Pharmacology, 2nd Edition (Lippincott’s Illustrated Reviews)

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lippincott's Illustrated Reviews: Pharmacology 2nd edition

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Lippincott's Illustrated Reviews: Pharmacology Mary J. Mycek, Ph.D. Department 01 Pharmacology and Toxicology University of Medicine and DentiSlry of New JerseyNew Jersey Medical School Newark, New Jersey

Richard A. Harvey, Ph.D. Department of Biochemistry University of Medicine and Dentistry of New Jersey~ Robert Wood Johnson Medical School Piscataway. New Jersey

Pamela C. Champe, Ph.D. Department of Biochemistry 01 Medicine and Dentistry 01 New JerseyUniversity Robert Wood Johnson Medical SChool Piscataway, New Jersey

Clinical Consultant (Antimicrobials):

Bruce D. Fisher, M.D. Department 0 r Medical Education Muhlenberg Regional Medical Center Plainfield,

Computer graphics:

Michael Cooper Cooper Graphics 48 Van Syckel Road Hampton, New Jersey

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lIpPINcan WILUAl'v\S & WILKINS

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UNrr VII: 'h,n-l,ojItu"",,,1ory Drup mid lIul~ Chapler 39: Anti-inIlatrVnalory Drugs 401 Chapler40: AulamMts and A,'aooid ArUgonisIS Appenlb:.llluslraled Case Sbdjes

419

429

I'- hMlr:..qy UpdIIl~ Chapter 8: Trealmen1 al Parkin$On'$ Disease 443 Chapler 15: Drugs USed to Treat [1-'_)1 445 Chapter 20: Drugs AIl«:tio '9 8Iood 446 ~ 21: Anlitlypeiipide",it: Drugs 449 O\apef 22: Drugs AfleiRary penneability is detenninecl by capillary slnJcture ard by the chemical nature of the drug.

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1. Capillary structure, Capillary structure varies widely In tB::lWaSl. l'IydI upI ilic tInJgI, ~ haIfe eilhef a fllII'UliIIanTl diIlrb.DJn of EI e bOi .. Of a postive or ~ charge, 00 not readiIV penetrate OBI membranes and IT'USl: go Ihfrogh lhe slil: ;.adioo~ (see FlgUfe 1.8).

c. BIndlng 01 druga to protein.

Flguffl 1.8 Cross section ofliYer and brain capillaries.

AeIfasible bii ... og to plasma fO'oteiI'\IleCJ,IeItefS(Wgs WI a rton-ditIu$llle form .00 slows Iheir trans'er out 01 the vaS" oIar ClClfT1lB."mef1.. Billdioog III relatiYely non-sele clive 8& 10 ctJeo,lical strucllKl and takes plaoe III siles on the protein to Y
VII. BINDING OF DRUGS TO PLASMA PROTEINS Drug molecUes may ~ to plasma proIeins (usualy aI:uTWll. Bou-od drugs a18 fl/'Ialr,,,," ... -..-
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Drugs arll most otten eliminaled by bioJranslomlation and/Of excre1ion into the urine Of bile. The live. is the major Site lor drug metabolism. but specifIC drugs may undergo biotransformation in othe. lissues. [Nole: Some agllnts arll in~ially adminislll'ed as inactive compounds (prodrugs) and mUSI be metabolized to their active 10005.1

Ited al pH

Cot.mn """ only • Wi8lllraetioo illroo. MDIlI d lhlg A is SOQl.lOSIC«ld on I'IIJu'I"M1 CUfonic acid to a drug

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A. deamlses its watcr solubility. B. l.lSUlllly leads 10 inactivation ollhe '*ug. C. is lin ClSlant foI total body eliminalion of the drug, 110. Thus, 50% of the tina! steady-state concenlratlon of drug is obsefved altor time elapsed since the Inlusion. I, Is eqoal to t"2. where 1"2 (or tl8W·l~o) is the lime fllquired 10< the dfug concenlrotion to change by SCI'%.. Wailing al10lher half.jile allows the drug concentlalion to approach 75% of C. (see FIgu'e 2.3). The dnJg COI'Centration is 9O'J. 01 the final steady-stale concentllltion in 3.3 times 1m. For convenience, ltIeiefOle. one can assume IIlaI • drug .... read1 sleIIdy ~te in abolA 4 hd·ives.. 2. EfIect of !tie .-Ie or drug WuaIon: The sole del~ ol Ihe rote thai a MIg ~ S1el1d'f ~18 is lhe 1m 01 Ie.. n this rate • inIuM>ced only by ltle l8aDrs Ihal aIlect Ihe hIIl-ile. The rate of approadllO steady stale Is noll a/lected by the f8te ol drug infusion. Although irlCfeasiOll the rile of infusion 01 a drug ira_the rale al ¥d1idl any glven CDce,balion of drug in the plasma is achieved. ~ does not innuence the lime ,equiffld to <eilCtl!he ultlmate steady-slate COllce"tration. This is because lhe steady·state concentration 04 drug rises di:ed--Dose. Fi~ed- Tine-llllf!fV31

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Rate ol altannent ol ~staleoonoentration ol dn.lg In plasma.. 3. R_ of !hog deo;llne when thfl Infusion Is Mopped: When the imlsion is stopped,!he p/lISmIl ca1C&lbaDon ol a drug dldrlilS (washes DUl)1o zero with the same One lXlUrSe obsefYed in ~.'!I!he$INdy $lllte (see Fq..-e 2.3). •. l.GedIng dose: A delay In IIdIie.iog the desifed plastnllleveJs of drug may be clinicaly ooacceplable. Therelore. a ~ dose· d drug can be ~ed as 8 slngle dose 10 1Id1l_ !he desired plasma level rapidly. 10110""00 by all 'Ilfusion 10 ma,ll,al" the steady slale (mainleMl'\CEI dose). 111 general. lhe loading dose can be calculated as:

III. KINETICS OF FIXED-DOSE, FIXEo.TIME.JNTERVAL REGIMENS Adl"iliblIation of a drug by lilted doses rather Ihar1 by oontinuooA i1fu. til::rl is ott-! mere ca ••aeol. Hl;wwa'. bed doses, given at filo:EIO:tIn'Ie intelY8Is, .E!5tM In ~dall "'",e.j B, GrIded cion response eulVfil At1 agonisl Is

deIined as an agenl that can b/r(I 10 a rec:eplor and elidl a response. The magUlude of the drug elled depends (lIl ~s ooncenlration al the receptor sile, lMlich In lurn IS determined by !he dose of dl'ulladminislemd and by lacton; c::hBfactlll1slie of the drug. wc:h as rale 01 absorption, distribution, and metabolism. The effed of a M.og 1$ mool easily analyzed by p10nlng the magrilude of !he respollse versus the log of the drug dose. lhus obtairing II graded ~ eurve (FlQUl"e 2.7). 1. EffleKy: Ellieacy is the maximal

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Figure 2.6 Predieted plasma concentrations of II I7vg gyen by repeated oral

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!he elfiderlCY with ¥ItlictI1he lIICliY!Iled recep!0I plodl Q1$ a eel... Iaf aetiOI'l (see Fogu.e Effieacy Is analogous 10 maximal 'IiIkJeiIy 101 1111 enzyme eata/yled ~. (Note: A 0Ji,~ may tww;IlO Ihe ,eoepIDl and nol eIdl I teSj)U 1Se. It is Ihus said 10 "-le«l~, an:! may aa as 1II111l0l3!lP_1

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2. Pllt8nc:y: Paenc:y, aIse .... "MOCl etIecliYII ex- OUIc:&.ation, is a ~ of hoW nu:tl drug is IeQIMed 10 eIaI I W>'en teSj)U _ . The loWer the dose required lor a given re5POf'lSe. !he ITl(lfe poIIenl!he drug. Pole cy is rTIOI5I oIIen ~essed as ... dose d drug Ih8t ~ 5O'Il. d!he maJlirnaI respulSe. EOso (see RguIe 2.7). A drug ...., a kJW ~ Is more potenl tIIII1 a drug will a "e ,!'! aGe 01 a neo.rornediatof s' I .... Drug!i IhaI prtI(U::;e lheir primary f'ler.Ipeulic etrea by ,•• ,i1ctiolQ or alIe,iI", the Iurdions oIlhe aulonomk: nervous sysI8m _ C8Ied auolOi,lit drug:s and are dsl::u5!;ed nile IoIowi"1g lou" ~ These ......... ,lit agenl$ act .... by 5lin'Ua,. porliorls of the autOl ....,lit nerYOUlii r;ysaem or by blod0'I0dsliDn at . - ......... ..-...... 0I1ood. WId ~

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A. The ~fIBIicsystem . . . nooopilflploi .. as

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REACTIVATION

OF ACETYL·

CHOUNE ESTERASE

2. Storage 01 acetylcholine In vesicles: The acetylcholine is packaged into vesicles by an active transpon process coupled to !he ellluK 01 protons. The malure veside not only contains acetyl· choline bUt also adenosme triphosphate and proteoglycan. The fundion 01 \he laller subslances in the nerve terminal is unknown_

Flgu•• 4.1 Summary 01 cholinergic agonlsls.

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OloIinefllic Agonists

3. ReP".. of -'Yk:hoIirlII: When 8fI aetlon potenIiaP propagaled by the acUon oIl1Ol1age-sensilive sodu'n channels arriVes at a I'lef"<e ~. voltage-sensitive caJci.om channels in the p«Isynap~ membnlne open. causing IIf'1 increase in the COl iCer ilnltioo'l of ilbacelUar ca:un.. EIeYated calcium ...... promote h Iusion of .synaptic vesldes wilh I~ cell membrane and relell$Cl of acelylcholine inlO the synapse. This release is blocked by bc**un klD\. 9y COl iIlast, bladt """doJo spider \91Of'II eao ...... 81 01 ..........., aoetyk:hclinB sb"ed in S)'"oIplic , . 1M to spill if*! . . synaptic gap.

4. 8lndlng 1O..cepIOr: AcetyIcOOIinB"*,o ad tn:rn hi ~ vesides cliltusBs across IhB syoepIic spIlOB and bn!s to eilher post. S)'I1lIIltic Al'OBJ)Iors on IhB tar-gBt oeI or 10 presynapIjc recepIorS in the membrane 01 the neuron that released the aCEItylchollne.

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AUTONOMIC

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II. The CholInergic Neuron

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ACETYLCHOLINE

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DEGRADATION OF I:!jI ACETYLCHOLINE

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""'~ 1>1' ~ high affinity l.ptake sys'em that trllO$fXll1S the moIewle beck InlO the neuron. where it Is ecetyleted and alored until released by a StbseQUenIeetion polenllal.

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3.. AdYtrM tff«:U: PiIocaqJrre tall enter lhe br1Wl and cause CNS listurbar"ce5. h stmlIat8s ~ ~ and aalivatIcn

V_ ANTlCHOUNE$TERASES (REVERSIBLE) Acetyk:tlolineSleraN Is an enzyme that apecIfIcdy cleaves acetyldloIl .. 10 lIOOWe and dloiollL Ills located bDlh pre-and posI-synap!icaIy r. IhII _ ~. where if: Is II'llllb bot.nd. lrtlibilors d ~ idiec:tly pnMdII a d gic IEIion by v ing Ihe 1il0lime 01 aoetyk:tlohI pmdI'CAd • iOOgeo IWlif'f 81 . . ct gic . - endings. TNs resulls In Ihe aco.orrU8llon d aost~ .. In thO synaptic space (FtgUre 4.8). These drugs can !hUs provoke a I8SpOnM at all cholilloooplors In Ihe body, rdudirlg boIh ".."sc:arnc and r..... 1Ic rilCllplOiS d lhe aukJI .... ,ic nerIOUS system as well as the neo.o~jl.n;:lion

and the brain.

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2. Actions: Actions include gene.allzed chOlinefglc: 5tJmulation. paralysis d fl'IOIOf function (causing breathing (ilfoc:ul:ies), and ~ ~ pnxllo::es . . . . . - " . . . and Ihus has k:u'lll t:h8rapeI.IIi(; use. Abopi1e in N\11..... age can _ many d the fl'USCaIiI lie and canual eIIecu d i:sorbl:lphale. 3,

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An ophlhalmic; oillb lie•• d Ihe drug is used lopicaly in Ihe eye lor the diU ... IfeaDn8nt cl open-angIe gIaulXlffIlI. The elleds fflllY last lor up to one week alter a single adnWrstration. (Note: Ect/OltIit:lpIIBl6(ek 08 n"l1 oh IlIIe] is a

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4. Reactlntlon of acetylc:hollnell-= P,/IlII;i;lMine (PAM) Is a syntheIic pyridi1iom COi'IJXlUld thai can reaolioa coooenlratlon althe nwromuscuIa, junction.

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D. may result In bowel hypennolilily. salivation, and SWIIa1ing. E, eX8Cf'llbates \I.Jl:>OCU'arine POisoning.

4.3. PiIocatpIne: Pc is used to Iow!H intmoculer pre6Sf.II9 in l,iaucoma.. B. is delIved by aoely\

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Cholinergic Antagonists I. OVERVIEW The ~ antagonists (also calecl choIio.... gic IllocUrs Of anti............gic drugs) bind 10 ddlloeeplOfS but do not lOgger !he usual ,eoeptor-mEdalecl eflBds. The most useful ollhese ageou selectively bIoc:k tile muscarinic synapses 01 the parasympathetic neI'WS. The enects 01 ~ InnBrvalion are lhus inIooupled. and the aclkYls 01 syrnpalhetic SlJ'r'Ualion are IetI Uhoppuswl. II second group 01 drugs. the ganglioric: bIod<ets. shoW a plelelence Iof the ,1ii>Jtit ole receptors 01 the S)Tll)iIthetic and parasympalhellc ganglia II third ramty 01 OOfTllOlJnds. ltle neurorTlUSClAar bIodtiog agents. irller1ere with transmission 01 effe<enl IflllUlses to skeletal muscles. F9're 5.1 summaridlS the dloIlnergic antagonists discussed In INs chapter.

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CHOUNERGIC ANTAGONISTS

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lhese agentS, lor eKample. atropine and SCClpOlanWle. bIodI ~ reoeptool (Figure 5.2) causing inhibillon 01 aI ITWJSC8rnc IU'lClions. ~ additioI'I. Ihese drugs block the lew llI(ceptlOIl8I IYmpalhetic neurons lhat are dlOlill8lgic:. such as lhOSe rnervatalg aweat glands. In mntrast 10 the ctIolinergIc agonisls. Mlich have iIriled l.Ill8!une6s IherapeuticaJy. ltoe ctdo I8lgic bIcckers are bllllllficial in a vaMry 01 diroicaI silvau.. Becllll&e lhey do not block ,icdiiM: reeeptOfl, ltoe 8fIlirrU;carini drugS have little Of no action al skeletal neutQ'llUICl.II il-cliolls Of "kAD,ic ganglia.

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III. Ganglionic Blockers

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5. O1oIinergk: Antagonists

C. Mecamylamine Mecamylamine [mek a MILL 8 rneoo] produoas a compelitive nicotinic block 01 the ganglia. The duration 01 action is aboot 10 hOurs alter a single adminisllalion. The uptake 01 the drug ~ia oral abs0rption is good in oontrast to lrimelhaphan.

IV. NEUROMUSCULAR BLOCKING DRUGS This S(lCtion plllS(lf1!s drugs that block cholinergic transmission between motor nerve endings and lI1e nlcotlnic leceptorS on the n8UfOmusaJlar end..plate 01 skeletal muscle (see Figure 5.2). These neuromuscular blodw's ara structural analogs 01 acetylcholine and act either as 8J1tagenists (nondepolarlzlng type) or agonists (depolarizing type) at the roceptOfS on the end·plate or the neuromuscular junction. Neuro· muscular bIodIers are clinically useful during surgety to produoa c0mplete muscle relaxation, without having to employ higher anesthetic doses to achieve c:orlll'Irable muscular relaxation. A second group 01 musc::1e relaxants, the central muscle relaxants, are used to control spastic muscle tone. These drugs Include diazepam (whictl binds at GABA receptors, see p. 9O), dantrolene (whidl aets direclly on rnusc::1es by intOOering will1 the release 01 calcilJm from the sarcoplasmic retial· lum), and badofef1 (which probablY acts at GABA receptors In the central nervous system).

A. Nondepol",rb:lng (competlti~e)b1Ol:kers

The first drug lhat was kMJnd cacabIe of bkx:king tile skeletal neon> musc::ular junction was curare, which the native hunters of the Amazon in South America used to paralyze game. The drug rl.Jt» curarine [too boa kyoo AR ean] was ultimately purified and Introduced irlto clirOcal praetk:e in the early 19408. The n8UfOmUSCIJlar blocking agents have siglificanl/y Increased the safely 01 anesthesia, since less anesthelk: is required to produce muscle rela.xation.

1. Mechanism 01 action

a. Allow doses: Nondepolarizlng neuromuscular blocking drugs combine with the nicollnlc receptor and prevent the bindftlg of acetylctloline (Figure 5.7). These drugs lI1us prevent depoIar· lzatlon 01 the muscle cell membrane and inhibit muscular c0ntraction. Because these agents compete with acetylcholine at the recepIOr, they are called compe~live blacken;. Thelr actiort can be overcome by Increasing the conoantrallon of acetyl· ctloline ., the synaptk: gap, lor example, by admini8lraliorl of chOlinesterase inhibitors SUCl1 as neosligminfl (see p. 42) or edrophonium (see p. 43). Aneslt1esiologsts oIten empk7,t this strategy to shorten the duration of the neuromuscular blockade. Figure 5.7

Medlanlsm of action 01 competitive neuromuscular bIoclIing drugs.

b. AI high doses: NondepoIarizlng blockers block the ion chan· nels oIlhe end..pIate. This leads to further weakening 01 neuromuscular transmission and reduces the ability of acetylcholinesterase inhibilors to reverse the actions 01 nondepolarizing muscle relaxants.

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FlgureS.S Onsel and duration 01 action 01 neuromuscular blocking drugs (remer coIurm); summary 01 therapeutic consi6erations. [Note: 'New drug' indicates drug approved aller 1992.J

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IV. Neuromuscular Blocking Orugs

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B. Depolartzlng agenll 1. Mectlanl5m 01 action: The depoIariling neuromuscular blocking drug. sur:dnyIchoIino ISllk !WI ~I KOE Ieen]. allaches to !he nico~ receptor and acts ~ke aceIyIcholine 10 depolarize Ihe jln:tion (F"1QUIll 5.9). Unlike aool)1Cholino. .....ncn is instantly destr
cllOioeogic8QDnltl), ~(",,~. Ing clo:a~ 1IgOtIIaI), pIoc:IaIplre la 1lI18C1«:1Ing choUnargic l\gon!Sl), _ neoatlgrnlne (an lnthcI-acIio:'I c:hOIl'*lllc ll(ICRsl) llJI mimic "" ellIIcI alpBl_'li.,alIlltk:"*'UaIlon a>d produce

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5.9. Which ONE ollhe following drugs woold btl use'uI In the IonltIeIYn Ireatmenl of myllSlhenia ",avis?

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0.,s. Alropine

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d ""'-.... gr8IIis, bulb _ d.:llon III too short lor etlocllve lOng-term trealment Alropl. . end SCIf1 "'''' \IeIlcIo ,,.,,,_ by ..... pIo .. 10

r;'1I RELEASE OF ~

NEUROTRANSMITTER

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Figure 6.4 Types 01 adrenergic receplOrs.

a, receptors: These receptors arc prosent on the postsynaplic membrane of the effector organs and mediate many of the classic cflccts, origillllily desigllllted as a-adrenergic, involving constriction 01 smooth muscle. Activation of 0., roccptors initiates a series 01 'eactions through a G·protoin activation 01 phospholipase C, rewlling in the go norepinephrine 'Seep.70Ior

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'-'''-'''''''---'' m. Characteristics of Adrenergic Agonists The II adrenoooptOfS can be subdiVided into two major groups, II, and lh. based on their affinities for adrenergic agonists and antagonists aRhough SC\Ieral otheno have been identified by gene Cloning. Ii, Receptors have approximately equal affinities for cpinephrioo and norepinephrine, whoreas 1\:0 rocepfors have a higher odllllllOn llUrMlon of boonet-.Ion

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l. Metaprote,enol

Melaprolerenol[met a proe TER a noIe). although chemically similar not a catecholamine and is resistant to metllyla-

10 hioproterenol, is

bon by COMT. It can be administered orally or by inhalation. The drug acts primarily at Il" re

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WlIocal_1O

_ o i o I i C I i ~ _

CATECHOLAMINES •

Ra,>lcl_ Of """""

•

BrW""""""'",_

•

_ _. _ orally

•

Do noI pooroebotB_

-

Nrnpl""pM ..

....

......

Quja'."

.~-

Compwed 10 _I>olaml.-; • •

..

Lnger duration Of _ All.,." "" _1nI.._ ~

r

...... ----

Dopoo,.... gi
he-,e.

Ce-oclure- nosPl deoooY*

~specific

_gonl.: thlt ~ ClUlp.t jlGIlpl'>... ,,! ....... nligI'Il in .YltOlIe: bIOOCl pren.url! end • • Ignlllc;..,t dIcr _ in 4 ... bIood~. AbIIerol end klIIMeIron 8ftI" • • • .... .,. Milo NOipb'lI. ?.clIlroterlMlol II I

_

c.1t is used 1O~ bl... d~'"

:

. . P'lI lID

1I1s.~ ~

)

1

11.5 A 58·yen.~kl temale hPl unclefVl. meloprolo( and esmolol: selective 111 8fltagonlllts

Agonists

l a _ ... __ ••••~.1 Orug$ Itlal plekM,ulialy t*lCk the IJ, tflOE!'l)tOlS Mw been developed: kl eliminate Ihe UI"IWW'lled blOnd "":::,,..strldor ellect Ok) of /Nopranok>l seen among asthmatic patients. Cardioseleclive p..t:b:Ufs, Sl.ICh as acebufDloIla se BYlX> toe klIe}, 81eno1011a TEN 011 1oM!). and mefDploId lme TOE proe klIeI. ~ ~ 'eceplOos at doses 50 10 100 tmes less !han Ih3se <eq.lired 10 tb:t Ilot reoeplOf$. n-s cardoouleetMty is thus mosl pronoooced allow doses and is Icl5l al higl drug doses. {Nl!'e: IV:et:xJtoIoI has some intrinSIC agonist actMty.! 1. Actlorls: These chlgs lower blocxl pressure in hyper1e1'1sion and increase e>ceroise lolernnoB in angina (see FIgUre 7.6). Esmo/GI IEZ moe lole] has II very 6hoft lifetime (see FIgure 7.5) due to metabolism or an esle, linkage. It is ooly given \ntravenously if reQt.Jlred durtng surgery or (jjagooslic procedures (fof e~arnple, cystoscopy). In oontrast kl proprclnokJl, the ca,diospeciJic bIocke<s haWl relatively little eflecl on pulmonary 1IJnction, peripheral resistance, and cartJohydrate metabolism. NeYerthe4ess. 8SlhmaDcs treated with these agenls tnl.I$I be \ """"P"O"of,lImo1ot, ea.dlac ~_.-

_.

.nd _ _ ""'"".

OIll

G.~

TIrnoIoI. and _

8 bloc......

-..ce _ ..... Ian 0 1 _

-----

Migraine

1. Actions: U!belaJol [lay BET a loIe] is a reversible I}blocker with COI1COrrent lXl·blod\ing actions thai produce peripheral vasodila· tion, thereby reducing blood pressure. Labetalolthus contrasts with the other [l-bloc:kers that produce peripheral vasoconstriction. and it IS therelore uselul in treating hypertensive patients lor whom iocraased peripheral vaSClllar resistance Is undesirable. Labetalol does not alter serum lipid Of blood gllJ(;(lSll 11Mll$. 2. Therapeutic u.... In hypeoteuslon: Labe/alol is uSlllul/or treating the etderly Or black hypertensive patient in whom increased perip/leral vaSClllar resistance is undesirable. iNoIe: In general biack t1)opertensive patients are not oontrolled with I}blod CW'c""" NIIuoe cmlloc raIe ..... Iore..

Figure 7.9 Some clinical applications 01 ilwIolg fi'\.IgI •

.-u In IreMing

8.IoopcOlUa",

C.PtIa_,•• o.P1upad>l

e - _ _ o.i\;p , '

..__ =... ,~

.-.

'

I

h

, 5

CIl I • tIliDcfI.- • I ca_hD' ,at

_ _ PI"\lI" ..... lIdlJ=...... ;

.........=.

7

..

i

.. ; .-.IIl to .;'• • IIbJd_~.' D til , ... T!'lIL ........ I

....

-.:II Q~ . . _tI5

__

a""'_ .. II6lIocl

1._ pcIlIIr'II ,

I ••

"",,'" aer .... ~ .. P ...........

••

7.3 A 6O-yN,-dd asthmllic man 0CInl8I .. lot. chedt·14I and 000' IpIaL os lllal he II haq -.... dtfIouIly .. "$tlIrto Ing 10 ..male". PItysIcaI examinBlion indIeD1ealMllhi man has • blood pressure 01 1601100 mm Hg and a sIilttdYer1Iarged proaale. Whidl CIt !he ~0lI fTl«I. cations wouIt:l bI usehA io1lrea1itlg boIh of IheSe oondI-

....,

C. Ept«lih,

•

>

7. Adrenergk:: AntagonisTS

Choose tile ONE best _ _. 7.1

....

• kit .,.,.

....

D. p,opalOlol

e. .........0IU ..... " " _ _ .. A

...... *"-

.. . _=..., l:ICaiade

C

'1

£

'1

.....--. 1

"

and . . .

