Principles and Practice of Pharmacology for Anaesthetists, Fifth Edition

373 Pages·2008·8.595 MB·English

by  T. N. Calvey, N. E. Williams(auth.)

BLUK100-Calvey November17,2007 20:30
Principles and Practice of
Pharmacology for Anaesthetists
Principles and Practice of Pharmacology for Anaesthetists, Fifth Edition T.N. Calvey and N.E. Williams
© 2008 Norman Calvey and Norton Williams. ISBN: 978-1-405-15727-8
i
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Thisbookisdedicatedtoourwives
ii
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Principles and
Practice of
Pharmacology
for Anaesthetists
T.N. Calvey,
BSc,MD,PhD(Liverpool),FRCA
HonorarySeniorResearchFellow
DepartmentofAnaesthesia
UniversityofLiverpool
FormerlyHonoraryConsultant,WhistonHospital
N.E. Williams,
MB,ChB(Liverpool),FFARCS(England)
FormerlyConsultantAnaesthetist,WhistonHospital,and
Part-timeLecturerinClinicalPharmacology
UniversityofLiverpool
FIFTH EDITION
FOREWORDBY
Jackson Rees,
MB,ChB,FFARCS
FormerlyHonoraryDirectorofStudies(PaediatricAnaesthesia)and
ClinicalLecturer,DepartmentofAnaesthesia
UniversityofLiverpool
iii
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(cid:2)C 2008NormanCalveyandNortonWilliams
(cid:2)C 1982,1991,1997,2001BlackwellScience
PublishedbyBlackwellPublishing
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Firstpublished1981
Secondedition1991
Thirdedition1997
Fourthedition2001
Fifthedition2008
1 2008
LibraryofCongressCataloging-in-PublicationData
Calvey,T.N.
Principlesandpracticeofpharmacologyforanaesthetists/T.N.Calvey,N.E.Williams;forewordbyJackson
Rees–5thed.
p. ; cm.
Includesbibliographicalreferencesandindex.
ISBN978-1-4051-5727-8(alk.paper)
1.Anesthetics. 2.Pharmacology. I.Williams,N.E.(NortonElwy) II.Title.
[DNLM:1.Anesthetics–pharmacology.QV81C167p2007]
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iv
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Contents
ForewordtotheFirstEdition,vi
Preface,vii
1 DrugAbsorption,DistributionandElimination,1
2 Pharmacokinetics,23
3 DrugAction,43
4 DrugInteraction,68
5 VariabilityinDrugResponse,86
6 AdverseDrugReactions,100
7 IntravenousAnaestheticAgents,110
8 InhalationalAnaestheticAgents,129
9 LocalAnaesthetics,149
10 DrugsthatactontheNeuromuscularJunction,171
11 AnalgesicDrugs,195
12 DrugsusedinPremedicationandAntiemeticAgents,227
13 DrugsandtheAutonomicNervousSystem,246
14 AntihypertensiveAgents:DrugsthatAreUsedtoInduceHypotension,271
15 AntiarrhythmicandAntianginalDrugs,287
16 AntiplateletDrugs,AnticoagulantsandFibrinolyticAgents,307
17 CorticosteroidsandHypoglycaemicAgents,328
Glossary,346
Index,348
v
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Foreword to the First Edition
Abookwithatitlesuchasthismightbethoughtmerely ofdrugs,andofthemechanismsofdruginteraction.Such
topresentanaccountofthedrugsusedinanaesthesia.In knowledgeismuchmorerelevanttoanaesthesiathanto
thiscase,theauthorshaveachievedmuchmore.Theyhave mostotherfieldsofmedicine.Theauthorsofthisbook
presentedtheirsubjectinsuchawayastogivethereaderan havestrivensuccessfullytomeettheneedsofanaesthetists
insight,whichwillmakehimnotonlyamorecompetent forabetterunderstandingofthesebasicmechanismsof
anaesthetist, but one who will derive more satisfaction pharmacology.Thisisillustratedbythefactthatone-third
fromhisworkbyamoreacuteperceptionofthenuances of the work is devoted to these principles. This should
ofdrugadministration. relieve the teacher of the frustration of having students
Theauthorsdemonstratetheirawarenessoftheunique who seem always to produce answers on the effects of
natureofanaesthesiaamongstthedisciplinesofmedicine. drugs, but respond to the question ’Why?’ with a stony
This uniqueness arises from the necessity of the anaes- silence.
