Medical Pharmacology at a Glance doc

Preface 7 Ho w to usethis hook 7 Further reading 7 Introduction:principlesofdrug act ion 8 2 Drug-receptor imeracnons 10 3 Drug absorption, distribution and excret ion 12 4 Drug metaboli

Medical Pharmacology

at a Glance

Profe ssor of Pharmacology

Division of Pharmaco logy and T h erapeutics

Kings Co llege London

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Preface 7

Ho w to usethis hook 7

Further reading 7

Introduction:principlesofdrug act ion 8

2 Drug-receptor imeracnons 10

3 Drug absorption, distribution and excret ion 12

4 Drug metabolism 14

5 Localanae sthet ics 16

fi Drugsacting at heneuromuscularjunction 1

7 Autonomicnervous syste m 2

8 Autonomic drugs actingat cho line rgicsyna pses 22

lJ Drug s actingo thesym pathe ticsystem 24

10 Ocular pharmac olog y 26

I Asthma,hayfe verand anaphyla xis 28

1 Drugs act ing on the gast rointestina l tract.l

Pepticulcer 30

1 Drugs acting onthegastrointest ina ltract.II: Motilityand

sec retions 32

1 Drugs actingon thekidney-cdiuretics 34

1 Drugsused in hypertension 36

16 Dru gs usedin a ngina 3X

17 Antiarrh ythmi cdrugs 40

1 Drug susedinheart failure 42

19 Drug sused 10 affectbloodcoagu lat io n 44

2 Lipid-lowerin gdrugs 46

2 Agentsused in anaemias 4

22 Ccnrrulrran srniue rsubstances 5

23 Generalanaesthe tics 52

2 Anxiolyti c sand hypnotic s 54

25 Aruiepile ptic drugs 5(,

26 Drugsusedin Parkinson' sdisease 58

27 Antipsychot icdrugs(ncurolcptics ) 6()2R Drugsused inaffect ive disor de rs-antidepre ssant s 62

29 Opioidanalgexics 64

3 Drugsusedin nausea andvertigo(untiem etic sj 66

3 Drugmisuseand dep endence oR

32 Non-ste roid alanti-intlamrnutorydrugs (NSA IDs) 7

33 Cortico ste roids 72

34 Sexhormo ne sand drugs 74

35 Thyro id andantithy roiddrug s 7

3 Antidia beticagent s 7X

37 Antibacterialdrugsthat inhibit nucle ic acidsynthesis:sulphonamidcx rrimctho prirn quinolonesandnitroimidazoles 80

3M Antibacte rialdrugs that inhibitcell wallsynthesis:

penicillin s cep halospori ns andvanco myc in X2

39 Antibacte rial drugsthat inhibitproteinsynthes is:

aminogj ycoside s.tetracyclines ,macrolidcs andchloramphen icol 84

4 Antifungal and antiviral drugs 10:6

4 Drug sactingonpa rasites I:Hel mint hs(worm s) 8

4 Drug sactingallparasite s,1I: Protozoa (}()

43 Drugsusedin cancer 92

44 Poisonin g 94

4 Adver sedrugreactions 96Index (}H

5

Thi 1:0*is nth:" primarilyfor m dicalstudc nt-,ootitshou ldal-ebe

use fulto 'Iuu 'nl"andscienn ",in Olh.:rd i 'oCirli ~ '"howouldlikean

eleme ntal)'andconcise imrod ucnon[0phannacology

In thi ooktheICAIha beenreducedtoaminimumfOf unders

tand-ing the.- figure Nc vertbc te I ha w a 1w m r 't.",j in each chapter IU

expla m ho the drugsproducetbeireffec,,,, and 10ou tline theiruse

Inrhi founh editionall [hi:"chapl('r haveteen updated.Arecen t

EECdirectiv e requiresthe U '\C ofRe commende d Inte rn ational Non

-proprietary Names Ir l~N) for drug For m.'" drug the British

Proprietary Name (BAN) and the rlNN arc lilt" sa me bUI where they

differ,lhavc used the new rINN.This will ave sluuen ts ha vi ng to learn

new names fo r drugs a year or,Ilinto the ir coursv bUI may result in

accusations of had s[1<;."lIing until the ne w names become gl'llt'r<llly

familiur.Thc o:h;rl1gcsofnoradre nalineto uorepincpltrmc, und adrenaline

'0epmcphnnc.arc likel ytoheparticukuly conn-nnouv Nevcrth lcsv,

thenew names nrcused except inthc arlychapters.whcrc1have gjvcu

hUlhther l~Nand BA N

How to use this book

Each or ttccha pte rs (lisled011page 51rcprc scmva particul artopic cor

shou ldslart al Chapter Iand liNread thro ughthete xt ontheleft-hand

conccmn teUlIlhcfi~lIrr·.1nile<II aumc.Some arc qeuccomplicatedand

and agreate r undcrvtandingofdrugaction,Once the infomuuionhasbeen under-rood.the ligu res vhuuld suhce q uc mly require lillie' more

than a brief look to refresh themem o ry,

The ligures are highly diagr.nunuuic and nottoscale.Furth er reading

}lriti,lh National F ornndorv. Brili,h Medical Association and '111C

Roya l Pharmaceutical Society of(jre.u Brit ain London(aNl utXOO

prj.The(JI'F isupdatedtwice a year

Ra ng,I P Dale.M '!.&.Riner.J.M ( I'J')')IP h<lrm,wolo gy 41h ron

Ritter.VII Le wis L.D s: \Ian l GX.(199'J l AT r l/ho o t of CUI/i n ti

P harma cology; 4thedn.Arnold, LondlMl(b!l7 pp)

1 Introduction: principles of drug action

Somedr ug S!inh ibit

trarll; po rtcecceeeee

Hormo nes

ENDOCRINEinsu lin

levor hy rodn ecortisol

Na -c ha n nels

(localanaeetbet.lc e )

- :.~•' : - -

,._ ~~ , <-

-Endocrine elandcell<~ -_~_-_-_-_

Som edruge inhibrt t h

Medicalpharmacologyis th.-science of chemicals(d rug ,)thatinteract

with thehumanbod y.The seinte ractio nsnrcdivid edintoIWol"la sse s :

• pharmncod ynamlcs.lilt"CHtdsofthe drugon the body,and

• pharmacokineticsthc way thebody affects the drug withrime(i.e

absorption.distribution,mctaholivm andcxcrcriuu)

Themost common ways in which a drugcan produce itseffectsarc

shown in the figure.Afew drugs tc.g gene ral anaesthetics,osmotic

diuretics)act by virtue of their physicochemical propertiesand this is

callednOIl sp edli c drugaction Somedrugs ICI,I',falsesubstratesor

tbcnomleft).However, most drugsproduce theireffectsby actingOil

specific protein molecules usually locatedinthecell membrane.Thes e

proteins arc called receptors (~§h and they normally respond to

endogenous chemicals inthebody.Thesechemicals are eithe r synaptic

lransmiller su bsta nces(toplen, + )or hormones(to p right , ) For

example.acetylcholine isa transmitter substancereleasedfrommotor

nerveendings and itactivuu-srece ptors inskd elal muscle initialing asequence of eventsthat result sin contraction01 the muscle.Chemicalsre.g acetylcholine) or drug s that acnvute receptors ami produce a

combinewith reccprorx.butdo not activatethem.Antagonists reducethe probabilityofthetransmittersubstance (or another agonist) com-biningwiththereceptorandsoreduceorblock its action

The activationof rec eptorsby an agonistorhormoneis coupledrothephysiologic al or biochemical rcvponscs b transduction mechani sm s(lower tigure)thatuftcn (butnot always)involvemoleculescalled'sec-und IUCSs('lIl!:t'rs-_ )

The interaction between a drug and the binding site of the receptordepends on the com pleme ntar ity of "tit" of the tWO molecules TIlecloser thelit and the greater thenumber ofbonds(usuallynon-covalcnu.thestrong er willhethe attractive forces between them,and the highertheaffinit)'of the drugfur the receptor.The ability of a drug10combine

wit h oneparticular type of receptoris called~ p d fi d t y.No drug is tru ly

specific butmany have a rel at ivel y sdedh l' acti o n on one type of

rece ptor

Receptors

Thesearcprotein moleculesthmarcnorm allyactivated hyrmnsminers

or ho rmo nes.Ma nyreceptors have now beencloned and theiramino

acid sequences determined The four main typesof receptorarc listed

below

I Agonis t(Iiga ndj-g atcd channelsaremadeup ofpro te in subunitsthat

form a central pore re.g.nico tinic rece ptor,Chapter 6: j-uminotiuty ric

acid (GABA) rece pto r, Chapter24 ~.

2 Gcpnueincoupledreceptors(sec below)Iorma family of receptors

with seven membrane-spanning hel ices.They arc linked (usually) 1

physio logica lresponsesby second messengers

3 Nuclearreceptors for steroid hormones (Chapll'r 34)and thyro id

hormones(Chapter 35) are present in the eel! nucleus and re gulate

transcriptionand rhuspro tein xynthcs!s

4 Kinase-l inkedre ce pt or sarcsurfacereceptorsthat posscss (usua lly)

intrinsic tyrosine kinase ac tivity.The y include receptors for insulin,

cyto kincx and growth factors(Chapter 36)

Truns m tne r su hstunces arc chemicals released from nerve te r

-minals which diffuse across the synaptic cleft an hind to th

re-ceptors.This activates the receptorsby changingtheir conformation,

and triggersasequenceofpostsyna ptic events resulting in, for example,

muscle contraction or glandularsecretion Follo w ing its release, the

tran sm itte r isinactivated(left of tigurc)by either enzymic degradation

re.g.acetylcholine)or reuptake te.g nore pine ph rine [noradrenaline)

GABA) Many drugs act by either reducing or enhancing synaptic

transmission

H ormones urechemicnls released i ntothe bloods tream; they pro

-ducc their physiological effects on tissues possessing th necessary

specific hormone rece ptors Drugs may interact with the endocrine

systemby inhibiting te.g.antithyroid drugs,Chapter35) orinc reasing

(e.g.oral antidiabetic agent" Chapter 36)ho rmo ne release.Othe r drugs

interact with hormone receptors that m(IY he activated(c.g.steroidal

anti-inflanunatorydrugs,Chapter~3)orblockedte.g.oestrogenuntug

-onixts Chapter 34), Loc al honunucs (autacoid s jsuch :;s hixtamiuc

serotonin(5-hyd ro xytryptam ine, 5HT),kinins and prostagland insur

released in pathological processes The effects of histamine can

sometimesheblocked withantihistamines (Chaptcr 11),and drugs that

block prostaglandin synttws is(e.g aspirin) arc widely used as anti

-intlnmmarnryagents(Chapter32 ),

Transport system s

The lipid cell membrane provides a barrier against the transport of

hydrophilic molec ules iruoor out of the cell

Ion cha n nels arc sele ctive pores in the me m bra ne that allow the

read ytra nsfer of ions down theirelectrochemicalgradient The open

-closed sta te of these channels is controlled either b) the me m bra ne

potentialrvohage-garedchannels}or by transmitter substances (lipnnd

-gated channels).Some chnrmc!s (e.g, Ca1+cha nnels in the heart) arc

both voltage and transmitter gated.Voltage-gatedchannels for s\l(!ium,

potassiumand calc iumhave the slime b;tsic struc ture (Chupter 5)and

,uhtypesexistforlo'achdifferlo'n tchunnlo'!.Impn rtant examplesof drug,

that act un voltage-gatl:'d l'hannels i1rl:' mlciulIl d lw md Mod.e n

(Chapter 10) thm hluck L-typc calcium channels in vascularsmouth

musde and the heart,and {0('<11 ill/<lC.I'liletin (Chapter 5) that bloek

~odium channels in nerves,Someul1Iinll1l"1f{.\(I/II.I' {Cha pte r 2:'i) and

Dru gsare prescri bed to produce atherapeutic effectbuttheyoften

produceadditionalunwun te l' fTl' t'lS(Cha pter45)that ra nge from thetrivialte.g.slightnausea) tn thefata l(e.g.aplas ticanaemiaI

some antiarrhythmic drugs(Chanter 17) also block Nat cha nnels Noclinically usefuldruguctsprim arily on voltage-gatedK+cha nnelshut

regulat edby int race llula radenosinetrip hos phate(AT P;Cha pter3fi),

Activetran sportproc essesare used to transfersubstancesagains ttheir concenuuuon gradients.They utilize special carrier moleculesin

the mem brane andrequire met abolic energy.Two exam plesarclistedbelow

-nismtlunderives energy from AT Pandinvolvesthe enzyme adenosinetriphosphatase(A'TPase) The carrierislinkedto the trans ferofK+ionsintothe cell Themrdi<i {, Mly {,V!Jidt's(Chapter18) act by inhibiting the

N a~/K +-A TP ase. Na and/ o rClrtranxport processesinthekidneyarcinhibited by somedillrdics(Chapter 14)

2 Nvrl'pilll 'phri/w transport, The Iricydic ({l1Iid cpl""SM/II1.\" (Cha pter

2li)pro lo gthe action of'norepi nephrineby hlocking its n-uptakeintol' nrru!nerveterminals

Enzymes

These are catalyticprotein,thatincrease therail'of chemical reactions

in the body Drugs that act by inhibiting enzymes include:

anti-dlOlilll'.HI'I"U.I'I'.I·,whichenhancethe actio nofacetylcholine(Chapters6and8):rur/mni c anhvdrase inhibitnrs which urcdiureticstt.c.increase

urine flo w, Chap ter 14 ); monoamine osidasc i nhib itors, which are

antide pressants(C hapte r 28);andinhibitors ofC yd()-(IXYf:I'/l(/.\ 1' (c.g ,

aspirin, Chapter32),

Second messengers

The se are chemicals whose intracellular concen tra tio nincre ase s or,

more rarely.decreases inresponsetoreceptoractivation by agonisls,

and whichtriggl:'rprocessesthateventu allyresult ina cellular res p onse

The most stud iedsecond messengers arc;Ca2+ions,cyclicade no s inemonophosphate{l'AMP ), inositol-l,4.5 -trbphosphate (InsP,) and dia-

cylglycerol (OC;),

cAM Pisform ed from AT!' by the enzyme udenylyl cyclase when.for example f3-adrenoce(lton.are stimulated The cAMPactivates anenzyme(protein kinase AI,which phosphoryla te, a prot ei n (enzymeurion channelIand leads to a physiologicaleffect

InsP, and DG are formed from membrane phos ph

-gerscan like cA MP,activate kmascs but Ins!', docs this indirectly

by mobilizing intra cellularcalcium sto res So me muscarin ic effects

of acetylcholine and ul-adre nergic effects involve this mec hanism(Chapte r7)

(i -prot eins

The stimulationof adcnylyl cyclase and phosphokinaseC followingreceptor activation is medi ated by a fam ilyofregul at ory guanosinetriphosphate (GT PI-bindingproteins(G -proleins), Thereccp tnr ~ago n ist

complex induces a (onfo nnat ionalchangein the G-pro tei n,causingits

because u-G T Phas intrin sit· UTPase activity and turns itself off byhydrolysing the GTPto gua no sine diphnspll<lte(G O P).a-GO Pthcn

rcassl")(,;iateswith the pyG-pf\ltcinsu bunit~,

AgO l'li,,!concentration[A]

(easierto se ema ximum and

70% ofcurveie straight line)

Partia laqol'list

complex Tral'lsdu cer

Agol'lis tlreceptorltraneauce-complexeiect-oet a nc

H-bonding

V1.mderWaal5

h ydro phobi C

The tisvues in the body haveonly<Jfew basicresp onses when exposed

10agonists(e.g musclecom racnon gla nd u lar secretion] and the

quan-titat ive reknionship between th sc phys iologica l responses and the

concentration of the agonis lcanhemeasured by usinghin;l'sa ys.The

first part of the drug-receptorinteraction i.c the binding of drug to

receptor.can bestudied in isolation usingbin din lISS l ' \S

Ithas beenfo und hyexperiment that for many tissuesandugonists

when theresponse is plotted ag,lin't the concentrationofthe drug,a

curve isproduced rluu isoften hyperbolic (cunrentrauon-response

curve top left) In practice it is etten more co nven ient to plot the

response against the logarithmof the ago nistconcc nuunon (Iu!:CUIl

-centra tton-res pon-e curve middle top) Assum ing the interaction

betweenthe drug( A )andthereceptor(R)(lowerfigure>obeys thelaw

of mass action then theconcentrationof drug-receptorcomplex ( A R>

is give n by:

[IIR] '" [Ro] A I

Kn +[ A ]

whereRo'"totalco nce ntr a tio n of receptors,A=agonist concentration

KI)'"dissociationconcam.amlAR'"concentration oroccupteoreceptors

IU

efficacy

(KAR==affi nityofAR

complexfortransducer)

As this i, the equation for a hyperbola the shape of the dosresponsecurve is explained if the response isdirectl yproportional to

e-[ARI ,Unfortunately,this simple theorydocs not explainanothermental tinding-csome agonists,called par tialagunisl s,can notelicitthe same maximumresponse,ISfull a!lunistseven ifthey havethesumeaffinity for the receptor(top len and middle, - ).Thuv, in addition tohaving affinity forthe receptor.an agonisthas anotherchemical prop-erty.called intri ns icd lkm'~ ' which is itsability to elici ta res ponsewhen ithindsroa receptor (lowerIlgurej

experi-Acnmp efiuv eanla!: u uisl has no intrinsicctficaryand byoccupy ing

a proportion of the rece ptor s,elfecuvely dilutes the rcccptor con ce m lion.This causes aparallelshift ofthelog conccntrauon-rexponsecurve

ra-tn the right{to p right •• )butthe maximum responseisnot depres sed

In contrast irreversible an lagu n ists depress the maximum response(top right ).Ho we ve r.at lowconcentrations a parallelshift of the logconcentrat ion-responsecurve may occur without a reduction in themaximum res po nse (top right.0 ) Because an irrev ersibl eantagonist

in effect removes receptors from the system,it isclearthat not all thereceptors need10beoccupiedto elicit the maximum responseti.e.there

is a receptor reserve)

Intermolecular forces

Drug molecules in thecnvirunmcmofreceptors areattracted initially

by relativelylong-rangeelectrostutic forces Then" if the molecule is

suitably shaped to titcloselytothcbindingsiteoftherece pto r" hydro

-gen bonds and van der Waals forces briefly hind the drug to the rccep

-tor Irre ve rsible antagonists bind 10 receptors with strong covalent

bonds

Affinity

This is a measure of how avidly a drug hindsto its receptor.Itisd1,1T

-acterized by theequilibrium dissociationconstem (K u).which is the

ratio of rate co ns ta ntsfor the reverse(k _l)and forward(k+ 11reaction

between thedrug "lid the receptor.111C reciprocalofKIlis called the

affinity constant (KA ) and (in the absence of receptor reserve see

below]is the conccmranon ofdruguuuproduces.'i()%of the maximum

respo nse

Antagonists

Most antagonists are drugs that hind tn receptors btu do not uctivutc

Them The y may becompetitive or irreversible Other types of

untag-onistareless common,

Cnmpetifive anlaAunisls hind rcvcrvihly with receptors und the

tissueresponse can here turned 10normalby increasing the dose of

agonist because this increases the probability of agonist-receptor

collisionsat the expense of untugcnist-cecepro rcollisions.111<;: ability

of higher doses of agonist to overcome the effects of the antagonist

results inapar allelshiftof thedose-responsecurve to the rightand is

thehallmark of competitive antagonism

Irrewrsihl t'anta ~uni s l shave an effect thai cannot hereversed by

increasing the concentration of agonist The only important example

isphenoxyhf'lI:a/llillf'thmhinds covalently with u-adrenoceptors The

resulting unsurmountable block is valuable in the management of

phaeochr omocytoma,a tumour that releaseslargeamounts of epinephrine

Other-typesofantag nnls m Non-compeuuve autagonl tsdo not

bindto the receptor site hut act downstreamtoprevent the response[0

,111 agonist.e.g.calcium-channel blockers (Chapter15)

Che mica lantagonists simply bind to the activedrug and inactivate

it.e.g.prolamine abolishes the anticoagulanteffect of heparin (Chapter

19)

l>h )siol uAicalanlaAlInisl.s arc two agents with oppositeeffects that

tend to cancel one another out, e.g pros tacyclin and rhromboxune-A,

on platelet aggregation (Chapter 19)

Receptor reserve

In some tissues (c.g,smooth muscle) irreversible antagonists initially

shift the log dose-response curve10theright without reducing the max

-imum response, indicating that the maximumresponse canbeobtained

without the agonist occupying all the receptors The excess receptors

arc sometimes called ' ,Ifl llre ' receptors hut this is a misleading tcrrn

because they are of functional ,ignificance The y increase both the

sensitivity and speed of a system because the concentration of

drug-receptor complex(and hencethe response)de pend , on the prod uctofthe agonist concentration and thetotatreceptor conccmrunon

P artial ago nist

This is an agonist hatcannotelicitthe samemaximu mre spon se as a'full'agonist The reasons for thisart' unknown.One suggestion is thatagonism depend, on the affinity of the drug-receptor complex for

a transdnrrr motocutc(lower figure).Thus,,Ifullagonistproduces acomplex with high uffinuy for the transducer (e.g.the coupling G-proteins Chapter II, while a pa rtial agonist-receptorcomplex has alower affin ity fo r thetran sdu c erand socannotelicitthe full response.Whenacting aloneatreceptors.partialagonislS stimulatea physio-logicalresponse but they can antagonize the effectsof afull agonist

