depot antipsychotic drugs should not be given unlessthe patient has receivedthe drug orally and respondedfavorably.Toxic results after a depot injection may be severesince the drug cannotbe removed. D. Specificagents 1. Phenothiazines

. Neuroleptic malignant syndrome

a. Aliphatic group. This group includes chlorpromazine and triflupromazine. These drugs causea high incidenceof anticholinergicand anti-o-adrenregicsideeffectsand a low incidenceof extrapyramidalsideeffects.This group is low potency.

In a Nutshell

b. Piperidine group. Thioridazine is the protofFpe of this group. Thioridazine causesa high incidenceof anticholinergicand anti-o-adrenergicside effects,a low incidenceof extrapyramidalside effects,and pigmentary retinopathy at high doses.This group is moderatepotenry.

Thioridazine isa particularly goodanticholinergic, leading to fewerextrapyramidal side peripheral effects, butgreater sideeffects.

c. Piperazine group. This group includesfluphenazine, trifluoperazine, and prochlorperazine. Side effectsinclude a high incidence of extrapyramidal side effects,fewer autonomicsideeffects,and lenticulardeposits.This group is high potency. 2. Thioxanthenes. This class includes thiothixene and chlorprothixene, which causes lenticulardeposits. 3. Butyrophenones. The prototype of this classis haloperidol. Haloperidol causesa high incidence of extrapyramidal toxicity and impotence. Drug interactions include increased metabolism by phenytoin and barbiturates. When used with lithium, it may cause encephalopathyand fever.This group is high potenry.

650

Pharmacology: Psychoactive Drugs

4. Atypical antipsychotics. These drugs have advantagesbecausethey are efficaciousin treatingboth positiveand negativesymptomsof schizophrenia.(The other drug ciasses are successfulprimarily with the positivesymptomsonly). In addition, they havefar f-ewer extrapyramidal side effects.Thesedrugs typically have a high affinity for 5-HT2A receptors and alsoblock other receptorssuchas D, and alpha, receptors. a. Clozapine (dibenzodiazepineclass)has a high affinity for 5HT2 and D4 receptors.It produces fewer extrapyramidal effects and is often effective in treating refractory schizophrenicpatientsor patientswith tardivedyskinesia;may improve tardivedyskinesia.Side effectsinclude agranulocytosis(in up to 3o/oof the patients).Frequent blood testsare necessaryin the beginning of therapy.Anticholinergic side effects, sedation,orthostatichypotension,and weight gain are common sideeffects. b. Risperidonehas a lower risk of extrapyramidalsideeffectsthan most typical antipsychotics,though it has a higher incidencethan clozapine.At doses>l0mg/day, the EPS profile is similarto tlpical antipsychotics. Risperidonehaslessanticholinergicsideeffects, orthostatichypotension,and weight gain than clozapine.Sedationis lesscommon. c. Olanzapinehas a very low incidenceof EPS.It hasa high incidenceof sedation,anticholinergicsideeffects,orthostatichypotension,and weight gain. d. Qeutiapine has a very low incidenceof EPS.I producesmoderatesedationand orthostatichypotension,hasa low incidenceof weightgain,and no anticholinergicsideeffects. e. Sertindolehasbeenat leasttemporarilywithdrawn from the market for further evaluation becauseof prolongation of the QT or QTc interval, increasingthe risk of arrhythmias. E. Drug interactions include potentiated effectswhen combined with other drugs that have anticholinergic,anti-alpha-adrenergic or sedativeproperties.They also decrease the effects of r-dopa and dopamineagonists.

In a Nutshell Highandlow-potency drugs produce a different spectrum ofsideeffects: LowPotency . Fewer extrapyramidal sideeffects . Creater anticholinergic, antiadrenergic, andsedative effects HighPotency . Greater extrapyramidal sideeffects . Fewer anticholinergic, antiadrenergic, and sedative effects

Clinical Correlate Clozapine isconsidered atypical because it generally doesnotcause extrapyramidal sideeffects ortardive dyskinesia. However, it can cause agranulocytosis. Patients musthave frequent blood tests if taking clozapine.

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