IItlIlIIf

..... _

tlr.-.,_"" ... '''101'' • 11ILr '

. . . I• • I'

_

'

-~

....................... I •• _ _ -. 1 ...., ........ ........ ' , _ ' 8IIlI1i

---....

;1,

~

. . . t;;I_..

_-*II

..... ,....,., ........ _,>

UNIT III:

Drugs Affecting the Central Ner\'()Us Svstem

Treatment of Parkinson's Disease I. OVERVIEW OF CNS

Mo6t dfUOS lhal at1eCIlhe centrall1eI'\OOS system (CNS) act I1y' artemg some SleP In Itle neuroI/'llIlSmi process.. DnJgB atl9cting the CNS may act pre$yrIllpIicaI by influencing the production. stomge, or temlinab'! of 8C\ion of neu'OIIlli 1SI,1itte,S. QIher agenIs may aetiva1lll or bkx:k po51Synaplic reoaplCn. Ths ~ P'oriOOs an ~ ol lhe CNS wi1h a!lX:Ul on fIOfiJIIlIIlU"OInInsmltlhM are ~ In lhe aJioios olllle dInieaJy ~ CNS dnGS- These 00l"""iJb are uselu In understancIng 'hi eliology ol and lhe ~ SlraIegies lor Part
""""*"*"

6.2 Which one 01 the following st.tements is lNCOR· RECT'! A. Parkinsonian patients a'e characterizfKl by an i.-.creased ratio 01 dopamInefQiclchol!ne ...... _ , >

.........- - : .....,.., """""," .. _

.... >

" .... _'empty w(noegon....)

""",,~a

. ~

"".0 -~

=L.. ~-" .... .

- ... " '. ___

9. Anxioly1ic and Hypnotic Orugs b. Temazepllm: This ~ is usclul in patients who experience lrequcnl wakerW1g. I-lowewr, the peak &«la1lYo efIecl occurs two 10 Itvee hours aftel' ilf1 oral dose. and thereIore II may be

gNen severaJ ho:us beIore be
~_

-~•

III. OTHER ANXIOLYTIC AND HYPNOTIC AGENTS

""0

A.

Zolpldem Although the hypnolic zoPidem IZOl.. pih dam) Is nof a benzodiazepD!, II. ac:ls on a a.t:J&el: 01 I1e benzaiazcpIne rflCCPIOl' 1ai'hIy. ZOIjlidem has no antialnvulsanl Of rrusde relaXIng properties. It shows no wiII1aaWal eflocts. edlib/I$ minimal rebound onsorrria and little Of no toletanee occurs wilh prolu 19t!d use. Z; is rapidly absomed 'rom !he gastrointestinal tracl, and has a rapid

"-IMI

onset d action and short eliminalion han-lite (aboul 3 hO'Hs).

Adverse elleets 01 zolpidem include nightmares. agitation. headache. gllSlfoinleslinal ups.el. dz2iness, and daytime dr0wsiness. Although ~ poler,1iaIy has advantages over tile benlO

95

v. Barbituratcs

3. Enzyme Induction: Barbiturates Induce P-450 microsomal enzymes in the liVflf (see p- t4). Therefore, dlronic barbiturate administration diminishes the action 01 many drugs that are dcpcndent on P-45O motabolism to rcdoce theiJ COflCel1tration.

C. Thenlpeullc: us. .

01 a barbiturate 1& strongly inltuenced by the desired dufalion 01 action. The I,lIra·lhort..acting b0rbiturates. such as thioper'l8I; are used intravenously to inclJClI anesthesia.

I. An8llhesls: Sek!c1ion

DURATION OF ACTlON OF BARBITURATES

2. AnllcorWUlunt: Pht!nDb8ttIitalls used in long-term management 01 \OfIilxlOniC selzures,. status cpilcp6cus, and edar'r4>sia, f'tlen(>b8ttIitaI has been regardod as the o:nog ot d10ice tor lreatrnenl 01 young ~cn with rllClnenl klbrile seinKCS- llo"wer. pheno-

bBtbiIaI can deprea oognitlwl pert:wman;e in d ildoCll, and Ihe drug shedd be used ca~. PNl/lobarbiCaJ has spec::n: amiC01Y\AsanI acWily thai is dislWlguIstled from the nonspeciic CNS

..........

3. Andely: BarbiUales hIMo been used as mid sedaliYes 10 teIilNe ~ I1l!f'o'QUS IONion. and w ... Most I\ao.e been leplaced

,.ia.

bylle~

....

'

n __ Barbdurales are 8bslOIbed orally and clstrbAed M:lely ltVoo.J;IhOut fle body. M ba~tes reclislJitule in !he body from the brain 10 !toe splanctrie Weal. IQ ~ nusde. and ma.y 10 + Ii· _ tissue. nws ITlCM!fflCfll is irf1Xwtant in ClIl.5ing !he short dlnlion 01 action oI'hiq;t6l1'lII and &imlar shor1«:ting derivawes (see P. lIS}. Barbitlntes lUe metaboliz«l in the 1iYet. and inaaMl mecaboliIes are exaeted in the ...... E. AdYene et1eeUi

I. CNS: Barbi1urates ~ oO"si IllS&, ifl1laired ooncertration, and menial and phy$iCal ~ 2. Drug hallgo...r: Hypnotie c;Io5es at barbilunlles pnxt..oce a Ieelng 01 tiredne$S welt after the patiCrll awakes. This drug haflQlM!f loads to irJlIairod ability 10 h.nction normally lor many hours after waking. 00casi0naIy, nausea and diZZiness occu".

3. Precaullom: As noled prev\ou$ty. barbiturates inl:luce !he P-45O system and tI1c<etore may dccmase the ctlecl 01 MJgs that are metabolized by those hepatic: enZymes. Barbiturates increase porphyrin synthesis, and .re contraindicated in patients with acute lntCflrit10nt porphyria.

4. Addiction: Abrupt withdrawal 'rom barbiturates may cause tremors. 8ll~icty. Wllaknoss, restlessness, nausea and ..c:rniting. selzurcs, delirium. and cardiac arrcsl. Withdrawal Is much more severe than that associated with opiates and can rCSlJiI in death.

Agure9.7 Bartliturates aassitied according to !heir duration 01 actions.

·.........,., .... _-,. "

9. Anxiolytic and Hypnotic Drugs

•

--

5. PoI$Of1lng: Barbilurate poisooing has been a leading cause 01 death among dn.9 OVCfdoscs lor many decades. severe depression of respiration is coupled with oonIral cardiovaSClllar depression. and msu~s in a shock-like OOf)ljfion with shallcm, InlmQl.lerJt breathing. Treatment includes artnicial respiration and purging the stomach of its contents if the drug has been recently taken. Hemodialysis may be necessary il large quantilies have been taken. Alkalinizatioo ot lhe urine often aids in the elimination 01 phenobaJtJilaJ (SCfl p- 24).

VI. NONBARBITURATE SEDATIVES A. Chloral hydrate

Chloral hydmt6 [KlOA al HYE dratc) is a trichlorinated derivative ot acetaklehydo that is corrverted trichlO h-"dd.

0nfJp/'e~~"*-". . . .

.... 01 the h....lIc cytoch.ome P'oI5O drug lI"IIlIebolizing .J$l..... Phenot>arbitaI is conI .. ,,***, ill ' " . _ , . , 01 _ porpl1yriL e, f Iedle . . , ~ ...., moa:kH' plopsnile '" ... boonzo
2. Actions: a. eNS; Nicotine is highly soluble in lipid and readily crosses the blood-brain balrier. Cigarette smoking or administration at low doses 01 nicotine produces some degree 01 euphoria. and

• ".".0.....' •• _ .... ...-,·

.""""'

..........

~'.....,.,...,.

....-.,...

II. PsychOmOtOr Stimo..dants

'"

arousal, as wei as relaXation" and improYes attention. learning. prOOlern llClIWog. and reaction time. High doses 01 niQ::UJe re$UlI in ceolral respiralOfy p8fB1ysili and S8\Ieflil "'fPOIension

•

caused bV mecUary paralysis (F"lgO.lfEl 10.3). b. """'''' ..... dfeds: The peripheJal elIects 01 rli::loli'16 llIe complelL SlimuIation 01 sr,mtM11l!Ik ganglia lIS well as 11'18 8OU>al ~ blood pressure and r - t rBIe.. Thus use 01 IOl» I >C> is ptlI1icUar1y I\;1ITllIU in twe is probably due to release 01 d0pamine rather than release 01 norepinephrine. Amphetamine stimulates the entire cerebrospinal axis. cortex. brain stem. and medulla. This leads 10 iJ'lCreased alerlness, deed freql&l use oIN aug. THe is SOI'I'l8!imes giYen lor lhe se.oere emesis c.used by some cancer thlilltAl"",,** agents (see P. 243).

C. Phencyclidine (PCP) ~ lien SYE kli dean] ("anoel cUI") i.,.,;ts . . ~ke 01 dopamine, S.HT. and ~ . It Il1&o has IlIllictlOliiier9C aclivily, bul suprisil'li'l produces "fpe1$3lil.ra1ion. Phlinc:)d:fne. an anaJog oll0lamine (see p. 117), causes Ois,odative anestnesia (lIlSenSiIMly to ..,. wWltA lo$s 01 consciousness) and analgesia. In l\js stale, ~ produces I'IUITIl:lness oj e ~ slaggered gail, sluffed speech. and musculaf rigidilV. Sometimes rIOslile and bilarre behavior oa::urs. In increased dosege, anesthesia, stupor. Of coma ,esull, bul Slrangely. Ihe eves may remain open. Increased setlsitivity to external slimuU exists. andlhe CNS actioos may persisllor a week. Tolerance often develops w~h continued use.

Figure 10.8 Adverse effects ol ampllelamines,

. " " , . . . . ., . , . ' - - - ' >

10. eNS Stimulants

'"

lOll Whid1 one 01 the Iollow'Jlg drugs is INCORRECTLY paired wiItl its to>:ic effec1s?

10.1 Which of lhe following is NOT cila,acleris1ic ot oo
c:.a:.r. - - 1*11:'_111

1

to.2 Which allhe tollowlng statemenlS aboul amphel· amine is (NCORRECT?

A, Overdosage of amphetamine ClIn be managed with dIlorp'OITIlIdne. B. Amphetamine is uSlld as an adjuncl wilh MAO inhibilors in 1he treatment of depression. C. An1l/>etamine has a IOroger oi.!,ation 01 action than D.

""""'.

~Iamine

depresses !he l\tIngIIf """Ie, In 1he

hypolhalamus. E. Ampne\llmine &'OtAd a patienlllistory p ggesWe 01 • geneti, : tyo:dele",i"ed sensilivity to h?logeoBted ~ maIigIlllIlllfper1helnia (see P. 113).

so.

B. Conc:oonlIanI UM of drugs

1.

8Cljunct.,a.: QUle oller\ Sl.Wgical plllienls ,ee IMl CI'IfI or more 01 the Iollowing preaneslhe,ic medications: benzodiazepiolllS (lor~. c:ialepam. see P. 89) to relieve ar1ICieIy and 1acilita1e h' barbiIurllles (lor exarT'flIe, penfobattJifaI, see P. 94) br sedation; antlIislarTWIes lor ple.olltio" 01 aIergic reaclions

~

&I,.

(lor

ex~, ~,

see II-

422) 01' to ,&Wee gastric

ecicliIy (dmefidir>e, see p. 236); antiemetics (lor exarfllle, droperidol, see p. 242); opiOids (lor example, fentanyl, see p, 139) lor aroalQesia; and/or IIIltkholirlergics {lor example, soopo/amine, see p. 48) to preYefll bradycardia and sectlllion 01 fluids in,o the A.lnduetlon During induction it is essenllal 10 avoid lhe dangerous exc~alOlY phase (Slage II delirium) cna~ !he slow onsel QI action 01 some anesthetics (see beIoW). Thus. general aneslllesia is nonnatly inlb;:ed wilt! an inlflMlnOUS anestt.elic ~ke Ihiopenla/: .... iCOi lSCiousfl&$$ teSUlts within 25 $8l;(Iil(ls aller illjection. Althal lime, adl5lional inll.alalion or inllllvenouS drugs comprising Che selected are r.etie may' be!JYen 10 prOOJce lhe desired depIh QI sugicaI (Stage MI) Illl£rt ·a. [Nelle: This otten ird!wlec; Q[)-adliiflistlalion QI an r.travenous skeletal muscle retaxanI 10 ladlOtate ....lbalion and relalulll0n. Currently used muscle relaxanls include YeCUrOrlit.m, 81racurium. and sua::inylcholine (see p. 52).1

B. MalntefWnce of lInesllw5lil

~_

,or.

.1

I

' .....1 " ... _1. _I

C,

Reeovery Fostopelalivety, the 1lIll!Slt5f 'agiSl wiIhdraws the llIteSU"oetic millI\Q and "r:nlilots!he i"meciale retln'I at me patient to consciou&ness. FOI mos. anesthelic agents. recovery is the f8Yf1(H of

maim; thaI is, redistribution from the site of action rattler than The 1lI ,..,.,' ·'ljiR mnIinues 10 "r:nilor the palienllO be sure thallhere are no delByed IOIcIe feat'tions, tor exa"pe. Iiltusion hypoIG8 lor nitrous QIlide, 8ft(j h8pBtOIOllicily ...,;., halogenated t¥lloc:Mloi....

metn-" UlderIies ,eoc oery.

D. Depth 01

.nes~

The depth 01 anestheSia can be liW:led into a series 01 IoUI sequenCial stages: each is characterized by IllC«!ased CNS depression thaI Is c:aused by accumulation Qllhe anesthetic: drug in the bmir1. With

t

~'"., -----~ '

.........

FIgure 11.2

Cu,~llIIltsat balanced

MU'IIenanoe is the lime dumg whid'llhe patienl Is surglc8Iy 8I'Ie5lhetizecl. Alter administering 1he selected aneslhIllic: milflUf8. the ane5lhesiologiSl monilors !he patienl's vital signs and response to various Slimu~ 1t"«lughoul the surgical prooedufll in order to caratully balaoce the amount 0' drug inhaled andfor In'used with the deptl1 01 anesthesia. Anesthes1a is usually mair1talned by the adminIstration 01 gases or ..ootlle aneslheties, sirlCEl these agents oller good lrinut&-Io--minule eonlrol OYer the depth at anes\t'.esi8.

...

" - _ V ' I'

ll anesthesia: Regular respiration and relaxation ollhe skeletal muscles occur in mis Slage. Eye reflexes decfease progressively. until the eye movements cease and the pupil is fixed. &Jrgery may proceed during this stage.

." "t.....

~~ ~ = , .z......

4. Slage IV--rnf!odulfary p3raly.,b,: Severe depression of me res.pira-

tOf)' center and vasomotor center occur during mis stage. oeam can rapidly ensue.

IV. INHALATION ANESTHETICS UEDuU..... ~y IV PARAl"SoS AN

Agul'flll.3 Stages 01 anesmesia.

ATH

Inhaled gases are the mainstay of anesthesia and are primarily used for me maintenance 01 anesmesia alte, administlation of an inlravenous agent. Inhalation anesthetics have a benefit that is noI available with inlravenous agents, since the depth of anesthesia can be rapidly altered by changing me concentration of the Inhaled anesthetic. Because mos! of these agents are rapidly eliminated from the bodY. they do not cause postopemtlve respiratory depression. A. Common fealures of Inhaled lInesthestlcs

Modem Inhalation anesthetics are nooeletie gas with I'igh blood soIubiIiry. suc:tt as haIt;ltIIane. ~ _ Ulmp1e1ely in Ihe blood. end gJealer amounls d the eneslhelic and IDnger pel iods 01 time 8fII rellt*ed to flIise 8f1eriRI tef llIiOi L TNs fesUIs in increased limes d irdtrim and fllUM!'lY. end sloM!r ctJanges in hi de4JIh of anesll • in to dlanoges in P1e

'ew

OOflCa.lralion d lhe imaIed~.

...... --j -,

..-

" ,E,,""'_

-,.

'l!SfJUf-

3. Tluue uplake: The 8fteOal CWCUalion dstritUes the _ _ ~ ...lic 10 various lissues. and Ihe pressure goadie < ............. , >

11. Anesthetics

'"

_I_

Therapeutic Advantages

Therapeutic Disadvantages •

lncompNle

•

No "",,",,Ie-.-lion

•

MuIU 1>00 used "~h _

Inhalatlon nesthetics

•

_ l o r eL>rgleOll

-._--....... ·--_ ·""""""'" ..._ "..111

•

• •

IlelllIc _

:>

renal

Nifroue cxl<M

__

PI.""'"

•

L.IltIemueclo_

•

RIIpkl ""....,,,."',,...

_ I agont In p6CliaI....

~,-

•

8
01_

•

RapId...-

•

Good_guIa

•

Goo
•

• •

Potent _ _

anaIl1nl.o

--

Aepid ""...

Lowers

Inlrec,,,,,1a!

Figure 11.9 Therapeutic disadvantages and advanlages ol some anesthetic agents. cardi<Mlscular syslem, but it may contribute 10 severe hypolension in hypoYoIemic or sl'lock palienls. All barWurates can cause apnea,

coughing, chesl wall spasm, laryngospasm, and bronchospasm; !hIs is a oonoern lor asthmalic patients. Barbiturales are con1raindicated in palieflls wi!h acute intermirtent or vaJiegale porphyria. B. Benzodiazepines

Allhough diazepam (see p. 89) Is the prototype benzodiazepine. lorazepam and mldazolam are mare poten1. All three facililale amnesia wtlile causing sedation. Etomidate [e TOE mi dale) is a hypnOlic subSlance lacking analgesic properties lhal can cause unoontrolled skeletal muscle activity. C.Opioids

Because ot their analgesic property. opioids are frequently used together wilh other aneslhetlcs: lor example, lhe combinalion of

"••" '0...,., ........ __ , •

."""" ... "

_~,

'""""" ..

_.....

'"

VI. Local Anesthetics morphine (see p. 135) and nllroos oxide prcNide good anesthesia klr cardiac surgery. I-lOWIM!f, opiokls are nor good amnesics and they can al cause hypotension, respiralory depression, and muscle rigidity 85 well 85 poslaoes1hetic nausea and vomiting. Fentanyl {see P. 139) is more Irequently used 1tlan ~ne. Opioid etEcts can be antagor&zed by nalmone (see p. 141). D. Neuroleplanesthula

The mmblnalion of droperidcII and IenfanyI is a filled ratio lJ"epafibillon 01 neurotransmiller uptake: TCAs inhibit the neuronal

Normal monoamine transmission

I RESPONSE

reuptake of norepinepl>rine, and serotonin into presynaptic terminalS (FigtJre t2.2). By bIoc:lo:lng the major roote of neurotransmitter removal. the TCAS Ielld to increased concen· trations 01 monoamines in the synaptic delt. resllmng in antidepressant effects. Tl>is theory I>as been discounted by some because 01 several observations. For example. the patency 01 the TCA in blodis suggests that decreased uptake oIl1e\Jrotransmitter is only an initial event that may not be related to tl>e anlidepressant eHects. It has been suggested that monoamine recaplOr densi· ties in the boain may change l)IIef a 2 to 4 week period will> dnJg use and may be important in the onset of actillity. ntlMl

2. BkldSafl1 Drugs POlenllele nflBClS 01 blognnlc ami,," drugs by ,,",v,,"Ung thnl, relTlO\lal from synaptic CIett

h alllllUlTVl1llrized in Figtxe 12.1.1..t1ss of Iibda, delayed ejaculalion and anorgasmia are probably uno:;let-reporled side eI1ecls ohen noted by dini::iBns buI: alii not proo,.... lIIy lealured In the list ol standard side effocls. lIS ol IIuoxBfjne do

o.e'"

not cause cardiac: alrhythmias bul can cause seizures. For 8IC8Il1ple. in a repoi_

The neuroleplic drugs can be dvided into frve major dassificatioos based

on the strucItfl! a the drug (Fogure 13.1). This classification is of modest importance, because within each chemical group. differoot side chains have protound eIfects on the poleocies ot the drugs. The management 01

Figure 13.1 Summary of nemolep!ic agents_

--.---- _..-..I. __.._ .... _c.O"'" .... P.,,"""" ......... _ £ _ _

121

..... '0...'... ·- ... _ , · 13. Neuroleplic OrllgS

I

.v

0;

psydlolic clison;llM can ~ be achieo'8d by lamiliarily wilh lie efleCls d
I.

...-

00 • DlbpiOO

,.

'.

---. _0,_ 0,., I. 00

•• _ _ 1ypiaIl

-

111-.,. f ...

--...... 00 •

I'MIopooIdol •

~

3. Other etler;ts: 0r0M;iness occurs due to CNS depression, usually dtri1g the tirsl 2 weeks of trealmenL Conlusion is 5(lITllIlimes encountered. The neuoleplics oI1en produce dry mouth. ..mary reIeRion. c:endIp8lion, and loss of iMXOir.,oey cao be COl/oI.rl'd 10 lOme degree by

B.

Cllf'j

Iharoby~.

..-....-nc~

D.-.e~eIlecIs""IO~.

E. ' - a ...., 0"IIet d a'llipsydlalic: Klicn

,,

......

0. II I. E.

iclaI doe:; 0CIl _

Neo.o'*'*'" may _

. . .

,

7

7

,

.:..

~.,

,,~

_ ....

~,

s

s

"

s.'

ed and 8l'llll*'o I8Iy influenced.

3. SI*'III COfd: RooepIors in !he SI.tlsIanIia gela.tnJisa 8tlI irMlIIIed wilh !he receipt aod intega1ion of jiiCOliijiiQ seoso

< ...- ........

lIl. Strong Agooists

,~.

, KI"OUJI .. _ . PI' >

'"

5. Umbic system: The grealest concenlration ot opiale rElCeplors in lhe limbic system Is located in the amygclala. These receptors probably do nol e~erl analgesic aclion, but lhey may inlluence emolional behavior. 6. Periphery: Opioids also bind 10 peripheral senSOfY nerve fibers and lheir terminals, As in lhe CNS, they inhibit Ca+o"5 0!*JldIl sl-..cnl8S seoillllolly. lila ,"*,111 : "" 81 . . . . . . . . . . abs

150

15. o.ugs Use
tOflic.donic seizures. Gabaper1tin does nOl bind 10 plasma proteins and is exaeted unchanged through the kid-1eys. minimizing the likelihood of drug inleraClions. Lamorrigine is metabolized in lhe liver. Its t,f.! is decreased by enzyme-inducing drugs (car/:J8mazep;fl8. p/16flylOin) and is wease
Study Questions

15.3 AI the IoIowing drugs a,.. usel... in lreatinQ oompIex

Choose the ONE best answer.

1"'"..1seizlX"" EXCEPT:

1s. 1 Fo< whidl one olll>e Iollowing 00Jgs is I!lfIlhefapeutic insfraoe """" .. NoI· cNIn ......yllctl_.

(II

-

~Qlr"''1L

~

.... ....

No·

,. ,,.

.

....

.

~

;-

••

PHASE 2: PLATEAU

1

0

I

•

0 3

.~

O. T1mol_l

" .."obo8l"

on_

• eo++-ch_ ~"'"". • 1(.

-d>Irl.-....--.gto """"' fft.UIIl :.S8 in bloacI po SIn. and !rigger acMIiOft of ~adrllllelgic 'eceplOrS in the heart. This f1!SUItS In an i 1tI Me in hear, ralB and a grealer Ion::e of conIr1lCtion of the heatt musde (F"9're 16.4). In addiIion. vasocotlst,ietion (a,·mediated) enhances venous return and inc,eases cardiac preload. These compensatory responses Increase !he wOO

16. Tfealmefll 01 COngestive Hearl Failure

~-

-1 ..

~- ----~-

D ec....•, ..' • ~.

HoI' ~ ...

AguNI6.7 Mochanlsm 01 action 01 cardiac gIycosides,

or di9ta1l$.

sodium aod calcium Ion Hows in the ca,diac muscle, thereby increasing C(ll1traetioo ollhe atrial and ventricular myocardium (pas. ~IWllooIrI;IpIo:: aClioo). The digitalis glyC06il;los 6hoW ooly a small dit/cfl;lflC;Cl bolwOOn a therapeu'ically e!llletlw lo1lc YOklme. lhus Increasiog !he efficiency 01 C(ll1Il&C!ioo (increased ejeclioo IractUll. The reWIing improved drcuIalion leads 10 reduced

n:reases

.,aetioo

~1he1ic activity,

wI*tlltleo reduo8$ ~ 'esisIance.

Together, Ihese etIects cause a rlll)Jclioo In heart rate. Vagal lone is als.o enhanced so the hearl ra'e decreases aod myocardial 0Ie normal heart, the posiIiYe i lObopic etleo::t 01 digitalis Is OOUfl\CfilCled by COfT\pef'IsatOfY lrictAar Itn:lion CU!"o'eS in he noomaI heart. in CCI'lgeSliYe heart laib'e (CH=). and In CHF treated ~ digilalis. 2. Ther.pMltlc uses: Difpdr!lhetapy is inlkated in pPeru wiIh severe left ventr~r SyslolN;: dysfunction after Inillallon of diuretic and vasodillllion therapy. DigoItin Is no! indis. Side efIeeIs caI'I often be managed by discontinuing cardiac glycoside therapy. determining serum potasshJm leVels. and ~ Indicated, by giving potassium supplements. In general. decreased serum levels of potassium prodlspMth diQoxin and othef digitalis ~ .

.. ElKbol)ltlc disturbances: Hypokalemia can predpilalll serious

anhyflrl'ia. Red!1Mjon 01 seo.wn po!a$siom IewI:s Is ~ Ireq..oenIty oI:l6eoad

""""""''II aggraw... a

aoTtIyn,..?