This isbecausesomeofthe receptors previouslyoccupied by the fullagonist become occupied by the partialagonist that has a smaller effectte.g.some~ -adre noceptorantagonists.Cha pters 1 and 16)

I ntrinsic efficacy

Thisis the abilityof an ugomsttoalter theconformation of a receptor insuch a way thaiit elicitsa response in the system I is definedas theaffinityof theagonist-receptorcomplexfor a transducer

Parfiala ~u nisl sandreceptorreserve Adrugthatis a partialnist in a tissuewith norece ptor reserve maybea fullagonistin a tissue

ago-poxscsxing m:II1Y 'spa re ' receptors bec au se its poor efficacy can heoffset hy activating a largernumber of receptor thant hat requ ired hy

afull agonist

B ioassay

Bioassays involve the usc of a hiologica ltis ue to relate drug uution 10 a physiological response Usually isolated tissues are usedbecause it isthen easier to control the drug concentra tionaroundthetissue and reflex responses arc abolished, Ho we ve r.bioavxayssome-times involve whole animals and the same principles are used inclinicaltrials Hioavsuys canf-c used to estimate:

concen-• the concentration of a drug (largely superseded by chemicalmethods]:

• its binding consranrs:or

• its potency relative 10 another drug

Meas urem e mo f the relative potenciesof a series of agonislS on differenttiss ues has been one ofthe main ways used to classify receptors, e.g.adrenoceptors (Chapter 7)

Binding assays

Bindingassays are simple undvery adaptable.Me mh rane fragmentsfrom homogenized tissues are incubated with radiolabelled drug (usually

·'H) and then recovered by filtration After correctionfornon-specific

bindi ng.the'Ii-d rug bound tothereceptors can be determined and estimations madeof KAand 8 m» (number of binding Sill'S),Bindin g assavsarc widely used to study drug receptors but have the disadvantage that

-no functional response is measured, andoften theradiolabclled drugdoes not hindtoa singleclass ofreceptor

"

3 Drug absorption , distribution and excretion

H ighly i oni z ed drug s are cc nftne d

t ot he ext racel lula r f l u id

(e g ub ocura rine )

D r ug s t h at are hi ghl y pro- tein

-b ou ndo rh ighmolecularwe l<'j h ( hepa r in) a re r etain,,-,d

t-In circ ula t- ion

I I

F lro; t ~pa% I ml'Ul b o/i!>.'11

Stomac h

B ucca l cavi t y

I I I I

5u l>IIn0 Ual -ie i flB I

Fore ~amp lea ~.fr ombucca t c.wit

weak b ase (B ) ,:;'- a VD i d l iver I

P ' ( j ) " 7 -;- " Intravenol' & in je-<::t;ion ~ "

Most drugsart." give norally andthe y must passthrou ghthegutwall10

enter thebloodstream(left offigure.c::» ThisabsorptlunpHKCS Sis

affected hymany fac tor s(left)butisusuallypropo rti onal tothe lipid

solu bililyofthedrug.Thus.the ahxorpuon of unionizedmolecules(B)

isf avouredbecuusetheyare far morelipid soluhlethan those thatarc

ioniz ed(BH')< II1Usurro unde d bya ' shell"ofwa te rmolecules Drugs

art'absorbed mainl yfrom the vmal I intestine becauseof itslargesurface

urea.Thisistrue even forweakacids (e.g.aspir in),whicharenon-ionized

in the acid (Hel)of the stoma c h.Drugsa bso rbedfro m the gastrointes

-tinal tractente rt he portalcirculation(left [ ]) and some are extens ively

metab olized as the ypass throughtheliver(first -pas smcrabolixm ]

Drugsthatarc sufficie nt ly lipidsolu bletohereadi lyubsortedorally

arc rapidlydistributed throu ghou tthetlI lywatercomp artm e nts(0l

Manydrugsare loose-lyhound to plasma albumin,and aneq uilibrium

forms betwee nrhehound(pH)andfree{ H )drug intheplasma Drug

thaIishoundto plasmaproteinsiscominedtothevasc ularsyste m and

isnotubleInexertitspharmacological action s

Ifadrug isgiven byhuracenousInjectlon,itenter stheblood andis

r apidly dist ributedto rheli ~suc s ,B y l ak ing r epealetl o hloll samples.the

fall in plasma co ncentratio n of the drugwith time[i.e.the rateof drug

elimination ) canbemeas ured(right o pgra ph) Often theconccnt ra

-non falls rapidly at first hut then the rate of declin e prog ressive lydecreases.Such acurve iscalled cxpon onuat and thismeans that at

any ivenlime.aconst anttractionofthedrugpresen tiseliminated inunit time,M:II1Ydrugs sho w anexponentia lfallinplasmaconcentration

becau se the rates at whic h thedrug elimination proces ses work are

themsel ves usuall y proportio nal to the concemnuion ofdrug in the

plas ma.Thefollowi ngprocessesareinvolved

I Elimination in theurineb glomerular liltralion(rig ht.E.l)

1 Metabolism usually bythe liver.-' Uptakebytheliverand suhsequcmelimination in the bile (soli d linefromliver )

A proc ess thaI depends on theconcentration at any given time is

calledfirstorderandmost drugsexhibit first-ord ereliminationkinetics Ifanyenzymesyste m responsiblefordrug metabolismbecomes

-satu r a ted.then the elim ination kineticschang e 10 ze r uenter.i.c therate ofclirninanonproceeds ata constant rateand is unaffectedbyanIncr eased c oncenrranon or th e dru g t e.g e thanm p henytoin).

12

Roules of admini stration

Drugs can beadministered ora lly ( I f parenterally (i.e b a n

OI1-guvtrnmtestinalroute I

Oral Mosldru ~sareab sorbedbyIhisrouteandbecauseofitsco

nve-nicncc it is tilt- 1110s1 widely used Howe ve r so me drugs (e.g ben

-zylpen icilJin , ins ulin) aredestroyedh)'the acid orenzy me, in thegUI

andmusthegiven parenterally

Inlr a\t' nlI Us inj t't'lion,The drug directlyenters into the circulation

and h)'pa.ss<:' Ihe ahSllrpi iooNITkrs.11is used;

• where a rapid eucct i, required te g furosem ide in pulmonary

forconunuoucedminivtration(infusio n):

• forlarge \'Olul11':s:ant!

• fordrug'Ihalca useI , al liss uc dam age if give nl>yotherroutes te.g

C)101m.icdrugs),

I nt ra muscula r an s ubcutaneous injrtl iuns Drugs in a<Jueou s

solution are usually ah<.l>rllcd fairly rapidly, but absorption can be

slowedby givingthedru g in the form ofan esrcrte.g.neurolepticdepot

prcparationv.Chapter 27)

Other rou lt'S include inhalation (e g volatile anaes thetics MHllt:

drugs u -d inaslh ma)andt""; ("( I/re g.ointmentv).Suh/ingUilfandre

c-tul admini, tr.ltillll avoi ds theportal circulation.and subling ual p

repara-tionsinparticularareva juablcinadmini'leringdrugssu bjecttoahigh

degree of lirsl.passmela holism

Dislribution annmd me od y occurswhen thedrugreachesthecircuta

-lion.IImustthenpenetrateli"ues toa t

'.illhalf· life )isthelimetake nforthe concernralionof drugin blood

1 fall byhal fih original value(righl lop gra ph) Measu rem entof'v a

allowsthe calculation of theelimination rate I"lJllSlal/t ( K d )from the

elisIhefr;lclioll ofdrugprescnlal anylimc thai wouldbee1iminaled

in unillime(I' g ,Kol'"0.02miml l~ 1mea ns that 2%oftht: drug presell1

iseliminall'd inIminule)

The exp0[lem illl curve of phl\ma C01K Cl1l ralio n( Cp)agaiml lime(I)

isd~ scrilx'db :

Cp"'Cue-Kcl '

\lohere CII'"thc initialappart'11lplas ma co nce nlra lio n Bytakinglo

ga-rithms,lhe expo.l11{'lllialt·urve l;:a nhe Imnsfunnt:dinlo amon: co nve

-nient s t ra i~ht line (rig ht hollnm graph) from whkh Coand ' wca n

read ilybedelemlint:d

Volumenfdi'lrih Ulion(VIII This i\the appare nl vol umeimow hich

lhedrugisdistribuk-d.Foll o w ingan intr.lvenou s injec tio n:

\'D-_ dO'<

C ,

Av31ueof1'0<5 L implic!>Ihallhe drug is n:laincd within the vascular

compnrtmcm.A value <1 Lsuggcsts rharrhc drug is restricted 10 the

cxuu ccllular Iluid while large vo lumes ofdistri bution H'D> 1 L)

indicate distributiunthrnu ghoutthctotalbodywatcrorco ncc m rauonin

ce rtaintivsucs.TIICvolume ofdistri bution canbeused10calculatethe

clea ranceof lhedrug,

Ulearunceis an importumco nce pt inpha rmac o kine tics Itisthe v

el-ume (IfhlnodIII'plas maclearedofdru g in unittime.Plasma clea rance

(C / p )is givenbvthc retanons hip:

Therare ofelunination'"Cl pxCpoClearance is thesum uf ind ividua l

cjearaace values Thus, C/ p'"CI ".trnetabohc clearance]+Ci tcrena!excreuom Clearance.bUInol 11r.'providesan indication oflheability

ofthe liver and kid ney1 dispose of drugs

Ide ally,indrug treatment.a steadY'S1ale plasma coocemrarion(C ~)isrequired within a kno wn the rape utic range- A steady sietc Will hea -h ie ved 'he n the rate of dru g entering ee system ic circulation(do!>agera te]t:l{ualsthe nileofelimination Thus.the dosingrate'"CI

xC This equation cou ld he applied 1 an in tra ve nou s infu!>ion

hec~-.clhe entiredo-c eruervthecircula no n at aknownrate.For oraladministra lion.lhe~ ua liOllbecomes:

Fxdosc

",-'c :"-",,=-:::; '"CI xC; average

dosinginte rval p pwhereF'"m/l(/,."i/I./hilit.\ ·ofthedru g.The 'Ir value ofa drug isusc'

ful in choosing a do ing in terv a l that due s nOI produ ce eJlce"ivdy

high peuks Ho xie levels)and lo w trough s (ine ffectivelevels)indru gconcemr unon

mmn ailab i il~ is te rmused 10 describe lheproportion ofud minis

-tered drug reac hing the systemiccirculation Biouvaila bility is 101»

follow ingan intra venou sinjectionfF=I),but drugs reusuallygivenorally andlheproportionofthedose reac hingthesyste miccirculation

var ies with differentdrugs and alsofrompatientto patient.Drugs s

ub-jcctto a high degre eoffirst -pas smetabolism may he almost inactiv e

orally tc.g glyccryltrinitratc,lidocainc)

E xcretionKenaiexrrt'l iull isullimatelyrc~pon,iblc fortheelim inalion of mo'ldrugs.Drugs<lpIX'ar in thcglom crular fillrate,hutiflhe y arelipidsolu-

l>letlK'yart' re,ld ilyrcal>sor ocd in lhe renallubulcsby passivediffusion.I\-kWholi sm of a drug Illh'n n'suhsin :lless Iipid·soluhle co m po und.aiding ren,llcJluelinn(Sl'l 'Chaple r4),

The iOllizalion ofweak ,Icid, and basc sd<:pends o lht:pHof lhe

lul>ul ar lluid Manipulatioo ofthc urine pH is some tinl<:s useful in

intTeasin g rena lexcrelio n Fo r exam ple biea roo nale adminislr.lt ion

m,lkesthe uritKOalla line:Ihis ionil-CSaspirin.makingi les" lipidsolu·

bleand inc rea sing its rolleof excrelion

Weak acid \ and wcak h,lses an: aclive ly "'-"l::n:ted in Ihe pro Jlimal

lObule,Peoicillins :lre elim ina led bythis route

Uili a r~ exrre ti u n Some drugs (e.g dielh )'lst ilbe strol ) are concen

-trJ.lo:dinlho:hile andexcreled into the intestinewhe n: lheyma ybesortx-d.This clllerohe palic circulalion incre ases the pcT"iSlencc ofa

n:ah dru ginthe hudy

13

4 Drug metabolism

Productll'

(hyd rophilic )

W ceer-et.ae-a w",,-ran.,

Increasem<':tal1ob!lm

ofotherd ruqe.e~.

wariarin

oralcontraetpt.ive9

So me dru g einc re.a5ee nl)"T'o(l

-IF,,"e t p a !>!!> m etatooll&mIAll orally , n,~Uro':d dl'Ulll~paMth~h

L ~Mliverto the ¥kmIC circulauon Some , ""0completelyrnn.tIl>oliu:<l they , "

,nac~we ora!1y - (e4 , lidocaine flyceryl ~nnft -au)

SomeI~enzymepeoplehave . ,~ AfewdnJgei n hilritt'nzymc& t(e.g,6Iowacet-ylaton;) . " e.g.cimctid int:.ethal'\Ol

Drug meraboliemh;ls 1\\.0importanteHl'l'h,

I The.Irug ismade mo rt:h.\"drullhilie- Ih isha"It'n sitsexc rcuonh)'111l"

kidneys (rig hI, Jbecaus e the It's lipid-soluble metabolite is 111'1

readilyrCllhsnrlx dinthe renaltubules

2 Th emel llhn lilc s arc usually Ies' activethan thepa re n tdrug.1I11

-ever lhi,i, nOIalwaysso,amlSl,rnclimesIheructubolites arc a, ucuvc

as ( or more acnve than ) the tlrigin; 11drug For example.diazepa m

101 drug used 10 lre al anxiety) is mt:laholi/ed 10 nordiazepam ;ukl

OX;lZI·p<lm.ht>lh ofwhichare active.I ·rnd ru ~ arcinac tive umilthcy

arc mt:lahtlliled in thebody10theucnvcdrug Forexample.Ievod opa

an allliparlin,<{lfIian drug IChapler ~tll , i mcaabofizcd to dopamine

hiktheh)poten ivedrugmt.'lhyldnpa(Clt;lpler 151ismetabolized10

U·m"'lh) InorepifK'phri11<'.

Theli \ e risthe main organufdrug mt,:laholi mandisinvolved inIW"

I!l·no.'ralI)pt ofre at: lion

l·ha 1rt'OII"liIJIIS

Thc-,e involveIhet>iOl r:m~ftlnn;lIillll fa drug10 a more polar mct a b

o-Iile \It'ft Ilf ligureltJyintrt>dul-ingor unnu, Linga funcliona lgfilup(e.g

14

lhi<laliuns arcthe mo Icommon rcacnons andtheseart' cataly cd

hy 1II importantcia of1"111-)' 1111" calledthemixedfunction oxida e

(l'ytut.:h ru llU' 1'-45U ).nil" subst rate specificityof Ihi, enzymeplcx i, very lo w andmanydifferen t drugscanheoxidized (I'XllIIll' le ,l"p left) Other ph ase I rcacuon, an,' reduction (middle kt'tl antihyd rn ly b(botto m tern

com-' ·ha II reac tio n

Drug or phase I mct a bolncs.Ihal arc nul suflieicnl ly polar 10 he

excret drapidlyb the Li.llley" an: mad.:more hydrophilicb)'cunju\:u·rillnwnhendog nou eOlllptlUlltl, intbefiver (cemrcof figure).Repealedadmim lralitlfl of "Ik:drug IIOpl incrca'ot: lhe,,)'nlhe i oll-)tochroee P -45tJ It'n/ yIIll'ind uctiu n).Thiv increase the rareofIllt:lahoh rn of the inducingdrug ;m.l alsO of olher drugs metabolized h)lhe s.:une enzyme (lop righn In contra I drug somclime, inhihilmicrosomal enzyme acuvuy nul'.D )and thi increase sIheat;lionofdrug metabohzedb Iht same enzymeltn pright J

In ad.lition 10 these drug-druguueracuon s, the mel a holi rn ofdrugmay be in fluenct"d h)' \:t'nt' tk fadnr:o Iphammcogenctic l ilge anti

stlllle tJi:\C<I:\Cs espl:dally 1110 '< ffn:lillgthe liver

Drug s

A few drugs re g gallamine.Chapter61an:' highlypolarbecausethey

are fullyionized al physiological pHvalues.Suchdrugsare

melaho-lizedlittle.if al all.and the termination of their al'li on sdependsmainl y

un renal excre non Howe ver nlOSt drugsare highl ylipophilicandare

ofte n bound to plasma proleins As lhe protein-bound drug is nul

fihered at the renalg l(lmeru l u ~and the free drugreadil)'diffuses!lad

fro m the lubuk imnthc blood suc h drugswouldnave a very prolonged

actioniftheir removal relied onrenal exeter! nalone.Ingene ra l,drugs

arc metabolized to more po la r compound" which are more easily

excrete dby the kidm-ys

liver

Themain organ of drugnwta holi smisthe liver.!lut othe rorgans.vuch

as the gastroi ntesti naltract and lungv,haw ('nnsi kr.ahleac tivi ty.Drugs

given orallyare usually'absorbed inthe small inles line andenter the

portal sys tem10 the liver, heretheymay hee\lcnsi'-elymetabolized

te.g lidocaine.morphine propranolol).Thisis calle-djirsl.panmctu

-!lfJIi " a term that dt ·s I10t refer on l)' ttl hepatic metabolism For

exam ple.chlorprom az ine ismetabolizedmorein lhe intestine than by

Iheliver

Phase I reactions

Themos t commo nreaction isoxidation.Other.relativelyuncom mon,

readi.m, arcred/wli"" andhvdrolvsis,

Mkro somalmlxeu runctfon u\idasc syst e m

~ hnyof theenzymes involved in drug metabolism ure located on the

smoothendoplasmic reticulum.whichtonne '111.111"",iele, when the

t" uc b homogenized.These vesiclescanbeicolatcd !ly differential

centrifuga tionandarecalle d nncro-omc-

\IiCfO'>Ol11.3.i drug oxidalion'in\'Oh'enicncinami& ar.knine-dinuc1t."l.lCide

phosphate(reduced form ) I:'ll A DPH ).oxyge n and 1 0 ley enzy mes:

(il ttavoproeem, :'IIADPII c )hx:hrome P-4~()reductase:and (ii) a

hae mopnxein.cytoc hro me P-4~O which a :ts as a lerminal n' i.!asc

Cyloc hrom e P-4 'i( )e' istsin a large numh -r of,uhty p<:'(isoe nzy mes)

wilh different.hUloflenoverlapping.sullslr.llespc'Citkities

Phase II reactions

llK"cusu all y on'ur in 11ll'live r andinvolve".,njugatiu nof a dmgI'rits

ph a ~c Irnetahulitc withant'lldoge nous suhst.rnce Th,' resulting "lHl

-jugatesarealmost alwa)'s1o.'ss active :111<1arc pul:trmolecuks thatarc

re'ldi lyexcreted hyIh,' ld drll' ys,

Factors affecting drug metabolism

E n / , ~ mt"induct iun

Some drugs (e.g p hrm,htlrhiwJ c arhama;rpi"t', rt hal/oJ and e,pe

-dally,rifampicin)and poUulants (e.g.p "I.I"l :,~ ·lil·' Iwmmic h \'dro.,:ar.

!If>n, ~ in tobal_TO smu le) increasc the activily uf drug-melaboJilin~

enzy mes The me :ha nir-ms involved are unde.lr bul the chemicals

~omeho affC(:t,ped tk D:'>lA -.et.juence , 'r-w itc hing.-o n' the pnxIucliull

"I'the appropriate enZ)-nl<:,which b usuallyac)'ltlChro me P-45U

suh-tyJ'l!.'(s) Ho we ve r, nut allcnLyme,,ubjccltoind uclional'{"mi<:rtlso mal

Fur example.hep :tlic lkoholdehydrog,'nase o.:t'ursin the cylop l'ISIll

E n l~ ' m cinhihitiun

Enzynll' inhihitio nm'IYc.tU\C :1l1vcrsedmginter:Kt ion s.They tend1

Ut:cur more rap idly Ihan Ihose invo lving en/y me inductio n hccau\C

lht:}' occuras soona~tht' inhihilingdrug I\';u:hn a higheno ughcnnn:

n-narion tocompete with lhc affected drug.Dru g, ma yinhi hit differe ntf0l111s ofcytoc hro me P-45U and'>0affect themet a bolis m only of drugsmetabolized h) hatparticularisoenzyme.C imnidilleinhibits the mete-bolism of vera l potentiallyroxie drugsincluding phenytoin.warfarinand tbeophyllinc E rvthromvcin a] o inhibits the cytoc h rome P-450

syste m and increa""s the ecuvuy tlf theophylline warfarin, ca mazepme and digo xin

rba-G enencpulymorphismsThe study of ho w genetic determinants affect drug uction iscalle d

phormocogcnctics,The response to drugs variesbetween indiv id ua ls

and, becausethe va riations usu allyhave aGau ssiandist ri bution itis

assume d tha tthe dctemunam of the respo ns eismultifac to ria l.However,some drug responses show discont in uous variation and in thesecases thepopol:lti"lIIcanbedivided illllltwO ormore groups sugg esling

-a single-genepolymorphism.Animport antexa m ple of polymorphism

isde brisoqnine hy droxy/ arion.Al\oul Rif of the population are poorhydroxylatorvandsho w exaggerated and prolonged responsestodrugssuch a, propranolol and mctoprolol (Chapter 15}.which undergo exten-

sive hepatic metabolism

D rug -oce ryta ting enzymes

Hepat ic N·acet)lase displays ge ne tic polymorphism.About50%otthepopulatio n acetylarcisomazjd(an unmuberculurdrug) rapid l) ,while

the other 511'.{acetylate it slowly.Slow acetylation i_~ caused by an

autosomal reces vive gene lhm is assl iared with decre ased hepatic

N.ace tylase activity.Sinw acetylnturs are more likely tu uccumuhue

the dru g and to experie nce adverse reactions.The re is evidence forpolymorphism in the ace tyla tio n of mher drugs re.g hyd ralazin e.procainamide)

P tosma p I('/IlJI - hoti nesrerase

Foursepa rate genes for this enz)'me occurat one IllCUs.Rarely t-el25(0) anatypicalfurm "fthe enzymeo c cu rsand this e\lends lhc dura-tiOll of acliOllofsuxarnctbomum (a fn."'IlICmly used neuromuscularblod.ingdrug )fromaOOtli 6 minutesto o\er2hOUThor more

A ~t"

He palic micro omalrnl)'meS and r"nal nlel'hanisms an: redu,'ed at

hirt h,espt:'ciallyinprcte nn babic~.Ro th systt'ms de vel o p wpidly dur·

ingthcfi"' t four eels of lift' The re trevarious melhod sforc:

lkulat-ingpaediatric doses (seeHr ;fi l h/1/(/1;01/111f ·om lli/(/ry).

