制药第13章抗癫痫

Chapter13:AntiepilepticsandAntiseizureDrugs

I.Antiepileptics

Epilepsyisachronicdisordercharacterizedbyrecurrentseizures.Seizuresarefiniteepisodesofbraindysfunctionresultingfromabnormaldischargeofcerebralneurons.Thecausesofseizuresaremanyandincludethefullrangeofneurologicdiseases,frominfectiontoneoplasmandheadinjury.Occasionallycausedbyanacuteunderlyingtoxicormetabolicdisorder,eg,hypocalcemia.1nafewsubgroups,heredityhasprovedtobeamajorcontributingfactor.A.History

In1857,potassiumbromide,catamenial(月经期)epilepsy.In1912,phenobarbital;In1938,phenytoin;Inthe1990s,aseriesofnewcompounds.B.Theformsofepilepsy

generalizedtonic-clonicseizures,complexpartialseizures,absenceseizures,etc.(seeTable24-1).C.DRUGSUSEDINPARTIALSEIZURES＆GENERALIZEDTONIC-CLONICSEIZURESPHENYTOINPhenytoinistheoldestnonsedativeantiseizuredrug,wasknownfordecadesasdiphenylhydantoin(二苯乙内酰脲).

1.Pharmacokinetics:

(1)Absorptionofphenytoinsodiumfromthegastrointestinaltractisnearlycompleteinmostpatients,thoughthetimetopeakmayrangefrom3hoursto12hours.(2)Phenytoinishighlyboundtoplasmaproteins.Drugconcentrationincerebrospinalfluidisproportionatetothefreeplasmalevel.(3)Phenytoinismetabolizedprimarilybyparahydroxylationto5-(p-hydroxyphenyl)-5-phenylhydantoin(HPPH),whichissubsequentlyconjugatedwithglucuronicacid.Themetabolitesareclinicallyinactiveandareexcretedintheurine.Onlyaverysmallportionofphenytoinisexcretedunchanged.(4)Theeliminationofphenytoinisdose-dependent.Atverylowbloodlevels,phenytoinmetabolismisproportionatetotherateatwhichthedrugispresentedtotheliver,ie,first-ordermetabolism.However,asbloodlevelsrisewithinthetherapeuticrange,themaximumcapacityofthelivertometabolizephenytoinisapproached(Figure12-3).(5)Thehalf-lifeofphenytoinvariesfrom12hoursto36hours,withanaverageof24hoursformostpatientsinthelowtomidtherapeuticrange.Atlowbloodlevels,ittakes5-7daystoreachsteady-statebloodlevelsaftereverydosagechange;athigherlevels,itmaybe4-6weeksbeforebloodlevelsarestable.2.MechanismofAction(1)PhenytoinaltersNa+,K+,andCa2+conductance,membranepotentials,andtheconcentrationsofaminoacidsandtheneurotransmittersnorepinephrine,acetylcholine,andγ-aminobutyricacid(GABA).(2)Phenytoinblocksposttetanicpotentiation(PTP)inspinalcordpreparations,blockssustainedhigh-frequencyrepetitivefiringofactionpotentials(Figure12-2).Thiseffectprobablycontributestotheirantiseizureactionintheelectroshockmodelandinpartialseizures.(3)Athighconcentrations,phenytoinalsoinhibitsthereleaseofserotoninandnorepinephrine,promotestheuptakeofdopamine,andinhibitsmonoamineoxidaseactivity.(4)Thedruginteractswithmembranelipids;thisbindingmightpromotethestabilizationofthemembrane.(5)Attherapeuticconcentrations,themajoractionofphenytoinistoblocksodiumchannelsandinhibitthegenerationofrepetitiveactionpotentials.3.ClinicalUsePhenytoinisoneofthemosteffectivedrugsagainstpartialseizuresandgeneralizedtonic-clonicseizures.Inthelatter,itappearstobeeffectiveagainstattacksthatareeitherprimaryorsecondarytoanotherseizuretype.4.Toxicity(1)Nystagmusoccursearly.Diplopia(复视)andataxiaarethemostcommondose-relatedadverseeffectsrequiringdosageadjustment;sedationusuallyoccursonlyatconsiderablyhigherlevels.(2)Gingivalhyperplasiaandhirsutism(多毛症)occurtosomedegreeinmostpatients;thelattercanbeespeciallunpleasantinfemales.(3)ChronicusemayalsoresultinabnormalitiesofvitaminDmetabolism,leadingtoosteomalacia(骨软化).(4)Long-termchronicuseisassociatedinsomepatientswithcoarsening(变粗糙)offacialfeaturesandwithmildperipheralneuropathy,usuallymanifestedbydiminisheddeeptendonreflexesinthelowerextremities.(5)Other:Lowfolatelevels,megaloblastic(巨幼红细胞)anemia,typicalskinrash,fever,lymphadenopathy,andhematologiccomplications(agranulocytosis,粒细胞缺乏症)mayalsooccur.5.