.'11_._

A. Dea II ~ ....... QIll:iom. 8 Dea p~~ C. Dou8.8~_sodl.m. O. Deaelll~ -.n P" m. €. Oauw:oe

Antiarrhythmic Drugs ANTIARRHYTHMIC DRUGS

,..... ,

I. OVERVIEW

I-

In contrast to skeletal muscle. whidl contracts only When ~ <ecei\les a stimulus, the heart contains spaciaijzed cells that exhibit automaticity. that is. they can intrinsically generate rhythmic action potentials in It1e absence 01 external stimuij. These "pacemaker" cells differ'rom other myocardial cells In showing a slow. spontaneous depolarization during diastole (Phase 4) caused by an inward positive current carried by sodium and calcium currents (see p. 152). This depolarization is tastest in the sinoatrial (SA) node (the nofmal initiation site of the action potefltial) and decreases throughout the normal condlJClion pathway Ihrough the atrioventricular (AV) node to the bUndle 01 His and the Purkinje system. Oys1unction 01 impulse generation Of ronducIion at any of a number of sites in the heart can cause an abnofmality in cardiac rtlylhm. Figure 17.1 summarizes the drugs used to treat cafdiac arrhythmias.

(Na' CMnnel bIc>cl<en) ~_(IA)

FI>ocUIIulse genera· lio

'"

III. Class 1AntiarThythmic Drugs actions relating 10 more than one class or they may have actiw metabolites wilh a difle,ent class of action. Ctilss I antlautlylhmic drugs act by blocking l'OIlage-sensai\le sodium channels by tI1e same mect1anism as local anesthetics (see p. 117). The decreased ... te 01 enlfy 01 sodium slows tI1e ralll 01 rise 01 Phase 0 ot tI1e action potential. [Nole: AI lt1erapeutic doses, lhese drugs hlMl little eflecl on the resting, fully polar~ed memtmme.j Class I anliantlythmic drugs lt1er&fofe generally cause a decrease In excitability and conduction veloe-

.,.

Group IA drU\IfI_ ph-. 0 ~1zatiDn, prCIDng _ _- concluClIOtI. pDf_ill

A.U~ndence

Class I drugs bind more rapidly 10 open or inactivated sodium channels than to channels that are tUlly repolarized folloWing recoIIBry from the previol.ls depolarilalion eN dlUflS _ .. rapid

. _ Of ••

_Ion wlfh

.O
ca" dw>naIa.",p .."..0

..........

..........,., .

on

IV. Calcium Channel·BIockers equaDy elleclive. However. agIenoln II

_- ......

Response med'-t8d by lhe renin-angIOlen-'n-aldo6Iefone.ysIem

Figure 19.3 Response 01 the autonomic nervous system and the renin·angiolensin-aidolitIlfOrle system to a decrease in blood pressure.

polent drculating \IllSOCOI'lStrictor. causing an ncrease in blood pres· sure. Furthermore, angiotensin II stimulates aldosterone secretion, teading to increased renal sod'Lm reabsorption and an increase in blood vollJrTl!l, which contribute to a further increase in blood pressure).

IV. TREATMENT STRATEGIES Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any 01 lour drugs depending on the individual patillnt: a diu.etic, a (\-blocker, an ACE inhibitor. or a caJcilm channel bIod<ef. It blood pressure is inadeQJ)lItely controlllld, a second drug is added. A J\-blOc:ker is usually added if the initial drug was a diuretic. or a dl ....etic is added if the first drug was a l\-b1ocket. A vasodilator can be added as a third step fof those patients who stililail to respond.

• • .0< . . . . .

",

'.'.
EPENDENT)

HVPERUPIOEMIA

:.•••.••••A'VOid•••••• --':

COHClESTNE HEART FAILURE

.-

-1c PREVIOUS MYOCARDIAL INFARCTlON

-1

CHRONIC RENAL DISEASE

ACE ••h,Me,,"

Diu","",

-1P ASTHMA, CHRONIC,EI PULMONARY DISEASE

KEV:

~!':'..;

!~_

j

ACE mM'lero

'--,~.=u=~=.--,I

I

:

I

ACE

I

ACE Inl\illilcd )

Inhibi~

)

--

Figure 19.4 Trealmenl 01 hyper1ension if1 patief1ts w~h oonoomitanl diseases. A. Individualized care

Certain subsets 01 the I1yper1ensive population respond better 10 one dass of drug than anottlef. For llJ
drug IherapJ klr ~ ll7 I' :'0 '5"' diuretic Ihefilpy is sate and etlediYe in prB'oBiolihg Slroke. tI1)'OCafdial inIardion, a ...,esliw heart Iaiure and kltill mortality. Reeerol d81a suggest IhaI diuretics llf1l Sl4l&riO!' 10 ~ in okXIr ~

AJ 0f3l diuretic Ougs _ etIeaiYe in the !fMlI1....... 01 ~ bulthe ltiazides IwIYB t:Jtnj Ihe mosl widespread use. 1. AetIons: ThiiI.zKle diuretics, soctlas h)Oor;hbrolfiazjde Ih'Je ctoe Idor oh THYE a zide). IcoIter l*lod pressure. iniriaIy bV IlCf lI5ing sodilrn andweter eJ
~~

.-

o

5

10

15

'rr"......::r:::::

F"rgure19.5 FI8Ql&ICY III oa:urrenoe III

OOIlCO loiLanl disease among the h)'pllrtllnSiYB petieroI P'lJ'.etion.

Thiazide diuretics

Pwrlpl.'"

-dd ...

Oacreasc In blood pres!lurl1 FIgure 19.6 Actions 01 thial:idll diuretics.


.. _ .....

I : -..._ .. -._... I I •0 Dm~1

I--=...

."'hl ....... ---iii'e •.";::::::, $

i

ACE Inhlbltors

-- - t ..' p

,

-,,",

.... ""

Agure19.9 ElleclS or ACE inhibilof's.

VII. ACE INHIBITORS The angiotensin·converting e~me (ACE) Inhibitors are 'lICOf'I'ImElf ideO when the preferred fIrst·1ine agents (ditlfetics Of 1\-I;lIodlefs) are ... 41..•• a,ed Of inefledil'8. Despite lheir vride-spfead use,. Is fIOI dear .. antihyper1eflSiye Ihefapv with ACE inttiors inc:feases the risk ol othe< major ciseases

The N:;E iolilbiklos kM$l:*lOd p < _ by ,lDJcing pelijAMIfIII VIISaAar resistanc8 wilhoul ref\eldy ioe lying Cllf(iac 0l/lplA, rate. Of ......ill...... ~ These 00Jgs t:b::k \toe 8I1gio...sili COf'M!rting llI1ZyITl8 that cleaves angiotensin I to Iofm the polenl v8SOCOf'l$lriclOf, lIf90teflsin It (F"IgUf9 19.9). These inhibilOfs also ~ the l'8Ie or b.adykinin Inactivation. Vasodilalion OCCUfS as a ruull 01 the combined eli&cCs or lowe. vasoconstriction caused by diminif>hed levels 01 angiOlensin II and the potenl vasoditating el1eel ot incfllllsecl bradykinin. By reduCing ei'CtJ!aling angiotensin II levels, ACE Inhibitors also decrease the secrellon ot aldoslerone. resu"ing In decreased sodium and water retention. 8. Therapeu1le UHa Lite ~blodo;e.s. ACE WliI:llon; are fl'oO$l. etleaiYe in hypeftenSive patients whO lIfelWhite and )'OI.Wlg.liowlMlr, when lISOO in ... ,tliollllion with. ditlfelic, the ells solACe ioihitlQs is.,..., in white and black hype.tensiYe palienls. Unlike ~bIockefS. ACE il~s are etIecliw in Ihe management 01 PilOOli1s wilh choilic conges'M1 NartIaiUe (see p. 156). ACe ioiotJibs life now a ~ da.d in !he care 01 a palietll loIIoWiflg a myocafdial infarction. TheIapv is &IatI8d 24 hcufs all&' Ihll em olthe ~

I·...

•

C. AdYerse eftectI, Figufe 19.10

Some 00fm"l0f1 adverse elleds or the ACE inhibitof's.

Coii.''''' side eIt9cls include dry oough. f3SheS. ilMI., 3lteIed tasle,

h)'polen$!on (In hypovolemic slalils), and hype.kalemia (Figure 19.10). Potassium '-Is rrust be monitored, and potassium supple-

..........,., .. _--,.

"-~""

"-',--_."".

'"

ments Of spifonoIadone (see II- 232) 8fe contraindiCated. Angi0edema is a ra<e but polentially ....Itate In '11OIpI d)jjic dl!WlgeS lind in the ~ '> I 01 pmteirB and cell ~ For ~ aller acIllllwl!I \0 R'Ip"'68d ooIagen in Ihe subendolt1..lia' layers 01 inlure
---

~idomoIoo

EpI_g-

~

0lIl1s, and !he coagulation cascade. This results in the lormelion 01 a platelet-fibrin plug. The I;feation of an unwanted thrombus invoMls many ot !he same steps, e.cept that !he triggering stirrloArs is a pathologic: alndilion in Ihe wscular system rather than pt1ysicel lrauma.

I

AlJCi.o_' A.,,;rin

f-

11_ NORMAL RESPONSE TO VASCULAR TRAUMA

~n~

. ...-TORS

f-

---C)a

fl, ... ;

f-

I

""'-..~

•....., (8.'" ,

ti..

.1

TREAnEHI'Ol' SIClU..ECEU. A""'M&

~

•• ..-TORS

I

L~_

flgUl'l 20.1 Suom'Iary ot drugs used in treating dysfuncbons of blood. 'Oescrtbed in Pharmacology update, pp.446-448

--

~--". , -_._" ... ~O"""" .......1 _ _ ...

... 0 -

193

...........,., ....... ...--,.

......

",""

"'..........'

"94

- .. _.....

20. Drugs Affecting Blood

D collagen Damage to vessel exposes of subendothelium

2. Roa. of fibrin: local stimulation 01 the CO"9' llallon c:ascade b'l1actors re'eesed from !he i~ed tissue end p1etelels ,esul$ in the Iom\eticn 01 thrombin (Faaor II). In tum, ltVoo'l'tWl. 8 serine pr0tease, catalyzes the 0Xlfl\IefSi0n 01 fibmogerllO Ibin. wI'idl is illXllpaated inIo!he pIl.t'!J. &aeque,,1 0' linking oIlhe fibrin strands SIllbiIiZes the dol and forms a hernolIlalic plUg. 3. Tt.Ol,obuII _ _ embolus: A dol \tIal . . . . es 10. vess:el Will is c:lIIed. lhou,tJus, whereas an -.meG 'W dot IhiIIlloats wit1in the b600d is termed an embolus. Thus.• detldled Ihl"anbus beooilles .... err'IboUi. 80ch Ihou"bi and emboli 01''1 dangeruJs. .......... IVO they mil)' ocdI de l*Iu:l 'I 5 5 5 and depriI.oe 1isSI!(l$ 01 0Ilygen and nutlienls. ArWi&l thfombosis most oIten inIIoIIIes meditm-l;izel;I'c ds '(lOldeied lhiUilbog."ic by A.rtIc8Iesions oIerldolt1elWll oeIIs ..... "Sed by iIItlenlIdenlslln WliIIIiiSl WInOUS hUilbosis is triggered by blood stasis or ~ IIICfiIralion 01 Ihe CClI\PoIliJIion CIISCll
f)

Platelet adhesion and release of granules

nortl'IlIl defense tN:vnostaIie mechlnisrns.

8. Abrinolysls

Dl.rif'Ig plallllet plug formation, !he libMotyllc palhway is locally adiV&tecl. Plasminogen is enzymalically p,ocessed to plasmin (fibrInolysin) by plasminogen actiwuors p4'oser'll in the tissue. Plasmin inlerte,es in clot propagation and dissolves lhe librin network as wounds heal. AI pr8S9f1t. a number of librlnolylic enzymes are 8\1il.ilable for treatment of myocardial infarctions or pulmonary emboli (see p. 201).

D

•

III. PLATELET ACTIVATION

Platelet aggregation and formation of fibrin plug P1......

'ibII'

The outer mernl:lf3ne of pliltelets oonl8in$ a va,ie4y 01 receptors that furlc:j;on lIS sensors Olpab!e ol lospoudillg 10 physloIogic $ign&1s preser"t in Itle pIa$mll (FIgUre 20.3). These dlemic8tI !itimuIi are das#fed as platelOlt-llClMlmg if !hey pomOle plateletllg(p'803lion end the Slbsequent release of granules Slored in ltlOl platelet. ConYerseIy, olher chemical 5Ogl'lllls classified as platelet-inhibillng. if they intibit

.,e

platelet attivlltion and the release 01 platelet glanules. Whether p1etdOllS remain in e ,,'iss (lOll state U" bOlc:ot'lOl activaled is oed by N balance 01 aetio.oalDg and iotitJilio 'Y ctl8i,.... signals.

deb.,.

A. CtMmIc:aI signals that oppose platelel KliVIlIiott

•

l.

prostac:ydln levels: In a norrTlltI. undameged ~ , pial lits dn:uIate lrMy. silce lha bd 101 01 d1el,lical S91llIs rdcates thlt the vascular system is noI damaged. For el1 0I1he IlClions oIlI$pftl O'l plalelels.IThe il'libibyelted is Iilpid, ~ oc:cumg il portiII ~Iicn. The ~ Sl4lP' • " 01 'ro,tloio.twle ~ and .... fe5IAli'lg Sf.4lPl EI '. I of pia 7 7 aggoegalioll last b .... iIe of Ihe I' " Wocil I 7 ')' 110 10 days. A!piTIis 1ts who cannol tolerate

-.

C. Olpyridamolli Dj:l)o,idsmolllidye poor 10 a mole). " GO'Ofl8fY 'oxyla.se fi~es to form the new COOH group on glutamic acid, and ledoced vitamin K oo-factor is converted to vitamin K epoxide. Viramin K is ragBr100lted from the epoxide by vitamin K epoxide reductase. It is this 6f1zymt! lI1at is inhiMed by warfarin. The y-earbOxyglutamyl residues bind calcium ion and are essential for interaction with cell membranes. Warfarin or dlcumaroltreatment results in the production of inactive dolling factors, since lI1ey lack the y-cartx» whic:h in Iurn may cause anemia. In addition, ~ritional anemias iIIe caused ~ dieIaIy deficiencles olsubstanees (lor example, Won, folic ~ llilamn B,,(C)al(lOObslsmitl)) necessary lor normal &fyIhropoiesis.

«garIS.

A. tron

Iron is SlOfed in intestinal ITIlXXIS3I ceUs as kl«itin (an ironIprotein complex) IKltil needed by the body. Iron ooficlency results Irom acule or ctwonlc I:*IoClIoA.. !rom r.tuIIident intake
C. Cyanocoto.~n (vitamin B,1l Deficier Des 01 \IitarlWI B., I3l.BllUIIIrom either low dieCiMy le\IeIs or. more (XlI1., .... y, from poor 8bIIorpliorl 01 the vitamin lUI 10 fle fai1ure 01 gastric: parielal eels 10 proO.Ic:e i1',illSic Iador (as in perricious anemia) or to B IoU 01 IICtivity of !he rec:eptor needed lor inIestinai upIak8 of me wamin. 5 Nonspecific malabsorption syndromes or gastric: resec:6on can allIo cause 1Ii/lltJli1 Btl defic:ienc:y. The vllam ITIIly be ad"si;lisIered orally (lor dietary defdeudes). 01' intramuse:ularly 01' deep subcutaneously (lor pernicious anemia). [Note: Folic tICid IIdmlnistfBtion alone feveBes lhe hemalologic abnormaIiIy end 1hu8 masks the B,ldelic:lenc:y, wtoic:h CiII1 \heI"l pnr ceed to sevefe neurologic (lysrunclion and disease. Therefore, megalobI8slic: IIIlllrria shoukl not be uealed INith 1oIic: acid alone, b:J1 rather wlIt1 a (XlI,lbiIl8lion 01 Io/a/ll end IIiIamin B.2-lTherapy nlllSl be continued lor the remainder 01 the lite 01 a palienl sufklring from pernidous anemia. There are no known ~rse ef/ec::Is 01 this vitamin.

'see p. 206 lOt ""'*"" ",--=-10 olll/lf _

..... _ .

,.

DIETARY OEACIENC'I'

•

.... ,

~po,,-,"'

.~

FOlATE OEAC1ENCY

J~t I

D.:=;:.. I O?= I ."'>-

,

t~J

Megaloblastic anemia

Figure 20.13 Causes and c:onsequenc:es 01 folic acid depletion.

_

......... _,., .. _--,.

..-.. ----. -..... .. .....

206

20. Drugs Affecling Blood D. E'ylhropoietin

Erythropoietin [ery throw PO IllItin] is a gIyf levels.

~ er..-.llrullbollo 01111.. ile& . - . . . - _ _ .... iillboUliI. 01 lcw..,..lin (00 _~

Figure 21.2 (continued).

III.

...... _ - , _ .. _

.... >

I:lf1.9S ThaI lOWCf Scrvm ljpoprotc;n Conoontra!ion

'"

4. AdvotfM etIect5

.. Gl effects: The most oonvnon side of1octs am gaSlfWltestA'lal distl.dJBnces. sud1 il5 <Xlf'lSlipatOl. nausea. and IIaIuIcnoe. b. .......eel 8tl.co ptlDilS; Abi:ujAio, oIb tlt-&ok.tiB Wiwrins, A, 0. E. lWId K can be i.lJldied if t"V1 dDses 01 the rosi'18f8 pescrL FoIc acid lnl asu.wbic aoo absorjAio IITlllV also be rCld'ooed

c. Dnlg inCetlCtior ..:

~

lnl I· ... op i inlcftcre with

the i ....... absorption 0I1TlIIfI'f ~ lor ~ ~ ~ ~ c:JgoUl. lOarlati'l; P:~4S' :li~ /Iv. sa.". aspmn. and thiazide diurelies. Therctore. dnJOs shou6d be tat.on .. Ioast 1 to 2 hotn betore. or 4 to 6 hours atter. the tlile acid bi oil III re9ns.

6);--= 0--l.Dl.

_E

>aI'..- J\"flqullr1Il\ ouVh efleclive '" mild ~ bII _ _ IOf _

..........._

_ld

..!olIo

...IlI_r1.....

01 plOlOO>go
,,-...

glucocre 23.1) ere tiso'Sssd in the Ofdef 0I1heir siIe 01 action along Ihe nephoOl , (Flgwe 232).

CHURETIC DRUGS

....,.,...,. CARBONe

f-

.--«.,-

....1ll10fl$

COO. DIURETICS

I--

T..__

=~

I-

II. NORMAL REGULATION OF FLUID AND ELECTROLYTES BY THE KIDNEYS

,

,b

a ..... CMoo •

Appooai"""tety 16-2O'Jl. 01 the blood plasmll ellterillllhe kidney$ is Iitered from Ihe gIomet ulal ....pilaries lnIo Bowman's .... psule. The fi1.trate, allhougl'l flOfmaly 'ree 01 proleins and blood cells, ooes oonlain mosl low !TlOlflcu'af weight plasma components in aPl)l'oximately the same COI'lCf!f1trations as are tound In the plasma. These Includa glu· cose, sodium bicarbonate, amino adds, and other organic liOIutes, plus elearolytes, sucl1 as Na', K', and C'-. The kidney fegulales the ionic OOlnposition and Iolered aM ISCS of ectema i"IdI.de:

.

o

•

E. Collecllng lubule and duet The principal and Inlercalaled cells altha cOllecting tuOOle are responsible lor Na'- K' e~change and lor H' secretion and K' reabsorplion. respectively. St;mulatjon 01 aldosterone reous d !he diuretic drUgs. because the ucendIng limb accounts \of !he reabsorption d 25-30% 01 fi~ered NaCl and down61raam sites 8fe nol able to compensate !of this Increased Na' load.

yo ................

F"tgu.e 23.6 RelaIiYe d1anges ~ the ~ d uflne Inl:tIoed by loop diuretics..



VIII. Osmotic Diuretics

5. Adverse effects: Because spironol8done chemicalty resembles some 01 the sex steroids. ~ does have minimal hormonal activity and may induce gynecomastia in males and menstrual irregularIties in females. Because 01 this, the drug should not be gMffi in high do!les on a chronic basis. It Is most elfectM*y employed in mild edematous states where ~ is given for a leW days at a time. At low doses. spironolaclone can be used chronically with lew side effects, Hyper1lalemia. nausea. lethargy. and mental coorusian can

occtJ,.

B. TI'Iamte
0'

Oplimaltherepy patients with peptic ulcer disease (both duodlll'lal and gastric ulcers) who are iflfeCIed with tI. IlY!sl!i requires antimicrobial trealme ...... _ , >

24. GastrointesCinal Drugs

DRUGS USED TO TREATPEPnc ULC~~!~SE

-

-

AHTlNUSCARlNIC

--_M

'Gem 0'

C. Hrreceplor antagonisls

Mhough antagonists of the histamine Hrrec:ep\Of (~antagonists) block the actions 0' histamine at all H2 receptors (see p. 421), their chiel dinical use is as inhibilOrs 0' gastric acid secretion. By c0mpetitively blocking the binding 01 histamine 10 H~ receptors. these agents reduce intracellular concentrations 01 cyclic AM? and thereby. secretion 01 gastric acid. The four drugs used in \he United States. cimetKline [sye MET i deent, ranitKline Ira NYE ta deen]. famolidne(fa MOE ti dean] and niZatidlnelnye ZAT I deen]. potently inhibit (>90%) basal, food·stimulated. and nocturnal secretion of gastric acid after a single dose. Cimelidine is the plOlOtype hist· amine HTrec:eptor antagonist. 1. Actions; The histamine ....receptor antagonists---amctidine.

faJli.

tidine. famoridine, and nizaridin&--3ct on Hrreceptors in the stomach. biood vessels, and other sites. They are competitive antagooists of histamine and are tully reversible. These agents completely inhibit gaslJic acid secretion induced b)' histamine, or gastrin. However, !hey only partially inhibit gastric acid secretion induced by acetylcholine or bethaned1d . 2. The",peutlc uses: FIgure 24.2 Helicobacter pylori in association with gastric mucosa.

a. Peptic ulcers: All tour agents are equally etfective in promoting healing of duodaf1aland gastric ulcers. However, recurrence is common after treatment with H,. antagonists Is stopped (60 to



24. Gastrointestinal Drugs

3. Pl\ilrmacoklnetlcs: 8. Clmelidine: CimclkJine and the other l-!z-antagonislS are given

orally, dislribute widely throughout the body (including in breast milk and across the placenta) and ere excreted mainly in the urine. Cimetidine normally has a short serum hail-life. which is increased in renal failure. Approximately 30% 01 a dose of dmelicine is slowly inactivated by the tiver's microsomal mixed lunclion oxygenase syslem (see p. 14); lhe other 7ll'l'o Is excreted Unchanged in the urine.

Clmel,d,ne

b. RlIflltldine: Compared to dmeticfne. ranifidine is longer acting and Is live to len limes more potent. Rani,idine has minimal side effects, and does not produce the antiaoorogenic or proIaclifl'stimulating ef'ects 01 cimetkme. Unlike cimelidine, ~ does nol inhibil lhe mixed lunclion oxygenase system in the liver, and thus does no! affect the concentrations of Olller drugs.

c. Famolkllne: Famolidine is similar to ranitidine in ~s pharmacologic llCIioo. but ~ is 20 10 160 times more potent than dmeli· d'ne and 3 to 20 times more potent than ranilirine. d. Nlzatidine: Nizalickle is similar to raniIidine in its pharmacologic action and potency, In COI'ltraslto cimelidine. mnilKJine, and farnofit:WIe (I'otiich are me!abolized by the liver), rizatidne is eliminated principally by the kimey. Since litlle lirs1-pass merabolisrn occurs with riza1idi1c, its bioavailabilily is nearly 100%.

...........,C/_ _

4. Adll(!fS(! effects: The adverse eNects 01 cimelidine are usually minor and are associated mainly with the major pharmacologic activity 01 the drug, namay reduced gaslric acid production. SiOO eltacts occur only in a small number 01 palients and generally do not require discontinuation 01 the drug. The most common side effects are heada4.0. arwadds also rewee pepIic lICtiYity. They may hIM! Olher ICtIons as wei. such as reduction all::L 0tlltl ...... . . . - ' >

24. GasllointestiMl Drugs ing. The vom~ing center also respoods to afferent Input from the YeSlibular system, the periphery (pharynx and gaSlrointestinall1act). and higher bminstem and cortical structures. The YeStibolar system runctions mainly in moHon sickness.

B. Emelle actions of chemotherapeutic agenls

DRUGS UseD TO TREAT CHEMOTHERAPY~NDUCED

NAUSEA AND VOMITING

-

-

-

----

PHENOTHIAZINES

SUBSTlTUTED BENZAMIDES

I

........