In lht' dderly hepatic met aho lism of drugs may ix' redlK'ed but

dC(: lining rcn.11functinn is u,ually mo re irnportanl B)'05 years.the

glomerularfiltra lionnul.' tGFRh1t'Cre a shy 'll'l and everyfoll o win g

yea r it fallsa further1- 2'l-(as a resullofcell 10\\anddecreasedren 1

hlood!low).Thus,olderpeopleTlCt.'tIsmallerd~of many'drugsIhaIlJoe a )Ollllge rpcN>rt ,opec-ially cenlra ll) acling drugs (e.g.opioids,ix'nzodi;uepirocs, ant ide pres<.ants) to hich theelderly ~ 'm to he-

come more, nsili H;" th)' unknownchangl" in lhe brain)

Occasiona lly.reao:tive prod uc lsof drug mctaholismare tmdeto various

organs, espt."ci:llly the Ih'er Pamn'/Ii/Il ol. a idelyused weal analgesic.nonmdl y undcrgoesglucurllnidnt inn and sulph:llio n !Io we ve r,Iheseprot:esscshc" 0 111Csatur atcd at h i~htl,, \Csm Ihe dntg is the n

-conj ugaleJwithglutathione Ifthe gluta th iunesupplyh 'COIl'll.'SlkplL-ted.then afl'a,'liveand potentiallylL-thal hl'p:lloto:l;icmctaholitean'umu-

l alc~I C h aplc r -Hl

"

He"

IC he lTlilt tly I

, , , ,

b

CH~CH.,HNI

co

ICN,I He"

, , , ,

I

, ,

6.1, , ,

thai existmainl yin a protonatcd form 'II bodypH(b tto mlcftt.The

drugs penetratethe nervein anon-ionized(lipophilic )form( 1 but

once insidethe axon.some ionizedmolecules art' formed and these

pnlt'nliab (lowerfigure)

-mal t-diameterfibre"eremore sensitive than large fibres.Thus, adif

-fer entialhlockcanbeachievedwherethesmallerpain and autono mic

pro-cuccsedationand light-hcaocd ncsv.althoughanxietyand rcslles<,fl('s"

sometimesoccur pres uma bly rccau-e central inhibit orysynapsesarc

and cardiac depression resulung from medullary depression Even

coc ainẹ which has central snruuluu tprope rties unrelated to its local

Lidocaineisthe mostwidely usedagent 11actsmorerapidlyandi,more stable than most uthcr I,>cal uuucsrhctics when gjvcn with

equipotent doses Hupi vucuine has a slowonset(up til "IImin te,,)

butavery lungdunuiunof ucuon u lUXhourswhe usedfo rnerv e

ophthalmology10anacsrheuze thecorneạ bettess toxic drugs such as,, ~ b u p rucai ne and pr" ~Illt"t ắai n which cause much less initial

sting ing.arebeuer

orn-emtnobcnzoicacid

N a ch annels

I:S-suhunil" of unknow n function, The II-suhunil has four identi cal

The2-1cylindrica l helice sarestad "etl loge the r radiallyinthe membr.me

figure.these const ant s arcshow nsch matically asp ysicalgateswihin

the channe l Al the resting pote ntial.most h-garcs arc open and the

In open (open chunnch hut the intensedepola rization of the actjon

Thissequence is show nin lhe upper ha lfofshe figure (Jefl 10 righ l)

closesu.

Action potential

If enoug hNaTchan nelsareope ned, rhcnthe 1';111.'ofNn" ntryintothe

axo nexceeds the rateofKTexitandat thispo int,the thresholdpoten

-tiul, entryof Na" ion s furtherdepolarizes rhc membrane.This opens

mo re Na" chan nels resulting infurtherde polariza tion that ope ns more

M echanism 01 l ocal anaesthetics

the lipid-soluble free base.Th!.'rc prultmakd mull.'(:ules arc fornll"t.!

(residu es of the S6 transm em brane helix) TIlUs,quaternary (f ully

protllnatcdj ocal anaesthl'ticsworkonlyiftheyart:injectedinsidethe

nerv I.'axon U n~'hll rged:tge nts (e.g.~n zoc ai ne )di olveinthemem

-hrane hutthechan nelsarc hlnt.-kedin anall-or·nolleman ne r Thus,ion

-iled and non-ioni zed muleculesaCI inI.'s ent ia llytile samewa y (i.e.b

bind ing 10a'fC("e ptor' unIhe Na+!.'hannel).This 'bloc ks'the channd

lar!!elyby preventing the upeningofh-gate (i.e by inercOL'iinginactiva

-tion).Evcmually.so manychannels arc inactivalc:d thai their number

-old and, b<xaus.e action poIem ials cannol be generated 11I.'1'"\ '1.' block

tx:cu, ,.Local anaeslhclicsarc·u e dep<:ndenl'(i.e.lhe degree of block

ispropol1ionalloIhe r.llcofnerve stimulalion).Thisind il;:atcsIhalmo re

dru g moll.'(:ules(intheirprotonaledfonn)ente rthe Na+channd \I'he n

Ihe y art:open andcausemoreinacti vation

Chemi stry

COlllllltllllyusd hll.·alaml<'sthe licsconsiSlnf alipophilic nd(oftenan

aro m at icring ) and a hydrophilic I.'nd (us ua llya scco nd a!)'or l'n iary

Ette cts

Thesemaybe:

smOOl hme-ere :

1 regi onal,comprisi ng loss of scnsa lioos(pai n te m pe ratu re.touc h)

syst emic.occurringbecause of a""-xption ori111r.lVenOUSadminbtr.llon

Hea rl

The etTctsoflocal anaesthetics on thehranarcdiscussedill Chapt e r

17 Cardiactoxicity probablydtJt:snot occurinsubc o nv ulvive doses

Yaccularsmoothmuscle

norcpincphine reuptake and potentiates sympathetic acuvhy) hile

procaineis vasodilator, 10-.1<Im idocause vasoconsiricnonat 10w

lidocaineandbupivncaine.The regitJTla leffect is vasodilatationcaused

Unralion ofacl ion

Ingene ral highpoten c yandlo ng duration are related10 high lipidso

l-ubility bcC:IU'<Ihis resultsin muchoftheloc llyapplied drug ente ring

the cells vasocon smcuonaholendstoprolongtheanaesthet ic effec t

b theaddiuonofa vasoconstrictorsuch as epinephrine(adrena line)01'_

Methods 01 adm inistration

Su r faceanat'sl ht'si a

To pica l appliciltionto cl\tcm al ur mu osll su rfac!.'s

In fill rOllinll aIllieslht'si a

Subc utaneous inje c tion to act on local nl'rvc end ings usu all y with a

vasoconsiriclllr

:'<ler\ehlockTechniqOt':sr.lT1gefrominfillrdlion of anacsloc lil;:arounda singlener\"(:

isinjcrted ouls idcthedura.Spina lanaesl he s iaistechnk a llyfar easier

toprod uceIhanepidura l anae sthe s ia bUltlle lalterlcrhn iqu e vil1ua lly

elimin alCS Ihe J'H)stanac,theticeOmpliCali l1 suc ha headal'he

Inira wnulisrc~ i llllil lan a esl ht' i'ii a

An:u:s thet ic is injn·te d intravl.'nou ly into an exsang uinat ed limb A

10um iqu L'lpreve11l' the agent rcachinglhesystem iccirculation

17

6 Drugs acting at the neuromuscular junction

blo ckl,,!!drug5

, ,, ,

" "" '.

AChreiea ee

Potentiate

tran llmllllli on

Acuonpotentialsarc conduc tedil111llgthemotor nervesII' their terminals

tq ),The acctylchohnediffuses aero"tho: junctionaldeft andhind "

to receptors located on th surface of [he rnu-cje-fibre membraneat

the moto r ndplatc.T1lI: reversiblecom binatio n of accrykholineand

receptors (lo wer lig ul\',0 1lri ggc Th ltw open ing ofcation-selec tive

channelsI111h cudplarcmembrane allowing aninflux of Na+ions and

membrane I I"rge enough this d<,pu lari/ <ll ion results in an action

potentialand mU"l.'l comracuo n,The acetytchulincrclca-cd intolhe

receptors

Neuromusculartranvmivsion cunheincreas edb antkllUli,wsll'rase

thehyd rolysi s of acetylcholine in the cynapric clef!(see als" Ch"ple rS\

J:ra\ isand1 reversecompetitive neuromuscular bloc kadeafter surgery

Overdosageof anticholiucsrcr.u,c results in cxccs,acrtylchohnc and

adepolarizationblock ofmotor cndplates ('dlO lir1l'rgic crisis') 'Owmu-curinic cffcctv ofacetylcholine("-<'I.'Chuprcr 7) arc alsopoten tiate d

ave ry sho ,acuon andis only sed10 diagnose myastheniagravis

;'I;l'uwmu"l.·u larblll(:kiu drugs(rig hl jan:u b tU);J<'>,lhetists In rela\ s"delal lllllsciesduringsurp.Ie,,1opcrarion-,andh Ipreventmu-clecou-

-tnll'ti,m sdurin gclcci roconvulsiv ctherapy(ECT ) , M O ' Ioftheclinically

usefulne uromuscularh lol'~illg,lruP.st:o l11!X'lewithacetylcholineforthe

rcccprorhUIdo not inuiarc ionchannelopening.Thesecnmpetittv eun

-t :l~(l n ish ft uccthe cndplatcdcpolarizat ionsproducedb acetylc holine

10 a sill'lha l is below lhernre hllid formuscle action IX)ICnlia l generation

and ,'·au"Ca flaccidparal)"i".I ll 'l x, la rilin~hl"l:keNal l ucton acetylcholine rcccptorv.bu tmggcrthcopening ofthe ionchannel They arenotreversedb nnticholinestc ruw s.Su\a nlt' thn niu lIIisthe onlydrugofthis

Some ugcms(lop left),!l'lpresynaptically,Intiblockneu romuscular

tranxmisvionb p revennnglherelease of accrylchotine

"

Acetylcholine i~ synthesized in motorncuronc terminals from choline

and uccrylcocnzymc-A by the enzyme choline acetyltransferasc The

choline ista ken up into the nerve endings from the extracellulartluid by

a special choline carrierlocated in the terminal membrane

EXllQlosi s

Acetylcholineis stored innerve terminalsin thecytopla manti within

synaptic vesicles thatarc anchored tothecyto kelctnlnetwork by aprotein

called synapsin When an action potential invades the terminal,Ca ~+

innsenterandactivateaproteinkinasethatphosphorylates synapsin.This

results in the detachment of vesicles from their anchoring and fusion with

the presynapticmembrane.Severalhundred 'packets'or'q uanta' of acetyl

-cholineare released inabouta millisecond This is called quarual release

and is very sensitive 10 the extracellular Ca-"ion concentration.Divalent

ions such as Mg2+,antagonize Caz+influxandinhibhrruncmitrcrrelease,

Acetylcholinereceptor

This canheactivated by nicotine and forthis reason is called amconnt c

receptor.«The receptor-channel complex is pentameric and is con

-structed from four different protein subunits(Uul31rin the adult) that

spanthe membraneand arc arranged to form a central pore (channel)

through which cations (mainly Na+) now Acetylcholine molecules

bind to thetworr-subunitsinducing a conrorm.nlonatchange that opens

the channel for about I millisecond

Myastheniagravis

Myasthe nia gravis is,IIIautoimmune disease in which neuromuscular

transmission is defective Circulatingheterogeneousimmunoglobulin

G (lgG)antibodies cause a loss of functional acetylcholine receptors in

skeletalmuscle To counteractthe loss of or damage til receptors, the

amount of acetylcholine in the synaptic cleft is increased by the adrnin

-isirationof anuruichulinest er-ase lnununulogicaltrcatment inchrdcs

the administrut ion ofprednisuln neoraza Ihin p r ine(Chapter 4 3)

PIas-mapheresix in which blond is removed and thecells returned may

improve motorfunction,presumablybyreducingthe level of immune

com plexes, Thymectomy maybecurative

Presynaptic agents

Drugslnhibiting acetylcholinerelease

Botulinum toxin is produced byClostridium hOllllil1l1111(an anaerobic

bacillus,sec Chapter37).The exotoxin is extraordinarilypotent and

preventsacetylcholine release byenzymutically cleaving the proteins

required for docking of vesicles within the presynaptic-membrane.C.

hotutinumis very rarely responsible for serious food poisoning in which

the victims exhibit progressiveparuxymparhcticandmotor paralysis

lIolulinum luxintypeAis used in thetreatment of certain dystonius

such as blepharospasmtxpavmodiceye closure) and hemifacialspasm

lnthcse conditions.low doses of toxin areinjectedintotheappropriate

muscle to produceparalysisthat persists for about12 weeks

Aminogtvcosidc l/1l/ihio/i I'I(e.g gentamicin) may cause

neuromus-cular blockade by inhibiting the calcium influx required for exocyrcs!s

This unwanted effectuxuullyoccurs onlyasthe result of an interaction

with neuromuscular blockers Myasthenia gravis maybeexaccrbmcd

Pcntamcric nicotinicrccl."plors aho,,.,;cur in autonomic'ganglia;lnd the hrain

TIICYhavcVUri,lnl"of th~ 0.-andP·'llbunir:lIldadiffcrcmpharmac"to~ )'.

Comp etitive neuromu scular blocki ng d ru gs

In general the competitive neuromuscular blocking drugsarc bulky,rigidmolecules and most haw twoquaternary N atoms.Neuromuscularblock-ing drugs art"given by intravenous injection and aredistr ib uted in the

exuacellulnrtluid The y do not pa.ssthe blood-brainburrier or the placenta,The choice of,Iparticular drug is often determined by the vide-effectsproduced These include histamine release.vagal blockade,ganglionblockade and sympathomimetic actions.Theonset of action and the dura-

tion of action of neuromuscular blocking drugs dependonthe dose but also

on other factors (e.g.prior usc ofsuxamcrhonium,anaesthetic agent used)

Tubocurarine was introduced in 1942 bur is no longer used

Cauamine docs nut block ganglia or release histamine hut causesundevirabletac h ycard iaby blockingthe M2-musGlrinicreceptors.thesubtype of ucerylcholine receptor that predominates in the heart(Chapter7).lti, rarely used

relatively long duration of action Itdocs nor block gangliaor causehistamine release.However it has a dose-related atropine-likeeffecton

the heart that can produce tachycardia

Vecuronium has no cardiovascular effects It depends on hepatic

inactivation and recovery canoccurwithin~O-30minutes, making it an

attractivedrug forshortprocedures.Atracuriurnhas a duration of action

of15-30minutes Itisonly stable when kept cold and at Inw pH.Atbody pll and temperature it decomposes spontaneously in plasmaand therefore does not depend on renal or hepatic function for itselimination It i., the drug of choice in patients with severe renal orhepatic disease.Auucuriummay cause histamine release with flushing

andhypotension

minutes but with a rapid onset of action(1-2 minutest comparable tothat nf suxurncthunium (1- 1.5 minutes) It is reported to have nocardiovasculareffects

D epolariz ingneur omuscu lar b lo cking dru gs

Suxa mc rho ntu r n(succinylcholine) is used because of its rapid onsetand very short duration of action(3-7minutes).The drug isnormally

hydrolysed rapidly by plasmapseudocholinesterase but a few people

inherit unatypicaltorm of the enzyme and in such individual, the neuromuscular block may last for hOUN Suxamethonium dcpolarizes thecndptatc and because the drug does not dissociate rapidly from the

-receptors a prolonged receptoracrivuuon is produced.The resultingendplate depolarization initially causes abrieftrain01'muscle actionpotentials andmuscle-fibretwitches Neuromuscularblockthen occurs

as a result of several factors which include:(i)inactivation of the scnslttvc Na"channels in the surrounding muscle-fibre membrane so

voltage-thatactionpotentialsarc nolonger generated:and (ii)transformauonofthe activated receptors to a 'desensitized' state, unresponsive tu acetyl-choline The main disadv<tntageofsux<lmethonium is that the initialasynchronousmuscle-l1bretwitches cause damage which often results

in muscle pains the nex! day The damage alsn causes pot,lssiumrelease Repeated dost's of suxalllethonium may cause bradyCi.lrdia in

the absence of atropine (a musc:trinic effect)

19

7 Autonomic nervous system

far-nearvisionmuch~c re tiOl 'l

of w ateryeallva

rateand fora

reducedl7r'on-chocon.,;trietiO

(+)Isc ri m".1 g l a n d,

,,-~_ (+)IUrlgairways

In the !lymp at.het.k: s~tem(+)and ( -)

Many systcms ofthehod)' te.g digestion.circulation} arecontr olled

autom atica llyh theautonomicnervous sys te m(a ndthecudocnnesys

-tem).Com rotortheautonomicner vou s systemofte ninvolvesnegative

feedback andthere are manyafferent(se nso ry)fibresthaicarryinlortna

-to n1 centres inthehypothalamusandmed uttc Thesece n trescontrol

the outflow of the auto no m ic nervous syste m, which isdivided on

anatomical grounds imo IWOmajorpa ns:thes~mpat hctic !>.\s h'm(left )

and theparu sympmheric sv tem(rightl.Man y organsarc innerva ted

b both system." which in generalha ve oppm;ing actions.Theactions

of s ymp athctic Ileft )and paravympurhctc (right)srimularionon Iiiffcr

-enttissucvarc indicutedin theinnercolumns andthe resultingeffec ts on

diffe re ntorgans' Ireshow n inthe oute rcolumns

Thesympathetic ne rves(Idl - -llea vethe tho racol um bar region

ofthespinalco rd{TI L]J,mdsynapse either in theparavertebralgallJ.:lia(0 )or in theprevertebratgan liaIe)and plexusesintheabdomi na l

ca vity.Postganglio nicnon-myelinated ne rvefibres(Io:fl,- -_ )arising

fm mncuronesinthegangliainnervatemust Or}!:;IOSoft hebody(left)

111Ctra nxmlncr substancereleased atsympatheticnerveendings isnoreplnephrme(noradrenaline;oplefl).lnactvauonofthistran smitter

occurs largelybyrcupta keintothene rvetermina ls,Somepreganglio nic

sympathetic tibres passdirec tly1 the adrenalmedullaIll)that ca n

releaseepine phr'IneIudrcnnlinclinto rhecircul.nion.Norepinephrine

andepine phrine producetheiractionso effec tor organsbyactingo

U ' ,~I 'or P 1 -a drelllll ' eptor:\ t cxt r cmc l cru2

In theparasympathetic system.thepreganglio nic fibres tright _ _ )

lea n ' thecentralnervou system via the crania l ne rvestc-pcctc tty III

VII,IX and XI and theunrdand fourth acr:ll spina l roots.Theyoften

travel much furtherthan sy m pathetic fihres beforesyna ps ing in g

un-gfia( e )thar art."oftenin thetissu eihelf(righ tl

The nerve endings of the J'Kl\tganglionic paravympath cric fibres

(rig ht, ,) release : :l' I ~ k h lll i ne (lo p righu, whic h prod uce its

action ontheeffectororgan<.(right)by artjvaringmuscurm ic re

ccp-tors,Acetylcholine releasedat ynapscs is inactivatedb theenzy me

acetylcholinesterase

All the pregangfiomc nerve Iihrestsyrnpathctic and para s ymparh

sympathomimetic uge/l / (C ha pte r 9), Ellio t sugges ted in 190-1 that

adrenaline waslhe syrnpmhe nc tran mine r suh ranee hutDalepointe d

out in 1910that IlOrl/ll r('//(/!im'mimicked syr npurheticnervestimula

-tion mo reclosely

Effe<: 1sufsympat hctlcstim u la tion

These(Iremost eu ilyremembered b thinkinguf what dllll1gesin the

bodyarc ap rop riate in the'[ri,lIhtor flight reaction', No tewhic h ofthe

follo w ingeffects;ITCexcitatoryand whicharcinhibitory

I Pupillarydilatation (mo re light reac hesthe retina)

2: Bronc hiolar dilatationrfacituatcs increas ed ve nt ilatio n)

3 Hea rtrate and force <Ireincre ased; bloo dpre ure rise s (mo re hlood

fo rincreasedactivityof keletalmu scles-crunnin g']

-' Va consmcnonin skinand viscera and vasod il.uauon inskele tal

muscles (appropriateredismbuuunof blood to muscles ),

STopro videextra ene rgy,glycogc notys i is sli m ulatc d and theblood

glucoseleveltncrea The gastro intest ina ltrac tand urinary bladd er

relax

Adrenecepturs aredivided io totwomaintype :a -receptorsmed iate

the excila tnry effCl'lsofsy mp athurn imct ieami n.·s, while theirinhi

h-itory cffee h are gl' ner<i Jly medi llled b /J · n 't"t'!Jlo rs (cxceptio ns arc

the sm oo th muscleofthe gut.wl1l're a-stirnulatinn is in hihito T)'.am i

lhe heart,wheref}- timulat io nis excitalory).Rcspon sesmedi ated!:oy{l

-and ~ 1\.'Ceplo",comhedi tingu i hedby:(i)phe nto la m ineand propra ·

nolo l which ,I'dec/h'dy block u-and f}-re ceIlIOTS, re pecti vel y:,ml!