DrugInteractionsDruginteractionsareprimarilyrelatedtoproteinbindingortometabolism.(1)Sincephenytoinis90%boundtoplasmaprotein,otherhighlybounddrugscandisplacephenytoinfromitsbindingsite.Theproteinbindingofphenytoinisdecreasedinthepresenceofrenaldisease.(2)Phenytoininducesmicrosomalenzymesresponsibleforthemetabolismofanumberofdrugs.Otherdrugscausedecreasesinphenytoinsteady-stateconcentrationsthroughinductionofhepaticmicrosomalenzymes.Ontheotherhand,isoniazidinhibitsthemetabolismofphenytoin,resultinginincreasedsteady-stateconcentrationswhenthetwodrugsaregiventogether.CARBAMAZEPINE

Closelyrelatedtoimipramineandotherantidepressants,carbamazepineisatricycliccompoundeffectiveintreatmentofbipolardepression.Itwasinitiallymarketedforthetreatmentoftrigeminalneuralgia(三叉神经痛)buthasprovedusefulforepilepsyaswell.Three-dimensionalstructuralstudiesindicatethatitsspatialconformationissimilartothatofphenytoin.1.MechanismofActionSimilartothatofphenytoin.Likephenytoin,carbamazepineblockssodiumchannelsattherapeuticconcentrationsandinhibitshigh-frequencyrepetitivefiringinneuronsinculture(Figure12-2).Italsoactspresynapticallytodecreasesynaptictransmission.RecentevidencesuggeststhatthepostsynapticactionofGABAcanbepotentiatedbycarbamazepine.2.ClinicalUseCarbamazepineisconsideredthedrugofchoiceforpartialseizures,andgeneralizedtonic-clonicseizures.Itcanbeusedwithphenytoininmanypatientswhoaredifficultiocontrol.Carbamazepineisnotsedativeinitsusualtherapeuticrange.Thedrugisalsoveryeffectiveinsomepatientswithtrigeminalneuralgia,alsousefulinsomepatientswithmania(bipolardisorder).3.Pharmacokinetics(1)Therateofabsorption:almostcompleteabsorptionapparentlyoccursinall.Peaklevelsareachieved6-8hoursafteradministration.Slowingabsorptionbygivingthedrugaftermealshelpsthepatienttoleratelargertotaldailydoses.(2)Distributionisslow,andthevolumeofdistributionisroughly1L/kg.Thedrugisonly70%boundtoplasmaproteins;nodisplacementofotherdrugsfromproteinbindingsiteshasbeenobserved.(3)Carbamazepinehasaverylowsystemicclearance.Ondosageregimensexceeding1month,theclearanceofcarbamazepineincreasedtwofoldoverinitialtreatment.Thedrughasanotableabilitytoinducemicrosomalenzymes.(4)Carbamazepineiscompletelymetabolizedinhumans,inparttothe10,11-dihydroderivative,whichissubsequentlyconjugated.carbamazepine-10,11-epoxide(环氧化物)stillhaveanticonvulsantactivity.(5)Typically,thehalf-lifeof36hoursobservedinsubjectsfollowinganinitialsingledosedecreasestomuchlessthan20hoursinsubjectsreceivingcontinuoustherapy.4.adverseeffectsThemostcommondose-relatedadverseeffectsarediplopia(复视)andataxia.Otherdose-relatedcomplaintsincludemildgastrointestinalupsets,unsteadiness(不安定),and,atmuchhigherdoses,drowsiness.Hyponatremia(低钠血症)andwaterintoxicationhaveoccasionallyoccurredandmaybedose-related.Themostcommonidiosyncraticreactionisanerythematousskinrash;otherresponsessuchashepaticdysfunctionareunusual.5.DrugInteractionsRelatedtothedrug'senzyme-inducingproperties.Theincreasedmetaboliccapacityofthehepaticenzymesmaycauseareductioninsteady-statecarbamazepineconcentrationsandanincreasedrateofmetabolismofprimidone,phenytoin,ethosuximide,valproicacid,andclonazepam.Propoxyphene(丙氧吩),troleandomycin(三乙酰夹竹桃霉素),andvalproicacidmayinhibitcarbamazepineclearanceandincreasesteady-statecarbamazepinebloodlevels.Phenytoinandphenobarbital,however,maydecreasesteady-stateconcentrationsofcarbamazepinethroughenzymeinduction.PHENOBARBITAL