BUTYROPHENONES

C. Antiemetic drugs Considering the cx:mptexity 01 the mechanisms involYed in emesis, ~ is nol surprising that antiemetics ,epresent a variety of dasses (Figure 24.5) and offer a range 01 er1icaaes (Figures 24.6 and 13.4). Anticholinergic drugs, especially the rnoscarirk receptor antagonist scopolamine (see p. 48), afld ",-receptor antagooisls, such es dimenhydrinate), mBCJizlne and eycIlzme (see p. 422), are very uselui in moIion sic:*ness, bUt are ineffective aglllnsl substances that act directly on the cl1emoreeeptor trigger zone. The major cate· gories 01 OOlgS used 1o control chemolherapy·induced nausea and vomiting include:

Dlup.. 1Q;JI

~-

-

-

BENZOOlA2£PlNES

~-

-

Chemotherapeutic agents (or their metabolites) can directly activate the medullary dlemoreceptor trigger zone or vomiting center; several neuroreceptors. including dopamine type 2 (DA:!. see p. 128) and serotonin type 3 (5-HTJl. play cribl roles. Otten, the ooIor or smell of chemotherapeutic drugs (and BYeO stimuli associated with chemotherapy, sud1 as coos In the treatmBr1t room or the physician or nurse who administers the therapy) can activate higher brain centers and trigger emesis. Chemotherapeutic drugs can also act peripherally by causing 0011 damage in the gastrointestinal tract and releasing serotonin from !he enterachromallin cells or the smell intestinal mucosa. The released serotonin activates 5-HT3 receptors on vagal and splanchnic afferent fibers. \'It1K:h then carry SerlSOIY s;gnals to the medJHa, leading to the emetic response.

CORTICOSTEROIDS

at drugs shown to be effective antiemelic agents, phenothiazines, such as prochlorperazlne (proe kIor PEA a zeBn], ac1 by blocking dopamine receptors (see p, 129). They are effective egalnst low or moderately emelogenk: chemotherapeutic egenls (lor example, IIuorotJracil and doxoru· bicin, see Figure 24.5). Al\hQugh increasing the dose improves an~emelic activity, side allects, including hypotension and restlessness, are dose·limiting. Other adverse readions inelude extrapyfBl11idal symptoms and sedation.

I, Phenothlazlnes: The tirst group

~.-

-1~_

f-

'---

-

CANNABINOIDS

15-KT3 SEROTONIN ; RECEPTOR BLOCKERS

I I

~-

--~ Figure 24.5 Summary 01 drugs used to treal dlemotherapy-ioduced nausea and vomiting.

2. Substituted benmmldes: One at several substituted beozamides with antiemetic activity, melocJopramk1e [met oil kloe PM mide] Is highly ellective at high doses against the hi\tIIY emetogenic eJsplalin), prBYenting emesis in 30 to 40% at palienls and reducing emesis in the majority. Antidopaminergic side effects, Including sedation, diarmea lind extrapyramidal symptoms, I1mit its highdose use. These adYerse rllllClions are most common in younger patienls. 3, Butyrophenones: Haloperidol, droperidoI and domperidone act by blocking dopamine receptors. The butyrophenonas are moderately eHectiYe antiemetics, but high-dose haloperidol was Iowd to

"""0._'.'.'_"'_"

'" 4.

ThB antiemetic potency of ~ and apa.wtvn (see P. 89) Is IoN. Theil beI~1claI eHect:s ITIIIY be due to their sedatiYe. MxioIylic and armeslc pnlpllItiM. These same ptq)efties make ~ useliJ ., lreatng ~toryIIQ , . ig.

~lMeplnes:

5. C001ic:osterolda: DeKameltlotsOne and ~ U5ed alone afe eUIldi'Ve agalnsl mildlv to moderately emelogenic chemolherapy. Thf!;r .. 1liemeIic mechlrism Is not kf'oI,n, bullTIIIY InYOlVe blockade 01 prostagllndlnS. T'he$e drugs can cause r'lSOI'IYIiI and ~ ., paIienls Mlh diabetes mellitus.

_.."'111·, .•• 8oIrze6-

6.

derivative$, ~ ~ (drOll NAB i no/] and natJib.. are etl9c:tiYe agan;t IOOderateIy ~ genic: c:hemOlherapy. However. they are seldom lirst-llne antiemetic:s bfaluse 01 Ihelr seriau!i $ide ettec:l$, ~ dy$+ phoria. halluc:inllion!i, $8daIion, vertigo, and cborienlation. In $pile of Iheir psychoUoplc: propec1ies (see p. 105). the .. iliemetic: ac:tion 01 c:annabinoids may n.ot invol.... the brain; synthetic: c:8NI&billOids I'\aImg no ps)d'lotropic: tldiYil)'. fle'o1!flheIe$s are '" Itieo 1ielic:.

.•

Cennat*l~; MI~

FIgure 24.6 ~ 01 poIencyoltype ol

aRier ..elic ~

7. 5--HT3 .erOlOlllo, rec:eplor bloc:l<en: The spec:il'ic: anlagcnIsts of the s-HTI rec:eplor. ondInMllOI'l [on o-.N $8h Iron) and gr.mise/fOrl [grtIn lZ e Iron). s I rtiw!foj t*xt< 5-HT1 rec:eplOIs in !he periJI.... V (Visc:enll aflerenI~) and in Ihe btlI*1 (=_ -.:lllium

~strk:

acifl produc1ion by lnhit>iting

D.U¥*amidI E, 14iIgI IT' "" . . .

F. Acw

I

rap "lli"e 2'-11 Brds 110 .....::ou k:Ifmo'lg 1lhl'iic8l bIotriet 110 HCla'd

-.

I

(I~CO~~'!~!:!.!'~IF~.~']_~·",;,~~t ~,~.~,~'~'~IC==I

Q 't"io"E 21 18-2422 IV fYdl .... ,Qq(I dMOipIlon '-klw. ulId IIw most "'llPiopriale dOug from ... loIooolI'lllisC

24,10 ClinlorOshes IIuid _lion in IIw _

I

co-:c _

.. A (8IIndl."

';7

I

.... Sodum 1lbrtJonlI'" B. CifT..,.;,s.

)

c. ~ lXllI'IpClf.O'l D.~

24.11 Irri!al. Ihe gut and causes inCf'e_ perklalsl,

,.""""""" F.

24.12 Relains ",al", and produces intestinal dlstenslon

[

e:e.-_.E~

__l

Proc:hloi ... osing hoo"lOilfl; ~H (l.HRH)=gonild: re'e r'ng horTTlOioe (luIeio iziily hoi" ... liH 'e sing hormone): f>IH,. prolactin-. tlI;lilii '" h(lrlllOi.. (dopilmil'le): lind PAH" ~ hoo"lOie; AC'Tli:a .,... lOCUlitxAJ..... hoImollil; TSH- ~ hoolilOilfl; fStl,. ~ hooillOi..; LH-1ullIinizing hOOlilOrlil I

1he anterior piluilar)l. The ~ IllllI8sOng holillOrleS 8I1l pOmarty used lor diagnostic purposes (lhal Is, 10 detenTlW>ll pituitary Insutfldeocy). [Nole: The hypothalalTlt1!i also synlhesizes !he hormones vasopressin and oxytoc:Wl. which IlI1l lranspor1ed 10 1he posterIOr pilui\aly l\ot1efe ~ ere slOr'ed until released.) Although a rurtler or pituitary hormone preparalions are currenlly used the~1y lor spec/fic: honnonaI delidencies (f!l(amples 01 which 1olIow), most ol lhese agents h3'-'Illimited therapeutic appIlc8.tions. Hormones oIlhe anterior and posterior pituitary are eclminlstered either intramusctAarty (1M), subcutaneously (SC) or intranasally but no! orally, because their

...... '0.....' ....... ...--'· 11. HypoIhaIamic end Anteriof p~uitary Hormones

'"

pepIidie nature mal<es !hem susceptible to deslfUCllon olytic: enzymes of the dgestiYe lr'aCl A. Adrenoc:ortlcotropk: hormone (ACTH

Of

tTt

the pr0te-

corticotropin)

ACni Is a proWd of tie posl:trin1Iatio pro' Euing of tle largeopnanor ~ pro.opial ' 00C0i\il~ Is Ultgel organ Is fie UenBI ttlf1BIl ....tlete OOl1icXJIopio. [lora ~ IoD8 moe pi'l] bnds to speciIW: reoeptoB on the eel 8diY8la G proleirH:cupIed fO''' Un slirrUates Ihe rale $yi.etic; pelhway (chJlest 01

",IiIii

Ihe S'J'i1ll Esis

~

The °a;"p1ed reeepIOrS 'e5 to ,lClE85a cNIP.....t'littI in

-

_,, .......

step in Ihe DtlllOC(ll1io '15'eroid prl9MlIdDooe). ~ wilh

anct rei: Bse of the adleroocortioo5lerokls, and lie

~.

adrenar androgens (Fogure 25.3). The 'Y8~.bility of synthetic ldoerll)(lCll1io;o:oerolds v.tt\ spedfic pope-'. (see P. 275) his ....... iIed tle use d cortiaJtrqlin 10 serving as a dialPlOde tool lor diI1er.

entiaIing bet1

B!lI'l pmwy adrenal nsutiden&y

'

0~

(Adlison's nise....e,

associBted wilh aci'enal atrophy) and l.OlCOi idary 8drenIl ~ c:ierq (ea"·' tTt inadequate secrelion d ACTH tTt the pituitary), 1l'oerapeutic o::orticttropin preparations lire ~ lrom fie ani&: rioI' pituitaries of domestic animals, or synthetic tunan ACni. The Ianer, COS)n~ 11'Br and oI1I!f l'ss1"'S 115 rni{;'II be expet1lld fie mlliDr to*iIy is Wider i,hi:alj"n and tryponalJefT'ilL II! biOi d'iOCiOf'" iclial 8I'\d tremor also can ()(ll;U'. Caulion must be lI$8d in treating patiems with WlOll3 < .....

< , ....

I >

~""""""""

252

- - .. _

.... >

25. Horrnorl8$ oIlhe Pituitary and 1'try'toId

THTiOOcaL

CXll' CWl

n.r"J

eo,

./""-

f)-iodide

3

6'• '6'

* '0'

4 Cond..... Ullon

•

H-(; 10100

?'> • coo·

T

• T.

H-(;-N1o'

?'> • coo'

* '.,'':''_ To

IodInation

~~==:

T

FIgure 25.6 Biosynthesis 01 thyroid hom'lones.

secreted (hyperthyroidism). tachyca,dia and cardiac arrhythmias. txxIy waSling, nervousness, trelTlOl. and 8Ilc:ess heal production can occur. In mammets, the Ihyroid gland also sec>etes the hom'lona caJc:I.. tonin. a se . . . . . . - . . . ' >

,.,

III , Insulin

PaIiens with TWe liliabetes are dten obese.. Type II dBbetes is freqIBllIy ~ by Iafgel 0fVilIl ~ resisIanoe !hal limits <esponsiveness 10 both endogenous and exogenous ...." In scme cues. ilsLllin' .!"lee is 0.. ID e dlIel i . . I'UTlb8t or mulalions of .i'lsuIi'l ,.... .."s. 1-IDwwer, ." 11$ yet U1ldeio llId defed in f"e IMlnls lhBt oowr aflet ilsLllin binds ID its 'e' ..... is b r !>'lId ID llCCDUI1llor resist.., ..... in lIlOSI pelielll:s.

2. Treatment of Tn- • diabetes: The QOBI in treating TWe II 6abetBS is 10 meinIain blood gucose (XlllCf!l ,trations within IlOfJ110I limits and 10 prevenllha de\leIopnel t of long-term /JOI'l'oPliCations of the disease. weight reducIion, exen:rse and dietary modifica. lion dec<eBse ~1kI resistance and 00IItld Iha ~ of Type II diabBtes in some patierlls. How8Yef, mosl are (i8pelldel. on phaflTlil' 'ologic: intervention with oral hypogIyeemil;: agents (Agln 26..4). In&ofn 1hefapf ~ be reqWed ID achleYe salisIadDry senm "'. .oose IeW!Is. INote: See F9J

259

IV, InsUlin Preparations

REGUlAR "'SUUN

",",,"""UN _ _ _ _,......

• OnIy _ _ ItI _ _•

.~d1O%l¥.I

• ~,;,..c:~':"':·:;C:-·

• _..-., _

•50

26. Insulin and Oral Hypoglycemic Drugs

Fogure 26.7 Effect 01 standard and intensive care on the Iong--term complications 01 diabetes.

ize blood glucose through more Irequent injections 01 insulin (three or more times daily in response 10 mooitoriflg blood glucose tevels). Mean blood glucose levels 01 150 mgfdL can be acNeved, with an HbA,c 01 approximately 7% 01 total hemoglobin. [Note: Normal mean blood glucose is approximately 110 mgldL. and HbA,c is 6% or less.] Tl1us, lolal normalization 01 blood glucose levels is no! achieved even in intensively treated diabetic patients. Nonetheless. patients on intensive therapy show a 60% reduction in the long-term complications 01 diabetes-retinopathy. nephropathy, and neuropathy-compared to palierlts receiving standard care (Figure 26.7). However, the frequency 01 hypoglycemic episodes. coma. and seizures due 10 excessive /nstJlln is particularty tjgh with intensive treatment regmens. See p. 452 lor a descriplion 01 the newty approved drug. lispro

"""" V. ORAL HYPOGLYCEMIC AGENTS

Sullonylureas

n

,-,

:=

-u _. u...., ----...... ...., CloiII>ose does no1 ceuse hypoglycemia. The drug can be used as mono1herapy in those patients being conlrolled by diet or In combination wilh oral hypogiycemic agents, or with insulin. It Is poorly absorbed and its major side effects are lIatu· lance. d'arrIlea. and abdominal cramping. See pp. 452-453 for a description of the newly approved hypoglycemlc dl'\J9S. gJinepIride. ropagiilidB and trogitazone.

,G,LUC06E, \GLUCOSE/

","=J "YPOGLYCE~IA

Figure 26.10 Su'nmary 01 the adverse elfects observed with oral hypoglycemic: agents.

~1rIr"", eflOC'lln IObout 3O'!i.

26. Insulin and Oral Kypoglycamic Drugs

Choose the ONE best oos_.

26.3 All QI the lolIcMing are correa EXCEPT; A. One 01 the most common &ide e1lects '" oral hypogtyoemic agents is gaslrointesti1al disturbance. B. The most serious oonseqLJlle lIonnone. D. SuIlonyk.Jreas am usetul in !he treatment 01 keload-

A. SIllIon)4ur8aS can traverse the p1aoenla and act on the 0slaI oeDs 01 the panc,eas 01 lho latus 10 deplete !ham orlnr;ul;n. B, SullonylurellS mey prOVQke pregnancy-Induced

OO&is. E. Inalllin eels by binding 10 receplors in the nIldeus 01 target tiSSile.

C. Insulin does not pass thJUgh tho pIaCoola. O. The,. is • gralllar demand lor insulin ;n pregnancy

hyperlension.

than can be provided by sulfonykJreas. ~ ~ wI1h lin ~ oa,ipI&lc lI\8Il WI ~

CormcI_ -C. .......... 10 101m

aboorbed. Inaulln II not admlcled.)"" ...... _ orl>olmoolaloegoJlltionol I ....'.

"SM

p.3'!".

'."I.. y(2nll ...po..........

or han>ogjotJO, A'e-

n. ~ .... • _6 tn P''ll''''CY. not 01"1I)' II

1hll ~ ....-.g _ - . a drug td 10 WI tie tonu.. In !HI c.M•• IIIn'9llf\IlnI _ tie ialet t * or h fetal pWc:reBI not brt llIlecBl by !he ~ ~!he lnIIonIls born hyp:>g!yaln'C.. ~ r-- no elIec1 on blood ~. The 'ect _ lneulin _ not pau ~ Ih8 pae.ma ........... W;I ~

f'IOlI'I'I8IIt, YMlIhe

~ d b I8lIls, ,.., aM _ on alllo::l\' .. II r M"d II'uI an ~ II> !III :t da",aoKl 00 lnk*I. ~

If_

'sa. p.2IilS .. e1 ' . ' 01 Typt._Typt "s.

p.

21'D" II

ollJb¥"

I y{a>clood.jloruh",.""

, . , _ , l2nd ".j tor ...........,

I ol~

._ .....

,.'~

......

_'~

Steroid Hormones STEROID HORMONES

I. OVERVIEW

...........

-,---....."""" --, ._-............

I

CtI..........."" • ..

_ ~ _ f n > t

SHlroid hormones include the sex hormones (androgens, progestins and estroglllls), and the hormones 01 the adrenal cortex. Sex hormones produced by the gonads and adrenals are nllCessary lor (X)r1(eption. embryonic maluration, and development 01 primary and seoondary sexual characteristics at puberty. The gonadal hormones are used therapeutically In replacement therapy and, In the case of estrogen, lor cootracepOOW) major classes of steroid hormones; the adrenooorticosteroids (g1uc:ocorticoids and mineralooortic:oids) and the adrenal androgens. Their synthesis is stimulated by corticotropin (previously caMed adrenocorticotropic hormone, ACTH, see p. 247). HormoMs 01 the adrenal cortex Ilre used in replacemer1t therapy, in the treatment and management of inflammatory severe allerdiseases such as rheumatoid arthritis, in the treatment gic reactIons, and in the treatment 0' some cancers (see p. 393). Inhibitors 01 adrenal cortical steroids are used to treat hormonal dystunctions in which these oompol.nlls are producecl in excess. Figure 27.1 lists the steroid honnones relerred 10 in this chapter.

~.-

~-

f--

I-

0'

II. ESmOGENS Estradiol less tra DYE oleJ is the most polen! estrogen produced by women; the other major estrogens, eslrone [ESS troneJ and estriol [essTRI olej, have about one tenth the polency of estradiol. These naturally occurring sleroids are subjecl to a large lirsl-pass hepatIc metabolism and when admislered oratly show low b'oavailabllity. PREMARIN-a preparation of conjugated eStrogens (contains suRa-te esters 01 estrone and equilin) obtained trom pregnant mare's urine--is a widely used oral preparation. Synthehc estrogens, for example, ethin)'I estradiol [ETH eye nil ass Ira OYE oleJ, undergo less first-pass metabolism and thus are elfeetive whet1 administered orally at lower doses. Synthetic nonsteroidal compounds with estrogenic activity, lor llJ

27. Stei'OO Hormones

A. Mechanism 01 action

STEROID HORMONES

I-

-

AHTlANDROGENS

----..---,-

I

C)........ "' .. ..,.,.~ ~~

I-

CORTICOSTEROIDS

I

-.b,..IfI
-

--

O. Estrogeos am mainly e><ereted ullChanged in the

D. sucnllS progesterone am widely used in olal traceplives. E. COImlOOIy Ino:luce weigl~ loss.

urine,

E. T""",.iIen is used 10 treat inIet1itity. Oofrecl answer .. B. ~ III II synthetic eelrogen that acts directly 00 ta'981 tis·

The 00trIIQ .......... C. P

, __ •

, . . . . . . , >< ...... _ _ L >

UNIT VI:

Chemotherapeutic Drugs

Principles of Antimicrobial Therapy

_"'_ ---+ -_.. -

... ......... --poo. . ,*,. ---"'.,• , ."•. EmP(Wi.... icIr' 8 1'1

$

,...•. Ooug

• d" I • ="' (lot Iloo....., 8I' I ll ""-"*' iii.. i.' 01 .... . . . , _ . . '

$

i

,

ptA ~

IIll' ~ OIl' ..,111 liIlliolb -'

. _ ..... - ~ ' ............ _

.... >

Folate Antagonists I. OVERVIEW Folic acid coenzymes are required lor the synthesis 01 purines arid pyrimidines (procursofs of RNA and DNA) and other compounds required lor cellular gowlh and replicaliof1. In the absence 01 folic acid, cells CBfIf10I ~ Of divide. The sulfa drugs are iIlhibilOfs 01 folic acid synthesis. They originated from the dye prootosil. whidl was shcMr1 if1 the early l~s to be effectiVe agaiost hemolytic streptococcal inlectior1s because the body COflYE!f1ed ~ to suJfanilamide [sulfa NIL a mille]. Marly coogeoers ot the latlar compourld were syfllhesl~ed arld found to be eIlec1i\le in Ihe treatmel1t ot infectiolls diseases. Today, particularly Ir1 da'.ielopillg COUr1tries, the sullas are still ~ because oIlheir low OO5t and efflC8CY in certain bacterial infections such as those 01 the urirwy tract, and trachoma. However, to the emergence of resislar1t bacterial strains. (Ie>oelopl'tef1t of palieflt allergies. and the l.ldYer1t of the penicillins, the sulfes were less IrequenUy prescribed lor a time, until their synergistic affect wiltL /rimethopItn was recogni~ed. With the .... trodUClion in the mld-1970s 01 the synergistic combination of sulfame/tK»lazoIe {sui III meth OX a roIa] with trimethoprim [try METl-l otl prim] (generic name. co-trimoxazolB [co try MOX a role]). there has been a renewed Imerest In the sulfonBmides. Cc-trmc»IBzoIe is etfaeti\l'e in trea~g conditions such as f'netJrnocmi.s Cslan::e 10 h! liUbs C8I'I .,;so ffom !*IS' nil! II'llnSklrs Of r.-iCb,. n1IAllIionL The resistance is ""'.......... irreYerstie and may be clle 10 tJnf 01 Ihe IolIoMng Iv1le possjbijties lNole: 0'g0Rsms resistant 10 one membet' 01 .... drug Illmily BIB resistarI: 10 1IlI. b.It!hey may be SllSCBPlil:lle 10 aH~J

"..,-_ca........-_bf.if> In_.''$.' · _

.......IIo ...

~

T'_'

.... 1eII

CNom""".",_ cr.

\1'

c_

''''''_

""'" ""-""'"

---

' ••

•

TRACHOMA

'

a ..

. ._

r

URINARY TRACT INFECTIONS .l"novIcuslyUi'b ••1

~_.

, - - - ' 10 " ' " _ .

well •• _"'~.

.0Wii COf1luncIlWl_ CfO.IfinlI _ _""'bll_ .7.-....... _._..,""._ "'.U = _t4Ido,

• CoUUl1,"" >genI. ~\lKbllmiI

In

_

'*...

ditl;Uld~

• £Klll:1Ic!!!Llillll ...... _ 1 _ _ co... '" cyatIIJ&,

InIlommti1lon,

~

• 50e FIgI.n 2t.71o

'tiro.....

flgul1J29.3 TypicallhfJr'apeI.lijc 8flpliadions 01 Sl.l/IorIan'Ode.

U_,.,'"'I

_un_Ul .... ·

un. urinary tract infec1icn

...... r...... 1.'

..... _

II. SuIlonaJrOcles

I.

_

....... ----' """"'" .. .....

1. Altered enzyme: Baclerial dihydropteroale synlhelase can undergo mutalion or be transterred via a plasmid 10 resutl in a decreased affinity tor lhe sulfas. The drugs the<etore become less ellective compelilors of PABA. 2. Decreased uptake: Permeability to sullas may be reduced in some resislar1t strains.

3. Increased PABA synthesis: Enhanced production 01 the naltJml SUbslrate, PABA, by the microorganism throogh selection or mutation can overcome !he inhibition 01 the dihydropterOllle syr>thetase by the sulfas.

D. Pharmscoklnetlcs 1. Administration: Mosl sulfa drugs are well absorbed atter oral

adrrinistration. Svlfasal<Wne (WI fa SAL a zeenl. when administered orally or as a supposilory. is reserved for treatment 01 chronic ;nftammatory bowel disease (for example, Croon's dis· ease or ulceraliw colitis), because ~ is noI absorbed. Similarty, suocInyIsu"all1lazo/e lsuks in ill sui fa nil a zoleJ is used for the lreatmerlt of salmonella and shigella canie<s. InlnlvenoUs sutfonamides are generally reserved for patiell1s who are unable to lake oral preparations. Because of the risk of sensilizaliol1. sullas are nol usually applied topically. In burn ooils, creams of mafen/de aretate (p-amltlomeltJy/bf:llllensv/fonamlde) or sl1v&" suJfadlazintJ have been ellective In reducing bum sepsis. However. superinfeclions with resistant bacteria or fu1gi may OOCU".

Sul/ollom/des

2. Distribution: Sulfa drugs are distribuled throughol.lt b<xJy water and penetrate well inlo cerebrospinal fluid. even in the absence 01 inflammation. They can also pass the placental barrier and into breasl milk. Sulta drugs are boUnd 10 serum atlumin in !he circulation; the extent 01 binding depends on the particular agent

3. Metabolism: The sullas are acelylated at N4, primarily in lhe liver. The pnxluct is devoid 01 antimicrobial activity, btJI it retains Ihe toxic poIential to precip;tate at neutral or acidic pH, causing crystalluria islooo formalion1 and therefore poIential damage 10 the kidney (Figure 29.4). Sulfasalazine is ellective in the trealment 01 infIanvnalory boWel disease because local inlestinal flora spIillhe drug into wlfapyridine and 5-amlnosich

one 01 the llJllo',o,;ng? A. Inlluerlza.

II...."""". T)l(! &esis. ~ _ . C. Trlmethoplim is 20 to SO times rAOnI potent than suIllimelt1o""zt"-. h inhiblls 1M lIflZyme dinydrokllll,. feductase.

hJS

Antagonists

p"ha"'oo bot> ~ and Pl"'fflCe. mOl''' than once, 0< not at aI.

A. SY~asalarine B. S'IaeetamiOe

5)'f>"

C. Trimethopim--sulfamelho.aroIe

thuls. T.imethopflm 'Silstancli has bllen _ in _ CWoISIld by ~

th. p..,..nce 01 II plasmid "'at COdeS !Of lin IIltlirod Iihydrololate .!lduclase with a 1Ow1l' -*Y do\.g.

10e troatment of ulCCrali.-e colitis

Gareet.-•• A.. ~ is--..db ~ l 01

D. They dininisllaetivily 01 wal1arin. E. They compete with p-aminobGn~oic ae;" !Of the enzyme dihyd:.II- ill omoIyIIc _ """"""'" in " " _ ""'" gIuco&e 6-ph:>sphate ~ doIiciencY.