(ii) hy lhe relati ve pot encies.un differcnt li ues.of nllrt'pinephrinc

(N El.l'pine phri ne(E)and isoprena line( I,The orderofpotent-yis l"E

>E>Iwhe reexcitatory( a)responsesare exa minffi,hut fo rinhibitory

( 13)re ponsesthisorderis reve rsed( » E>NE)

e-phrine isan effect ive slimu lllnt ofcardiac p.rcceptol"1;, hUI has lillIe

or noacl ion on lhe~ - r~'CC plors.l1R'diat in g vaslxtilala lio n On Ihe basis

of Ihety peof difft' rt'nthtlsensitivil ythey exhi1"lil to dru gs,f}-receplurs

are div idl' d intotwotype s:P I(he,ln,inte tinal sm oo th muscle )and f}2

(bronchial.vasc ularandU1eri llCSlIlUOlhmusel e)

depending on whelhertheirIO~'al i\l1lWllSpo tsynapti c(UI)orpresynap

-tic{ U l Slimul alion of the pre )'nuplic a2-rcl'cplo rs by synaptica lly

relea Sl.'lI nn repillCphrine red uce fu n he rlransm iller release (neg at ive

fccdhal'k),Post syna ptic(ll -reel'ptors occu r ina few tis sues,e.g.br.lin

vascular smooth mu cle (butma inlyul).

eric _ _ 1aremyelin ate d and release acetylcholine trom the nerve

rcn ninals :the ace tylcholine depola rize the gangl ionic neurone b

activating niconmcrece ptors

A sma ll proportion of autonomic nerv e do nlll release eithcr

acetyl cholineor norepinephrine For exam ple.the avemou ner ve sreleasenunc oxide (NO) in lhepenis.Thisrela xesthesmoo lh muscle

ofthe corpora cave m osa (via cycl ic gua nos ine-J.5-rno llophos phate(cGMPl, Chapter 1 ) allowin g expansion of the lacunar space v and

erection Sildl'lm lil, use d in male sexual dysfunction, in hibits phosphodie terasc type 5 and, b)'tnc rce ing the co nce nuauoo of l-GMP,

-fad litah.· erec tion

I All preganglion ic autnrunnic nerves rl.e both sym pat hetic and

para ympathcricI

2 Poslgan gl ioni cparasymparheucIlCrvCS

.1Some postganglionic sym path e tic nerves ti.c thermorc guhuory

sWC:L1glands and kclctal muscle vasodi lator fibres),

,J Ne rvetoadrenalmedu lla,

S Soma tic motorne rv es1 skel et a lmuscleend plutcs (Ch apter6,

(, Somencuroucsin the centralnervoussyste m(Chapter22)

A ct' l ~lchnlme receptors(chlilin uccplu rs )arc divided intonicotinic

and musc a rinic ubrype s (orig ina lly det ermined by measuri ng thesensiuvity of various tssues 10 the drugs nicotine and muscarine,respectiv ely )

M UJ('ur i n ic receptors Accr ykhclinere le ased at thene rveterminals

ofpo stgan glion icparasympat heticfi"res acts on muscarinic receptors

an d canheblock ed selectively hy atro pine Five subtypes ofmuscarini c

rec eptorexist.threeofwhich have been well charactcnz cd:Mr'M2and

~ 1 l'Mt-f'Cl."eptol"1;{lccur ill thebrainandgaslriCparietalt1:11 ,M ~- TCl.-"'Plnrs

in tbc heart and Mr-rec eptorvin moo th muscle and glands EXCCPI

dink-allyuseful muscar inic ugonists and,mlago nistssho w lillieor nilselectivityfor thedifferent uhtypc s of musc ari nicrece ptor

Ni""fi"ic ren ·f 'f wSoccur inautono m icgan g liaand in the ;Klrcnal

medulla,wherethe effeetsof ,ll'l't ylcltolinc( Illnicotine ) canbehlodl'd

se lectivcl)' with heXlllnethonilllll.Thenil-olin icreCephlrSlllthe~k e kt;i1

tnuse k ne uro m uscu lar junct io n are not bkll'kedby h<.'xa rnet honi um, hut

arc Nod cdby tuhoc ur.lrine,Thus,recept o l"1;atgangliaand ne u cular jurll'tions are different , although hoth types arc timulated hnicolineand therefore ca lled nicotinic

romus-Actio n s vj flcet y ll'lwliflt'

W/f ,l'(·<Jri ni ce1f{'ff,1are mainlyp:lra, ymp,llhOln imetic (exceptswe,u ingandvasod ila ta tio n),,md iogene ra l arc lh :opJ'Klsite of thosccau., edb

sympat hetieslimulat i'ffi Musea rini ceffeclsindude: con lriclion or lhcJlI.lpil.a ~'Co111m(l•.blionfor nca r visio n (Chapler lU) ,pmfu : walerysal-ivalion bronchiolarco n trictil,n,bronchllscl'retion,hypolension (,lS a

result ofbradycardi a andvas od ilata tio n), an inl'Teaseing,."tmin tes tinal

mOlility andsceretion,contral'lio n ortheurinarybl;lddcrandswe:lling

w- :ver,lhl' ction(JfIKc tylcho linc nn ganglia isrelatiVelyweak ellrnp:rn'dwithit effl'elon muscarinic fI.'Ccpto rs.aml 11para.' ymp ,llh tie cfli:c ts

system",Ill bedenlllll.'-lr:lled , fllrexa mple, un cat blllllll pre sure, b)'hlorking its musC:lrinicactionswilh atrnpirll'.Hig h inlnl\'l'nousdose

ofal'ely kho line then ca u ari einblotlll pr.:ss u re.hccau sc stim ula tion

of lhe~ y mpa lhelicgang liaand ad renalmedullanowresults invasocon

-slricti' l11 andladtyca rdia

"

8 Autonomic drugs acting at cholinergic synapses

IC I1olin o m im ol'tlc 5I

1 $ ",'31; 0"I , , , ,

,

, , ,

,

r

, , ,

.

, , , , , , Nicot inic8goniets

a t.agoniete

at.ro pine

bycecneipra:trOplum

benzatropinecthere

AcetylcholineTekolsl'lI Inunrhctc rminalv ofpo stgan liu ic puras

ym-patbcnc nerve s (h:ft D )produce s ih m,:lions on vanou-, tfcctor

organs by activating mu-.c:arin ic receptors ( 0 ). The ettcctv of

accty h-hnlincan:usually excitatory.buranimportantexception isrhc

heart which receive inhibitory choline rgic tlbres t'W11l the vagus

(e h.lrlcr171 Drugs that mimic llll'cncce,Ill" acetylcholinearccalled

• drugs Ihal,WIdirectly"11~C ph ll " <nkolink nndmU"l'a rinka ~"ni~ l ~ ) :

and

• anl k hl)lin l · sl t' ra "l.~ which inhihilacetylcholinesterase.and sll act

prod uceuseffects

cycdrops) is IIM ' d tu redu ce innaoculnr prc vsure in pariems with

glaucoma (Chuprer 10) C:lr h;chu] and hethunechul are used 10

vrimufutclhl' bladder in rinary rete ntion u derconditions where Ihere

is no ubvtrucrion IIIIhe bladder nutlettc.g in ncurologtculdi~ e3~eorpostopcrativetyl

Anlichlllint<St c nlws (bottom left) ha ve rcfauv et y little cttect ,II

ganglia and arcuse dmai nlyfur theirnicotinicenCl'"on lhenL'uroT11US '

cularjunction.The y arcusedinlhclTt';Llnll' nl of myastheniagravis and

to reverse the cttect-,of rompctitivc muscle relaxants used during

.\lu"l.'3rinklI n t a~onhls (bottommiddl(')block (he effect sof ac

etyl-cholinereleased from [-"lslgan glionicpa ruxympathctic nerveremunals.TheirelTec's an.in general.heworkednut by ex.unma tion oflhcfigure

in Chapter7.Ho weve r,parasympathetic effector organ s vury in their

wnsi livilyInthehlockingeffectof aruagonist v.Secretionsof thesaliv

-ary.bronchialuml swearglalH.baremovtSl'nsilivetoblockade.H her

doses of umagonist dilate lht: pupils paralyse accornrnodution and

produce tachycardia b blocking vaga ltone in the heart Sti ll higher

Atro p ine.h ~" n' dn c(-.co po la mi nclor ruhe r antagonisrvarc: used:

1 in anaesthesia In hlo<:k vagal slo wing of lhe hcart al1<l 10 inhibit

(Chapter13);

. inParkinson ' sdiSC:,ISC:te.g.benzatropin e.Cbaprcr26 ):

Cholint'rj!, icnerv ete rminalsinthe autono micnervou s syste mvynthc

(;a n ~ l ionstimulants

increased sa livaryandbro nchia lsecre tion.Theyhaveno clinical use s

Mu, carini c IIAlm is ls

exclra-tory effects An importantexce ptionis the heart herea tivat ion nfthe

predom inant lyMz·f<.'CcptOI'1\hasinhibitoryeffectso therateandforce

protein(GI)toudcnyly lcyclase which expla in, the negal iveinotTll pic

efectof AC h.Suhuni sil3y)or GIdire,lly Increa,eK +cnnd uc I1\llt'C'in

, imulalesgland l1,r","'CretionandC;IU Sconlracli nn of moothmu-.cle

by activatingM1·ft.'Ceplol'i.which ar<:cnupkdtolhefo rm a lio nof nsPI

mn'l hlood ves ·l ha ve no para"ymp;tlhelic innerv ation and so the

physiologicalfunctionofva-.cula rlIIuo;c arinicrecept o rsi unccrt ain

Ch nlilleesle rs

Car bat' ol ami hl'l hanl'(·hol arc tjualem,try l·o m po u nds Ih11\do not

chuline te rase,

Pilocarp inl' po ""cs'\Csa h:rtiary N'11m, hichconfen; increa d

,\ nt il'holinc,lcra, c,

hltxld-bra inoa rril-°ralldhave neg ligible "ntraJeffOXh.They are poorly

aosorbed orally l·h, "l i~lI1in e (eserine) is a tert ia ry am ine ,Ind i,

' l ~ h a n is mor al'l io n

.& 10 I'rc ventmotionsid d les sthyoscinc.Chapter 30);

Nicotinicagnni.,ts arcofn clinical uschutgang lionblockc rshave a

limiedusc: inanae sthesia

Edruphnnlum isthe mainexa mpleofare versible unnchotincstc rasc.It

minu tes).The carban uue esle rs (e.g , l ll"o,t i~lllill l' II,ridl l!>li J!llIine)

Fo rrhi-, rca- on,the orga nophosphor us "'Ol11pOll11<1s are referred to as

insec tic idesIparat hion.mala th ion)and che m ica lwarfare: agent "

The erTl'l·"orantkhulin'-"'It'ruo;eo; arc generally vimllar 10mo-e

Tox ic dllo;eo;initiallyC;lU.-esigns of eXlre me mu-.carinic stim ulation:

mimi , salivation.,wc aling hrOiKhialconstrictinn hronrh o"e cretion

so luo le(e.g.phY'osligmine orgallophos pho ru,co m p<lund'l.cOlwusinns.Com11andres piral Or)'arrcslmay occur.Strong nude ophile, (e.g.pralidn, in u:) ca nspJitthe ph< phoru s-e nzymebondinitiallyfo rme d

l-h organnpho"phorus clmlpo unds and 'regene mtc' thc cn/y me Later

lhisht."C1H1lCSimpoo;siblt' ht ·a u"·a pnx.""of 'ageing'streng the n,lhe

Cholinergic receptor anlagonists

Ga n ~ li o nhlud , er s

cOlllru lk-J hypulen ,ionduringcenainsurgica l pru<."d u res

A1rullineo<.-cu rsin deadly nighl,ha.1c( Atrop a hd im/olll"' ).1li ~aweak

caus<: hrad ycardia.Hig he rdo s cuu.-etachycard ia.lI,u, cin c(S/'Ol}(l/

-amilli')ismo re sc:dalive lhanatwpinc an often prtld uc.:sd ro\l, ~ille",

hallu"'inatinn and coma Thl"\."ffect , uf musc<trinicanlagonisl " canbeworked nul hy tu ying lhc ligurl' inCha pter 7 n le sludell!sh uld

mouth con,tipa tio n anddiflit'uhy withmicturition

23

9 Drugs acting on the sympathetic system

Nor adre01U~ tCMrve

a · ~OC"ER5

U ,/ U 2

phenoKYVcnZSminephentolamine

- a,, ••.prazooin1l - 8LOC " ER5

The sympathe tic nervous syste misimportantinregulating nrgml'such

as the heart and pcriphcrulvascul.nurc( C h p ler , 15 an.llll).Tlu-tran

s-muter released from sym pathetic nerve enuillll-s is nurepineph r fne

(I\t: l(noradrenaline.c:» bur.in response to some formsofstress

ep illl'ph rine (adrenaline.isalso released Irotu the ndrcnalmedullu

The-e carecholami nesa TCinactivatedmainl yb reup take( .J

S)llIpa lhmni melics Od"T) arc drugs uuu partially or completely

mimicthe actionsof norepinephrine andepinephrine.'111<:yJcleithe r

directly on(1 -.mdlo r ILldrenoceplors (left.open colum n)or ndin·ctlJ

on the precynuptic terminals (loplefl.,halkd/.usuallybyca uvingthe

release of norepinephrine( c:>l.TIll'effcct-, of adrcnoc cptnrsrimulu

-tioncanbewen in the tigureinChapter 7

p1-,\dn'/lll('epl"rugoni 'sc use bronchialdilatuuonandarcused in

thetreatmentof asthma(C hapte r II).Theyarc aho used 10 relax uter

-inemuscle in an auem prto preventpretc rmlabour.P.-Adrcn ' l('t'plor

al:onisb (dobuturniucj arc some times used to stim ula te Ihe force

ofheart comracuon in severe Im"'-OUII'UI heart failure (Chapter III)

<tndin manypopulardecc ngcvtunt preparations.a l -A~o n i sb ,notablyc1nnid i nl' and met hjldnpu (w hic h (ll'l" utter ib co n ve rs io n 10u-mcrhytnorepinephnnc.afalsetransmitter).arecentrally actinghypo-

tc ncivcdrugs( C haple r 15),Symp;lthnmimclk amine" that<letmainly by causingnnrel'inl'phr int'

release(c.g.amfe la mi ne ) havethea iu !selectivityornorepinephrine,

Ephed r me,in additionInca usi ng norepinephrine release abo has a

direct action ls effects rese m ble thoseofepinephrine hutl a ~tmuch

longl'r,Ephed rine is amildcent ralstim ulan t,hut amfetamine,~ 'hk h

entersthl': brain more readily,hasamuchgreate rstim ulanteffecton mood

andalcrmexs and a depressant effec to appetite.Amfe tami neandvim

-ilar drugsha vea high abuse potential andarc rare lyused (Chapter31)

~ Adr enn t' t 'pI Clr anl ~l~unisl s (fl-hlut'kers)(bonom right) are im

-portent drugs in the treatment (If hypertens ion lCh apte r 15 ),ang ina

ICh a pter 16),cardi acarrhyt hmia-,(C ha pte r 17 ).heart failure(Chapte r

18) and glaucoma (Chapter 10) a-Adrt'llucellln r a n b.~u n isls t

(Uptake I) in rh nerve terminals 'reca ptures'mostof the transnuucr

and isthemai nmethodof tcrminaung itseffects.A simi la r(extrane

u-ronal)tra nspo rt syste m \Upta ke2)eJlists in lhelissues butisless se

fec-rive andless easily saturated

tCO:\IT) are widely distribute d enzyme s that cata bolize ca tec

hol-amincs.Inhihitionor M AO and("01\11'haslittlepotentiatingeffect on

respon sestosym parhcnc nerve stimulatio nor injectedcarecholaeunev

(norepi nephrine, epinephri ne)because the)" are largelyinactivated b

reuptakc

tissues te g sm oo th muscle, salivary g l;lnd~) ca uses an increase in

inositoltnsphocphareandsuhse q ucrnlycytos uliccalciumtC hapte r I),

which trigge rsmuscle cont rac tio n(exceptgUI)or glandu larsecretion,

activurionb norepin eph rine inhibits aden ylylcyclase Thec OI1~ quem

fall incA\ IPcloSt'SC a ~+chanllCb and diminishes furth er tr ausmiucr

release,

cycla inc re;lsing theCOilvers ionorATI' to cA MP,The cA MP ael s as

a'secolulmc,sl'n ger ' co pling Tl'eeptor;lclivationtllTl'S p'l n~e,

n orepil1~'phr in cdOSl'lyl'lloug h1 0 hL' t ran ~p',nedbyUptake I intn ",:TVe

tenninals wherc the)' displace ve~ ic u l<tr nnrepinl'phrine into the

c)'lo plas m.Sonw ofthe norepine phriueis nwtaholil-LxI by MAO ,but

Ihe remai nde r i ~ rdea sed b)' earricr-m diat<.x1 tr.mspon to adi vat e

ad re nllcepto rs

Am felam ines areresisl<lntto MAO.1llcirperiphl'r;ll acti on s (e.g

\;lChycllTllia, h Yp'.'nl'n~i lln ) ;m d l'l' ntralslim ulanl act iol1 s arl' mainly

eaus<:J by catcc hn l:lIn ine rdca'c ,I)t"\ anl ft'lalllincand lIIl'l h ~l jlh t ·ll i

dale resometimes uloCd inhypcd illt.'tic ehi ltlr<: n Dcllam fe tam ine;u,,1

IIlfld a lin iimayheh.:nelidalinna rct>1ep~y ,IA.'pe ndenceon amfelamilw ,

likedru g ~is C0 l1 1111011(Chap te r3 l

Coca ine,in add ition1 being a loc a lamW~ l he lic \Ch upt r51, is a

s)mp,Uhnm ime tic t->ceauSl'il inhihilsthe rl'upla keofmm'pilwphrineh

IWTVetc nn inals.Ithas aninle nseCl'nl ralstim ulantefFel't hut has made

i a popu l:lr drug of lthu"l'tC haptcrJI)

Uirecll )':.!'tinJ:s ~mpa thumin ll'l k s

The effec t of sympa tho m imd ic drugs in hum;lns dq".' nds on their

r ec~pto rsped /ic ity1.ltantl/nrJi )andonl hectlm pens at"ryr etle~c ~they

c\'oke

~ h o n lasling whe n inj cl'!etl hcCHU SC of uptake ;llld ml.'l<lbnli sm,

Epi nephrine incr ca es Ih c blno d p ressure b y s limulaling th t.' r ale a nd

hl d ' r ~ l(middle right )havelimitedclinical upplicatiuns.Prazo-tn a

selectiveIll-antago nist,is so me times usedin thetreatment ufhy pe rte vion I·h en u\ ~hen/.amin e ,an irreve rs ible antagonist,i"used 1 hlockthe n-effccrs ofthe large ;Illltlunts ofca techolarnincs released fromtumours of the adre na l medulla tphaeochro mocytonnn.~1any u-hloc kershavebeen(andare Ju -dinthe trea tme nt of peri phe ra lvasc ularocclus-

n-ivedisease.usuallywithlittlesuccess

, \ d rent ' r~ k neu rune-blucklng d ru~s (lop right ,haded) either

depk-t ethenerveremnnalsof norepi nep hri netrcserpinejor pre ve ntitsrelease.Theywereuseda ~hypotensiv eag~nh(Chapter 15 ),

forceorthchean hcal( 131-cfk cls).Stiruulatioe ufvasc ular a-TL'CepIOTScaus es vasoconstncuon tvisc e ru, skin ) hut P ~ -stimuratio n causesvasodilaunion (sk ell'tal mu ccIc'andthe totalperipheralresista nce mayact uall ydec rease

Norepinephrine has linlcornoeffec t on the vascularp ~-rCl'I'ptorsandsothe u-me diated vascconcmcr tonisunopposed Theresulti ngrise

in blood pressu rercnc xtvct y slowsthe heart.usuall yover comingthedirectPI-stimulantactiononth~heart rare