Phenobarbitalhaslongbeenconsideredoneofthesafestoftheantiseizureagents,theuseofothermedicationswithlessersedativeeffectshasbeenurged.Manyconsiderthebarbituratesthedrugsofchoiceforseizuresonlyininfants.

Thefourderivativesofbarbituricacidclinicallyusefulasantiseizuredrugsarephenobarbital,mephobarbital(甲苯巴比妥),metharbital(甲基巴比妥),andprimidone(去氧苯比妥),.Thethree-dimensionalconformationsaresimilartothatofphenytoin.Thecompoundspossessaphenylringandareactiveagainstpartialseizures.1.MechanismofAction

(1)Likephenytoin,phenobarbitalsuppresseshigh-frequencyrepetitivefiringinneuronsthroughanactiononNa＋conductance,butonlyathighconcentrations.Alsoathighconcentrations,barbituratesblocksomeCa2+currents(L-typeandN-type).So,phenobarbitalmayselectivelysuppressabnormalneurons,inhibitingthespreadandsuppressingfiringfromthefoci.(2)PhenobarbitalbindstoanallostericregulatorysiteontheGABA-benzodiazepinereceptor,anditenhancestheGABAreceptor-mediatedcurrentbyprolongingtheopeningsoftheCl-channels.(3)Phenobarbitalalsoblocksexcitatoryresponsesinducedbyglutamate,principallythosemediatedbyactivationoftheAMPAreceptor.BoththeenhancementofGABA-mediatedinhibitionandthereductionofglutamate-mediatedexcitationareseenwiththerapeuticallyrelevantconcentrationsofphenobarbital.2.ClinicalUse

Phenobarbitalisusefulinthetreatmentofpartialseizuresandgeneralizedtonic-clonicseizures.Thereislittleevidenceforitseffectivenessinotherseizuressuchasabsence,atonic(非强直性)attacks,orinfantilespasms;itmayworsencertainpatientswiththeseseizuretypes.PRIMIDONE

Primidonewasmetabolizedtophenobarbitalandphenylethylmalonamide(PEMA,苯乙基丙二酰胺).Allthreecompoundsareactiveanticonvulsants.Themechanismofactionofprimidoneitselfmaybemorelikethatofphenytoin.1.ActionandUse

Primidone,likeitsmetabolites,iseffectiveagainstpartialseizuresandgeneralizedtonic-clonicseizuresandmaybemoreeffectivethanphenobarbital.PrimidonehasananticonvulsantactionindependentofitsconversiontophenobarbitalandPEMA(thelatterisrelativelyweak).2.Toxicity