..... '0''''01 > . . . . . . . _

L>

< __ • , . .

0' K>
5. Pwllc:lIlne .M ...-....y~: The atdJaderial eIfeds 01 aI the jl-Iaoam .1lU . . . . . ..,..... gistie wWl .... • I.~ The abMy 01 pili ~ " (a'ld 0It8" agents thai inhibit c:ell ..... synthesis) 10 alIor peo II I lbifty 01 the baderial c:ell c:an IacilitaIe ertry 01." ..... that ~ not CI'dI'Iariy gain ace 1110 tatget sites, thus ,esulting in ~ .,lir,liaobial actiYity. AIthoogh the ~ is ~ djliieall~ IIle&e drug types stlOlJd_ be pIac:ed in Ihe _ infusiOn IUd, ........- on poloued oc:n-tact, the positively ctlarged ~ Iorm an Inactive ( 0 .............. Ihe negatiY8Iy

III. Cephalosporins

.. ow' - . " -~.

-.~_.

__

._~

~~hualongoo­

t.II-II.lIIan - .-.lean 808'1tS. l>a " .......... _ _ batriar __ lor ~8dbOll

30. Inhibltors 01 Cell Wall Synthesis 2. O;slribulion: All 01 these antibiotics distribute very ~I into body lIuids. However, adequate lI1erapeutic I~s in the cerebrospinal fluid (CSF), regardless of inllarrmatiorl, are achieved only wilhlhe third gene'ation cept1alosporins (lor 8)(ample, ceflriaxone Of cekr taxime are ettecIive In the treatment 01 neonatal and childhood meningitis caused by ~ (nllueozael. Celazolin (se FA U> lin)linds appIicalion in OfthopediC SUfgery because of its aaiv· ity against penicillinase,pfOducing S!.<whylocOC!'us i!Jllim$, its half.lile and lis ability to penetrate bone.

""nl cepllalosporln.



...,....

---.. - .. _..... '

""7

n mIl' laB ~,

althoUgh at- pseudomonas strains Resistanl stsaN 01 py."'''Jlll!W! illlfI'liOCM haw been ,eported 10 arise cbing 1tleraI¥1

PM'

are reslstart. [Note:

2. I'twmacoklnetlca.: ~ ill adllli"ilihhed intr!W8l'lOUSly and penetrates wei irlkl body IissUes a'ld lIuids including cereb.... ss*l8I fluid when the meninges are irlllamed. II Is 8lOCfeted by gIornef\.IIlW and w1deigoes dell'.age by a ~ due tound irl the bfush tIon* 01 the JIfOIlftIal t1..tll.Ae 10 lorm an inactiVa metabolite IMI I. potentially nephrOlOxic. ~ !he .'¢le7l with ..... $fI>fioI, e ~ W.Ilib. protects the par'" drug trom deltiorge and Ihus pre......... the b"iMlol. 01 a IaIIX: me&abolile. TNlIi lIIowto ..... drug to be adiY8 irllhe Ifearment of urinary !fad Iollecllcw-. [Note: The do5e must be ......... irl palient$ with r8fllll1nUlcient.y.1

1iIIl""'"

r.,.

.tNoC!.,

3. Ad\oeIM 11l ....... l&itcilasta~ can
--Does not pe _ does enter CSF K

.........

Vancomycin

bul

3. Resistance: Qc:curring rllrely. valll:omycin reSiSlanl:e is due to plasmid-mediated changes in penneabmty to 'he drug IlI1d is aloo due to deCfeased binding of vanromydn 10 receplor molecules.

4. PharmacokinetiCS: Slow intravenous inlusion is employed lor treatrnerll of systemc In'ections or for prophylaxis. Because vancomycin is not absorbed alter orill administration. this route is only employed for the traatrnerll olllrllibiotic-Induced colitis due 10 ~ djtllclle. Inl1llmmation allows penel/atlon Into the mer1lnges. Metabolism is minimal; 90-100 % is eKallle(! by glomerular fittralioo. [Nole: Dosage must be adjusted in refl8t 'ailure Sifl(;e the drug will aoloa _ E. Un!IIo""" .....

Entry 01 these agents into susceptible organisms is mediated by transport proteins unique 10 the bactllfial inner cytoplasmic membrane. Binding ot the d'ug 10 the :lOS wbunij of the bacteria! ribosome is believed to block access ot the amino acyl·tRNA 10 the mRNA-fibosome comrex at the acceplOr site. thus inhibiting bacterial protein synthesis.

B. Anllbaclerlal speetrum As broad spectrum antibiotics, the tetracydines are also ellective against organisms other than bacteria. Tel1acyclines are generally baCllJfiostatic and are the drugs of choice tor intections shown in Figure 31.2.

..J

CHLORAIrIPHENICa

I

-l

WND""""

I

Figure 31.1 Su'nmary 01 protein synthesis iMibitOfS.

Usee p. 322!o< InI>despead ref513flCe 10 tetrae)dineS irTib Iheir clinical use. The mosl WI, .IOIty IlnIXUltered ~ occurring R laaof WIllets an InabiIily 01 !he organism 10 aa:urnulate the rhus prcl(IlJcing

cn.o.

'esistance. Ttis is aocolllp'stoed ~ a Mg" -depillld,iid active eflk.ol 0I1he drug metialed ~ f>e resiscanoe ptOlein TilIA. 0Iher mechanism5 liUCh as I" siJMl fT'NdifCalion 01 !he tetrlPeyl;lWle binding site hiMi also been reported. Ani organism 'esislBtt 10 one tetraeydine is resistanI to all. The majority 01 penici'l~ staphylooocd are (I(JN also ioseosiIive to ~

g_

--IIn9-

, . . lymp!'lw'll .,

31.1 WtOctl _

"" _ NOT W-...;I

ns",

"Ii

lle

10

.... 1If ...._

]

'11'. llllIlib

It. They a.. poorly IIIlaoot>ed fmm ll'l$IfQinl8Slinal

,

._e _ , If.- dII*:aI . - 01 ,... drug. 0ep0ribI 01 blllac:ydIne in ""*'lI)Io'll ...... 01 .... leila ..., lI'owinO cHdnln c... OCCUI. ThIt

lty ift

paleo1i;ll 1m ~

-.... t

31.3 v.tich _

al'~

Il;\ldI:-

mol..... o.Jty food, in

_"orb"

...

uaet

B. They ""... bIcI&ricidIIl propertilll. C. ThlY c.rl ac.... v. adrKlUall "rUm ... VilIS alto'" oral ~flIlicn. O. n.y tond 10'" 3DS ribotomIlI ~ E. ThIoy _ flCII ~ ~ ~.

3,2 v.tIocII • 110l bene and 1lJJI1s lX>I'I> • • 1Io j Iol cN:pllrim8IItII anlmIls. which 101 wrly K Ie cont

•



IM:AIIJI . . _

Antimycobacterial Drugs

,I. OVERVIEW The modern era ot tubefculosis lt1erapy began with the introduction of streptomycin. isornazid. and p-i.HTIinosalicylic acid and today multidn.>g lt1erapylllCludes drvgs liSled ir1 Figure 33.1. The number 01 cases of tUberculosis waned and Ihere was hope 01 complete eradication. Indeed. predittions were made lt1at tuberculosis would be almost nonllllislent in the Uniled Slates by the year 2002. However, In the past decade, tuberculosis cases have signifil:anlty increased, dlielly among AIDS patients and the homeless (FlQUre 33.2). Today tuberculosis is still the leading cause of death by Inlectious disease throughout lt1e ~.

ANTlMYCOBACTEmAL AGENTS

II. CHEMOTHERAPY OF TUBERCULOSIS MYcobaetf!rjum tuberculosis, O!1e of a number of mycobacteria, can Jaad 10 serious intllClions 01 the lungs, the genitourinary trae!. skeleton, and meninges. The myoobaeteria are class~ied 0!1 the basis oIlt1e1r staining propertles. [Note: Though difficult to slllin oocause 01 the presBOOB 01 an outBl coal of mycolic acid, once stained they hold the stain BYIlO in the preseoce of destaining agBf1ts such as acid. Thus they life referred to as "atid,'asl".) Treating tUberculosis as well as other mycobaclerial infections presents therapeutic problems. The organism gows slowly. and thus the disease may have to be treated lor I..P to 2 years. especially it it is caused by a resistant organism.

I-

Amlr7 • 'ig therapy is employe
ice '" C. Rlfoo',",'

me.

IhII

lind . . . irIlIlIlI fW

34. Antifungal Drugs

1. Mode at action: Several polyene molecules bind to ergosterol pre!llIOI in cell membranes of sensitive lungal cells to form pores Of channels that IrMllve hydrophobic bonds between tlle lipophilic segment of the polyene antibiotic and the sterol (F'9Ure 34.2). This disrupts membrane function. allowing electrolytes (particularly potassitxn) and small molecules to leak from the ce~, resulting in celi death. Since the polyene antibiotics bind preferentially to ergosterol rather" than cholesterol, lhe sterolklund In mammalian membranes. a rela~ve (but not absolute) speci1icity is conferred.

,.

Figure 34.2 Model of pore formed by amphoIericin in lipid bilayer membrane.

2. Antifungal spedrurn: Amphotericin B Is either fungicidal or fungistatic, depending on the organism and the (:(If'lOOntration of the drug. It Is ellective against a wide range of fungi, such as Candjda a1bicans. ~lOOtasma lSled ill patients with c0mpromised renal fi.o::tioo.

FLUCYTOSINE

AMPHOTERICIN B

..........,., ....

_-,.

340

34. Antilungal Drugs

5. Adverse effer::ls; Some oIlhese adllerse effects may be related to 5-FU tormed by irlteslirlal organisms lrom 5--FC.

a. Hematologic toxlcily: FlJcytositJe causes rewrsible

~

nia. thrombocytopenia, and occasional bone marrow dapres-

sion. CaUlion must be E!>lOOsed in patients undefgoil '9 ra(ialion Of dlemolherapy

wiltl drugs that depress bOne

marrow.

b. Hepalie dyslunctlon: RfMlI"Stie tlepatC dysflsction wiltl ekMItion 01 serum transamlnases and alkaline phO$phatase may occur.

c:. Gllstrolntestinal dlsturbllnces: Nausea. wmiting. and diannea are common. and severe enterocolitis may occur.

C. Ketoconazole

Keloconazo#e (Koo 100 KeN a zola). a SUbStituted imidazole, is one ot a lamity of azoles uselul in treating systemic mycoses. In add~ion to its antilungal activity, ketoc:onazole also Inhibits gonadal and adrenal steroid synlhesis In humans by blocking C17-20 lyase, ltp.. hydroxylase. and choleSlerol side·chain cleavage; thus, it suppresses testosterone and cortisol synlhesis. 1. Mode of ac:tion: Ke/OOO'lazOle inte
"""'lcir,

~ ~ ..a.G .... olIl .... B ""'Y t. .... .... hlKlol.9'I ~ cIl:.c:a.o ~ II'Ill decreIuoId 1Ibidu,_ I'lOUI'd nor t.. 01 Pf\'n8ry CUfIU9lT\.

< _

'0...,.,

>< . . . . . _ _ t >

Antiprotozoal Drugs ANTlPAOTOZOAL IJAUGS

I. OVERVIEW protozoal infections ara comrr.oo among people in underdeYeloped tr0pical and subtropical countries wh&ro sanitary ooncliOOns. I¥.lienic practices, and control of the vectors of trensmission are inadequate. However. with increased world travel. protozoal diseases such as malaria, l¥nebiasis, leishmaniasis, lrypllnOSOIT'Ii, tridlomoniasis, and gianliasis BnI no longer confined to specific geogaphic locales. Because they are eukaryotes, !he lricelluar prolozoal cells ha'we metabolic pr0cesses closer to those of !he hJrnan hosl tI1ar1 to proka~tic baderial pathogens. Protozoal diseases are thus less easily treated tI1at1 bacterial infections. and many of the antiprotozoaJ dllJgs cause serious toxic affects ir11he host, particul8.rty 0f1 cells showing hi{tl metabolic ac1ivityneuronal, renal tubular, intestinal and boI'\e marrow stem cells. Most ~zoaI agents have not pru.ted safe for pregnant patients. Drugs used to treat protozoan inlections are summarizad in Figura 35.1.

-

--_. -..... ............. ....... -= --,. .....-

-

.............'"

-

'w

01"'7

D ooh)-'-" ,~-

-

OP _ _

CI_ q....

Pt., ..,.....

_ ~ M

II. CHEMOTHERAPY OF AMEBIASIS

-

Amebiasis (also called amebic
A. Life cycte of E. hlstolVtjn E. his!rlMira exists in ~ Iotms: cysts thet can survive outsidB the body, end labile but invasive ~~es that do not persist outside the body. Cysts, irJ9!lStecl thl'OU\11 feoes-eDf1taminated food or water, pass io1to the i1testine whera lrophozoiIes are liberated. The lrophozoiles fTIlJlllply, ood either IflIfade and ulcerate the mucosa of \tle large ir1tesline. or simply food on intestinal bacteria. [Note: One stral· em' for treating luminal amebiasis is to add antibiotics. such as telra-

mlBW"YOP TJmfANCl8OlI'_

, ..",~-

'-

............,'" , ............,'" .........-

.,..,.-

O""IlI'W

~

Agure35.1 Summary of ootiprolozoaJ ~

..--.. _ _ ". ......... , . - . _ ..

_ _ 0-"''''

a. _ _ c..".,....

....... 0"""""

345



35. AnliprotozaJ Drugs

o

Pe.-.etratiDfl Intestl....1 well

Muttlpllc8ttDfl of trophozoltes within colon well

•

tAIKcd omeblc,de

CyoI_

w.o.u.

(lurnlnel8nd

•fI."",,_. 0++-

systemiC 8Cl1Vllyi

Lum.nal ameb'cldes • 0."'..,,,,,,, '"",,"" • ....omomycm

• ''''''
B. Clssslficetlon of antlprolozal drugs Therapeutic agents are classified as mixed, luminal, or systemic amebicides accordif1g to the site where It1e drug is effective (see Fi!ll.Jrn 35.2). For example, mixed amebicides are ellective against both the luminal and systemic forms of the disease, though luminal concenlm!ions are too loW lot single drug t,eatment. luminal amebicides IlCI 00 the parasite in the lumen 01 the bowel, whereas systemic agents are etlective against amebae in the inlesliroe wall and

the rlVer_

-lil<e eIt8c:t 00Cl.Q (see P. 96). D. luminal amebk5dw: Dilounlde 1~1e DiloJranide ruroale (dye lOX a rjOOl Is U50hA in the trealmefll of Its Ol'tv ildice~: ,it in h treabT"8I of ~ anM' $i. Af\ef 0f8II ad""inilllatiol'l. 'in: SewraI ~ heYe been icIentified by 'oONctl d*»oqui'Ie Io:.lIs fle organism .rw. aocurruatrog ., ltoe UiglWi&ll

•• D• ...-g. mediated by accumul.t.d h.....: Chloroquine ent.rs the red blood cells atld Interferes with a unique enzyme Nt is esse eSal to the SLnMlI 0I1he paraslles" fle red t*xId OBIs.. The parasites ligest the ho5I CIlI's henJo. glat*l to get essential arrWlo acidI; 8nd lion. HoweYer, tis poe s also re'e"SB$1arge ~ 01 ~tIIe hlIme thai is toKic to the parasites.. To proted itseM. lhe parasite ~ polymerizes the heme to hemozoln (a pigmenl) \hat is sequestered in the parasite's Jood vacuole. Chloroquine Inhibits the polymerase and thus soluble heme kins the organism by inhibiting proteinases in the looe treatment of eKlr8inleslWlBl amebiasis (see p. 346). The an!i·inllammatory action 01 chloroquine eKPl__ its UiX'8sionel use in rheumatoid arthrtli$ and discoid

.....

-

4. Pharmacokinetics

.. Admlnlstrll110n and dlsltlbutlon: CNoroquine is rapidly and c:omplelely absorbe

353 !a!cioarym. Us e.ac1 mechanism of action remains to be determined, bUt ~ apparently can damage the parasite's membrane like quinJ'ne dOeS. Resistant strains have been Identified. Me~ is absolbed well at1er oral administration and COiICel,trates In the liver and llong. t1 has a long ha/l-lifa (17 days) becalJSe 01 concentration in various tissues and because of its COI'11inuous circula1lof1 IhrolJ!11 the en1erohepatic and enterogas1ric systems. The drug undergoes e.tensive metabolism. Its major excretory fOute Is the feces. Adverse reactions at high doses range !rom nausea, YOmiting, and dizziness to disoriental1on, hallucinations, and depression. Electroca~abnormalities and cardiac arrest are possible if mefloqulne is taken concurrently w11l1 quinine, or quinidine or ~

-"

TRYPANOSOMIASIS

I ~

F. Blood schizonticide and aporontoclde: Pyrimethamine The antifolate agent, pyrimethamine, Is lrequently employed as a ijood schizonticide to effect a radical cure. It also acts as a strong Sj)Oronticide In the mosqu~o's gut y,tlen the mosquito iflge$1S ~ with the blood of the human host. Pyrimethamine inhibits plasmodial dihydrololate reductasi' at much lower concentrations than those that inhibit the mammalian enzyme. The Inhibilion deprives the protozoan 01 tetrahydrololate, a cofactor required in the de novo blosyn\hef;is of purines and pyl'lmklines, and Interconversiof1s 01 cenaln amino acids. Pyrimethamine alooe is effective against taldparum. In combirlalion wlfh a sultonamide, ~ is also used againsf IIliIlill: il.llI. and I""gp!asma goolii. If megaloblastic anemia occurs, it may be reversed with /euc:oIIorin (see P. 379)

e

e

,-//f

soe

prole] is a derivative 01 mefSalyi O>Oide, a

1. Mode of action: The drug reacts wi'" sulfhydryl groups of vanous substances Including enzymes in bolh the orgal1lsm alld has!. Parasitic enzymes may be more sensitive !han are those of the host. There is evidence that mammali.m ceUs may be less perine· able to the drug and thus prolected from ilS 10l(i(; ellects. 2. Antlmlcroblal spectrum: MeIarsoproIIs limited to the treatment of trypanosomal infections, usually In the late slage with eNS Involvement, and Is lethal for these parasites. ,""" .. ""'.'" _ _

in,._

nIl

L ___ ,II . ,

AFRICAN

-[_. -. 'll -_. -I ~I

11blel

ll8l

....

e-

_

0

!

•

: , CI

Trv~Mrtf

rlOOdIfi,....

~

A. Melarsoprol

trivalent arseoical.

Chagas';'1

,..... :t..., TfYpaI'ffl'Nl

Trypanosomiasis refers to /WO chronic and eventually fatal diseases caused by species 01 Tryoaoo§Qma: African sleeping sld-Ied. ew:senee exists f,aj the drug binds to the parasite's DNA, Ilfld interte,es in lhe synthesis 01 RNA. DNA, plJi:JstJtUlipid and proter. fA the parasite.

."",

... """'-"'-"

. . .-

......_ _... , -

.. _

..... >

355

IV. Trypar1OIiOffiia

2. Antlmicroblal spectrum, Penlaas 8 very ShCf'l MII'Iito In 11111 body,

ot lho kldQwlng slatements about dllofQquino ar1,l

1" EXCEPT,

(=:..~::~':~ )

A. II bk>Cloa P"l!(lZOlll DNA and RNA synlhoM.

B. InleClod cott, can concenltal0 the dlug

Ie

a

IIflallH eXlQnt llan can UfW'Ilec;lod cdIs. C. II II lhe dnJg '" Ch one oF the ~isa><ma?

' _ _ 'C2RI_lb ......

I'

0I'._10I~_00lb"

._-

"sMp. 250 ..

01"

ha _ , C2'r'
Figure 36.1

SlJfI'dnllfy of anthelrrinthic agents.

B. Pyfantet plImoale

Pyranlel pamoal8 \Pi RAN tel] along with mebendazoIe is eltective In the Ireafment 0' Inledlons caused by roundWorms, pinworms (see Figure 36.4), and hookworms. Py,antel psmoale is poorly absorbed orally and exerts its effeds in the intestinal trae:l. It ads as a dePOlariZing neuromuscular bIod _ _ ~

1fqIIc8l A......

_

e

CII8o.""a:'.:l. ."" _ _ """"'*,oft...

~.Idn

MA>aJfanecuo

TRICHURIASIS (WHIPWORM DISEASE)

_ n g In bllnd-.

_.

eTlwapy: _ _

e c....- __, Trlc!>utillridlluno. e=,..:~~~:.,

ENTEROBIASIS (PINWORM DISEASE)

e ea-.... ~

Ep!e(OtJluI-...k:uIao1..

...... ,-

e_ e

c:omnwnor, helminthic Inl_In tlw

HOOKWORM DISEASE

1' , _ llk:ef1lka.",

1_1lIaod .... 11I..

e

ASCARIASIS (ROUNDWORM DISEASE) e~"""'_.""oboF

•

,'' '

T'Mb"..." "'.

e '"'-f>Y: PynnI"~OI>rO-.oIy _1II1n:l " ' _ .........

e

. . . . - caualng ,. _ _

,ng ....

e

e

e e--rv.--.oa' _

bal .. otl!,

""" ""'"_""""""'''''If''''

of ,'''''''''-:

1IIlo... I,

e --~ "'_IIiII""' e

n.-p,:

-

1lI1_IIuIicu in the ueatmenl 01 whipwo<m infections. ~ 0; elfedive by orel admlnislr1lllon. D. II is active apainsl ceslOdes. E. II inlerleres with gluooso uptake by the parasite.

C.

CorNcl_ .. D. ~ Is eIlec:tlYe 19InoI:.- • ... In III' dooa I 'II gUxIMo ......, IIu -...Ir4l h ~ 11> _ _ t h8I bien " - ' II> tle ~

,e

'*'

MICl'"'*'lJef*: In~"""'"

• "'" '0...I., ....... __ , >

-_

..."" ....---.--' .. .....

Antiviral Drugs AHTMIW. DfIUGS I. OVERVIEW

-

Viruses are 00l1ga1ll Intracekrlar parasites. They IactI both _ eel waI and _ cell membnlnll and do noI carry 0lA mel8bole ptOOllSse' Viral •eproductlon uses mllCtl 01 lhe host's metabolic n'lIII:Nnery, and lew drugs are seledr.e enough to prevent Wal replk:alion wilro.rc Injury 10 II1ll host. For 8UIlllle, Wuses 8re noI aflacted by antirnlcroblal egents. Nevertheless, some drugs sutIicientIy discriminate beffieen cellular and viral reactions to be eltoc1ive and ~ relatively nontoxic. Uni:)r1LJf18tety, only a lew virus groups, Including those thlll cause tI1a v1mllnlections discussed In tI1is chapter, responOlO It1ese drugs (FIgure 37.1),

-

-_., ... ..... •

FOIl HEN'OlA.NDCYTo-

""""""'" Ac,._. -~

,C/III'hen I'r'lI::I61 of the YinJs plMlides hlMl 'Olj • •...., [Note: This oonlrasts wilh bedeic. (lsea5!1 In ¥It"ich Ihe dn:al 'Y"lpIOl'lS are usuaIy wi ....d.... with b8cIeriIII plCOMlIioq /4J !his late. 'YUlpiOh Illlic: stage ollhe virBI i ,Iedioi ~ ao,.lisba!io, 01 drugs .... blrdt "'rill repIio:alio, hlMllmled ellectioollioess. ~. some riviral agents are usehJ 8S ~1Hojr, agents. For emm~ _fal1ile I_ MAN 111 deen] and lis col'lgelle., rtnantadine [m MAN 111 deerl] hlMl been shown 10 be equtIIy eItectMIln preo.ec lI:i l{l Influenza A h'lfecllons. [Nole: AmantBd'ne Is also elfectivll in the trea1menl 01 sorne cases 01 ~'s diseese (see p. 87).J

_.,1' ' S"" ._1'

*

1. Mode 01 .etlon: The pmcise antiviral rnecnanlsm of amantadine

.sa ..... IoN')

, . , : .• ..-:;1 t,

-

FOfI

..... (An)

HEP_m.,u:'.""

_~"'1lOl)MA

".1000",

FIgure '.fT.1 SufTtll8l'Y of antMml drugs. lDesabed In Pharmacology update, p. 457.

I


5. Adverse efIe..

nine Bf3bIrIosIde) is one 01 !he most effective 01 1tle nucleoside iWl8Iogs end is also the least IoIcic. HoweYef, ~ has beef! ~ dO"icaIy by «)dlMr. I'ofIict1 is more ef..... b 1$ ancl safe.. Although vidarablne is active againsl herpes simPlll< virus type t (HSV-t). HSV·2. and variceIa·mster virus (VZV). its use Is limited to lreatmenl 01 Immunooompromised patients with herpes simplex keratitis or encept1aflIs. or vz:.J infections. Vldambinll. an adenosine analog, is converted In the cell 10 its 5'-lf1>hosphate analog (Ara·ATP), 'M1ich is postulated '0 inhibil viral DNA synthesis. Some reslslnnll1efpes vifl,J$

0 0

3

• • " " " "'olltl.

Flgur.37.4 Comperison 01 wrvivalln patients with ~herpes ~xenceph­ alitis treated with "'dilfllbine or

..-

• .,._ • . . . . -.........,.. , l

37. Antiviral Drugs

368

mutants haVe been 6eleded

-

_ell,

"

ltlat haVe altered DNA polymerase. To be etlective systemlcally, poorty solUble vidarabfoo must be aQ-ninis· tered iolraveoously in large volumes rmr a ptolotiged lime, usually 12 hours. Vidambine penetmtes into the brain and tl'o..Js Is ellecllve In !he treatment of herpes simplex encephalitis. Vidarabine ointment is effectiva in !he treatment or herpetic and vaa:irIiaJ keratitis and in hef· pes simplex keratoconjunctivitis. Vidarabino and its metabol~es are found in the urine. AcMlrse effecls during s!lof1·te<m use are r(lI serious. CNS disturbences and fluid overload. however, eat1 be a prOblem in patients wilt1 impaired hepatic or renal 'unction.