Epine ph rine h inje cti o n has an imponant use in the treatment of

al1aphyla ct ic \hod ;(ChapterII)

of the heartbeatand cauvlng vasodilutarion.Thesee rfec t~ result in afall in diastolicand meanarte rialpressu re withlillie changeins)'sto licpressur e

pro-ducebronch oditatanon al doSl'sthat cause minim al effects on theheart

Theyare resistantltlMAO"luIare prohahlynl'!takenup into nl'urones.Thl'ir main useisinthl' trcaln ll'1llof asthma(C ha pte rII ),

Adrenoceptor antagonistsa-IUucke rs

pcriph-er<l l rt:sist:lIu;eand hypotension(Ch,tplc r15),The yrcwrselhepr e s~orcffL·I.'lsofcpinl·phrin hecau itsl}2-med ialed vasod ilato reffec tsan:

unoppose d hy(X·mediat ed \,asOl'(lllSlric tio nand IhI': periphc r.tlresist;tnce

fa ll ~ (epinephrine re wrsa ll, t -BIOl'ken cau, a rene Jl ta hyca rdia

~ h khis gre;lll'rwithm m-~IL't ' l ivedrugsthaialsoblt, oku -pTC'i)'napl ic

r crerlnr~nilth heart , hL-cau Iheaugn wnted rel useof nn Tl'pinephrine.timulat<:s furth~rthc card inc Il - r~!·cp tnr s. Pr :lI.nsin a scle cti ve ul-

antagonis t,causes rel;ltive ly linletac hycardia

~ 1I 1()ck c r

fl-H1l1t:kersvary in the ir/iflid , fai li hili t y and (' ,m !i o.w l n t i l';ty 11

0 -cver ,theyall hloek Ilj-rcceplurs and arecquallyeffectiveinfl.'ducing

bloudpTl'ssu reand pre venti nganginu Thl' mo rc lipid-soluhlcdru g~are

nw re rapid ly absorhLxll'rom th•.'gUl,u nd~rgomorelin.t -pa~shL' patiemewbolislll ;md aremmerapidly elim ina ted.The yare alsomore likely

to ente rIhe brain ;md causecentr.tleffects(e.g.b;K1dreams1.Cun!i(Jw!t'l:

-lidlyis onl)'relativelIml dim inish es with highl'rdose s NC\'en hcless,selecli ve l}j-bIIX:kade 'l'elll S10produce Ie~ s peripheral vu_socon.stric _tion (cold hand sandr<"l,t)anddoesnot rcdul'e theresponsetoeJlcn:ise-ind ul'e d hYp' lgl yeaem ia (sTimul;ltionofglucol'lCogenesisin thelive r ismetliat<:Jb l} ! -rec~plur~ l.CarJiosdel'ti vedrugsmay have~u nkil'nlfl! -ael h'ilyIIIprct:ipitatl' Sl'\'creb ronch""p;I~ minpat icnt ~ ~i thasth nlaand the y sho uldaHlid l}-bllx:k c n Snme l}-bl t :ke r~ po 1SSl'S ~illtrillxi sl'mpu lllOlllinWlic (/I"lhity(i,e,;IT!.'rani al "gnnis ts,Chapter2),Theclin-icalimpo n:mceof lhisi~dehu(;lhle ,bulseeChapt er 16,

10 Ocular pharmacology

Cata ractformatio n

RetinaCiliary pody

"'GE ~ E LAfE D MAC ULA~ DEG E N, EI1AnON("'MDl

The~ )' cis<In inflated spherical shelf, i l~ OUI"'f layer hcing th",tough

ccllagcn nc hsclera.Thenormalilllnu/I.'ularpressurenOP)i~about

15 mmHgandbmuimuincdbyubulunccof aqueoushumourformauon

b)'ther i iarv"'1</.1' ( )and outflow throu ghthet rohccutnr mesh ork

into lhec na lt1f Schlcmmi_ _),In open-an gle~ I au{ ' n ma the lO P

remainsabtlve::!-tmmUgbeca usepalhulug ica lcha nge'intheuabecu

-lar mesh work decrease theoutflowtlfaqueous Because the eleva ted

lOP will eveurually damagethe optic nerv e ,the pressu re isreduced

usuallywith ,[rugs.This can heachievedeither byincrc ,inguqucous

outflowwith muscarinica~ nnis " such a.' ilul:arpinctbottomld t),

orbyrcdu dngaqucou -,tormauonwitha-eanet yofdrugs(m idd ll' righ t)

b UIespeciallytinmlnl,a~- bl od er.

At therromIlf theeye,the sclera run, intothecor-neaIllIp[dO host:

tran sparency i, obtained by ulignmcm of the collagen Iihrev ~hny

superficialmanipulations.such, I'tonometr ytmeasurcmcntofthe lOP)

and the removalIll'corneal foreign bodies.require the instillation of

reveal damagod areavof cornea lepithe lium, which are 'l:linedbright

greenbythe dye.In fla m m al it'nof the cornearesult ing from allergy('I'

dwmil·albumsi>treatedwithtopical anti-inflammatory drugs(C hapter33), lntectionsare not treated with unu-intlamnnuory agents ex c ept

together ith an effective chemo therapeutic ilge nt because ant i

-inn amnl iuory dmgs reduce recistunce toinv adi ngmicroorganisms

The ir i,[middle rem11I" '><: ' '><: s a sphinc ter muccle.which receiv esparavympath ctic nerves,and a dilato r muscle which isinne rv ated by

sympathet ic fibres.Th us muscarinic antugonixtv ,ulli n-adrenoccpror

agoll i'hdillli ethepupil(rIIJd r ia, isJ.whilemuscnrjnicaglln islsand adrc noc cpt orantagonictsranstrictthe pupiltminsi ,),

-Coruracuon of the par;\Symp athcl ica lly in ne rvated dli,l rJ musd e

ncar\·i,iullI)CCIlI'S ·11111 ~. muscari nic amago ni sh ,,,,m!.nf' the cilia ry

muscle (("J d llp l t'~hl) ,HId pre vent accomm oda tion for ncar vixiou

hilcugonist sca ust' nccommodatien and a loss offa rvisio n

TheI'n s (middletop jprovide stheadjustablepart of theeye's refrac

-tivepo er.Opacityof the lens is calle d acata rac t.Sm ile drugs,notably

co rt ic c tcroids,may cuusccutaructs

2

Theretina is "pnrt(Ifrhccentra lnervoussystem hUI itsee rnvlilll.:

affected hydrugs,prob ably Ocl',IU"":: ofthe euecuve blood-rcrinulhar

-rie r.\"t'rf t'porlin is a newllrug used 10lre al age-related maculardegcn

-Ciliar)' hcd y

ThepTtlce, sc softheci a ry body are highly vascularized and arc the

sil':sofaqueo us humou rformntien The l;ilia r}epilhl'lialcells.which

connunAT Pase arul cartomc anhyd rasc absorb Na+selectivelyFrom

thestromaandtrans port itunothe intercellularclefts,whic hopenonly

on the aqueoushumou rsid e.Thehypercs molalityinthe clefts cuuscv

water no wfrom tile saromu.producing aconnnuo usflow ofaqueous

The cilia ryepitheliumi,leak y.allowin g sig nificant pa ive titrrunon

and up ttl JO%of aqueou smayhe formed b uttrafiluuuon

Tra becutarIlIl".h'lur k

Theaqueoushumo u rcirculate-throu g h thepupilandisdrain edintothe

ca na lnfSchlcnun, whichisa circul argutterwithin the surface of the

scientutthe limhu The sieve-Hketr abec ularmeshw ork isthe roofof

the gutter.throughwhichthe OIIJUt."tlllS mustpa before il is eventu a lly

drained awayinto the epis clc rulveins

Glaucom a

This h a gro up of ocular dise aseswith theco m mo nfea ture sof abnor

-mallyhighlO P andultimate10 of vision if untreated ItII\:CUrsin,tho ut

1%otpeopteover40 yea rsofage viewed through an ophthalmoscope

theopticdisc apJlc 'arsocp re sed (cupping)beca us of th lo,;.s ofne n e

fibn.·s The rnechanicm b which the ne rve fibres are destroyed in

gla uco m a isundear,bltl may in vu lve l11edlal1 i<:alfal'tnrs amI/or Itl\:l\1

Ischa ,'mi".0Jlc 'n-an g le (chro nicsimple)glau<:oma Islhetllo,;.lCOml11lln

fo rmoflh di ,,-.e.Inclosed-ang le glauco ma, Ihe anglehel\\t- n Ihe

conlL'a "ndthe iris is ,Ibno rma lly sma ll o.; casionall)', heangle c1uses

co m pletel y prev t-'nling ;Klue lJus outflow ;Uld the 10 1' <Iuickl)' rises,

Bt'cau se IX'nn a ne nldamage 10 lhcn:linacan occurduringthe :: allal.:ks

the pn:,suremU,1hereduce da ~t.juil·kly a"!",-"sIblcb illU'fls i!'eimlifl<l

-(;0 /1 of l'i!o('jlrpiIWe)'ed ro pslo lJlhi ned if necessary.with intr.tveno us

lI{'{'(lI :ollltl/ideandi l1l ra v entlu~hY l lI'rtonic lII alln itol(anl'lSmo lic agelll ),

to ren lllve wale r Acetalo lam ide inhibitscarho nie ,tnhyd rdsc in lhe

cilia ry hody and prevents bical'fMlna le synt hesis This leadstoa fa llin

sodium lranspon and a'l ueo m fnnnati nn lM.'eau se hicltrhnnal c and

soclium transport,lI't:linked,

PiI'K:llrpirw heing " lertiary amine diffuse-sreadily Ihrough tile

cornea illln Ihe :l'lu<'nus humu ur II red UCt-'S the lO Phy o;onlraet ingthe

ciliarynm,cl Thispulls thesclera lsp ur;mdrcsulls in thelrahee 'ular

mesh wo rk being strl' tcheJ and M."pa ra led The fluid p,llh ways arc

oJlc 'nl-'d up and aqueous oUlllowis increase J.Allpar.tsy m p'll ho m ime t

-ic,; cau""mios is.n.'sult inginpon r nighl visin nandl"< mrl airll"of'd

im-mingof vision '.Cilia rym u~d espas m that incTt'asesnl·ar -sight ed ne

ca us ing nlurr ed v i~ i o l1 isnot usuall y a pron lcm in lhe ;lgegroup lhat

de-\'c1o p glaucoma bu t can cuu"" hea da c he and brow'll·he Some

p<.l ti nls lind lhe-.e effl-'I:ts inlole run te

!J.ll hll." ers.Timolulis the drugofchoic ein upen-an l!.k glaUn ll\1a

[t bl ol.·k ~ 132-ad re nol.·epl or s on lh<'cilia ry prll\:es;,cs anti so red uces

aqUC'I'us"I.'Crclion In addit ion.limo lol mllY nlock !'S-fCl'eplo!"); in the

afferenthllMxi vessels ,u ppl)'ing the cilial1' proce es.The resulli ng

vasocllm lril.' liu n resuh sin rCllul.'l·d ultrafiltrat ion amI,lq Ue-OIlS fnnna

-lion.Timol o l avo ids lhe unpleasa nteffecl sofpiloca rpin<' on the eye,

hut it is ahsorI:>W syslemieally and ma y provoke bn lllehospa sm in

asthma lics orbrddyca rd iainsll'oCeptibk palic nts.ThC' TI.'fol'C'.l3-hloch·rs

cnuiou(A MD).Theretina rnayoccaviuuallybedamagedby drup te.g

bonum rightI orbyhig h oxygentenvlon innew born hallies

tcvcn sele c tive I3I-a l11 ag o nisIS) should he avoided in p.uicnrs with

as lh ma hear! failure he artblock orbrad yca rdia

l.at anopne-t is a prudru g of pru st;lgl;md in-F2 The dru g passes

throu ghthe comcaand reduce sthe[01' hyinc reasin gtheuvcoscleratoutflow ofaq ueous

Epinep hrilll'tudrennlin c ) and rr-adrcnoc cptorvtimularuslowe rthe

101' b)' an u.mcdiated vasocon-aricuon of lhe dlial')' body arrcrcm

nllM lllvesse ls,Confusing ly u-antagoni slsand 13-,ulreno ceplOr ago nislsrespcci ally 1i2"Slim ulanls )alsolow erthe 101'.Thesedrugs inc rease theomnowofaqucous ratherthan reduc ingil;,form auon.pres um ablybydilatationoflhe aqueousvein,;.and/o repisc le ra lwins

IIrim unidin l'andapru clunidiuearc u2-adrcmM:epI Uragonists.The y

decreaseaqueou sformation h)' stim ulat ing ({2-TC"cpwrson the

udre-nc rg icnerv e terminalsinnerv atingthecihury body (lIIUs redu cing

nor-epinephri ne rctca-e j

Illlr wiami dl.' is a topicall y active inhibitor ofcarbonic anhydrase(CA-21.Itcan heused alone in paricms in whom ii-bindersarc co n-

truindicated Itis a sulp honamide andsyste mic side-effec ts may occur

c.g.s"i n rashes,bronchospas m

gfuucom a.Underlocal aruu-crhesiu the urge onuse -,an argonor dilx!

la r1 place ahtlUl 100evenlyspaced lesion, on the ioncr su rface of

the trabe cula rmeshwor k 'I111.·laser'h um,'cau,C'k><:alilt':dsh ri nkage.whidtcxc ns ll'n~ionon lheadj,!t·elll.untrealedtissue olX'ningsp,tccs

inlhl'meshwork and allo win gincrl'a,ed l lq Ue-OU.~dr;lina ge.Inclose

d-anj!.kglaul'oma,an ll riu malum ini umganwt(YAGlla-.ermaybeu""d

10ma ke a hole 011 lhe periphe ry oflhe iris.Thisprc ve lllsthe forw ard

mowtllentof the irislhm pl'ecipitatl' s anne- gla Ul' o llla anti isuSllally

ca usl'dbya pa n ialblockIll'a'lueo us llowIhroughlhepupi

While lhehc 'nclil\ of trca tingpalie llls wilh closed -angle glaucomaare

dear,thesamec n nothe Iid furpatient s with 1lJlt,' n-ang1e glauo;o ma ,

",-'Cause the vail ahleevidencedol' Sm,tc ' ll lvi ne ' i n~ l ysho wlhat lrcatmcnt

wilh drugsorla rsurgeryan -cb thelong-tennprog re,;.sufl bedisc a-.e

Mydriatics

MydriaSiS (d ilatation of thepupil ) isrcquin'd for ophthalmoscop y.The

drops most commo nlyused arc the rc1<il ivclyshllrt-al'ling mU'oC"rinic

amagonis" Irnpk amideand('~ dll pt' n lf) hl le ,whichprlx!uce rolhmy

-d riasi ~"nd cycloplegia The1.t-adrcnol.·l'pIOr stimul an tI lh en ~1l'Ilh r ine

maytM:usedtopnxiu eemyd ri;tsi s wilhuUI:lffecling lhe 'pupill;lrylightI'I."tk\oraccomrnlx! alion.Myd ria sisilia )'precipilate a>:utec1oscd-an g k

glauo;olll,l insu- ::epli n1epat il'n lswholire usuall y agl'l.lllw r 60yea

Age-related macular de generation

-'!!eordaledmm;ula rde!!el Wralion(-'\ 11))affectsnlOcr p.:nple and is

the most eom mlln>:auseof hlimlne,s inIh UK Nl'lIo'hloll<!\'e el-.fonn unl!<:rthe re-tina ;lI1dIe;lf." age of lluidand hloodfrumthe vaWlllar

c om ple \ e~ c a u~e ""veTt'loss ofv i~ ill nwithin a few years.Ve rll.·Il<,r lini,; alighl - ::nsiti vcdyeth"l s given inlra wnuusl yand isla kenup hythev;\'oCularendolheliu llI.A la,,-'r is the nap plie <llo theIl'siol1 andthis Cli-valesthedye releas ing IOxi>:freeradil.'alsthat dcst roythenew\'C~s e ls

(pho l,l<!ynamic the rapy ),The eflic acy {Ifthis imcreslingIrcalmcnl has

yelillhe eSlablishedbUIi " l nls tobe mos t effec live inpalielll s with

da" ic~ u hfovC'a lol.·{lva- ::ulari/.at ion

27

1 1 Asthma , hay lever and anaphylaxis

Cortll;:oeteroi d!'J

l.ANl'l1I!'o1Eetheophylline

Antlhi l!ltami nee

ipratr opium

L TD,I'IN f l'lGO NI5T

mcntefukaet

~ ~l'STIMU LAN T5ealbutamol

Asthma.hay fever and anaphylaxis (shadedboxcx) nrc rauwd hy (he

samcbasicpro c esses:I ~ Eantibody attachesto mastcells(toplef t)and

o renewed exposureto the"lllWantigenH~ l.d granul;uion ofthe

mast cellsoccurswith thepr oductionand rek-aseofIUl'dia lurs(mid le

lctn If the release of mediators is localized, hay fever 1I0P righo

or asthmatbonomrighl) result but , massive g nera lreka :causes

anaphyla xis.whichisa rare hutlife-thre atenin gre ac tion1Il beeSlings

an d penicillinI l fothe r drugs, Ant igl'n , that cantrigg erthl" l'reactions

are calledalll·rj.!t' Usrrople n l

Bronc htat acthmuis an inrlammatury diseasein which thecalibre

of the airways i, chronically narrowe b oed ema and *' unstable

Duri ng an unack the patient,urfer,Irom wheezmg and difficuhy in

breathing ;1' a re,ull nf bronchovpavm mucosal tll.".kma and mUl'US

fo rmuuon rbouom right}.Eventually 'hechro nic intlunuuatiencauses

irrev er sible dHl nges In the airways thn lln m righI), When tIlt' ac ute

attack has an allerg ic hasi s the term j ',IIrIII.I'icasthma *' often used

Whe n there is till obvious allergic has*, fo r the disease, it isc lled

i n /r i ll.lit"

In mild III moder ate axttnuu the tirst-Iinc drugsarc short-acting1i! -adr"noc<'pIUra onis tsI ~J ~ l i m l1 l a n l ~ middle right)inhaledfrom

prcvsurizc dcontainers when req uired I (l Igo ni,rsnrcrequiredmore

thanoncea ay.thenn-guluradminis tratio n ofjnhaledsteroldorcr

o-nlO' j.!l k alei added(b num righl).In mo re severeucrhma,short-ac ting1J-:lgolli\ IS arc retained either with theadd ilion of high-dose inhaled

stl"milh,or with thead itio ofaregularinhaledIllng-,u.:tingl3· st im ul;Ulltc.g.sllrnl'le r "l)togetherwithsuurdurddose inhaledster oid.I necessary.high-dose inhaledsteroidistriedwithsarmctcrol, inhaledIpratropium(a muscarinic untagonivtl.lIT IIT Isustainedr ell " a M ' lh l ''' l lh~Hlnc Somepatients are controlle d only hy oralsteroids (usually prednisnlun e.ChapterJ ~I \lnnlelukll'lis an "r.dl)'admin istered jcu cotnene antag-

onislIhal reduct',thebronch constncroramIin jhunmaro ry effects of

L T D ~ , IIisused inrhc trcauncnr otaspiri n-induccdasthma which is

lhoug ht lobel;;lusedbyuu-rcased teucorrtene sy11lIK'si,

Anile severe a!t;u:k s IIfll\l h lllll(statusa s!hlll;lti~'u s )that arc no t

controlled hy the pauc ru'sU\ U;lI drugsnrc potentiallyfatalnndmusthe

dealt wilh s an t:lllctj;.eIlCY.rt:tjuiringhuspi lal adl11i),ion,

A naph, la\ i ~ [bottom len) requires prompt treatment with epine

-phr ine(adrenaline)(Cha pter9),givenby iruramuscuta rinjectionth.u

is repeatedevery5minut esuntilthe bloodpressureand pulseimprove

Oxygenis administered(if avail ahk )andchlurphen amine(an

antihiv-mmme ] givenmuavenoudyafter theepinephri ne isusef ul.In severe

or recurrentanaphylaxis intravenousor intrumusculurh,dnlClJrli:otlml'

is given

11:1-:isthemajor class of reaginicantibod y.In allergicpatients,specific

umibody levels may heinc reased to 100 lifllesgreater than normal

Bindi ng ofthe F portion of the unubody \(l receptors O il mast cells

followed b)'cross-linking ofadjaccm molec ule s1:1)'antigen lriggers

degra nulanon hy amec hanism involvingCa2+inllux

!\Ia sf cellscontain thebodystoresof histamine andocc urin ulnmst

alltissues Within thl' must cell" histamine is hound with he pa rinin

cytoplasmicgran ules Histamine release normallyinvolv es aninnul\ uf

Ca" ion s lind,because thepermea bility of hecell membrunc10c , >inns

isred ucedwheninlraeellular cAMI'le vels are raised drugsrhurstimulate

cAMI'synthl'sis(J1~ -a drenocePlOrugunislS)reduce histami ne release

Medlururs

The ini tialphaseotunasthmaattack is brought aboutmainly by spas m

of the bronchialsrnooth muscle caused bylhe releaseof"pa ~ nu~l 'lIs

(middle left) from mast cells In ma ny us thm a tics.asecond del a yed

phaseresult sfrom ther cj e as e1' 1' chcnunaxms (centreleft, shade d) rtuu

attract ntlarumutorycells, especiallyeosinophi!s These inrlamrnutory

hron-rttospasmandarc atlirs lreve rsible.How e ve r.permanentdamageto me

bronchia lepithelium and smooth muscle h pertrophy eventually lead

to irre\"Crsihleairways obstruction.This damageseems1 becaused

mainly by subs tances releasedfro rnthc eosimlphilgranu lestespectany

eos ino phil major bas k proteinandgranule pero xidase )