thetist to induce in his patient a much more dramatic Those sections of the book which deal with specific
attenuationofawiderangeofphysiologicalmechanisms drugsshowthesameemphasisonmechanismsofaction,
than colleagues in other disciplines seek to achieve. He thusgivinglifetoasubjectwhosepresentationissooften
mustalsoproducetheseeffectsinsuchawaythattheir dull.Thetraineewhoreadsthisbookearlyinhiscareerwill
durationcanbecontrolledandtheirterminationmaybe acquirenotonlyagreatdealofinvaluableinformation,but
acute.Theanaesthetistmaybecalledupontodothison alsoanattitudeandapproachtotheproblemsofhisdaily
subjectsalreadyaffectedbydiseasesanddrugswhichmay activitywhichwillenhancethewell-beingofhispatients
modifytheeffectsofthedrugswhichheuses.Tobewell- andhisownsatisfactioninhiswork.
equippedtomeetthesechallengesheneedsaknowledgeof
thefactorsinfluencingtheresponsetoandtheelimination JacksonRees
vi
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Preface
Inthiseditionwehaveagainattemptedtoprovideacom- flurane. The structures of many commonly used agents
prehensivescientificbasisandareadableaccountofthe have been included with their sites of isomerism, when
principlesofpharmacology,aswellassomepracticalguid- appropriate, as we believe that these are generally more
anceintheuseofdrugsthatisrelevanttoclinicalanaes- useful and informative than their chemical names. As
thesia.Allthechaptershavebeenthoroughlyrevisedand in previous editions, recommended International Non-
updatedwiththeseconceptsinmind,andanadditional proprietaryNames(rINNs)havebeengenerallyusedfor
ChapteronAdverseDrugReactions(Chapter6)hasbeen genericagents,althoughpreferencehasbeengiventothe
added,withoutincreasingtheoverallsizeofthebook.We currentnomenclatureforadrenalineandnoradrenaline.
hopethatitwillbeofvaluetoFRCAexaminationcandi- Asinpreviouseditions,acomprehensiveglossarycover-
dates,butalsoofinteresttoallanaesthetists. ingtheabbreviationsandacronymshasbeenincludedto
Ingeneral,thebookonlydealswithdrugsthatarecur- aidthereader.
rently available in Great Britain, so there is little men- Both authors are indebted to their wives for their
tion of previously common but now discarded agents help and forbearance during the preparation of the
such as droperidol, trimetaphan, methohexitone or en- manuscript.
vii
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1
Drug Absorption, Distribution
and Elimination
Drugscanbedefinedasagentsthatmodifynormalbiolog- Passive diffusion
icalresponsesandthusproducepharmacologicaleffects. Inmostcases,drugscrosscellmembranesbypassivedif-
Thesearefrequentlydependentonthetransferofdrugs fusion down a concentration gradient due to random
acrossoneormorecellularmembranes,whosestructure molecularmovementsproducedbythermalenergy.The
andphysicochemicalpropertiesgoverntherateandextent rate of drug transfer is directly proportional to the dif-
ofdrugtransfer. ference in concentration, and to the solubility of drugs
Cellularmembranesareusuallyabout10nmwideand in membranes, which is extremely variable. Highly po-
consistofabimolecularlayerofphospholipidandprotein lar substances (e.g. quaternary amines) are insoluble in
(Fig.1.1).Thelipidlayerisrelativelyfluid,andindivid- membrane lipids and are unable to penetrate cellular
ualphospholipidmoleculescanmovelaterallywithinthe membranes.Incontrast,drugswithahighlipidsolubil-
membrane.Extrinsic(peripheral)proteinsarepresenton ity(e.g.diazepam,fentanyl)readilydissolveinmembrane
theexternalorinternalaspectofthemembrane.Incon- phospholipids and rapidly diffuse across cellular mem-
trast,intrinsic(integral)proteinstraversetheentirewidth branes.Otherlesslipid-solubledrugs(e.g.morphine)dif-
ofthecellmembraneandmayformanannulussurround- fusemoreslowlyandtheironsetofactionisoftendelayed.