F, Trlliurldine Trif/uric1in(J [try fLQO ri dean) has replaced Ihe eariier drug, idaxurick>e [eye doll 'ltor I dean], in the topical Ireatmool 01 keratoeorljlrdiviti due to herpes sifTlllex viruses. Uke idoJaJridir>c, tllis p>,'rimklr.e analog is inrxlfporaled into the viral DNA to disrl4lt its f\n:tion.

See p. 457 loI' a description of newly apprcwed drugs, pendclovir and cidofovir. V'darabme

IV_ TREATMENT FOR AIDS Presently six drugs ere epproved to light human immunodeficiency virus (HIV] intection. FMl are either pyrimidine or purifle nucleoside analogs, and must be COOV'erted to their nucleotide torms to exert their antMral etfect. [Note: The 3' position ollheir deoxyribOse moiety eilhe, Iad<s a hydroxyl group or is bIodo:ed by an azide subSlituerl1 (Figure 37.5) II1us prevenmg dlain elongation.] The sixth drug is an HIV protease inhbitor. AIIhou\tl not curalive, these agents Interfere In 1I1e mutllpocetoo of the virus and sloN progression of me disease to possibly prolong survival. A, Zidovudine j3'-A,tId0-3'-Deoxythymldine, AZT) One of the most eHeclive drugs currently approved lot treatment of HIV Inteclion and AIDS is Ihe pyrimidine analog, S'·azido·3'dooxylhymidino (AZ7). AZT hes the generic name of zidovudine [zye DOE vyoo deenJ. AZTis presently employed in patients shown to ha~ documented HIV Infedion. Improvement in immunologic status (increese in absolute number of helper·induced T cells) hes been reported. Most elyuridine (ddUl· The urine is the main foote of excretion 01 ddC. although fecal e1iminelioo 01 ddC, along with ~s metabolile ddU, occurs. Rash and stomalitis are common bUt resolve on continued treatment Peripheral neuropalhy is tile major toxicity and Is probably a consequence oIlhe inhibition of the mammalian m~o­ chondrial DNA polymerase y. Pancreatitis resulting in death has occurred, especially ~ ddCis given with pentamidin8 (see p. 354). D. Stavudlne (d4T)

Stavudinc [STAY vue deen) is an analog 01 th~idine in wt1~h a double bond joins the 2' and 3' carbon of the wgar (see Figure 37.5. Uke the oIt1ers in this group staVUdine must be coover1ed by the Imracellutar klnases !O the triphosphate (d4TTP) whktl inhibits the rEMlrse·transcriptase to cause DNA d1ain lermlnation. In adelltion it inhibits cellular enzymes such as lhe II and y DNA polymerases thus reducing m~ochondrial DNA synthesis. I' is loa early to assess lhe Clinical advantage or resistance to staVlJdinc. The drug is almost completely absorbed on oral ingestion and is nOl sHeeted by rood. Sta..wine penetrates the blood brain banier. About hall the parent drug can be acalUnled for in lhe urine. Aeflal impairment interferes wilh clearance. The maier and most common dinieal 'oxie~y is pedpMlIuenza i11teG1i01.. B. If is iQ)ollCl'altd ~ the vftII DNA C8UIIng pl. lfIIII..a DNA

ttIIlln 1""'*'t11ion.

C. If i. lhe 11. .'''''''1 01 etlOlee in herPee Umpie_

eo lCfIIIheMiI.. o. If

r~ !he euallion 01 '-'anI associeled \MIh g.nilaI hIlrpIIII i~ .. E. 11 inhibits only flCtftre!y replialting ........ r>ol

--

Q!

lilt lollowlng .1II1ernff11. Ibwl lklowdlo.

(AZT) are Cfltfect EXCEPT:

A. II nUS! be oonveII.

"4

.....

c-"-,,c.~,p

..'"

••",IM"",

Figure 38.1 Summary of cancer cherrv>therapy agents. See Pharmacology update. p. 463, for Illklitional drugs.

......-.--_....-.......,.J.-._,,

...__ ..-..._"'

c.e-.oo ,,"""'-

373·




'"

38. Anticancer Drugs

Purine

_ .... _.

Md

~

""""""'"' .". .....01,...,......

pyrimidine synttwasls

by chemolherapy, immunotherapy, ment modalities (FlglJrEl 38.3).

or a combination 01 these treat-

2. Indication. tor treatmenl: Chemotherapy is indicated wtlen ~ plasms are disseminated and not amenable to surgery. Chemolherapy is also used as a supplement to surgery and radiation treatment to attack micrometastases. INOle: Tumors most susceptible to current chemotherapy are undiflerentiated and have hig1 growth fractior1s.]

3. lIJmor susceptibility Ind the growth eyde: The \raclion 01 tumor

"""em.'"". RIbonucleotide.

cells that &e in the replicative cycle ("growth rraclion1lntluences their susceptibility to most cancer chemotherapeutic agents. Rapidly dividing cells are generally more sensitive to anlica.ncer drugs, whereas nonproliferating cells (those in the Gc phase) usually survive the toxic e\feCts 01 these agents.

and tumor cells go through a growth cycle (Figure 38.4). Howevef, ncmnal and neoplastic tissue may diller In the number 01 oolls Itlat &e In \he various stages 01 the cycle, Chemotherapeulic agents tl1at are etteclive only in replicating cells. that is those ooP' ·"at are cycling, are said to be cell-cyde specilic (see FlQure, '), whereas other agents are ceU-cycIe nonspecilic. The nonspealic drugs such as the alkylating agents, allhough generally more toxic in cycling cells, are also uselul against tumors wiltl a low percentage ol replicating oolls..

I. cell-cycle specificIty of drugs: Botl1 normal cells

_1fTW.,.•

--

CYTA1U'rI1ItJe

Tso". ,

DNA_

Deolily-

b. lIJmor growth rate: The growth rate or most tumors in vivo is

DNA

.. ",._01 ..........

--_ . ----DACJWClMYCW

8. Treatment regimens and scheduling

00'''''''''''''' DA""""""'"

_ ,*.. ,..

"'lIItA

IlHA_

.

initially rapid, but decreases as the tumor size increases because or the unavailability of nutrients and oxygen due to inadequate vascularization (see Figure 38.3)_ Reducing the tumor burden through surgery or radiation promotes the recruitment 01 the remaining oolls into active proliferation and increases their susceptibility to chemotherapeutic agents.

J

Proteins

Figure 38.2 E~les at chemotherapeutic agents affacting the availabitily at RNA and DNA prec~.

1. Log 11111: aestructioo 01 cancer cells by chemotherapeulic aQef1\s lollows lirst-lo" abaut 1 11'''''11'_.

ot llboIIt!he.1zoe 01 • _

•

_.tthl

.

uaIIy Q....

~~(

10"

".

CHnll:al .ympt."".

. . - ...·4

----nU.-

.......... i

. 44 0 •

.. -......-

•----''7,.Tr

,,'

CURATIVE CHEMOTHERAPY (dlaemlr'lllUld cancef1O, ......... Ie<Jl. ~

''''P'''ide _ _

3. Toxicity: Therapy aimed at killing rapidly proliferating cells also affects normal cells undergoing rapid prolileration-lof example, buccal roocosa. bone marrow, gastrointestinal (Gl) mucosa, and hair cells-contribumg to the lolOc manilestatiorls 01 chemotherapy. a. Common adverse effects: Most chemolt1erapeutic agents have a nB/row fherapeutic index. Severe vomiting, stomatitis, and alopecia ocaJr to a lesser or greatBf eJ

38. Anticancer Drugs

whereas othe, adverse reactions are confined to specific agents, lor exaflllle, cardiotoxicity with doxOflJbicin (see p. 385) and pulmooa.y fibroois with bleomycin (see P. 386).

b. Duration of adverse effects: The duration of the side effects varies widely. For example, alopecia is transient, but the cardiac, pulmonary. arK! bladder toxidties ara irrevefslble.

c. Mlnlmldng advers.e alleets: Some toxic reactions may be ameliorated by interventions, such as perlusing the tumor locally (lor example, a sarooma ollhe arm), rernovil1g some 01

,

the patient's ma"ow prior to intensive treatment then .eimplaming it, or promoting iolteosive diuresis 10 prevent bladder

toxicities. The megaloblastic W1emia that occurs

w~h

mc/hlr

IroKafe (see below) can be ellectively oounleraeted by admin-

---

istering lalinia add (/evcovorin. 5·/ormyltcrrahydrofolic ar;KJ. p. 379). With the availability or human gfllnJlocyte colony stimulating 'actor (filgraslim), the nelllroP€'nia associaled with trealment 01 cancer by many drugs C!II1 be partially '€!Versed. 3. Trealment-Induced Iu~; Since most antineoplastic agerrts are mUlagens. neoplasms (fo, example. aCllte nonlymphocybc leukemia) may a,ise 10 or more years atle, the original call00r was cured. Treatmem·indllOOd neoplasms are especially a pr0blem aile, therapy with a1kylaMg agents (see p. 387).

III. ANTIMETABOLITES

---- ..... .......

Arltimetaboliles a,e struau,a11y related to no,mal cellular components.

They generaJly Inlerfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibl~ng their synthesis Of by competing with them in DNA or ANA synthesis. Thel, maximal cytotoxic effeas P"", S-phase (and lhe'elore celk;ycle) spetille.

A. Melhotrexate

~

myeiosu"", uian

Figure 38.6 COrnpariSOll 01 mye!osuppressiYa polefltia! 01 at1ticanc:er drugs.

Metholrexate [meth oh TREX ate] (MTX) is structu,ally relaled to toile acid and acts as IlJ'1 arrtagonist of that vitamin by inhibiting dillydrofolate redllctase'. the enzyme lhal conve,ls tolic acid 10 its active, coenzyme form, lelrahydrofolk: acid (FH.); it theretore acts as an antagonist 01 thaI v~amin. Folate plays a central role in a vari· ely of metabolic ,eactiofls involving the transfer of one-cartlon units. (Figu,e 38.7f. 1. Site 01 aclloo a. Inhibition 01 dlhydrololate reductase: Aller absorption 01 toIic acid from dietary sources Of 'rom lha.t produced by intestinal flora, the v~amin undergoes reduction to the telraltydrotolale form (FH4) by tha irltracelllliar NADPH-dependent diltydrofolala reductase. Metfl(]lroxafo ente's the cell by an actiw transport process, Which normally mediates the entry of N5·methyl FH4. At high MTX concentrations. the drug can diffuse irlto the

,

........ _..,.,---,.

'"

III. Antimetabolites cell. MTX has an unusually strong Ilffin~y for dihydrofolate reductase, and effectively inhib~s the enzyme. lis inhibition can only be reversed by a thousand-told excess of the natural substrale, dihydrofolate (FH;e. see Figure 38.7) or by administration of /eucxM:Nin, """ich bypasses the blocked enzyme and replenishes the IoIate pool. [Note: LeUCOKllin, or fo/inicacid, is the N5_tormylgroup-carrying form 01 FH".j b. Consequern::es 01 decreased FH4: Inhibition 01 dihydrololate reductase deprives the 0011 of the varioos folate coenzymes and leads to decreased biosynthesis of thymidylic acid, methionine and serine, and the purines (adenine and guanine), and thus eventually to depressed DNA, RNA and prolein syJ1thesis and to cell death (see Fogure 38.7).

c. Polyglulamated MT)(: Like tetlahydrofolate itself, MTX becomes potyglutamaled within the 0011, a process thaI favors intracellular retentiOl1 ot !he compound due to its larger size and increased negatiV(l d1arge (see below).

2, Resistance: Nonprolilerllting oolls are resistant 10 mefhOtrexate. Resistance in neoplastic cells can be due to amplifICation (production 01 aOd~ional copies) of the gene that codes for dihydrofolale reduCtase resulling if1 increased levels of this enzyme, The enzyme affinity lor MTX may also be dimif1ished. Resistance can also occur from a reduced infkJx of MTX, apparently caused by a d1ange in the carrier-mediated transport respof1slb1e tor pumping mclhOfrexate into the cell.

-- . ,.~

~

•

.0"-- Uo llw;;Oex.m •

0'". /

~'~FH~~:~:eFH.~

)

""".-

dUMP

N"toI'· I.IeU"k,-.ft\,

I I ~mlcIytlc_

Leucovorln rescue A!ale coenzyme Is requifecl in the lhymidylate synlhelllse reaction. Lack 01 SlJfficienl coenzyme (educes the etIecliveness of the amiA',imidioltl.1 S-FU Is also incoIpoIaled no RNA and kJW IeoIels haYe been detected in DNA.

','->c:r.

2. R. . Resis.ant eels Ble enmunteled thaI have lost !he abijity to convert 5-FU into its adlve Ioim Of have altered Of 10 iCl ad ItTfmid'Ilale synthelase Of haII8 an ifICIfllSed rate 01 50FU 0IfabrAism. ?

3. Thenopeutlc appIic:a~ FbJrourlJd is ~ prWn;riy in the treatmenl 01 sio¥o1y ~ so5d ll.mOfS (lor ~ colOfectal, blBllsl, O\Iarian. pancreatic. and gastric Cllfcinomas). ~!heIap¥ Wth le\a'lIisoole. a Y8terinary ........ agent, 10'''''0•• the surviYaI 01 palietots Mlh aU.. cancer. 5-FU is also elleetive tor the llealrnen1 of superficial basal cell c:a,,::illOi'•

,.&

..nen !JWi"d 1Opically.

4. I'hannllc:oklne.: Beca'lSe 01 its severe Iolcicily to the G"rad, 5FU is gillen Io1J3WnOUSly Of, in the case 01 sm canc:ef. tqlicaIIy. Tl1e drug penetra'es well into al tissUes ~ fle eNS. 5-FU is melaboized in the wer. Ia.-geIy to COr. ~ Is apired. The dose rnJsl be adjusted in the case oIlmpaired hepatic fu.-.cOOn.

. . . . 10• ..,.1 > .............. I >

< ..............._

. . , " " " - .. _

.... >

III. Antimetabolites

o

~:-Jr' I

O)...N

"

5-FI<Jm....,~

(s.FlJ)

Figure 38.9 Mechanism of 5·f1uorooracifs cytotoxic aclion. 5-Fluorouracilis converted to 5-FdUMP, wtich competes witll deo"YIJlidrne mooophosphale (dUMP)'or the erllylTlB tIlymidytate synthetase. 5. Toxlclll...: In addition to nausea. vomiting, diarrhea. and alopecia. severe ulceration the OIal and GI mucosa. bone marfOW depression (with bolus injection), and anorexia are frequently encountered. A denTlopaltry (e.ythematous desquamation of the palms and soles) called the "hand·tOOl syndrome" is seen after

0'

extended infusions.

e. Cylarabine Cytarnbine jsye TARE a been] (tyIOsil'le arabinoside, ara-G) is an analog of 2'-deoxycytidine in whid1 the natural ribose residue is feplaced by o.arabinose. It acts as a pyrimidine antagonist

1. Site of action: Uke the other purine and pyrimidine antagonists, ara-C must be sequentially phosphofylated to t!le corresponding nudeotide. cytosine arabinoside triphosphate (ara-eTP). in order to be cytotOllic. It Is $-phase (hence celI-:: oh ROO bi sin) and daunorubicin [!law noe ROO bi sin) are classitied as anthracycline antibiotics. Doxorobidn, ollen relerred to by its trade name adriamyc;n. is lIle hydroxylated analog of daunorubicin. ldarubidn. the 4.-Qemethoxy analog of daunor~ bicin is also available,

DaclinomYCIrI

1. Site of acUon: The anthracydines have three major activities that may vary wilh the type of cell; all are maximat in the 5 and Gz

phases: a. Inlen:alalfon in tIM DNA: The drugs insert nonspeci!ically between adjacent base pairs and bind to the sugar-phosphate bacldlone 01 DNA causing a loca1uncoiling, thus bIoding DNA and RNA synthesis. Intercalation can ioIel1ere with the topolsome.ase II-catalyzed breakage·reunion reaction of DNA strands to cause llflreparable breaks. b. Binding to cell membranes: 1l1is action afters the tunction 01 transporl processes coopled 10 phosphalidy1inositol activation.

c. Generatlon of oxygen radicalS through lipid peroxidatlon: Cytochrome P-450 reductase (present in cell nuctear membranes) catalyzes reduction ot the anlhrac:;yc:;!ines to semiquinone free l8dicals. These in tum reduce molecular 0,., producing superoxide ions and hydrogen peroxide that medi· ate single strand scission 01 DNA (Figure 38.tO). Tissues with ample superoxide dismutasa (SOD) or glll!athiOl1e pelOICidase activity a,e protected. s Tumors and the heart are generally low in SOD. In addition, cardiac tissue lacks catalase and lhus cannot dispose ot hydrogen peroxide. This may eJIPlaln the cardio!OlW;leIy used ;lll.icalll:e 0\.95. II is used b' treatmenl 01 $lIfcomas WId a variety 01 carcnlmaS. in::lucIing bfOOSI and IunO. a5 well as acute Iymphocylic leukemia and lymphomas. ~ is used in the Ireatmenl 01 acute ~ and ~~

4. Pharmscoklnetics •• AmofptlorI .00 dIllltfbutlon: Bolh drugs must be ad'nillisleled inll'llYlll"(lUS/y since !hey ara inadiYated in the gastrOOt8$tinal traeI. Extravasation is a serious problem that can tead 10 tissue

necrosis. These drugs bUld to plasma PfO\einS as wen as 10 tissues whefe they afe widely distributed. They do r'lOI perletrate In.o the central nervous system. DoxorublCOIl Dllunorublcm

b. Fat,: Both dfugs U1dergo e~te . . . . . . - , .

reso.oe

guanine in Ole 01' 004tl strands d a DNA rrdeo lie (F9Jre 38.12). TtiIi alkylation IeiIds 10 ~ between ~ .....0 ~ in the DNA chains, andiOf depurination thai IaciliIaleti DNA 5I/lIfId /)l e ill 'l'.}e AkyIaIion ClIfl also caJS8 i' liscc:df 'll f'l'Uao lions. AlltW:lUgh al(y\llion can 0C0Jf in boIh cycling and fes&lg cells ("ebe oeIqde rKAlSf*ilio), PO' fali'll cells are_ senslMllo the drug. "'"1-' 1ty ..... in G, and S ~ 51

Resis'anr:e has been llSCIibed 10 deal!ased permeability d ... drug. roeased COfliI.9alion wilh It** Sf.dl as glutalhiotle. and Po ssHy increased DNA <epa;'.

2. RetbtwlcR:

3. 1llefap'MIc ItflplICllUonS: MecIYoIelhamine is used primafily in the treatmenl 01 Hodgkin's disease as part ol the MOPP regimef1 (MechlOfethamloe, Oncovin. PfedniSOOll, Procarbazine). and Is also useful in the trealmef1l 01 some solid tulTlOfS. 4. JIt'Illrm.ooldnetlc:s: Mechlarelhamine is very unstable. and solulions must be made up lust prior 10 administration. ~1hamin6is also a powerflJl ~t (bIis1llfif'og agent). and is administered only IV. beaM_ it can cause seYefe Iissue damage if ecbansation oa::ura Bel;at_ ol its reaclMty. hllldy

:.tnt dfug is excreIed.

s. r ..

... _

::o:t: . ",.

.-

C=.I,_

et1ecU: Its adIo'erse etIects inc:lude severe _ and medaI-'). (NoIe: These effeds ean be ~ ished by pelreatment ~ ~ (see P. 243J 01' ~ thiazine (SM P. 242).1 SeYoere bone marrow depression limils ~ use. LaterC vifaI il'*':lioflll (lor exat\'llle. I PReS Zt:lliIll[) may appear beca_ d immunoliuppfession. Extravasation is a serious problem. " it oox:urs. Ihe area shoUld be inliltnlled ...mtl isoIo..ic iIIOdit.m Ihio5tMiIe 10 inadNate . . drug.

_,iiIi.., (........, Actgef . .

e. Cydopho5Phamlde and I10slamlde These drugs i1re very closely related mustard agents lhat share most ollt1e same Ioldc:ities. ThlIy are !rique in !hal (1) they can be taken 0filIly, and (2) lhey are cytoIaIic only oller generation ollheir alkylal' Ing spade$, lolIawWlg!heir Ilydn::IIyIation by cyloc:hrome P"'50.

1. M-.;h.nlsm oj .c:tion: Cydophosphamide (sye kloe FOSS iii midells the most commonly used atkylatlng agenl. 8

•

.,... K

..,

............. _

.....

'"

VIII. Other Chemotherapeutic Agents drug are excreted through the kidney. Bone marrow depression is lhu major loxicity. Nausea yom~ing. and diant1ea are common. The drug is alSO neuroloxic. causing symptoms ranging lrom droWsiness to hallucinalions 10 pa<esthesias. Because il inhibits monoamine oxidase, palienls oooold be warned againsl ingesting fOOds thaI c0ntain Iyramlne (for example, aged cheeses. beer. and wine). Ingestion of alcohol leads to a disulfiram-type reactior1, sea p. 96). ProcarI;Mine is both mutagenic and teratoget1ic. Nonlymphocylic leukemia has developed in patients t<eated with the drug.

O. l-Aapa.aglnase

l-Asparaginase [a SPAR a gi nase] catalyzes the deamlnation 01 asparagine 10 aspartic acid and ammonia. The lorm 01 the enzyme used chemothl!faPlllJlicafly is derived from badena. 1. Mechanism 01 action: some neoplastic cells .equire an e~temal source 01 asparagine. because 01 their ~mited capadty to make SlJI· Iicienl L·asparagine to support QKNIlh IV'Id function. L-Aspamginase

hyO"oIyzes blood asparagne and thus depri'v'es the IumDI cells 01 this rutrienl required br proIein synthesis (FlQUre 38.19). 2. Resistance: Resistance is due to increased capacity 01 tumor cells to synthesize asparagiM. 3. Tl1el8peullc application: l-Asparaginase is used to treal child· hood acute Iympttocytic leukemia in combination with vincristine (sea p. 390) and prednisone{sea p. 393). 4. Phllrmacoklnellcs: The enzyme must be administered eilh&r IV or 1M because it IS deslroyed by gastric enzymes. Disposition remains undefined. S. Adverse elfeelS: Toxicities include a raflge 01 hypersensitivity reactions (since ~ Is a foreign protein). a decrease in clotting faotors. and IMlr abnormal~ies, as well as pancreatitis, seizures. and coma due to ammonia toxicity. E. Interferons

1. Clas.slflcallon: Human inlerlerons have been dassilied into three type"S, «, ~. and"/. on the basis of their antigeflicily. The« intef1erons are pnmanty leulfTr>el cell. haw high .~_

....tH

to ....... sulllc'-"t _ . . . 10, "'Ohln synthosl...... cell gn>WIh

3. Therapeutic Indica lions: «2(A)/nterleroo is presently approved lor the management ot hairy cell leukemia. More than 90% 01 patients treated w~h« interferon have shown resolution ot cytopenia. reduction in tim incidence ol serious inlection. and reduction in the need t:.tr transfusions. DIller interlerons are being fested in lt1e freafmen! of various tumors, including squamous cell carcinoma. melanoma. and mutliple myeloma, among others. 4. PtUllmacoleo

_oven

C. Cylarabino. O. Mec.:hloretharrne.

E. l-Asparaginase.

pIn ..... 1h8 """"PIOiIioo, al purine Syr1_.

'See p. 3SO irl BIoc_ry (2nd ed.) ... olism.

<see p. 1 '4 on BIoc,*"lolry (2nd eel.) for """ 01 r1!1lCli>-e I&,e p. 365", BlDc:hftnlOlry (2nd ecl.) lex rolIl 01 topoloorneraoIl"' DN"'~

,.""

.....'.,.'

'.