Bronchodilators

~ _ A drt' mll 'e ll t llr st inu ilanls TI,e airway smooth musl'1e has few

u re ne rgic nl'r,'e fibres bUImany [} ~- reeeptors. stim ulatio n of whkh

r;auses hroochodilalalion.AClival ion(If 1l2-adre mw 'I.'ptoNrelal\esSmlMlth

musl'1e by increasing inlrace ll ular cAMP, hich activales IIprotein

kinasc (sec nitr ates Chapter (6).ll,i, inhih its mu,d e cnntradi nn by

pt\llSphorylmingandinhibitingmyosin-lig hl-t.'huin kina-.e.~ ~-Ago n i'l"

such as salhula mol are usually given b)' inhalation,The y are not

specific but Ill""fects (cardiac stim ulat ion) arc nul us ually see n at

d , t:sIhutca use hronehodilatutio tl, Advcrse.'dfects incl ude line tremor

ne rvou ste nsion and tach ycard ia bul lhesearetlo tusu al lylnl uhlc 1l11e

when thedrug is given hy inhalatio n Or.aladministr.atiun is usually

rcstrkted 10 r;hildre n amI othcr p.llicnt s ho l'unnnt usc iln aew so l

pl"l.'pa ratio n Salnlt' lervl i mueh lo ge r la' tin than salhul;HlIOI [n

COrilrolst 10 ~hort-aet i ng Il ~-ago n i'h. regular treatme nt ith inhaled

s;t!me te rolhas hcndki<lleffeclsin "sthmatics,

Ip ral rllp iumis aO1u ~carin i cantagon istandanuxln ;ttdy effeclivc

hron eh od il;tlor pres um ahly beeau-.eil redul'Cs retle' va!!.11 bronch

o-cllnstrict ionlhatresultsfromh i ~talll i ncstim ulationof -.ensory(irri tanl)

rcl.:eptorsin theairwuys.Jpm tmp iumgivt:nh inhal atio n r;m:lyCilUWS

atl\l pine.Jikeside-effects

XlInlhin es

Tlwullh ,lIhwtll<ly benelill'hildrellwhocan nut usc inhal' ltlls, andadults

wilh predominantly noclumal s) ' m plum~. Theophy llineoften cuuscs

advcr : effccls,evenornlsustained-I'I.'Je<lsetheophy lline pl"l.'puration s

lIa, rever is mosl commonly caused by allergy to gras" pollen

, · \ n h i ~ l a lll i l1 l "Scont rolsome symptomsand nava!corncocrcroidsarevery cffe cnve.Cromlll:lk a teeyedmpsmay he a valuable adjunctin

allergicconjunctivitis

thatarc effectiveforup to 12 hours,Even whe nplasma conccmrationsare in thetherapeuticrangeiI0-20mgL-t I nausea,headache,insom-

niaand ubdomiunldiscomfort arc cnnunon

Above 25 mgL- t toxic effects include serious arrhyt hmias and

convulsions lhal ma y be fatal It is not known how theo pb ylfinccausesbronchoditaration inasthmatics Theophyllineinhibitsphospho-

dies k'ruse and increasescellu lar cAMP le vels The concentrationof

theophylline lhal inhibits most phusphodievtcruses is high l"1' than

the therapeutic range hut he reis some evidencethata sublype ofthe

enzyme inairwaysmoothmusclei mo re sensitive to rho ru g.Cromoglicate

This is aprophylac ticdrug ,HI dis ofno value inacute auackv.It has

unu-inl1mnm altlryucnons in some patients(especiallychildren Ihut it isnot pn~s ible topredict whichpatient willbencfu.CromoglicalCmU.slhe

given regula rlyandit maybeseveralweeks before bcnenciat effectsare

apparent.The mechanism of actionorcrornog ficarc isunclear [tmayact hydecreasin the sensitivityof bronchialsensoryne rves, abolishing

loc al reflexesthat~Iimu lil\einflammalion

Cortico steroids

Steroidseffectively mc reasc the airway calibreinasthma by reduci ng

bronchial mflammatory rcacuons (e.g oedemaandmucus

hyper-cere-riun ) and by mod ify ing allerg ic reactions Drnl admi nistra tio n of

sll'wid,is associated withmany serious adverse effects (Chapter 33)

hut.exceptfo rhig doses,these cenbeavoided in asthma by aerosol

<ldrninis trJ tiunofthedrugs (e.g Iwd ulIlt'la sulle l.InhaledstemidsareusuallyeffeClive in3-7 days, bUI ura lsteroids Illay beneccs~ ary in

!>Imle palienls,where 111other lhe rapy fails Sternidnas.;11sprays (e.g

bcclllnie lasllnl",hudesnnideJ arc very effective inha yfe verand;lre

especially usefulinpat icnl ~wil nas:11co nge ~tionthat isnotal'feck'dhyantihis tamines

l h : n~e n (40-60%) is given logethe r with neb ulized or ill1r:lvctlouS

f} ~ -llg ll nisls (e.g.s.ulbulllnmh The n intravenou s h ~d ru,, · nrli ne or

nr.a.1 rcdni :otl lhmt' is giwII Nebulil'edipralrn"iumma y alsobeUM.'d

if rel]uired, If thesedru gsti not produ ce a r esp{ln ~c ,.mintrave no us

in fusio n ofuminoph)lIi nemay hclp hUlthere is lillie evidence that il

dill'S.Anilkialwntilation nlilYlM:I\.'ljuil"l.'d

Antihistamines

Antagonisls lh'l blOCK lit-histaminel"I.'Cepton;ureusedin thl:lreatme nl

of allergic ellndilions sueh a, hay fe ver unicaria, drug nsitivity

ra ~hcs ,pru ritis andin'Cct biles un '>lings.Older antihis tmnine drugs(e,g l'h lo r phenam ine.alillll'lnali nl' prollll'tha l inel ha ve amimus-earinic lletion, and pa", the hlOlXl~br.ain barrier,commonly cau~ing

dro wsinessand psychomolor impaimlen t.Ne wc r ugents(e.g Inr a

lOl-dine,(·t'lir izille,fexul'l'nlld ine)d nll1ha vc atl1ll' ine-like acti on sand.becau lhe y do nOl crosslhc blOl.Mi-hraintmrrierto any Cl\lem.the)'

cau\Cmuchless dro ~iness.

,.

1 2 Drugs acting on the gastrointestinal tract I : Peptic ulcer

/ pH7HCC,

(proot a gilina ine.)

Thete rm peptic ulcerrefersIIIany ulcer inan area wh rethemucosa

i bathed in the hydrochloricacid andpep in ofgastricjuicet c Ihc

stomach andupper part ofthe duodenum) Drugs, rb,n arc ct fccuv c

inthe rteanncnr nfIIl'plic ulce reitherreduce l!a ~trkad dsecretiun

tteftccntre and right)orincfl'aM'munNl1r i ren ee10 acid- pep-in

attack(h<ll1 nm tetu

Acid secretion from the p oll'if l<ll cdl.' I J i, reduced by Ill"

hi'lam inl.' antal!lIni,l!> tright)orh ~ rll lullpum pin hi h it n r, (right)

thatca n produce vinual anacidity b inhihilin g th ' pump I J lhat

trunsport-, II' il.J n ~ uut"fthe parietalcells,Protonpump inhihil\.lrsarc

ve ry effective in prnnlOling ulcer healing, eve nin patients who are

revistaruto1!-ant ag<lllisIS,The'l1t'Usai'lren lo:l ht' ner,'tbouomlefl/

increase ulcer healing by binding to the ulcer hilS'" (k h,• J ,This

provides physica l prutt'cliun and allows the secretion of IICO,- to

rc-esla hlish the pll gr diem normally prevent in the mucu layer

' 01that ongimuc, from mucus-secreung cell,U=» Jli wl'ro , l/ol

is a prostaglandin analogue thai promotesulcerhcalin gb stimulating

prolc cliH.'mechnni ms in the gastric mucoxu and hy fedul'in l;acid

-cretioll It i ~ Jln timc' u J 10 pre \'cnl ulct."f' in palients rakin g

non-slcl1lidalami·inllammato rydrugs(NS AIDs C'hilptcr3 l

Pepticulcers.how e ver healed.will oncn recurwithoutco ntinuo usdrugudmmismmon ThisisIx ' C.lU S<':chronic infectionof the stomac h

ulcer formation /I p ylori intccnon is a-vociatedwith ahoul 95%of

duode nalulcers and 7l1'l oft!- a l rk- ulcers The infection111<1)' rcs ull

ina chronic hyperguvtrinacrnla.whichstimulate-, acid production and

cuuse v ulcers(bonomright) Uncomplicated peptic ulcers aSSlll'iat cl!with H f'y{o ri inf ection are treated by the eradica tion ofH 1 '.I ·lori

u~in gacnm hinalioo llf:1protonpumpinhrhiturte.g omcprazulc}Yoith,m tihilltics (Icft centre) Before treatment.infection with II pyl" ri isconfirmedh a urcu breath 1,' 1in which some PC-Url';[ is mgc vrcd

1/ pyluri p!'sse,ses urease, ,III cnymc Ihal IJreab down the ure a,md produce I.lC-hic'lmo nalc thtu ca n tv detected in a sam ple ofbreath.'J11C breathIl" 1i also uvcd after treatment Itlverify1/ fl yl"ri

eradic anou

Anlacilh [lop left) are base , that raise Ihe ga~l ric luminal pll byneutralizing gas tric add (middle lcftt The)' provide effective treat-

mcnl fur manydyspepsiasand sym plo ma til'rel ief in [lI.'plicuker and

o".''iOphage.1! rcll u Manypropril'tary mixtureswhichu,",lIly conlain

ma gnesiumI1T aluminium 'ialt'iaf e ;lvai lahll' ,

Acid secretion

intr ace llula r 11+for extracellu lar K+.The secretionIll'IIC Iis stimu lated

0)"avctylchotine (AC h ) released fro m vag a l pnstganglionic fibre s

(righlofIlgu rcl.andeastrin,releasedintothebloodstrea mfromCi-cel ls

in theantralmucosawhenthe y detec taminoaddsandpeptides (from

rcttcxcs

Altho ughthepa rietalcells pllSseSSmuvcunnic (MI and gavtrin IG)

indi-recrly,b releasin g hi.\/<llIIilll' fromparucrinc cdls trig ht,CJ )located

parieta l cells.whe n:aClivlltio\1ofh btami neII: -rel'e plo rs (H resulls in

!'flc cts on acid secretion uf both vagal vtimulution and gastrin arc

red uced hyII:- rece ptn rantagonists

Cholinergic agonists can powerfully~ Iirnu lateacidsecrenon inthe

vag us mustha ve limited accessto the parietal cell muscarinic receptors,

sccn-rion hut his lsgreatlypotentiated whenthe histaminereceptors

Protective factors

,\ l uCII'"l a ~e r

su rfact' ofthe stoma l'll and rro ~illlal duo"l<·nlll1l iln co nsis l.' of a

whl'nthe ~ I()machcOnlc nhare atpH2,I'm stag land insE: ;1001 arc

syn thcsil.<.'d by the g:lslr k mUt·usa Whl'f'C they :Ire though tto cxc rl

a cytllilrutec!ive al"tion hy sti m ula ting the Sl.'cret iun of mucu,lind il;a

r-htmale,undbyinc re as in theI11Ul'(NIIhll,udHow ,

Ulcer healing drugs

Acid Sl'(T(·l in n r!'dlll· r'"

II ;sramifll ' II~- rt'("t'pl/Jrtlllfll!-:tmistJ

l"iml'l id int'andranilidiu ('arcr:lllid ly ahso rbetl orall y,They hllKk the

actiun of hi,t :lrninl"on th" pOi rid al n ~ lI s and rcducc arid sent.>!ion

These drugsreli e veIhepa in of peptic ulet'r ;lI1dincreasetheratc ofu <'r

healing,~ inci dc nce of si.le-e ffeCls is Inw,Cimctid ine has sli{!h l

;mt iandmgenic actions and [;Irely C;lUses 8yml<'eom;lslia Cimclidine

;lho hind, Itlcytochrome 1)-450 and Ill;ly reduce tht' hcpaticmew hnli , m

of drug, (e.g wa rfarin phl't1)toin :lnd theophylli ne )

P rolon/111/1//1in hih i lor \

sulp hydry lgroupsin theI ·/K·-AT aselp tonpump ) responsihll' for

transpl)rl ing11+io ns out uf the pa rieta lcells Becau se the ell/ynlL'is

irrcversihlyinhihited ,otrills"'l'rdiononly rl"lIl11t' , afte r thesynlh<'sis of

condition caused by an is lcl -i,'ell gastrin-secretingtu mo u rofthe pan

-crcus andin patients withreuux oesoph agiti s whereseve reulceration

isusuallyrcsixtururo nthcrdrugs

themucu slayerwhere a I'l of7.11 i, oprirualforib gro tn The bactc

am mo nia produced by'trong urease activity maydamage the cells.Ga,triti, avsociated withII , pyloriinfectionf\t.·r, i\ b foryell", or urlife.and is assoc iate dwitha sustai ned increase ingastrinrelease which

caused hy cy lolinc~ resulting from inflammation whic h also com

ill\:re a 'o<-" the mass ofIhl' purjctalcclls causing an exaggemll'd acid

intlamrnaricn of these ccfts le:ld,tuulcer auon Eradicationof1/.pylori

of acio inhibitionand anti hiotics caneradicateII pylori inover/'x ) 'k

ofpatients in I week ~ tost recomm e nde ddrugcombina tionsinclu declarithnuuycin e.g, ctnrirhromyc in omeprazolc and metronidazole(o r amoxjcillinj.If clarjthrom ycin canno t beused,amoxicillin.ruct ron-

common,

\1Ul'11\;111!oolr e ng l he nl'rs

Surnilfate polymcrizc s hclo w I'll! 4 to give a vcry ,tick y gel tlwt

ad lll"resstw ngly tothe 1'0;1 ofulcer cra teN Bism uth che l:ltcmay act in

-prolein " espcd:llly inthe necrotic lissue ofthe ulcercr,Jlers, hich

Bism uthma)'hlacke llt helel'th:lndstooh, Hismuth :lndsucra lfat"'11lu'l

hegivcno anem ptyslo 111llC hor thcywillnH\l ple' with foot.!pwtt'in s

Antacids

An l aci d~mise tilelumina lpllof the s[om;lch.Thi,increaSl 'sIht'r;lIt' of

emptying :lnd so Ihe dIcet of a nt;leid~is shun, Ga ~tri ll releil is

illl're;tst.'<.l:lnd, hccausethis~ti m ul<llcsadd rdcasc, l:lrgeramn unl~ofantacill, arc[weded than woulu hepredil'tt'd «ad drebo und) Frt'4u t'nl

ra re l)'prae lic:ll

S.,di u lll bicarbonall"isIhe only useful wille r'!Mllu!:lle;lntacid,It a s

UOSt.'smay cause~ys tt'lI1it-alka losis

I\hj;tlll'siUlll h~ 'd rn \id l 'anl!tlwgn esiumtri,il katl'arc insn lu hk inwOlter amih:lw a fa irlyrapidal"lioll I\la gncsiu111 has ala, ative efft'l·t

comr le~cs with cenain drug~(e.g te tmcycl inl' s )and tend W ClIU

constipltliotl,Mixlures of1II00 gm: s iumand alum iniuml'umpo u ndsmay

belIscuttlminim izethel'ITt'l'!s nn mo!ilily

31

13 Drugs acting on the gastrointestinal tract II: Motility and secretions

~· r; IOJ._ _Lo '3it udinalmU!lClc

1 'O'trlf Clreular mu,;clc

Musculu r conrrac no nsott hegillandsccrcuon of acidand nzymesare

vyxtcmc nsists of g,ulg linmlledplexuses(_ /withcomplexinter

from thevagu~andinhibitorysymparhcuctibrcv,Other trunvmittcrsin

theg tinclude SilT,ATP,nitricWij de;mdneuropepridc-Y,

motilityand may cau c colicamidiarrhoea.Th eyarcwry occu ionally

med intheteatm en t ofparalytic ileus (Ch pter8),More

andgastric~t asis.I.a \ali\,stbonomtemarc drugsusedtoincreasethe

tirnu-lurethemyentericplexus and SOl11C drug., acta, luhrk;lllls( 1

J2

Muscarinic antag onivtv(lopright)reducegastrointe tinalmotilityandarcIl cd10reduce pa m in irritable howe!syndrometa tis pavmod-

hUIrl'f, I<ln' t1!t'lII ,,[ water rllUl dt'clrulwl'10-',1' i,l!i elll' ra fty /IIO/'{'

im-1""'1<1111 Ihull (/ mg In 'UII/WIIl. especially ininfants and in inlectious

diarrhoe a

Anli-inllamm:lln r, comco-rcrolds andaminosalicylatevuop ieI'l l

arcu I 1inulcerativel:olitis:md Crnhn'sdisease.To reducethe need

h I TSy rcm ic tertlids itisusual to add a/alhiop rint: an irnmunosup

-pres um(Chapk·r4J)

In theduodenum.bile from thelive r( ti ll'right) and pancreatic juice

opening that is re trictcd b the phinctcr of Dddi nileadds ( 1 0 1"

middle] are s mcume-, used1 di ofve chele terot ~ar "toncs (e)

sccrcnonofpancreatic juiceisabsent or educed

Motil ity stimu lants

Mt'lod ull r amid l'anddUlIlllt' r idnm.'arc dopamine,Hllagn nistsand,h

block ingcentraldopaminerece ptorsinthe chemorece ptortriggerlone,

theyprod ucea antinausca/antierncticaction( M."C;'alsoChapter30 ) The

drugsalsoin reasecontractio ns inth stomachandenhancethetone of

th lo wer oesop hagea lsphincter ,It'tions that combine to speed the

transuofconte ntsfom thestomach.The pmkinctic ucuons of mc

to-clopramide nd dom peridonc arcblocked byatropine ,~ uggest ingthat

they resultfroman increaseofacetyjchohncreleaseIromthe myente ric

plexus.This effect on acetylcholin e relc:lse isthou ghttobecausedb

activanonof 5HT4receptors on the cholinergic ncurone s.T egascrod,

a5 J1 ~ untagonist,mayprove tohebeneficial insome patients with

irritable bowelsyndr ome

laxatives

Constipationis characterize dby xbduminul discomfort,os sofappe tite

a d malai se re.'ult ing from ins ufficient frequ en cy of defa ecarion;

this resulb in abnorma lly h rd and dry Faeces The freq uency and

volume of dcfae cunon are bestregulated by diet butdrugsmay be

needed for specific purp"ses tc.g before surgery of the colon or

rectum; colonoscopy)

lJuJklax ativesincreasethe volumeofth intest inal contents.stimu

-lating peristals is.They include indigestihle polysacch rides such as

ceuulo,c (hra n) andisp:lghula.{hlll"lit' laxativ esinc reasehulkinthe

bowelbyretain ing water by an osmotic effec t The yinclude salts

con-tainin g poo rlyabsorbedions(e.g.I\1 ~SO~ ,Epso msnlls) andlactulu e,

whichtakes 48hou to acta dmusthegivenregul arly,

Slimulan l laxativ es inc rease motili tyb acting ou themucosaor

nerveplcxu es whichmaybed maged b prolo geddrugusc.They

often causeabdnrninalc rump.Amhmquinoncsreleas edfrom precu or

glycllSidcs presentin sennaandcascarastim ulate the myenteri cplexus

Bisacud,\ 1may ;tct by stimulatingsensory nerv e endi ngs.It i ~rn'linly

usedbefore investi gational procedu res

Faecalsofte ne rs pro mo te defaccauon by softeningte.g.docu satej

and/or luhricaling (e.g,<lnlchi suil.li'lu idparal1in) :tl'ces anda ~s i-, ­

tingev,Ll; u,Ltion, Chronit'uscofliquidIl;lr ffin mayimpairabsorptionuf

the fat-soluble vitaminsAandDandc use paraffinomas

Anlidiarrhoeal drugs

Infecto s diarrhoeH isa ver y coml1\oncauseufillnessamirt:sultsin,

high mortality in devel upin g countries.Bac ter ialp;uhllgens euusethe

mcv tsevereformsofinfeetillusdiarrhoea but mill\' lllkndiarrhue a is

c au~db a virali n f ~t i un ,

An l i lllut ilit~ dru ~ sarcwidely uscd toprovide sympllllll tic re liefin

mildtomo erate formsof acutediarrlillea.Opiuid s stich asm orphi ne.

diphrlltl )·/<1teand("l /(/d/l/'activatcV-R-cl'ptorso myentericnt:urolles

andcause hyperpolarilation by illcreasing tht:ir p tassium oofliluCI

anee.This inhi bits acetylcho line release from the Ill)'e meric plt:llUS

und reduces bowel motility Lup ram ide is the must ;tppropriate

opioid forJoc aleffectsonthe gutbecause it doc sn teas ily penetrateto

the brain Uenl' ,it h s few ccntrJ.1 "l;tiunsand is onlikd yto caose

dependence

Rehyd r ation ther a py.Oralsotuuons conta ining electrolytes and

gfucos caregivcntil correctt heseveredchydnuionthatcanhecaused

byinfection with toxig enic organisms.,\ n lih illl icsare usefulonlyincertainspecificinfections e.g choleraand severeb cill ary dysernry,which arc treated with tetrac ycline.The

q inolones [Chapter37) aremorerecent a entsthatseem tilheeffec

-tivea ai nstmost importurn di urrhuculpathogens

Drugs used in Inflammatory bowel disea se

Inflammatory boweldisease isdividedintotwo types:

I Crohn'sdise a se,whic h canaffectthee tireg t and

2 ulceruttr e colitis, whichaffect sonlythelargebowel

L(II:alorsystemicanti-intlammatory t'ur lic vsl eru ids e.g.pred nisulnn e(C h,lp tt:r.13) arethe maindrugsu -dfora me attacks.butlheir serious

adverse effects make themun-uhablcformainte ance treatment,However ow lbudesunlde(slow relea se )isaconlco tcroidwithreducedabsnrpuon and maynotcause adrenalsuppressio \ minllsa licyla lt'sre-duc Ihe symptom-inmilddiseasea dmaintenance trcutmem reducestherelapse ratesofpauernsinremission,Sulfa'kl la /inl'is acombinauon

-of;'i min osalicy licacid with asulpho nmnide th:!t carne, the drugtothe

colon where it iscleave d by bacteria.releasingS<,lln innsalic) licachl

whichistheactive moiety.andxulphapyridinc,whichisabsorbed andmayproducelh adverseeffects characterisuc ofsulphonamideste.g

nausea,rashes.blooddisorders seeChapter 35),Newer, essro xiedrugs

aremt'Sl.llalin t', which is 5-aminosalcylatein preparationthat release s

th drugin th colon,andolsatazlne(azodisalicylatc).whichconsis ts of

IWO moleculesof 5-anlinosalkylil;acidjoined by anuzubon ,cleaved

by bacteria inthe colon.Themecha nismofa tion of5-aminosal icylate

isunknown.Inllhhn ah isamonoclonal antibod y totumour llt'I.'rosisfactor (T NP·a) Inhihition of this prointlammarury cytokine can beveryeffective intreating sev ere refractoryCrohn' sdiseuse

Drugs u sed to dis solve gallstone s

Bile t-olllains cholcstt.'rol and hill.'s lts,thc I:lller being important lit

kccp ing l;hnlestcrol in solution,An inneaseinc o le, terolconce ntra·tion oradt"erea.'>Cin hil<: salts may resultinthefOfOlalion f choles tero lstones,Ifthey gi\'crise til symptoms, a aroseopicc nl ec YM~IIHn yis

the tre;llnlCnt ofc o ice.However.small non -ca1cified stones m y be

dissolvedb pro lo ged oraladmin istrationof thehileacidur sud l"il'\)'<

chulit'llcid,whichd C~' f easesthel;ho!es lt.'roll;n tcnt ufhill'h inhi bi

-in an enlymeinvo lvedin chn!es tt'ro l formation.Pancreatic supplements

Pant'reati<.' jukecontai ns imponmllen/ ymesthaIhreakdown pfllteins(trypsin, chy motrypsin), starl;h(ulllylase) andfats!lipasc),In su mediseases(e.g chro nic pancreatitis cysticfibrO'iis).the reis an absencc (lrreduction inthese enlYmcs Patients wilh parn:reaticinsufficienl;yan:given plillc re 31in anelltrJ ctorpancre ascontai ning pro tease lipase

anda m yl a ~ e B e l; au ~ elhe m:ymesare inactivated by gastril; ,Kid, tisusu.d togive an H2<receptor antagon ist (e.g.d nlf'lidine)beforehand,

Ne wer t:nteric-eoatedprep r.tlions that delivermoreof the enl)·rtIl:Stotht: duode numMeavailahle

33

14 Drugs acting on the kidney-diuretics

Diur eti c s an' dru g s thatne t Oil 1 K' kidn eytni n c r c a» 11 1<.' exc rc non o f

W; II rand sodiu mchlorid Normally reabsorptionof'a ll and W' I [<."T i s

roetrullcd byaldoslero llc:Illd\a 'IIn in(antidiuretichnm 1UI\<,.·.,' DIB

baluncc Diuretic art.'usedh -duceo e demain 1"001/:(',I/i\"l'II1''''''[ailure,

come1"<'111//diW'l1.\('.I'and IWI'/lic";I'I"/IOSi.l.SOlliediun:lics llowhlythe

Th e rhtaztdcs and rehu d compounds (lop r i ~ hll arcsufc orally

c lins:or Inllp diu rt-l io (tor kIn These drug-, hove ,Ivery rapid

theten n'highceiling.'Jand cancau se serious electrolyte imbalances

amldehydration :\1elolat UIll' is athiazide-related drug wuhactivity

betweenthe loop and thlazklcdiuretics.IIh;ls apowerfulsyuc rgixucncuon with furosemide and the combin ation may he effective in

JII) ta,~iulllsupplementsmay hl' required 10preventhypokalaemia

S nil'diuretics are 'put " illl1l ~ p ;l r i n ~ '\ho.m omrighll They arc

weakwhen used alone bUIthey cuuw potassium rciennon.LInd arenftcugiwilwiththiazide ortUlIPdiuretic s 10prewnlhypokalucrula

Car hn nic anhydra selnhlhlturstbonomk-tt}arcweakdiuretic sami

and<,(, ml'l i me~10main tain ,Idiurc i ~duringsurge!)'

d ecrease th e: ctirninarion u f d rugs.

.14

:\ ld" ~ I t'rtl m ' slim u l:ne~ Na" !'t'ahsorptio n in the distal tub ule and

inr re usesK+an II'secretion.It, 1l'1~o cyto plasmicrece ptors(Ch,lpk'r

-me:Lhilit)'ofthe Na+channels,Amort: rapidincreusein Na' chan nel

Diurc uc sincrrnxethe Na"lo adinthedistaltubuleand,exceptfor the

high:for example if vigo rous diurl't icthe rapy has depletedthe on ly of

Na+stores,

Vusu prl'ssin(,\ nil)isreleased from theposteriorpituitary gl;lI1 ll.l

increaseslhe numberIll"watcrchunnctsinthecollecting ductsallowing

thepussive reabso tptionofwater.In'cra nia l'dia bcre-,j n~ ipidus,absence

istreatc-dwithvasopressinordl'SI11Upres sin alo nger,K linganalogue

in theproxima l tubul 'by in hibitingthe catalyvis "If CO.: yd rat ion ami

de hyd ration reactions.Th us,11K' excretion ofIICO,-,Na" nd Ill ) is

effectsof thedrug becomeselflimitingusthe bloodbicarbonate falls

-lion.Acetazolamide is used in the treatment of glaueomu to reduce

intraocularpressure,whic hi docs byreduci ngthe secretionof ICO.1

-and associated 11.: into the aqu eo us hu mourIChapter 10) Itis also

useda' aprophylac tic ugcm fo r mount ain(a ltitude ) sick nes s

Thiaxidc-,were developed from rh , carbonic anhydrase inhihito l"1i

effects onthi,enzyme.Thethiazidesarcwidelyusedinthetreatmentnf

mild hea nf:lilure (C h;lpter18 )andhy pm e nsion(Chapte r15), in which

1;ondi tion the y have hcen shown III reduce thc indden ce of rtlk

The re arc many thiazi dcs but the unlymajur d ifferen,,;ei ~Iheir dur,uion

of a,,·tio ll.ll cn rullu lIU'lhi:llide is wide lyu~ed

:\-Ict:hani smoflc t io n

Thiaz ides ,,;tma inlyon lh earlyseg01en!sof Ihed i.\1<1/ f/lfmll' , he re

they inhihil NtlCI rr u/J \'orfl/i""by hindingtothe synpo ne rreslltll1~ihk

for lhe ekctrnneutr al,,'otran spo n uf Na+/CI EXlTetinn uf Cl', Na+

and ;J1;,,;o mpanyin j:! Iii )is inn e a d." n il'inc rea-.ed Na+load inthe

distaltuhule stimulatesNa ~exchange withK·andIl ~ increas ing lhe ir

cllcrction:Uldcausing hypokaluemi a ,Uldame la bolicalkal~is.

Adler,el'!ll'Cts incl ud e Wt' <llillt' iJ illJflOlt'lJn ' and llcl'asiona lly.d:i"

(tH/II'.I. Serio us allergic reuctions IC.g thromhoc yto pt' nia l are mre

More COllllllon arethe followingl11etaho.\liceffect s

pa tients on igital is,This canheprcwnled by givingpUlussiu01supp le

diurelic

2 1I ~'p e rlJ ri cll em i a llricadd le vel s inthe hloo<.larcuftenine rca"",d

hc1;a U~ethia, idesare sel'rete d hythe organicacid sl'cn:tnry sy,t"'111 in

lhe tuhu1.:s :Uld1;omp"'tefo r uricacidsel'reliun.This tn,l)'predpila , \t O Il I,

-cated inpatic lilswilhnon·insulin-dept'nde llldiahetes

the tirst(jruomhs ofadmirustrutionhUI this is of nne nains i~ m i licance.

Loop diuretic s(usuallyfur':- lIlide);ITCused10reduce peripheraland

pulmonaryoedemain moderateandsevere heart faiure (Chapter IX)

resullsfromacutevent ricularfa ilu re.Unl iketheIhi:llides.loopdiuretics

Loopugenrs have athiazide-likeucnonon the ea rly dista ltubule hut

much mo re im port aruly.the y il/hihi l NIlC/ fj 'lIh arption in the IIJid;

lI.\('t'",JiII~lovp of111'/1"'.This segme n thas a highcapacil)"forahso

much greaterthan th at ofother diureti cs LOIIJldiuretics ncron theluminalmembran e whe retheyinhihit thecotrunxport ofNa+/K+I2('I-

(TheNa"isa tivelytranspo rtedo tofthecellsinto the inter s tit ium hy

ars;a' /K +-A'FPa ce-dc pc nde rupumpin thebasolateralmernbrane.jThespccilici lyoftheloopdiuretic sis becauseoftheir high localconcentra-

tinn in the rena l tubules However al high doses, these drugs may

causedeafness

Adver se effec ts

Like the rhiazidcs rhc loop ag,,'nl ' have h Yfln~IY(,(/l"mi(', carmic , hypotensiveandhypo}; ,,/al '''';' 'effec ts,Potavvium loxs.as withthe IhiiUides.isoftenclinicall)"unimportant unll'ssthereareadd ition a lriskfacto rsfur arrhythmja e, te.g.digox intreatme nt) Ove rent h usiastic

d l'lIjIIl'H 'hichmaynor~rt'vt'r sih1e

The e diure tics at·to thealdo~Ierune - respons ive"",gme ntsofthedista l

nl·phrnn wherc K+homeosta si sisco n trolled ,Al dm/l'I"OI le,limu!:l!es

Na' fl'ubsn rp tion.gcnerati ng ane g,ltivcp tentiul n lhe lumcn which

The pnt;lssium-sp;lring diure tics rt:t!Ul"C' Na+rea hsorpl ion by eilher

unlugoni/ ing aldosterone (spirono la l'tuneJor hillt.>king Na+,,'han ncls(a m ilu r idl' Iriamtc r en e l.Thi, cau 's lhe c1el'lrkul!""Itentialacws s

Illc tuh ularepithdiulll to fa ll,r cducin~ the driving forl'eforK+sec

re-ton The drugsmay 1;a use.~I' r l' rt'h.I·/II'r};"'lIemill,espt iall yin p;llien ts ithrenalimpa imR'nl.Hyperk alao.' m iuisulsolikelyto occurifpalil'lll sare alsu la kingin hihi[(lrsof angi utl'ns inl'o nven ing enl ym.: {e g.l':lplO-

prill,occause lhes,,'drugsreduce aldoste ro neseerelion(;lnd lher efore

K+e:l.crelio n)

SpiftllluladoneeOlllpt.'litivel)·hlocblhebinding ofaldostemne to

itsc), topl; !~lI1 icrece pt o r :lndsu in1; re ases theellnetio of Na+1('1 aml

Hz O)an den ea, e ~lhc'c1en rica llycou pled'K+s"·l·retinn 1li ~(I wea"

diure tic,heeau'iC"only2%of theto tal N,,+r.:absorptiun isunderaldo

-sterone ,,'OIltro! SpironnlaClollt:is u'iC"d mai nly in livl' rdise ase wilh

a ·ites Conn's syn,trollle (prim a!)' h y p.:ra ld ~t e ro" i s m l and M.'Vereheanfa ilure

penneah il ilyinthedista lnephronh)' eom hining ithNa+1; :lI1ne ls;1Ild

lJlocking the mo a I; I basis.Thi inc reasesNa+(Cl-,lIId1 1 20 I e ~ c rc­

35

15 Drugs used in hypertension

t>endrofi umet hlazid

High blood pressure is (lssol.'i:ucd with decreased lifeexpectancyand

increased rsk ufstroke roronnry heart disea se and other end-organ

disease te.g retinopathy rena lfailure).The problem isthaI therhkis

gradedan M11~rt:isno otlViollSline bctwc -npatientswhoshouldhe

ne ared and those wh should not Lowering the blood p R 'ss u re of

patient switha diastolic olund pressureofabove 'XlmmHg dccrcu ':s

mo rtalit yand morbidity hili this could incl ude 2;'i%ofthepopul.uion

In theUK.itis gene ra llyaccepted thai.in patients without additional

risk rectors.therapyisindica ted ifthetlia,I ,lic pressureisgreaterthan

100mrnllg and/or the s)'Slulic pressure is greater than ](,(lmmHg

Otherriskfactors for vasc ulardisease thatmaybe,y m:rgis ti~ 'include

smoking Idiscourage strongly ) obesity hyperfipidncrnia dillh<:tes

and left ventric ular hypert roph y, A fe w p licnls have hypen envion

secondarytOl"l.'nalore docrinedisease

Insome patients wih mildhypertensio n.weightreduction ifa

ppro-prtatc reduced alcoholconsurnprion andmoderate reduction in sail

consumption maybesufficient bUIusually drug treatment is required

The !>-lllln· IIlH.'eplllr a la l:unisl s (l3·blnckers cen tre kfl) (HId the

thiaz ide diuretics ttopright) arepresen tly the first-linedrugs in the

treatment{If hyperte nsio Inncune rcaseisthe irmode ofactionclear

Severa l groups of drug s.b differentmechanisms reduce bloodpressure

hydecreasing vasocnnsmcto rtoneand enceperipheral resis tance.The

mll, importantof the searcthean~ ill lt ' n~ i nconver tingenzyme(,\C E)

in h ih it o rs(midd lertg tl,wh ichdecreasecirculanng nngjorensin II ava-oconsmctorj.311l:inten"i nIIreceptor(Al'lsubtype!3nI31:0ni t

and thec lciu m ant ~oni"l~(m idd leright)thatblockthe entryof cal

-ciumintovascular smo oth musclecells,Me ta -analysisof clinical rials

indica le,thatthialide s 13-blockc f'l.AC Einhibitorsandcalc iumurnug(lni"", significantly reduce the ri ,k ~of stroke.coronaryhe ar!disc se

-<I nt icanfiovasculur death Other vusodilutcrstbonomrig ht)have been

la rgely super ded by the ACE inhibitors an culcjurn antaglJlli'b,

although there is MIme interes tinsele ctiv ea l-lId n' IU~ t'pl "r anlll ~o ·

ni,ls,mainly becauseitisclaimedthattheyhowe'fuvouruble' elf'ects

on bloodlipid s,Ce l all):Jl ;t i n ~ dr u ~ttopleft)dec rease symp athetic

outflow by slim ulating centralu2,adre noce pton; butarc nuteused

currentlybecause oftheiradvers eeffects

Mihlto moderateh pe rte ns io nca rloftenhe controlled by a single

drug tus uatlya rhiuzide or l3-bluck e rJ.bUIi thi-, fails the traditionnlupprouc h isto combinetwodrugs (e.g.diureticandJi·hlocker; diurencand ACEinhihil\Jr)andadd athin! ifncu'ssary

.16

Thiazide diur etics

Themechanismbywhich diureticsreduce arteri al hloodpressu reislint

known.Initiall y,thehlOtll!press urefall s because of a decrease in blood

volume.venous returnandc rd iac output.Grad ually.lhe card iacl

JUI-pUI returns10 normal hut thehypotensive effec tremains becau se the

peripheralresistance has,in the meuruimc, decrea sed Diureticshaveno

direct effect on vascula rsmooth muscle and the va"od ilata tilm they

cause seems to beassociated witha small but persistent red uct io n in

bodyNa Onepossiblemechanism i"that a fall in"mon th mUM'IeNa+

cau ses a secondaryreduction in intr acellularCa"' "0Ihat the muscle

becomes le vsresponsiv e.Thiaz idediureticsma y causeh.l'POli.ll !Ut'f!lill ,

lli "ht'le.\ mdfiwx ,1I01l/andcha nge the blood lipid" in an'urhero gemc

way(see also Chapter14 ) Side-e ffect" suc h asimpotence and lossof

libido were reported to he more common with lhia/idc usage than

with Ii-h lock cr s but it isnow appreciated that thia zidcs have a lIal

dose-response curv e and the lo w dO'>C"ofthiazj de-, curre ntly used 10

lowerblood press ure causeinsig nifica ntmetabolic effec ts

p- Ad renoceptor antagoni sts

p 81od ,ersinuiallyproduceafall inbjoodpress ure b)'decreasing the

cardiacoutp ut, Wilh conti nued treatment.the cardiacoutpu t returnsto

normnl butthe Mood pres sure remain"low because,by an unknown

mechanism,till'peripheralvascularresistance is 'rc-ct'iltalowe rlevel

(individ ua l drugs are disc u" -.J in Chapter 9), Disadvuma ges of ~­

blockad e are the com mo nadverse c1T«:ts suc h as cold hands and

fatig ue, and th less com mo n hUIse rious advers e effects suchasth"

provo cat ion01asthma 1 11'</1"/ [ailureorlWl d llt"/(II1{'l 'hlm'Ii Ii-Hlo{: h' rs

alsotendtomise serumtriglycerideand d "l,: r'l'ilsehighd ·nsitylpopmh

.'in-cbole-ac rollevels All theI}-blockers lower bloodpress urebutatleast

some of the side-effec ts can be reduced by using curdioselectivc

hydrophilicdrugs(i.c.thosewithoutliverrucrnbolisruor brain pcncrra

-tion)suchasatc nol ol

AL E inhibi lllrs Angiol(.'nsillII is a pll erful circ ulating V aSl ~(ln ­

strictor and inhibition of ils synthes is inh)'JlCrten siveP:lliclltS re"ults

inafa llinperip he ra lresistilIlce and a lowerin!! of bloodpressure.ACE

inhi bitors do no t impair cllrd iova.scular rel1C1lCS and llrCdevoid {If

m.IIlYof th(.'adve rse elTel't sof the diureti csand Ii-hlock er s.A COllllllon

unwanted eff(.'c t of ACEinhi bito rs isil dry coug h that mayhe(;auSI.'d

by inneased l>r.ad ykini n (ACE also melahol izc s hmd )'kinin l Rare ,

hut serious, adve l'e enl'CIS ofACE inhih itors inclu de angin<.-dcma

proleinuria and neutropcnill Thc first do'>l'ma y CllU'>C11 very "tee p

fall in bloodpressure , e.g in p<ltientsn diureti cs (1"lI.'Cuu"e they are

Na' depl et ed ).ACEinhihito rsmay cau'>l' renalfail ureinpatienls with

bila teral renal artery stcno" b,hecausein thiOi, eonditio n mg iote ns inIIis

,lpparc ntly required tocons lric t ptl"tgl nm erulararteriol esand maintain

adequateglolllerula r tiltr.uion , Inhihitillilofang iote ll"inII fommtion

red uces hut dflCOi, not seriou sly im (l<lir, aldos te ro ne sel'retion and

ellccOi,s ive K+retent ion only occurs in patil'ms takin g p tassi um su

p-ple ments or pot assium -sparing diureti cs (aldoste ll.ne incre ase s ~ a '

reahsnrptionand K+excre lio n, Chapter141

A Il ~ i u le l1si nrt·1.'eplllfanta gunbts(e.g osar lan)lower the hl'lIx!

prcs" ureby block ingangioten sin (ATt)l\.'Cepto rs Theyhave sim ilar

properties to thl' ACE inhibiltlN bUId not causc coug h pcrhap "

hecllU sethcy do not prcvenlhradykinindegradation

Cliidu m-c han lwlblockers(calciumanlagunists)(secalsoChap

-ters16and 17).TIll'toneofvascularsmooth muscle isdeterminedby

thl'cylOsolicCal+concentration Thisis incre ased b)'O:I-adre mx:epto ructivmio n(resulti ng from sym pathetic lone )rhar rrigger-,Ca1+release

from the sarcoplavmic reticulum via the second messeng er inositoltrisphosphate ICha pto:: r I), There are also rece ptor- o pe rated catio n

channels thatarlo'importantbeca usethe entry ofcat ionsthrou gh the mdcpolarizes the cell.openingvoltage -de pe nde nt(L-I)'PC )Cal+channels

and causing additionalc, > to enterthecell The calciumantagonistste.g.nifedipme.amlnd ipint' ) bind to theLaypcchannels and.b block-

ingthe entryorC al'intothe celt.theycause relaxanon ofthe arteriolar

smoothmuscle Thisreducestheperi phe ral resistan ce and res ult s ina

railin blood press ure Theefficacy ofcalciu mantag onists issirnilur

tothtu of thethiazides.ff-blocker sand ACE inhibitor s.Theirmost com

-mon side -e ffec ts are caused by excessive vasodilatation and include

dillinc"s.hypotenvion ,flushingandankleoedema (lI,Adr e m lol:eplllf antagonists Pnllosin and the loug c r actingdn\ lllll"in ca use vavodilatution by selec tively blocking vascular 0:1-adrcnoc eprors Unlike non-sele ctive u-blockc rv, these drugs arc norlikdy to cause tach ycardia but they may CHUsepostura l byp oten vion

Se ve rehypotcn sjon mayoccurutter the tirstdo-,e.Prazovin and

doxa-zos !nrelieve thesympto msof prostarichyperplasiaand therefo remay

heindic ate d in hypertensivepatientswiththisco nditio n

II)dralazjueisused in combtn anonwih a Ji-bhx:ker and diuretic

Side-effects include rcnex tac hyca rdia hich may provokeangi na,headachesand fluidretent ion(asa resultofsecon dary hyperaldosrc ro-

nisnu.!nslow accrylutors in particular,hydralazine mayinducea 11I1'1l,1'

SY /l J I"lIIIII'resulting infever.arth ralgia.malaise and hepatit is

.\Iinu\.id il is a (Xltcntvasod ilato r thatcauses severe lIuid rete nuo n

and oede ma Howeve r hengivenwitha Ii-block erandloopdiuretic,

it i" effective m se vc rchypert ensionresistantto otherdrug com binations.Minoxjdilrelaxes vascularslTKlI Jlh musclecellsby ope ningATP- sensitivc

K'chan ne lscausinghyperpolarization and closin g of vohugc-scns uive

Cal+channels.ThcseK+cha nnels arenomlall yI pl closedb imraccl

-lular AT!' hil·hisapparentlyanta gonil_cdb minoxidil sulphate ("n '

oralalllidi ahetic drugs,Chaple r]6).