ingsmallporesorionchannelsapproximately0.5nmin Molecular size is a less important factor in the pas-
diameter(Fig.1.1).Bothintrinsicandextrinsicproteins sivediffusionofdrugs.Somelowmolecularweightcom-
canactasenzymesorreceptorsandmaymediatetheactive pounds may diffuse through ion channels, or penetrate
transportofdrugs. small intercellular or paracellular channels (particularly
Approximately5–10%ofthecellmembraneconsistsof in ‘leaky’ epithelial membranes). In contrast, molecules
carbohydrates,mainlyglycolipidsorglycoproteins.They larger than 100–200 Da are usually unable to cross cell
arebelievedtoberesponsiblefortheimmunologicalchar- membranes.Thepermeabilityofvascularendotheliumis
acteristicsofcellsandplayanimportantpartinmolecular greaterthanothertissues,andmostionizedcompounds
recognition.Manycellmembranesalsocontaininorganic canreadilycrosscapillarymembranes.
ions(e.g.Ca2+). Mostdrugsareweakacidsorweakbasesandarethus
Lipidcellmembranesareexcellentelectricalinsulators. presentinphysiologicalconditionsinbothanionizedand
Consequently,theremaybedifferencesinelectricalpoten- anon-ionizedform.Theirionizationordissociationcan
tialacrosscellularmembranes,whichcanfacilitateorim- berepresentedbytheequations:
pedethepassivetransportofchargedmoleculesthrough AH(cid:2)A−+H+ (foracids)
ionchannels.
BH+(cid:2)B+H+ (forbases)
Weak acids and bases are predominantly present as the
speciesAHandBH+inacidicconditions,butasA−andB
Transfer of drugs across cell membranes inalkalineconditions.Thenon-ionizedformsAHandB
arelipidsolubleandcanreadilydiffuseacrosscellmem-
Ingeneral,drugsmaycrosscellmembranesby branes,whiletheionizedformsA−andBH+areeffectively
(cid:2)Passivediffusion impermeable.Astheproportionofthedrugthatispresent
(cid:2)Carriertransport inthenon-ionizedformisdependentonpH,differences
Principles and Practice of Pharmacology for Anaesthetists, Fifth Edition T.N. Calvey and N.E. Williams 1
© 2008 Norman Calvey and Norton Williams. ISBN: 978-1-405-15727-8
BLUK100-Calvey November27,2007 13:44
2 Chapter1
Intrinsic or integral protein Extrinsic or peripheral protein
(enclosing an ion channel)
Phosphorylated Fatty acid tail of Fig.1.1 Thephospholipidandprotein
head of phospholipid of phospholipid structureofatypicalcellmembrane.
inH+concentrationacrosscellularmembranescanpro- trast,ataurinepHof7orless,theconcentrationofAH
vide a diffusion gradient for the passive transfer of the isgreaterinurinethaninplasma,andtheexcreteddrug
non-ionizedform. willtendtodiffusebackintoplasma.
Consider a weak acidic drug that dissociates in the Inasimilarmanner,pHgradientsgovernthenon-ionic
manner: diffusionofweakbasesthatassociatewithhydrogenions.
AH(cid:2)A−+H+ Intheseconditions,
B+H+(cid:2)BH+
From the Henderson–Hasselbalch equation, it can be
shownthat From the Henderson–Hasselbalch equation, it can be
[AH] shownthat
pKa−pH(cid:2) log [A−], pK −pH(cid:2) log[BH+],
where [AH] and [A−] are the concentrations of non- a [B]
ionized and ionized forms and pKa (the negative log- where[BH+]and[B]aretheconcentrationsoftheion-
arithm of the dissociation constant) is the pH value at izedandthenon-ionizedformsandpK isthepHvalue
a
which[AH]=[A−].IfthepKa ofthedrugis6,atpH2 atwhich[BH+]=[B].IfthepKaofthebasicdrugis7,at
(e.g.ingastricfluid),almost100%ispresentintheform pH2(e.g.inthestomach),almost100%ispresentasthe
AH(Fig.1.2).Thisnon-ionizedformwillrapidlydiffuse ionizedformBH+(Fig.1.3).AtpH5.5(e.g.inthesmall
into plasma (pH 7.4) where approximately 96% will be intestine),only3%ispresentasthenon-ionizedformB,
convertedtoA−,providingaconcentrationgradientfor and thus available to diffuse across the cell membrane.