,

_

...... --_.,....,.".". .. ..... UNIT VII:

•

Anti-inflammatory Drugs and Autacoids

Anti-inflammatory Drugs I. OVERVIEW

ANTHNFLAMMATORY

DRUGS

......

tnllammalion is a normal proIediwI response 10 Iissoe iflury ........ed by physical trauma. noxious chemicals. or mic.oblolOglc agenls. InIl8trwrIalion is !he bod(s efb110 I'Ial;tivale Of c;Ieslrt¥ hIeding orvanisms, _ ft&ants, and set .... stage tor Iissoe ffJPlW, WIWI heaIrlg Is complete. the inflammatory process lISUally subsides.. IIo"eO'llf, ~Iion Is som (,_ iI'lapproprial:ety Iriggeled by an Irron'",s agant. suctI as polen. Of by an ~ resp:n$e, as In asdil", Of mec.matoicI arttrils. In suctI cases. 1he defense reactlollS themseM!s may C8U5e prOQl: SNe tssue injury, and antHntlammalory or i'nnu1o~
39. AntHflflammatory Drugs

A. Role of prostaglandins as Iotal mediatOf$

ANTI.-lNFLAMMATORY DRUGS (contlnued)

I-

c_ --

DRUGS FOR ARTHRmsl

~N~

Me_",,'"

~-~

C-

I

DRUGS FOR GOUT

Prostaglandins and related compoonds are produced In minute quantities by vinually all tissues. They generally act locally on the tissues in 1Itlid1 they are s}"1thesiled. and are rapidly metabolized to Inactive products at their slles of action. Therefore. the prostaglandins do not circulate in the blood in significant concentrations. Thromooxanes. leukotrienes. al'\d the hydroperOlent,,,'Ie tinII. The m<MI

_ ..",,", CDnfiVur..- ere:

'1'

0


15% 01 paDenIs takirIg aspirin experiel'lee hypersensitivity reac1ions. Symptoms of uue allergy irdlde ~ b .. dlOCUlStJie drug. Mosl8dll8tse eIleds 1lAI" I ,elated. Gl O)f,~1ts oonsisl 01 nausea. 'IOi'illil(j, ........... lIarrhea. and alxb,lilial pan Uloeraliol, dille upper Gt lraCl can OCOS, !iOO'eIi'leS ..... perto. ration arod l\efTlOf'fNgll. The most _ e and frequent CNS etlecl is frontal her :ladle, ¥otkh o:x:urs In 2S 10 50% d pa1ierts ...tIo ct...dcalty use .lCb1~ Olt'er tr~ CNS eIIecIs are daiI e5S, Yl!f19l. ligtII-neadlldl and manlaI confusion. AoIIe p;n;:reatilis has been knoWn kI 0lXU'. Hepatic eI1ects are flIfe. tr..rl some lalaI cases ct t'i8pa1itis and jaIrdoB I1a\Ie been reported. Hemalopoietic reactions repor1ed with i'Id:trnettIIIc Include neut,0peni8. th~ and (flIf~) aplasticanemla. HypersensiliWy reactions i"lcUle flIShas. urtiearia. itctWlg. !lCIJle altad<s ct IlSlhma, and 100% cross-mactMty ....,jth ssp;rn ConQJffent 80111nlSlration of Indomelhacin may decrease !he iII'llilypertensMI e11oc1s d fu/ClS6rl1lide, tha tI1ilQil:le (liuf(!lics, IlbkxtJng drugs and ACE irNJ/tora 5

Figure 39.10 Some advef!8 effects of indomelh8cin.

."".,........ ,

.. -... _,. 39. Anti-inflammatory Drugs

2. Sullndac: Tills Inactive pro·drug Is closely related to indomelhadn. Metabolism by hepatic microsomal enzymes pr0duces the acWe form (a SUlfide) 01 lhe drug, which has a long duration of action. Although the drug is less potent than indomethacin, ~ is useful In the treatment of rheumatoid arthritis, ankylosing spondyUlIs, osteoarlhrlHs, and acute goul, The adverse reactions are similar to bot ~ severe thart thOSe 01 the Oltler NSAtDs, ~uding indomelhacin. 3. Elodolac: Tnis drug has effects similar to those of the other NSAIDs. Gastrointestinal problems may be less common. Hcmever, otl1er adverse effecls such as fluid retenlion and abnot'· mal kid1ey and liwr function have been repoaicw

,

1""''''''''''''

."""

--............. .•='" '" .... _ --_.,..-

........ £ a . -

Pytatoln.:

. . . . . . . . . . . . .J=.,..,=, I ......·.,.·.·.·'. '. ·1 I l _ GI irrilIlion .... ~

~ldcl!BC etJc IlClds:

,.....

Fa.,

~ ~=~-.g

) , ,

_

~

111:

Figure 39.12 Summary 01 noosteroidal anti-inllalnmalory agents (N$AID$). A. Acetaminophen and phenacetin Acela"oi~(e seat a MIN oh ten] and phenacefin [Ie NASS e lin] act by inhibiting prostaglandin synthesis in lhe eNS. This ecp6ains theW arwip(reljc and ar'olIlg . properties. They have less efteCl on C)'doooYgenase ., ~ 'issues. wtlidl aocDUnts for their weak anti-inflammalory aclivity. AcetamInophen and phenItcetin do not atlect plalelet U'lClion or;,o 8se blood cloning time, and they lack many 01 the $ide-ef1ects of aspirin. INote: Phenacerln can no longer be prescribed in the United States because 01 ils potential lor renal 1000icily. However, it is present irl

some proprietary preparations.!

1, n-&peutlc: uses: AcOOmklopOOn is a suitable substitute for the analgesic and anlipyretic etlects 01 aspirin irl those paIienIs wtth gastric lXln'¢lints and in those for wtoTI prolongBlion 01 ble ;lji'll lime woukI be a disadvantage or who do no! require the antiinIIatrmalory lIdion 01 aspIrtl. lNote: 8ecal15e of its Iowet lmlidly. ~ has repIal:ed ptrenaoe6n in virluaItt 811 hea """, products J ~ is Ihe ana'gesic-antippelic of choioe for dillcll... ,....., WaI i ......... or d'IidIen poll (recallhat aspiYI increases the risk 01 Aeye'$ $yndrome, see p. 407). Aceta" • .....,... does not an&agcrize flB unc::os...lc agenl plooenedd ancIlhefet;lre may be used in patients wilt! gout ~ hlI drug.

.... '0...,., •• _ .... _ , .

.~

_----,- -

..

-

- . w·

2. PhaffTliOCOklnelb: Acetaminophen is rapi(Iy absof'bed In:lm the Gttracl. A signil'icanl first..pass metIlbolism OCClJfS in !he luminal cells of the lrlles~ne and in the hepatocyte$. Prlenacetin is largely conve tlyJl

.." .

::+0-"',

-

-te _

u •

'd

'd

~-

au-

See p. 467 lor a deso""lioi, ofl'll!My appI'OYell drugs used in treating rheumatoid disease

VI. DRUGS EMPLOYED IN THE TREATMENT OF GOUT Gout Is a metabolic disorder chamctetinld by high lBll8ls olurlc aticl in the blood. This hypeMil)emia reSlJRs in the depOs~ion 01 crystals 01 sOOium Oilile In tissues, especiaUy the kidney and joints. Hypeniticemia does nol lllwayS lead to gout, bot gout is aIw8ys preceded by hyper' u'icemla. In humens, sodium urale is the endproduct or pu,ine melabolism. ~ The 0ep0siIi0n 01 urate Cf}'SIals initial" 811 inllanYnalOry process moMng the inlillralion 01 granulocytes thel phagocytize the utlIte crystals. Tllis process genero!" UiCYliJIlfl metabolites. wI*:h damage dssue, resulting in1he re6ease of !ySOSOfTlllI enzymes lhat eYOI<e an inIlan'wnaIOfY fl!SPUilSe. In addi60.., lactate prod' 'dian in lhe synovial Ms,*, increases. The resulting IocIll decrease in pH losters fui1hef deposition of uraIe crystals.. (500 F9I'e 39.14 Iof a ~ of this ploe s ) The cause of Ilypen.ft:emia is tlI"l 0\ ec po\"" IC'ljon of \Iic relaliYe kl 'tie patierV'$ 8biIiIy 10 eJlO"N it Mo5I 1lenIpe'" straIegies tor gtll..t irM;M IO\flIef'ing lhe uric acid IiIMIl baow if1e ~ poW. . . . ple'lnOng the "epos!O;)n 01 urale crystals. ~ Cllf1 be aocompWled by (1) inIec1eliolg ¥Iilh uric add SY"" . with ~ (2) ilo E'Sing uric acid excrelion wiItl probentJQd Of ~ . (3) il~iIliIii"" Iel*ocyte entry ioVO the 'flecled joio"II wifl ",ddlidue. Of (4) ad"M1istJ1llion of NSAlDs.

--" .. .,(._.HI ,.

_ < A ..."

.....

-*'

A. Treellng KuIe gout AaJIe gouty anacl<s C31 resut tmm a noo1ber 01 OOUdtioolS, if1dud..ing llIlCeSSiIIe 8Icohol ~. II die! rich in pumes. or kidney d1seaSll. Acule llllacks lire trealRd wi!h colchicine 10 decrease ~ of grarUocytes into the alfeClod lilfea, and ¥lith NSAlDs to decrease pain and inIIammalion. [Note: Aspft'1 is conb'aindialted, because It competes with uric acid lor the organic acid secretion mechanism in the prOlllmaltubole or !he kidney.]

_

::'!";\':.'~~

... ",..,.."..,-J

---,.~ ..;,:",:;;'=---Flgure39.14

Role 01 uric acid in the inlIammation d """.

'"'''''''' ..... ,

'"

.. _...

_"

39. AIlti-inf1ammalOry Drugs B. Treating chronic gout

can be ca"sed by (1) II genelic deIect, lor eK8f!1)Ie. one r8Sl.Alil'lg in atI increase in Itle l8le 01 pwine 5)'1111 nil (2) renal defio ienty, (3) l.esd1-Nytrlwl s.,ilcflo"'.... or (4) e' sT. syntl sjs 01 Uric'" tlScocia1ed ...... cancer ~ Treatmenl $lJ1lIlIgies lor chronic gaul indude lhe use 01 uricosuric drugs lhal increase1he excretion 01 uric acid, Ihereby reO.Jcing its c:a1Oili1b. lion in plasma. and the use 01 aNopurlnol, which is II seklctiYe irttior ollhe lern'*lal S$et)S in the biosynlhesis 01 Uric .:ill Qworie gotl

C. Colchicl..... CoIchII;;IN lKOl c:t1i seen]. a plant alkaloid. Is reservecllor!he treatmen! ot acut.. golrty at1ad'"•

...~sls

m.nl of "'eumelllld arthrills. Low ooaea '"

"'1'''.110 d&a

iact>amlf;: ar1adesis, C. They f""lue
ca........ "ontal headache. Long haH·lifil ""'mils daily or

A, Indllmelhacin:

SoAdac:

C. Nap'0""":

EXCEPT: A, II Is a asPirin.

weak., anll·lntlammalory agent lhan

...,

B. II 'edt.ces f""'" '" vi'8/ infections In c!1ildren. C, If is an aspirin subslilUle In pallent. wilh ptlpIic o II exacelbales Il"lJl E. II causoa hepatolO.ic efIects 81 high dll$e$.

'see p, 1r.'1n l1li ' _ olIN

~

III. Aotihistamines

----_.. .. _..... , """"""

Histamine H1 - receptor blockers

-

-

-

«-Ado ..... gI'Co\>IJI _ _ •

w

>

I_ OVERVIEW These extended case studies complement the basic information presented in Chapters t to 40. They reinforce basic principles of pharmacology, such as the role 01 patientlaetors in empiric antimicrobial therapy. Most 01 the cases provide dinical informa~on obtained from a single patient: some (;BOOS deSClibe a oompos~e 01 typical fee· \1.Jres derived from SlMlral patients. These cases illustrate simple pharmacologic principles, as ronsideration or kidney function in drug dos!ng--ooncepts useful in answerir.g examination questions, and in the dinics

sum

CASE 1 A 53-year-old man was admined into a hospital with fever, a cough that produced purulent sputum, and wortness of breath that had been present lor several

"''' Two years eartier he had developed Kaposi's sarcoma and was human immunodeficiency virus (HIV) positive. In the interim. therapy with anti-HIV drugs had been disc:onlinued because of his inabmty to tol· erate them. However. the Kaposi's sarcoma was treated with anticancer drugs, includir.g doxorubicin. He was being maintained with oolrimoxazole. fluconazoe. and rifaoolin (a r~amycill antibiotic similar to rifampin) and receMng weekly treatments with fiJgramstin {granubcyle slimulaMg fac/ol} and e/}'lhropoielin. At the time or admission lor the CO\.Illh his hmper-indJced T-e:ell (CD4) rount was 131llL A roest X-ray revealed a cavitary lesion of the rigtlt upper lobe. Cultures oblained from brom::hoscopic biopsy and broncho-alveolar lavage specimens yielded methicillin·resistant St8phyl0CQC(;lJS aureus (MRSA) with no evidence of lungat Of acid-last organIsms. Treatment with the normal therapeutic dose of vancomycin. 1 gram intravenously (IV) every 12 hOUlS, was begun. Because he insisted on receiving his treatment at home, he was disd1arged with a peripherally-inserted central venous catheter in place. Though his revers abated initially, he again experienced Ireqoont dlitts, fever, cough producing white-toyellow sputum. and progressively disabling weakness 48 hours after the YllfIOXlmYCkl had been started. Several days later he was admitted to the hospital, wtlere it was noted that he was alert. fully oriented,

and extremely weak. His temperature was l03.6"F, his plJlse 130 beats per minute (BPM), his blood pressure (BP) 80160 mm Hg, and his respirations labored at a rate of 28 per minute. He was eldremely cadlelic at 6'4" in height and weighing 135 pounds (61 kg). There were purple lumorous plaques rover~ ing parts of his body. His chest revealed dullness and coarse crackles throughout the right upper and rridlung fields, suggesting pneumonia. A chest X-ray oonfirmed the diagnosis (Figure A.l), llUl 900 mg per Oose. only .lighly lcsa ~ ..... 1he dose IhaI he was r~. D (le"""""nis} does noI ot itself result In d""'l/
lhe

«- _.

Dl1he 1DIloooil'O ""...., . " , _

a.-Ion A.5: Wl'dI _ .... Ia r:eIIazidimd/

to'lClly .t "Igh ilium I.....'.) .. """ cDlrect E ceI'.udt>o iI WI_ .... "ed 1\1 0/ ....1IMJIQ.8tr (N) ~

",

E. Hec:uld not be r,j-Jf!n 10 Il'egnant worroen. A (........ lTIIlllriiI Glnl t". eradicalen by ~ but is.l'kan~ by ~ 8 ladeCJ.8CY (II (II""""",-in "--"'lI f.liiiiIIJ tor the just stat..:!. D (Ihe ulen? 011.... ..................) is inco'I'ewWIg agons QOUId r:.. used 10 CO'IIitm .... cIagncJsi:s. B. Acef>IcI'lofu. C. E"ltqJu""",,

~'*""'IS_CU1I-.~ lhecdf

0._

lCml (II _

E. PIIJcapii..

'eq..a"9"

....... tt:aI does net IIllID'ICl d ""'A' is _ _ • ~ b ' ( - - " .... 01 tlIDCId aCl>l ... II"diw:t..III.~.... f . - . ~

,-

srao .... iI ... ~ J R t s e i n _

This pelien1 iIustraIes the ~ 01 pregnancy in guiding the choice 01 an any drug! AdYerse etlects 01 drugs are 001 only eJrierted on the patiEnt. bIJl also Ihe fetus, IItt1lctl cannoI awid exposure '0 drugs ItI&t ale taken by the mother, and wI'Och cross the placenta. With this patieot. mdical curB had to be delayed until the delivery 01 her baby (who was born perleclly

Corect _

~c.

AdiIO_oI

gas

.,.. be COli' i el. and his BP 135170 fMl Hg. An oral examirlalion revealed carious

seve."

" " - ' flee.... 01 h pIIIotrJI's _~..... 15. ... absceM IlJ'\d _ a I Cllfious \Ieetf\ end ~ .. J)'_ ence 01 11 " nurTUS lWId lOw grade !adeJ'Io::i.

dol. Flap(! . _ '... io ~ 1a' . . ~ Oog c:ce odilJOl,

."""0' ..'.' .... _ _ ,·

."

This patienl was treated empirically wilh ~ a60ne because hs pITisldans suspected 1tlal. he had .. Idoc:an:litis, caused by Sl(l~' .5 •• If 01 the yjrjde"'i group. The hislOl)' indicated that the origin 01 the ~teal ... do no! have ICIMfy

fIM:rmrr... _ n .. IBclIlllt CIJII6. • a ~ pIaee. !he . . - . .. riok of . .

~

_

~ _ _ C II inconect ~ ........... If'lIedOIIO be _eaIed II ~ V ~ " ~ agansI """" . . . . . d ftWrrgxp § buI In endocArdills • is ~ brIcleridcllll Cl1Iy """'" ~ is used in rorrbnaIion WI1h . . ~ so..dl

U

g.nlarnicin. Th. comllinlll'on il syne'olslic

bec/luse V8f'lCcmycin', efleel on eel WII~ synthesis lacijiUl1es ttllO entry 01 Ihe &rrinogIyc05l.' CXlI_I5 Cl1Iy !IIlm, , , ' " n bIcW& nu I _ no cell ,... ••• ~ I
CASE 7

palpable nodules or masses. Pulses were strong blIateraily. Heart sounds were normal. Hand tremors preser1ted as well as sJighI hyperreflexia.

A 32 year-old homeless. HIV-nega~ve man lU'lived 81 'he clinic complaining 01 general malaise and a d1ronic productiIIe cough.

Laboratory TeslS reveal elevated !hyroItine (T.) and slightly decreased Ihyroid·&Iimullllinli hormone (TSH). AI olher 18S1S were wiltW1 normal ~mi\s.

The patient stated thaI he had been Ieeling poorty lor abotIt 5 weeks and thoughl he was losing weight Upon ~ eKalTlinaIion. a sI{;IIty eIlMlled 1e"l)Bl'atu.e and chest congestion were noled; no other apparent irJeg.lIariIies were presenl. Lab tesls were

The woman was treated with ~ lClOmg every 1I1loUrs, and propranolol 40 mg I¥ke daily. OuIIstlon A.16: WI*1I_ at lhelall;Mioog'" dllIaibM 1hlI,1W!id• •" at ao;:Iion at ~ A. t«O.lrlg Ihe~ hoo,IO ............ 8. UiOIiirg ItllI """" ......, at f¥dd tOilO .. c.......-onatltlll.~., . ............. _ .. ~

ordered. including a complete blood count (CSCI. sp.cJ.m ClAIre. and an aQO.fasl beciIi (Af8) stain. A chesI X-ray (F.gure A.7) was oblained and a purified protein derivalive (PPDI was administered. The palienl was k*llo reLm in 2 days lor alolow1Jp IItsit.

fly........

D. UIitIiIioI, at iId'oII ~ lnIClltlll rJyroid gland. E. il~lbiIia, at TSH releeM ~ piIkMary CclmIcl _ _ 8

~~"'b­

.....,df¥oid'..."o..

A_ 1..11:

~ u*og ~or ~

"'. .KonI

,. . . . . . . ,1""'''''.

mclII ~ - . -

mug

'-..ioI'1ll moNIor tor.7

B.f..... C. M) 1;011 D. G

oil

¥ OIl (Gllo,.-

E """" CorTei;l • _ ClClIO::n .-.:l ~diIo d ~ roldlsrn In lI>e lirll lew ......... d 'llIf~. In ~

adrllflllfgic .ltCeplorS I.' upregulaled (thele is a higrIer popula\lQn In U.. visculll~el in lhe hyP'""IIly'oitI patient th" II Is IlT\flOftanl to block lhese P .ecepilors....., ltIOreby leo1>ce It\e bIooc:l preuure, lVolt> 'Cll.fn 10 ee visual syfTllloms? A. Isoniazid

B. Riklmpitl C, E/tlambulol

D. Pyrazinamide

The c
Coreet M$WeI is E: Sumatffnan a~ered so.t>colaneously is ,apidty absorbed and prOYi • _ ... _

",.

• e - .........._ _.. ,

I >

>UOIUl _ _ ....

>

AppendiX: IlIust,ated Case Sludies

~

OS

ft

P06sibIe

~e&lJtIe(II

oplkn Howevee(Ofe_""",' ...... nDllll!oeey ere_in w,tIio Ii, _GjjO I" II. 1J"tCOfect.

_

.. h

~iII

__,

",

_

~

~ancI

'*"ll ....

paroc - . . . ••

D. (.I".""•..,.....-

ncI Rloc:aMld lei '" pru-__ irIcuIl!Cl So, ....,••• po. mriI' III _ ~ sOr-. """ ,.. .... &'&(IJIQc

etlettEosio_,..;L,.".._bIaI• • _' a.o:allil

.. _

'''C(antl . . . ~ ~ ) _

~.

FIYe days later the chid .et!Jmed 10 the dinic.. His haflds, lo.earms, and chesl eoythemalous, swollen, and covered with blisters. His motile. ecpIained the poison i¥y was star*lg 10 dea" ~ bUI .-.en her son disobeyed her and wertl if*' .... woods

.,e

...........

Rash and _ . lei on paIillnl's arm.

boJ

had .eoantIy been playing more oulside ~ Ihe yard, due to the Ilol weather, and his rnotIler asked if ltle JastI ClOlJd hIll/ll beencaused bychiggeJs (larvae of miles Ihal attae:hed 10 the $kin). Wdtl Itlll pa6enl's IVstofy of playing 0\.IICI00rs, and Itlll dlar/lOo terislic hili vesic:les. the doctOJ' belMMtd that the dlild had an aIergic oonIaCl I'fVpefsensitMt reaction to poison ivy, and InstJYCted the mother 10 apply c:toehs soaked ~ BurovIs solution (aft.n\hlm acelate) lXltif the Yesides crusted over. The molhef was also told to thinly appIyt"" hydrooOJ'6sone cream (a low poIency steroid) twice pe, day.

The

Question A.22, Thlt hypersensiIivi! ,eaction was no! S 10 wallent stlonger phalll""""4'>g Ihclmp)r, blA Iha palienl IOQuests IOITl8 romody 10 SlOP Iha pt..tIUS (~cNng). wtW;h til Iho following drugs &hooItl be

,-

~""'. Dundon A.23: wticn one "' . . Iooii... ~.".'. g Iheo~ $hIlUId '-'oe bem poNtitleol nea 10 atlBnu-

_ . . ~ ........-.? A. AfIPY hl tr,ckc:atisOl"'aearTI mcoelfequenly 8. OoaIp«dlisollfl~,l8pereddown_ 2 ~ C. HosP\3fiZaIion O. &llaliE'll'_ _ oio.,."..... occlusion E.

AR>lY ice It~

11)'"

lte COI'fect IIJlSMlI ill B DA iflCI'ellse-

ptolnce C II IIICOJ,eet H05pIla~n1Jon mooN be ,equ;ed ~,. d*l's ~ ..... 1*...... _ ~ C6 , , _e se>o",~ detillf og• .,.. d'ikl • A"Ib.IaIaY _ .. no _ disftsa, _

'Ij)IU'=d.-

,.-.roo.

-..ed en an Q "l ife I bIso5. D ill irco'. a ....ong IDpcal _Cfll INl ......., be a.<Jded ..... ~ ~"-.:id _ lIrge _ _ InlI pc8ti,r bfd<M _ e. lnlI l<JICIty I: I i _ · recI. 101....,. dlIo • SCfM of IUI\30 described her paio as sharp aod IlX:aIized, and stated thaI it had 0CClJrTed ,.equeotly wmg the previous :I week$. One week prior to the clinic visil. she had Slafled IakIlg IoIMl..Oll (ak.ominurnImaooesiu'n l¥i'wide antacid) and it seemed 10 ~ al first, but lhe pain penisled and shof1fy thereaher fie leg sweRiog appeared. Her pasl medical history irduded • prior .-.. F1an ... Q8IiIr( hosIay....... "00 ~ ID IcrloIfIlIIIIf>cU ......... ........Iig..im ~ _ _ DCIIo:lfVelI - . t1 mlI;D. D is raxrect. FuO$4lO,Otif Ii a loop diur~ used ID eIirrf. nate lIuId in patienls wiIIl I\uod _ such 1$ . . CHI' C6 pat,anlS •• pa,....eing pulf\'lOf"11fy _ f'utos8rrK1e is , Ia!;I ac:Dng lIiurelic will oilIe effects Ihat indo.de: hypci.W carlJi. ""lIOn lIIlladd 1hM OS L.ose<J lo treal 003rlt>..o"n ane COl'lblnaIia> arwacid I>as bIlf.:o1 .........., lo cause CMSlipati 'ecepIOI artagoNsts. They wry in 1Ilei' side etI8C1 !yOlile and to some extent in IMi, pha,macokineli(;s. Cimelidioo has Ihe mosl side etleclS. which include croluS'Ot'l. d,u,ness, d,a"l",a, muSCle pa,n. and gyne. 'eeeptor an~1gorHst Ihe,aPl' l\fId Ihe antaCid cOUld M"" e fme 1f3COOt of digt:»g worse an:11he ge!l polaSslun tor sodced by aSlhma sulfe'e's ck6ing an aUadoc:oI'Is1ric Sfld an IISItrna 1lI1ad< H their lI>'eceptors are blocked. Also. I\-blocl<ers may cornpHcale "elll1'rl91l at bronIJI . . _

......

This aooondum provides a current update on important drugs that have been added to the clinical arsenal since the second edition 0/ UppiI'lCOtt"s Illustrated Reviews: PharmaookJgy was published. The addendum is organized by chapter, and eadl drug is presented e~her as a continuation at a preexisting section co.ering similar·acting drugs (!of example, add~ions to the list ot drugs used to treat Parkinson's disaase. below), or as totally new types ot drugs (see the section on th'ombin int1ib~o's, p. 448), Extensive cross-references 10 relBllant pages in the body ot the t!lld allow the reader 10 pIao9 these recently approved drugs in their proper dinical COO1tBllt.

Treatment of Parkinson's Disease V. DRUGS USED IN PARKINSON'S DISEASE

(continued from 1188)

The following a,e new, nonoflrgol dopamine lIgonlsla that have been

apprOYllCllor the treatment 01 Parmson's disease. PramjJexOO 99 percent), and has a smalllllliume or dislribution (0.13 L1kg). The plasma hat1·life is approximately two hours, although inhibition ot COMT may lasl considerably longer due to ~S affinity lor lhe ElnZ)'1OO. ToIcapone is eldensively metabolized, and its metabol~es are eliminated in bolh the urine and teces. Dosage may need to be adjusted in individuals with modefale or severe cintlosis.