Centrally acting d rugs

Meth)ld np ais co ve rted in;d re l1l'rg ic nel"\le l'n ings tothef,llsetrans

-milll'r,a-mclh ylnorepinephrinc hich slimulatesaI-recepl or sinthl'lTh.-dullaand redUCl'S ,,)'mpa thelicoutflo Drowsines sisC(lIlun onand

in2()<fofpalicn ts itca usesapo siti" e antiglobulin ,Coomhs'Jtesl and,

rarely,haemolylic anao::mia (Cha pter 45) Clnnid ineca use" reboun d

hypcrt l'nsi nllifthl'drugissudde nly ithdrawll,

Acute se vere hypertension

In hYf'l'rtensivc cris is, drugsm y hegivenhy intrave no usinf us iontc.g.h)'dntla/inein hypt.'rrl·nsiona"<lCilltedwith ecl llm psill o f pregnancy:

n i lrup ru ,~si d e in malignanl hypertcnsinn ilh ence phalopathy)

Ho we ve r,intravenou s drugsare mrel)'nece_ssa ry,and thl'lreoo isto se

omla g~'nt s whe neve r possible(c.g atenolol amlnd ipinc ).Nitropms

-sidl'del'Ol11posCsin theblood til rcll'a"cnitric oxide (NO),an unstable

ctllllpt.und thmca usesvas od il;lta tio n(see Chilpter 16forml' chan ism l

37

1 6 Drugs used in angina

Calmo<:!ulin

Yaecula rsm()Ol;hmuscle cel

The corona ryarteries~ opr lyI1I'MMI tn thcheurt With increacingage

utheronuuousp I;1 4 U"'~prug re~ ~ iv clynarrowthcarterie s and theohxtruc

-nontilblood flowma y eventua llybecomeSl.lsevereth.u.whenexercise

produces thechuracrcrl-tic sym pl\lms ofan/;: ina pccturts probably

because waste pn ucts released duringmuscleco traction accum ulate

inthepoorly perfusedtis'lI'·

The basicaim ofdrug treatmen tinanginll is' 0reduc e the wurk of

tilt.'heartand hen ce ibovygeudemand The nttrar e, Inuddl ) areIhe

hrvt-line drugs Their main effectisto ca useperipheralvaxodlhnarion

especia llyinIh.· veins by an act io non the vascularsmooth muscle

thatinvolves the formationof nitric oxide ("01 and an increasein i

ntra-cellularcG i\lP (right figure) The ro:,ulting pooling (If blood in hc

capaci ta nce ves,d, (veins) reduces veno usreturnami rhc ventricular

volume i,deen-ascd H,'<.IO.·lion in the divteuvion of the heart wall

dccrcascvoxyge ndemandand the pain isquick ly relieved ( ;I H ·l'r~ 1

Ir-initrutegiven sublingually 10 avo id' i r.t·pll'~met a bolis mi ,~ u~d10

trra'acuteanginalallacb.I hi, i, ind"fective.•hen cnmhint:J'herapy

i, re4uired in which !i-adTl'nuCl'plur b >l ·kl ·r~ (lop ldt ! nr fald lllll·

{·ha nnd hlc >l.·k er ~lmidd lct"p ) are",kenin a,ld iti" ntllg lycer)"llr ini~

Irate.which i,rl'1aino.-'tl for aeu.eanal·b

!i-Adrenllccplorhll1ckl'rs de pressm)'llClml iltl l'unl nll'lili,y lmdreduce

tho: hcan nile In addi tion " the effects hieh reduce the oxygen

dema nd.13-bllx.' kers may ab,o increase the perfusion ofthe ischacmicurea becausethe decrease in heart Tateincrease ,the durat ionofdiastoleand hen ce the rune uvailuhle for coronary bloodIlow I necessary a

Ii·BI IlCkers arcIh.·~ta1lt llm.ldrug,u,ed inangina.buttheyhavemanyside-effcctv and comraindkmions (Chapter 151.I !3 bll ko:r-.ClIlIllO.he

used c.g,in paucut-, with avthma, then aculcium -vhun nelblocker

canheused as an adjunc tto short-actingmmucs Calcium umugonivrs

ha w ucu u-, on'he heart bUI the)'relieve ungtna ml.inl)'by cau,ing

perip her alarter iola r dilat ati onand unerload redu ctio n 111ey arc cs

lIngilla j.HCCl: n'evidence~u ggesl'Iha short-actingcalctcm antagonistsrc.g nitcdipinc anddillia/e mJ ma y increase mo rta lity illpatients withungiuu land perhapshn -rtcnsion).Lon g-actin pre parationsIll'these

dru g,lire nowavailable.hutl he lfe'tchoice ·ems 10beverap amilor

e,po:eiallyuseful in patients unabl etiltake13-hhll:ke rs

InllO"lablt: an/;: ina.rbc rc i, a highrisk ofrnyocurdialinfa rc tio n(Mil

In :uldiliontol-I1II · er' thesepatienl s are trell,,'d ""ilhall1iplateleldrugs(centre.htlllllrn ) andhc p;u in (C hllpter 19 )tor"d uce plateletaggregation1I11d I h rornbo~i , When lilt.· ,ymp tom, CantHI' hecnmrolkd urgo:m

rl.'\:l"rulil r i/al iml is considered

An/.:inll~ l nrio;io; a descriptionof a typica l0;<."1of symp tom-rl.'l.,l.·d10

receru'lfl :l.Of are ~Il:'>,ing in :\crn) or fl\'l.lUCocy.occurring

Nitrates

lon J.:·ll(·t inl:nil r at t""lar nlUfe Iahlc audma ytleeffectivefo r v·

,\dH'N:' dft'Ch.1bc alt.'fial dilalati(ln pnJl1llt."ed b~ lhenilr.llI.·

howlh ('OM!'C " UM."S re l a ~a l i n ni"nolcl nUlil venlUa llyre.ullsin

Tule r an('tomay oc.-urhinilr.lle ForC'xampk.chron ic~n l "l·f)l h ·

C alcium a ntagonists

nifcrlip in e amludi p inlr' l have relatively little effect on IhL' hcan

jdi-hllalion rc ullsina ret1c\ illl·rca e in 'y·n1p"lhelictn n",lhal cml " a

, nll.>d ipin hichh " alon g duralionof a ·ti'l(l produce"It'""lach)

dcf"l"e""the sinus node cau ing a mildresling bfad)'canlia Vcr,lpamil

Toha,'co nmkin~. Smol.ing i prnlhnlffil'oulic and athen.genk, il

Rev ascularization

(:on'llllry arlery' bypa l:raflini:l<:.-\ IU;,,II' perculan("(lU tran·

"olIrlt'rial~,ronafY an~i"I'I ;I IY1"T e,\)m yhe indi,'alel! in p;lli,·nl

17 Antiarrhythmic drugs

Cardiaeactio n potentia l (AP)

(Ccmpcette diaqrampacemakerpounUtl ls

occuronly in theSAN 811d AVN)

5uprav"ntric ular

CLI'65 II

IH' lock" repro pranololatencloloot.8!ol

Therhythm of the- hearti"normallydeterminednypacemak er-1;c11"ill

ways.produ cin anythingfrom occasionaldiscomfo rt1 the sympto ms

upparernly healt h)'heart, hUIseriousones(c.g.ventric ular tachycanlia )

arcusuallyassoctat ed withheart disease te g.myocardial infarction)

amiu o rprognosis.Therhythmoftheheartisaffected h)'both1Il;t

'1}1-fhulinl'(AChj an noe-eptnephrfne (NEJ.rcle a -d from puracym pa

-llll·lil.'and vympathcticnerves revpcctivety (upperligu re J,

Supraventricularurrhythuuaxarisein theutrialmyocardium or

commonly.Ar o{·nlr, mechanismisinvolv ed, where ac tion potentials

which.being olonge r refractory.againdepolarize.eSlahl ishinga loo p

cf xtivc ref act o ry pcn od ofatrial,ventricularandPurkinjcIibrc v

I those whicharc efec tive insupru ve nt r h-ula r- lIrrh}lhm ias (loP

righll:

1 lhl e effectiveinvenn-lc uta r arrh,.lhmi" ( bottomleft):and

incre ase in adrenergicactivity (emotion excuemc nr thyrotoxico sis

my' lI.'a rdial iufurctlonjmay ht treated withJ}-bloc kers tbouomrigbrj

An arrhythm ia com mon ancr ac ute myoc ardial infarelion is inu

bradycardia, which can hetreate d withinrruvenous atropine i u.c

classified011 thebu isofthe irefcctrophysiologicaleffectson Purkiujc

car diac "el innpeteutialare showniujbc lower figure.h t l is notu su

~13Il Yantiarrhythmicdrugsca nactu ally ind ucelethalarrhyt hm ia- espc

myoc ard ial infurcnon there isn evidencethurantiarrh ythmic drug,

reduce rucrtahty inany'condition

4

Cardiac action potentia l

Mll ~tcardiac cells have twodepolariz ing currents, a fạ' tNa" urre nt

and a slllwe rCa1+current.Ho we ver, inthcSA r\ andA VNthe reis only

a Ca1+curren tand tecu u-e pure 'Ca1+spikes"conduct very slowlỵ

there isa dela y between atrial and veruricula rcontractio n, 111e long

refractory period ofcardiac fibre s normally protect s them from re

-excitat io ndur in a he art bea t

Pacemaker cells

In theSAN amiAVN there aren f ã tNá channelsan the ups wing

les';Cntjall )'phase2) uftheaction po tenti alis slow,becausethedcpo

-larizatjo isprod uced b)' Ca1+enter ingthroughslowlyactivating Ce"

channels.Thepacema kerp te nt ialdcpc nd~onseveral currentsinclulling

an outward K+currentt h nt gradua llydecrea ses ami two inwardNa"

currents(,andIb)that graduallyinc reasewithtimẹWhentheresulting

depolariz ation reachesthre shold anactionpotenti al is initiated The

s[upeofthe pacemakerpo ten tialsintheSAN is greatertha n in the A VN

andsothe SANnormallydctcrmincsrhcheartrate(sinusrhythm).The

pacemake r an cond uctingl'ells rece ive autono m icinnervat ion

Ắ"e l ~Icholin e

Vagal fibresrelease acetylc holineonto ~ l l- m uscarinic receptorsthat

opena K+channel(Kill,,)via G-prot l'inco up ling The increasein K+

conducta ncecauses ahy pcrpul a rizing currentand decreasesthe slope

of the pacema ke rpotential Thus thet h re ~ h ldfo r firingis reached later

lind thehcenbemslow s AChalsoinhibits uriov cmncularconductio n,

Nu r epine ph r im:

Sympathetic nbrcs rel e use no repinephr ine onto lJl-rec<pto rs in the

pacemake r tis,uẽ and myo c ardium Norepine phrine increases the

inwardNa"current(I I )' <;UthresholdIs reac hedeurlicrandtheheartrate

increases Norepinep rine also inc reases the force ufcoruracnon by

increasing the inllux ofcalcium du ring the plateau phase (pusitive

ino tropiceffect)

Drugs used I n supraventricular arrhythmias

Adeuosinestimulates Al-mk no l,ine~ 'l 'p tUf'<and opensACh·sc nsitị e

K+channels.Thi ~hyperpolari /.esthe cell lllem hrane inlheA VN amI,

hy inhibiting the ca lciu m l'ha nnds ,lows con uction in lhc 1\ VN

Ade nosineisrapidl)'inactiva ted(lI n '"!'I IOsjamiso side-.effel·ts(ẹg

dyspnoeạ hronehospa srn ) are ~ h n-lived. Intrave nous ade nosint.' is

USl.'d10 tennina te acutesupmvcntricu lartach ycard iạ

l)ĩlIxin ~ tim u l atesvag ala tivity (Chapterl ~ ) ,e;!Using the relt'ạ :

of ACh,which~ l owsco d uc tionandp ro l nn g ~lh refracto ryperiodin

thc AVN 3nd hundle oflIis.Or31adm inistrat ionofdij!o xin is used in

atrial librillation.wherethe atriaheatats(lr h high ratesthOltthe vemri

-des {'"an onl)'follo wirregularlỵByd <lying atrioventricularl'o nduc

-tance digoxinincre asesthe ,h gret:of hlod.andslows:UllJ~ l rt: ngt l1l'ns

tll' venlriculnr be:i1.Intraw nn us digoxin is used in lhe treatm ntof

mpiduocontrtllll'd atri a llhlller.md Iihrililltio n

Veraparnil acts b hllll.·k ing L-ty pe c;llciu m l'han ncl s (ciạ IV

a ~e nls )(sec 1ĨoChllpler s l:'iami lti l and hilSpan icillarly powerful

elleetso th A VN whe reco nd uc tion is ent irely de pt.'mlento calci ulll

ikes,Itaho inhit>i ts the inlluxofCaloduringlhe plateauphạ e of lhe

al· o potenlb l and the re fo re has a negative innlrop ic aclion,

Ade nosineh." larg elyreplaced illlruverllHls v(,'rapam ilf"rlhe tre:ttment

of su pra ve ntric ula r t,lChyCirrdiast>ccau sc i is afer,ẽpcc i a t ly if lhe

patientrea lly has a ventricular tachyeardiOl.in hich casethenẽativ.:

irl< trop icdfl't.:t uf \'erdpamil lllaybedi,;aslmus,Oral wra pamili ~sti

used in the prophylaxis of suprave ntric ular tachycard iạ Vera parnil

xhouldnOIOC'used with1}.t>I IIl.·l crs orquinidinebecause ofcumulative

negativeinotropic effects

Drugs enective In supraventricular and ventricular arrhythmias

Ciạ 1:\ ãl;' nhuctbyblocking(open)vo ltage-depe ndemNa"chan

-nel s They slowphase0 and len g then theeffect ive refractoryperiod

C lãs IA agenh produce a frequ enc y (uscj-dcpc ndem block During

diastolewhen the Na" channe ls areclosed class IA agentsdissociat e

relativel y slo w ly(<5s)sọ ifthefrequen cy is high drug is slillhound10

the channe l.which the re fo re cunnot contributetothe actiofl poten tial

Di s oll ~ r ;llnidt' is mainly used orallyto preve ntrecurrent vcmriculararrhythmiạ Disopyramidc hạ.; 1negative in tropic ucuon and maycause hypotension (cspecia lly intrave no us ly) an nggravore cardiac

fa ilurẹOtherside-effects includ c nauseạvomitingand marked an ti

-chohnergic effects.whichrna)'Iimilitsuscin men (urinaryret e ntio n),

ven tric ulararrhythmias.but tsusc islimited b potentiallydanger o uscardiac andfreq uent non-c a rdtac side-effec ts.Side-effectsinclude :lnt i·choline rgiceffects,nauseạvomiting,diarrhoeaandarrhythmias

(,Ia ~sIe agen tsdissociateveryslo w lyI om Na channels (10-20 s)

andstrongly dcpreo,conduction inthemyocardium.f<ll'l'lIinid l;'ismainl y

usedinthe prophyl axisofparoxysmalatrialfibrillation ut lhạs a negnnveinotropicucriun andmayca use seriousvcnmcular arrhythmias

-Cla IIIagt'nlsact by slowing repolurivauon (phase J) and pro

-longing theaction potentialan retructoryperiod in allcardiactissue s Amiudaront"h.l.sblocking ael io ns on several channe ls (ẹl1 K+and

inacti va ted Na"channels] and l!-adrcnoccptllf'<.Amiodaroneis ofteneffecti ve whenotherdrugs hawfailedhUIits use isresmctcd tn patients

in whom other dm!,!s are ineffectiv e beca use it may cause se rio us

adverseeffect includ ing pho tosens itivity, hymiđiso rd e rs,nc

urop-athyandpulmonaryalveolitiv,Sutal olhas classIII acuons as well a

classIIIl!·hlocl ing)a nons.Itlac b the ide-effectsofamiodarone but

has the usualvide-effects ofI}-hlllders,

Drugs used in ventricular arrhythmias

Clas IIIaJ,!c nlshllll.·k(in;ll'tiva ted ) voltage-dependent Na+ ha nnds.Ịidlll:aint'givenintra veno ụ.l)·is used in thetreatmcnt ofvem riculararrhythmias.usually afteran;\l'utl' m}Tl(:ardi :11 infa rction,[nc nnt rã t l n

cla,-sIAãe nts.which block pen :'IIa+ehanl1l'ls.lidoca inchlocksma inly

inactivatedNa+ch;mnc ls Innormaleardi:lctissuẹlidol.·ai ne hOlS little

t:ffect b<"eause itdissociales l"dpidl y «O,:'is) fmm the N:l cha nnels

whidl th refo reret' ve r duringd i ãtolẹ Hn wl' wr nisd lacmicarea s,

whe re umxiaf;;lUsesdepolarizatilillandarrhythmo ge nic;Ict ivity,many

Na+chan nels;Ireinacti vated 3ndthere foresuseept ib leto lidoca inẹ

trealllwniwithdisop ral11i dc Surgic a llIhlutin nofthe l'Clo pic focu s or

bund le ofHis is a successfulmethod of cuntnl ilingsupmventric ular

arrhythmias.A mUt'hsOlfer methlld is abl;uionofthefoc us orhund le ViOl

eleclrollcso aninlracardiac t.·alhe le r(l"mllll."lvity ahla liorll Ik caus

atrinwnt ric ul arhllll.'kis produeed.Ol peml;lllent p;lccmal eris rel.l uired.[n thoSt.,plltients at risk ofIife-lh re te nin g tal·hyarrhyth m ias an im-

plant able aUloma ledcardiO\'enerdcJibrillator maybeinsc n cd

41

1 8 Drugs used in heart fa ilure

DeCTl!:ilSCboth pr""load

anda ft.erload

captopril

ena lap ril

Ca n'leH i ~e ~ym pwm~ End' ,> 'i1"to llc LV p"e(>tlure Dy6 pr'lllea

Diur~IC!l

THI"llDE Sbendrefl umet.hia ld

-quatclyperfusethe li""ucs.despite nomlallillin gofth heart.Thislends

reducedexcrcisc tolerance COII.Cf'.I/h'{'1, '</1'/ [ ailureisusually taken 10

hypertension valvular dise use cardiomyopathyand most commonly

increased sym pathetic nervousa tivity whichstimulate sthenne and

resistance againsl which the heart has 10 pump (afterlnadl further

dcprevses cardiac output.Reduce d renal hloud tlnw rexult-, in renin

secr etion •md increased plasmaangiotensin and aldosterone lcvc-Is

centralvenouspressurelpreload!andthelilo.elihoodof oedemaf

dil.datinn)thatmcrea morbidityand mortality,Onlydrugsthatinhihit

l3-blockeT1OJ

('( Ill\ c r l i n~t'nl}mC\,\C E)inhihitnr(loprighll.ACE inhihitn (e.g

t:aptnp r ilJ reduceIll\'load on the heart [diagonal arrow.right tigure)

excretionofsodiumand water and,by reducmg the circulating volu me

diuretic is necessary te.g.Iur osemidej f heart f'lilure isso severe

udcquuteresponse,thendil:H\i ll, aninut r npicdnll:(lopem.rnayI'C

calcium that occurs witheachaction potential (left figure) HiJ;:ll,in

-branccurn-rnx

failure.lh addition ofal!-hlnt:"l'rtbomun lefllfurt herdecreases mor

u controlled with standard thenupy th addilion (If spir unnlaClu llt·

\Chapler 1 ~ 1has hcen shownILl redw (.:!-year) I\mrta1ilyfrom ~o %

10 35~ 42