thecontinueddiffusionofAH.Subsequenttransferofthe AlthoughtheeffectivepHgradientdoesnotfacilitatethe
drugtoothersiteswillalsobedependentontherelativepH non-ionicdiffusionofweakbasesfromthesmallintestine
gradient.AtpH8,asininterstitialfluidoralkalineurine, (pH5.5)toplasma(pH7.4),thecontinuousperfusionof
theconcentrationofAHislessthanatpH7.4.Agradient intestinalcapillariesprovidesasmallconcentrationgra-
isthuscreatedforthepassivediffusionofAHacrossrenal dientfortheirabsorption.
tubularepithelium,followedbyitssubsequentionization Bycontrast,weakbasesatpH7.4(e.g.inplasma)are
toA−andeliminationfromthebody(Fig.1.2).Bycon- mainly present as the non-ionized species B. In these
BLUK100-Calvey November27,2007 13:44
DrugAbsorption,DistributionandElimination 3
Cell membrane Cell membrane
pH 2 pH 7.4 pH 8
(e.g. gastric secretion) (e.g. plasma ) (e.g. alkaline urine)
Fig.1.2 Non-ionicdiffusionoftheweak
AH H+ +A− AH H + + A− acidAH(pKa=6).Onlythenon-ionized
(100) (0) (1) (99) formAHcandiffuseacrosscell
membranes,andthediffusiongradientis
dependentonpHdifferencesbetween
AH H++ A− compartmentsortissues.Numbersin
(4) (96) parenthesescorrespondtothepercentage
ofthedrugpresentasAHandA−atpH
Eliminated 2,7.4and8.
conditions,thereisalargeconcentrationgradientthatfa- thenon-ionizedspeciesB,wheretheyareconvertedtothe
cilitatestheirdiffusionintothestomach(pH2)andinto ionicformBH+andrapidlyeliminated(Fig.1.3).
acidurine(pH5).Followingintravenousadministration In theory, modification of urine pH can increase the
offentanyl,theinitialdeclineinplasmaconcentrationmay proportionofweakacids(pK =3.0–7.5)andweakbases
a
befollowedbyasecondarypeak30–40minuteslater.Fen- (pK =7.5–10.5)thatarepresentinanionizedformin
a
tanylisaweakbasewhichcandiffusefromplasma(pH urine,andthusenhancetheireliminationindrug-induced
7.4)tothestomach(pH2),duetothelargeconcentration poisoning.Althoughforcedalkalinediuresiswasonceex-
gradientthatispresent,anditssubsequentreabsorption tensively used in drug overdosage, as with salicylates or
fromthesmallintestineisresponsibleforthesecondary phenobarbital,ithaslittleornoplaceincurrenttherapy.
rise in the plasma concentration. Similarly, weak bases Itisapotentiallyhazardousprocedurethatrequiresthe
rapidlydiffusefromplasma(pH7.4)tourine(pH5)as infusionofrelativelylargeamountsoffluidandtheuseof
Cell membrane Cell membrane
pH 2 pH 7.4 pH 5
(e.g. gastric secretion) (e.g. plasma) (e.g. aci d urine)
Fig.1.3 Non-ionicdiffusionoftheweak
B + H+ BH+ B + H+ BH+ baseB(pK =7).Onlythenon-ionized
a
(0) (100) (1) (99) formBcandiffuseacrosscell
membranes,andthediffusiongradientis
dependentonpHdifferencesbetween
compartmentsortissues.Numbersin
B + H+ BH+
parenthesescorrespondtothepercentage
(72) (28)
ofthedrugpresentasBandBH+atpH
Eliminated 2,7.4and5.