2. Adverse ef1eets' Diarrhea is the most common side effect of teJ· capone. As eKpOCfed. leIiI:XIopa-reIaled adverlie effBCls increase when tokapone is added. These include postural hypotension, nausea. sleep disorders, anorexia, dyskinesias, and hallucinations. Most seriously, IUlminating hepatic necrosis is associaled with /Q/capone use. Baseline and Ir9Quer1t, regular detenninations of hepalic serum en:tymes are suggested by lhe manufacturer. Any elevations above normal are cause lor discontinuation. Because of the hepatotox\city, toIcapone should only be used as an adjunct in patients on JevodrJpaIcarbidopa who are experiencing s~tom fluctuations.

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Chapter 15 Upcla!e: Drugs Used 10 Treal Epilepr;y

ny two petOOI1l is 8llcre1ed lrIChanged. The ma;ooty 01 Ihe 8IlCfe1iorl is biiafy (65 peroent). 'Nitll 5QfTlEI 00nary excretion (25 percent). The hall-lile in healthy ..ounloors is SlMlfl kl hours.

.w.e

2.

aflKts; Decreased mantenance doses fTIIlY be necesroary in individuals wilh hepalic impalrmenl. Ac!YerSe sHeets include ~ dizmless"" gasl' .... 'ls I-oal t.piel..

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eo pen::ent.

Peak ............ 'lrations 0C(:tJr In aboUt lWO hours. some 30 perceliliO\IElil. ...t1ich accounIs lor !tlei" spedlic ilrUgOlliY" lS It*! I... OJ ...... These otWlJP()U'ICI$. like abciximab. can decrease the illCidel lOll 01 d.onobolic COI,_!!lWlns asrotia*, wiIh IICU18 coronary Sy,,(1I(l111ElS. Wherl ~ irII'usioo is stopped. flese agen1S are rapilIy cleared rrom !he plasma, but thW etlect can persist lor lou" ho\n. E¢fjOaJide and its met8bdrtes al8 eKC"eted by the klclney. TIfOIfben is 8llcr6led I.W'ldlangecl by !he k01ey. The major adYerse etlect 01 both d'ug5 is bleeding. Fl\iUre 20.15 Sl.IIOOlaril:es some dinicaI ertects 01 the GP 11bt111a reoeplor antagonists.

These

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Agure 20.15 Effects 01 ~ 11b!l11a leoepklo' 8flIagOrists 0I'l the iliOdeoa 01 death or nonfillal ~ Warction !clllo¥Iing percuIaneOI.Is transIln1inal

eoronary angioplasly.( NoIe: Dala are rrom 50lMlral studies; thUs reported incidBi ICe 01 COI'tl'Iicalions with slandard therapy Is noIlhe

same lor each d' ,, _ _ ,)

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'" Insulin and Oral Hypoglycemic Drugs

26

IV, INSULIN PREPARATIONS (continued from p. 260) Most 01 the insulins derived Irom beel end pork have been largely teplacad by lhe human form, synlhesized u1ilizing recombinant DNA technology. For example, lispro insulin is synthesized by recombinant DNA techoology, using a non-pa1hogenic strain 01 E. .leoossary to maintain r10mlal bIoocI ~uoose llIwIs in 10 normal

.-,.

Glimepiride [gty MEH ~ rlde] is a new, second generation sultony\-urea. II was the first sullonyllnlR to be l\IlPW'o'OO for C()I"l(UTllI'\t use with insulin, but has no adciIionaI acWantage 0\Illl" the oIher sullonylureas. Elimination is through the urine and feces. Like all sulfonylUI'(las, ~ can cause~, t?,tperlnsulioemia, and ~ht gain. O. Repaglinide Although repaglinide [lett PAG lih nide] is not a sulfonyltJrea, it has actions in C(lfM'lO(\ with this groop of drugs, Repagh'nide binds to the ATP-sensltive polassium channels 01 the pancreatic II cells, causing the lelease of insulin. Repag/inide is Willi absorbed orally, and is taken thraa t;mas a day before meals (its tu:!" 1 hr).




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Pharmacology Update

1. PtoarmacokJoetlcs: Oral absorption 01 the drug increases when taken with food. It is exlensivel~ bound to sefUm albumin, and has a plasma hatt·l~e 0116 to 34 hoors. Troglilazone is metaboliZed to several inactive metabolites, and can induce cytochrome P-4SO. The primary excretory route is in the laces. The drug is contraindi· cated if! breast·feeding women. 2. Adverse eftolcts: There have beerl deaths due to hepatotoKidly in patients taking IrogNlazone. INafE: The FDA and the manufacturer have restrided the use oIlroglilazooe to patients in hospitals and convalescent homes.] It is strongly recommended th3tliver enz~mes and bilirubin levels 01 patients on the medication be measu.ed initiall~ and periodicall~ thereafter. [Note: A related, less hepatotoKic lhiazolidirnldione, rosiglirazone. has recenll~ been approved b~ the FDA.] Adverse effects that have beef! reported include: upper respiratory inlections, headache, anemia and edema as well as weight gain. Trogli/Bzone increases metabolism 01 oral oontraoeptives. Which ma~ result in O\IUlation and pregnancy. Levels of other drugs such as cydosporine, whidl is metabolized by cytodllOr119 P·450, ma~ also be atfacted.

Steroid Hormones II. Estrogens (oontinued lrom p. 266) E. Anitestrogens (selective estrogen receptor modulators)

5e-Iective estrogen receptor modulators (SEAMs) act as estrogef! agonists in some tissues, but block the action 01 estrogen in others. The first widely used SEAM, lamoxifen (see p. 266), has the anti· estrogenic etfect 01 reducing the risk fOf breast cancet as well as the benelicial estrogen ellects on serum lipids and bone densit~ in women (FIQllr9 27.14). However, tamo"illlnalso has the l.fldesjrable antiestrogen ellect 01 causing hot Ilashes, and the undesirable estrogen effect of increasing the risk lor endometrial cancer and venous thromboembolism in women. Raloxifene, a second-generation SERM, increases women's bone density without increasing the risk lor endometrial cancer..

3. RalOllifene: Lika larnaKi1en, which is also a SEAM (see p 266), ralc»rifena's (ra LOCKS ih loon) actions a'e mediated through the estrogen receptors, and it has both estrogenic and antiestrogenic effects. Its dinical use is basad on its abilit~ to decfease bone resorpiioo and overall bone turnover. However, unlike estrogen and lamoxlfen, it apparenll~ has lillie to no ellect on the eodometrium, and therefore may not predispose to u1l1fine canoer. Rak»r:ifene lowers total cholesterol and LDL in the serum, but has no elfact on HOt. Of lrigl~oeri
'-''''''''''>'---') Chapter'D Update: Steroid Hormones

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ReduCerapeotic advantages and adverse e!f1!ClS of quinolones.

F. Trovalloxacin

Troll1lfloxacin [TRO vah IIocks a sinlis a new fluoroquinolone, whict1 has several properties that gi~ it some clinical advan· tagllS. These proplIrties include a long hall-life ot aboull0 hours, which permits OfIOO-a-
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'"

Chapter 37 Update: AntMral Drugs

Antiviral Drugs

37

III. DRUGS FOR THE mEATMENT OF HERPESVIRUS INFECTIONS (COI1tinued from p, 368) Herpesviruses are associated with a broad spectrom 01 diseases, for eJu<s.

Rgure37.10 Summary 01 seleded a.ntiviral agents.

IV. TREATMENT OF ACQUIRED IMMUNODEFICIENCY OISEASE (AIOS) (oontinued'rom p. 371) Traatmef1t of human iml'Tll.lOOdelicieoey virus (HIV) irlleclions has b8en radically mod~ied during the past two years by the introduction 01 p0werful antiretroviral drugs, and by the deveIopmDfl1. of melhods to determino the viral burden in plasma. The introduction HIV protease inhibilofs and non..flUCleoside rEl\I(IrSD transcriptase inhibitors has made this breakthrough possible. However, lhe Iong-torrn therapeutic benefits and salety profiles of these agents are stiN bDing evaluated.

0'

f, HIV protease inhibilors (continued 'rom p. 371) These drugs are peptidyl analogs that rlMlrsibly inhibit the proteinase that is essential tor the tinal step ot viral proliteralion. Protease irlhibitors have revolulionlled HIV therapy, reducing infections by opporturlistOc organisms, and prolonging and improving the

lives 01 roost patients.

.

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Chapter 37 Update: AnliviraJ Drugs

.._.----,--_.....

t. s.qu;navlr lsa KWlN a veer]: TNs drug is taken ornIy. ~ has ~ ,_~y reIom'U8ted ... a sdtiIal ""'4'5'Mlorm Ihal Wrpoves lis billa 3 ti!ioy, aIf'Q.9llhe <Wl'llUll absortJed ,~ !he IowesI fA aI lhe protease il~ibilufs atlltlPi....."atBly 12 fA ltle 00II dose. III ordef to maximize ab5orption. ~ rl88ds to be Iaken with t'igtllal meals.. DistrbJtioo io'*l tissues is good as evidenced by II la,ge volume 01 disllibulion. Elimination 01 saquinavjr is prYnarily by metabotism loIIowed by biliary excretion; its hall-lite is 5 hours. Plasma levels can be sigldicanlly irlcreased when saquinavir Is !XlI ubilled with other antiretroviral agenlS lhat Inhibit ~s metabolism. such as rJelavirrJine (SIHl P.kXM). On the other hand. drugs that enhaoce the metabolism 01 ssquimtvir. soch as rilampin (see p. 333). ritabvtin (see P. 333), and other ~ indu< ...... _ _ , >

Pharmac:ology Update

nephrolithiasis and reversible hyperbilil\binemia. Aclequate hydration is i'nportant 10 reduce the irocideoee 01 kidrley stooe formation; patieflls should dmk at least 1.5 liter.> oj water per day. 4. Nelfinavir (ne! FIN II _J: This CWg. when used in combination with zidovudine (AZT. see p. 368) and Iamivudine (3TC. see p. 370). decreases viral load by at least 10C1-Iold, and increases CD4+ oounts. These effOCls hall(! been sustained lor as long as 21 months. Nelfinavir is well absorbed and does not require strict Iood Of fluid conditions; however, it is usually given with Iood. A hydroxylated metabolite appears to be the ac!ill(! agem. The halflite 01 nelfinavir is 5 hours. Diarrhea is Ihe most common side etlect, and can be controlled by !operamide {see p. 244). Like other members of the class. nelfinavir can inNbit !he melabolism oj other drugs, resulting in required aiteratioos ot drug dosages. Of !he prohibition of COI'I'\bined use. 5. Amprenavlr [am PREN II veer}: Like other prOlease inhibitors, amprenavir is used in combination with a least two fi\.lCleoside reverse transcriPlase inhibitors. Its long plasma hatf-lilo permits twioo dally dosing. but the large size and I1UlTIbef of capsules per day (16) day may reduce patient compliance. The drug may be less well tolerated \har1 some other protease inhibitors and it is unclear whether amprenavir offe's any clinical advantages 0Vilf Olher protease int1ibitors.

6. Common lIdIIerse effects of protease Inhibitors: As Protease Inh,bltors

FIgure37.12 Drugs thai shoIJld nol be coadministered with any protease iflhibitor.

e~perience

with the protease if1t1ibitors has grown, two important adverse reactions that are corrwnon to all 01 them have been UOC(l\l(lred. a. Inhibition of cy1ochfOrlle P-45O-dependenl OJlldalions: All of the protease inhibitors inhibit cytochrome P-45D-dependent oxidations. The following drugs should not be coadmirristered with any prOlease inhibitor: 1) antian1lylhmics such as ambdarona or quinidine; 2) antihistamines such as astemizole or terlenadine; 3) antimigaine-ergol derivatives; 4) antWllycobacterial drugs such as rifampin (it decreases protease inhibitor kMIls); 5) benzodiazepines such as midazolamor IriazoIam; or 6) Gl prokinelic agents such as cisapride (Figl.Jre 37.12). b. Upodyslrophy lind hyperglycemia: The protease inhibitors can cause these two disordefS. These eNecls are primarily associated with indif!

Pharmacology Update 2. Phartnilcol
G.MollOdolllll.,tll:l:¢ •

UonodOllal &ldhdu ani! pIOdi'Olld by hybrid eels oeated from B tymphocyIes fused wiIh r.,WIl0.181'" B ~)'1e \UTIor cell&. The .esdting I¥Jo'ids can be incilIDJalIy doned, and each done wit pr0duce aftibodies (lirected against • sWlgle tltItigetl type. Two . ff1Oi1cxluoal ar1Iibody IypeS have been creaIed that llIe useI~ in ~ Ireametll 01 cen:.er. 1. T...~ In metastalic breast cancer paIients. 0Yef~ sian 0I1'unan epidermall10wth IactDJ I....... protein 2 (HEA2) is seen in 25 10 30 peroent 01 patients. TIlISlIlZlIrIab (Ira STEW zoo mab) is a monoclonal .. ,~ that bn:ls 10 1-ER2 sIles in breast caocer tissue, and inhibits lhe PJol~enItion 01 cells that OYefexpre5S the HER2 proIeh Thus. trasluztmab specifically targets the undeftying getl8tic delect that causes the cancer. The drug can cause rBgres&ion 01 breast cancer and metastases in these ~Is. Trasturom.9b Is 8dr1'Wiislered intriIYenousty; ils metabolism and elimination hlMil not been deSQibecl. The most serious toxlciIy assodaled wiltl IraslUcwmab use is congestive heart failure. Othel" adVerse ellects incIode headache. dizziness, nausea, vomiting, abdominal pain and beck pain. Cautious use 01 the drug is rocomnended in patieflls who are l1ypersensilive 10 il. to Chinese hamster ovary oeU proteins, or to ben~ ak:oI1ol (in which case slerile waler can be used lor preparation of the injection). Extreme caution should be exercised in patieflts with a preexisting cardiac ~ion.

--

dol 1111 hIIbl

impilicaboo, since COX-2 is constitulive in the kidney and brain, but Is lndu
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PIlarma: whm binds to calcioeurin (FlQure 41.2). The latter is responsible tor dephosphorytating NfATc (cy1osofic Nuclear Factor of Activated T cells). The cyclosporine'calcineurin comple~ cannol carry out this reaction and thus the subsequerrt reactions required lor the synthesis o! a number 01 cy1ok1nes. including Il·2. canroJi occur. The end resutt ot cycJosporine action is to oecrease Il-2. the main stimulus for increase in the number of Ihe T lymphocyles. Cyc/D$por;ne is used to prevem rejection of kidney. liver. and cardiac aJlogeneic transplants (FiQlJre 41.3). Although it can be used alone, il is more effective if glucocorticolds are also administered. and this is the usual practice. Cydosporine is an alternative to merhotrexate tor the treatment of severe. active. iheumatoid arthritis. It can also be used !or patients with recak:::iIrant psoriasis that does not respond to other therapies.

\

Figure41.3 Effect 01 cycIosporine on liver transplant survival.

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474

Pharmacology Update b, Adverse effects: TacrDiimus is more toxic than cycIosporine. For example, nephrotoxicity and neurotoxicity (tremor, seizures, hallucinations) tend to be more severe in patients treated with tacrolimus. Other tOllici1ies are the same as those lor cyclospa/ine, except thaI lacro/imus does oot cause hirsutism or gingival hyperplasia. Anapflylactoid reactions to the injection vehicle have been reported. Tho drug it1lefllClions are tho same as those dest::ribed aboIIe lor cycJosporine.

42

Drugs Used to Treat Obesity r.

ANOREXIC AGENTS

Obesity reters 10 presetlOO 01 excess body fat The amount 01 body fal is dllflCtJ~ to measure directly, and is usually detefrnined from body measures that have been shown to correlate with body fat in mast poopIe. Tho body mass index (BMI) is a usetul dinical calculation lor diag10sing obesity because it oorreIates with total body Iat, and Is relatively UIlaffected tl'j heigh\. It can be calculated BMI" (weight in kgY (height in meters)2 determined Itan tables. The normal range for 8MI is betwOO/\ 19.8 and 26.0. Indil/iduals with 8MI between 26.1 and 29.0 are overweight, those who have a 8MI greater than 30 are obese by definition. Obesity is a serious health problem, and its treatment is difficult, because individuals find it hard to adhere to a program 01 dieting and exercise. Currently, two new ll:1oreJdat1ts (appetite suppressants) are available. They are phel1lermine [FEN tur meeo) and sioorramine [SI tl'joo tra moon). both amphetamine-like agents (see p. 103). Of

A. Phentermlne and $ibtttramine

These agents have many properties in common. Both are syrlllathomimetic amines that exert their pIlarmaoologic aetioo by interfering in the reuptake of serotonin and OOfepinephrine into the presynaptic nerve terminal, thereby increasing their brain levels. In the case 01 phentermine,!here is an increased release 01 dopatrino, \\ot1ereas with sibvtmmM1e, the rO\4llake into the presynaptic Ill!t'IIe terminal 01 senr tanin, /\Ofl!pinepIlrine, and toa!esse< extent Oopamrlo,Is hirldered. 1. Pll8rmaco1mellcs: SibtAramine undergoes first pass demethylation to aetM! metabolites, which are turlhef biolranslormed it1 the Iivet' and elfCfeted primarily in the....me. Tho haIf·1ife is about 15 hours.

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Chaptef 42: Drugs Used 10 Treal Obesily

2. Adverse effects and contrllindicaliof>s: These are similar for both drugs. For example, they are both controlled as Schedule IV ageols (they have a low liability for depeIlde!1ce or abose). Heart rale and blood plessure may be increased. and dry mouth, headache, insomnia, and constipation are common pr~ems. Pulmonary hypertension has occurred {rarety} with phenrermine. especially when it is in combination with farlfluramlne. [Note: Thfs combination. referred to as "1en-phen", was widely used as a diel aid. II was nol only reported to cause pulmonary hypertension, but also heart vatve abnormarities. Fenfluramlne has since been withdrawn from the market.] These adverse elfects have not been reported for sibu/ramlne. Sibutramlne should be avoided In patients taking moncamlne oxidase Inhibitors. selective serotonin inhibitors such as fJuoxetine, or serotonin agonists lor migraine, such as sumalrfJran, as well as lithium, dextromelhorpllan. and pentazocine. Drug interactions can occur when slbrilramine is administered with drugs that ifItlib~ CYP3A4, such as /ai/oronazoIe, erythromycin and dmetir:1ine. The increases in sibJ/ramine are smail. and no untoward conSBCpJences have been reported.

II, UPASE INHIBITORS ~ stat] is the first drug in a new Class of r.onsystemicaJly acting anliotlesity drugs know as lipase inhibitors. QrllsUlI is a pentanoic acid ester that inhibits gaslric and parcrealic lipases, thus decreasing the breakdown 01 dietary fat into smaller molecules. Fa! absorption is decreased by about 30 percent The loss of calories is the main cause of weight loss, bot adverse gaslrointestinal eflects associated with the drug may also contribute to a decreased food intake. OrtiS/af is indl· cated in iflvidl.l8ls with a body mass index of 30 or more, or in persons with a 8MI ot 27 or more who have other risk factors. such as high blood pressure. high cholesterol l(!\Iels and diabetes. In dinicaJ trials, individuals treated with «lIsta/1ost an average of 10 percent of their body weight (compared to 6 peroont for the placebo group) wilhin one year (Figure 42.1). Total and low-densfty lipoprotein {lOLl docreased more In the treatmem group than the placebo group. The most corrmon side effects associated willl ortiSfat are gastrointestnal s~toms, such as oily spotting. flatulence with discharge, fecal urgency, and Increased defecation. Orlistaf interferes with !he absorption of the fat-soluble vitamins, II caroleoe and carotenoids. Orllstat is OOIltraindicated in patienls w~h chronic malabsorption syndrome or cholestasis.

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• Figure 42.1

Effect of orlistattreatmenl on body weight.

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Pharmacology Update

Drug Used to Treat Osteoporosis

43

I. OVERVIEW OsIeoporosis is a cordtiCfl 01 skeletal lrag~ity ..,.. '"

lid .lOOOIlUl irJ5Ulic:Ienc:y pmary. . - - . 2 7 4 ~.1I811""'"274 1llr1iMy. III ", .... 274 L• • ' .... 274 '-O.lOOOI ....... opiI; I... ,' ..... See CookOLqllll ...cAIAMYc:»l. See~

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.".." I8nlZOf;lin, 71/. 73, 73, lB01. 189 IWnok:f. 711. 741, ro. 76, 78'-79~ 1791 ~"'dr'erwglc blodI& .. fIIlllCific agera,

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I,,,.. ""lamlde, 272, 212. m1, 3)4, 390\-395,

3." goserelin, 247/, 250, 25Q m1, 394, 394, 395, 3951

gosereIin """late. 394 ldal\ltllcW'l, 3731, 385 iIOOamlde, 373t, 388. 38lI-389, 3891 ImeoolOll5, 3631, 371, 31 r, 371 I, 3731, 397-398, 3991 ~,2471, 250, 2!(), 3731, 394, 394. 395. 3951, 3991 meo:.:t>Ioretha"*'tl, 241 ~ 3731, 381, 3ll7368, 3881, 3991 6-mercaptopurine, 3731-3741, 3Ef(),:J80.. 381,381/,399'.417 navelJine. m1 padila>.tll, 3731, 391, 391-3$1, 392'.

endazoIe. 359. 359, 359', 361/ rOdosarrOdll. 359/, 362, 362 pmziqua1tef, 359/. 300-362, 362, 362 pyt'S(IWl pamoll1e, 359, 3591, 359-360,

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1hiabendazoIe, 359t. 360, 360. 361' Ao1ihislarrines, 9Ot. 96, 96, 1071 a,~le" ..1ic potency, 243/

as autacoids,

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in oombinalioo therapy, 243 preanesthetic. 108 to< ttWills, 221 specific "Il"flIs. 217t Antihistamines, speclllc ....ts aSlemizoie (HISMANAL), 214, 221, 341.

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azatadne. 422/ ~lne.422/

carbWlo>:amlne. 4221 oetirlrine,422/ chIorpheriramioe, 221. 422/ cimelidine (TAGAMET), lOB, 147, 147/. 201/, 235/, 236. 236-238, 2371. 326. 340,347,362.419/.440 demasline (TAVlST), 4221 cydizine, 242, 4191, 4221, 424, 424 cyprdIeplaCWle,4221 de>:.dlIorpherifamIn,4221

dimenhywnine.96, 108, 221. 243, 243/.392. 419f. 4221. 423-424, 424.

""

doo:ylamine. 96, 422/ lamoereulosis '*"Ill, spec:lflc 8gefI\I amr.osalql;c acid, 331 I, 335, 335

cyo:toseme. 331'. 335, 335 -.ambulcl. 331. 331( 3J4, 334-335, 3361.U1 ........,idIIl,331(33S,335 ~ 141. 141.1.1481.2fI3.283#264(331. 331(332..m. ~ 332333, 3331;3301. 3351; U1 pyqt.ii.,oidIt.l2&l( 331. 334. 334, Df. 335. 437 Ibi,lJlO .. 2ll1t. 253. 2&1(285. 28Sf. 2m(300. 331, 331~.m. 33W34, 3304.. 340-341, 437 AnliwJl . 3Ili6-a67

il1etleu.. 363l, 371. 3", 3711, 373( 3IIl7-3ll8,399f ................. 457

~363'.364.36'365 rimIlilllldine. 363. 3631. 363-364

slaWdine (d4T). 3631. 36Ell. 370. 370 IrifIwidine. 363f. 368, 368 Yk\aIlltlio1Ii (ara-A). 3631. 367. 'Jlj7f. 367)68

, ...... atWle (ddC), 363f, 369(37ll; 370 lIclortudifIe (A2'T). 339. 363L 367, 36a 3158 3M. Df ~
• •......, _ _ itiyl& 8ftd 2

8ftd~.40

ae::tiDna. 41. 4" ~_.4

don :lepeo ideo Ullec., 47 ~1i$elliCb.. 42-cl. 606 n '"'--ilic ............ 461

.--.220, 220'

"''mOVENT. See Ipatr""*,",,, AaenIIiDn d8ic::lI sy,iilltu, a_'811, 11M AI)opI;aldlp .• '..... ,24 ~.1:H14

......... 9ia-e,.1:H14

,.."""*'" 41l1-42li

~ polenll8l. 1001 dntQ In!e

'"

Index estal:olam, 92f flurazEpam, 91, 9" 92. 92.:aLOein Caimustine, 373', 389. 38W1O emetic pdllftIaI. 2Cl I

Cascara, 244

C8se

51...-, C~2

Caslo< oil, 244, 244' CATAPRES. seeClorildirle CaI8dloIlInira, 69/ C81ecto:lI, Slruet\Jre, 61 f Calecf"ooloO.me1hyllratlSl8nlS8. 444

..,

~aod~N8g8I.

ca..EBREX _ C? "'ib CI'mwib C66-467 CEli.CEPT 588 ~moIetiI celk:)RET0ll, 143( "7,

end

CEClOR.5e9CeflldOr CECA>: _ cehilulen

Ce4amerdole, 296', 306. .:0;

~,8,81

ClitJIdor (CEClOR). 2981, 3051 tor te. 204, 298/, 3051, 306,

cephalosporins, specific lIgefltl, 2981

""

'"

'"

C(liotaxima, 2981, 304. 304, 3C6( 306 oeflazidime, 2981, 304. 304, 305/, .,.."

OIlltizoxime, 2981, 3051

celtria>:ona, 298~2991. 304, 304. 3C6/, 306. 3281, 435

moxalac1am, 204. 2981 fourtt> geeoeration oeIepio,Ol, 304, 3051 Coeptlalolhin, 2981

lhernpeutic advanlages and

d:sadvamages, 3051 ceptlaphin, 2961 lhernpeutir; adva ntages and

disadYanli>ges. :lOO1 Cephradine, therapeutic advaotages and d1$l1dvan'ag