Theadverseeffectsaresimilartothoseofitsmetabolite,phenobarbital,exceptthatdrowsinessoccursearlyintreatmentandmaybeprominentiftheinitialdoseistoolarge;gradualincrementsareindicatedwhenstartingthedrugineitherchildrenoradults.D.DRUGSUSEDINGENERALIZEDSEIZURES

VALPROICACID&SODIUMVALPROATEValproicacidisfullyionizedatbodypH,andforthatreasontheactiveformofthedrugmaybeassumedtobethevalproateionregardlessofwhethervalproicacidorasaltoftheacidisadministered.1.MechanismofAction

(1)Likephenytoin,valproateblockssustainedhigh-frequencyrepetitivefiringofneuronsincultureattherapeuticallyrelevantconcentrations.ItsactionagainstpartialseizuresisprobablyaconsequenceofthiseffectonNa+currents.(2)SeveralstudieshaveshownincreasedlevelsofGABAinthebrainafteradministrationofvalproate.valproatetofacilitateglutamicaciddecarboxylase(GAD),theenzymeresponsibleforGABAsynthesis.Atveryhighconcentrations,valproateinhibitsGABA-Tinthebrain,thusincreasinglevelsofGABAbyblockingconversionofGABAtosuccinicsemialdehyde(琥珀酸半醛).(3)Athighconcentrations,valproateincreasesmembranepotassiumconductance.Valproatemayexertanactionthroughadirecteffectonthepotassiumchannelsofthemembrane.2.ClinicalUseValproateisveryeffectiveagainstabsenceseizures,preferredifthepatienthasitantgeneralizedtonic-clonicattacks.Valproateisuniqueinitsabilitytocontrolcertaintypesofmyoclonicseizures;effectiveinpartialseizures.Otherusesofvalproateincludemanagementofbipolardisorderandmigraineprophylaxis.3.Pharmacokinetics(1)Valproateiswellabsorbedfollowinganoraldose，withbioavailabilitygreaterthan80%.Peakbloodlevelsareobservedwithin2hours.Foodmaydelayabsorption,anddecreasedtoxicitymayresultifthedrugisgivenaftermeals.(2)Thedrugisalso90%boundtoplasmaproteins.Sincevalproateisbothhighlyionizedandhighlyprotein-bound,itsdistributionisessentiallyconfinedtoextracellularwater.(3)

Clearanceforvalproateisverylow;itshalf-lifevariesfrom9hoursto18hours.Approximately20%ofthedrugisexcretedasadirectconjugateofvalproate.Theremainderismetabolizedbyoxidationtoanumberofcompounds,subsequentlyconjugatedandexcreted.(4)thesodiumsaltisprimarilyforpediatricuse.Thecapsuleof1:1"coordinationcompound"ofvalproicacidandsodiumvalproateisabsorbedmuchmoreslowlyandispreferredbymostpatients.Peakconcentrationsfollowingadministrationoftheenteric-coatedtabletsareseenin3-4hours.4.Toxicity(1)Themostcommonadverseeffectsofvalproatearenausea,vomiting,andothergastrointestinalcomplaints.Thedrugshouldbestartedgraduallytoavoidthesesymptoms;atemporaryreductionindosecanusuallyalleviatetheproblems,andthepatientwilleventuallytoleratehigherdoses.(2)Theidiosyncratictoxicityofvalproateislargelylimitedtohepatotoxicity,butthismaybesevere.Theriskisgreatestforpatientsundertheageof2yearsandforthosetakingmultiplemedications.Theotheridiosyncraticresponsewithvalproateisthrombocytopenia(血小板减少症).

ETHOSUXIMIDEEthosuximidewasintroducedin1960asa"purepetitmal"drug.Itsroleasthefirstchoiceanti-absencedrugremainsundiminished-inpartbecauseoftheidiosyncratichepatotoxicityofthealternativedrug,valproicacid.1.MechanismofActionProbablyinvolvescalciumchannels,alsoinhibitsNa+/K+ATPase,depressesthecerebralmetabolicrate,andinhibitsGABAaminotransferase.Ethosuximidereducesthelow-threshold(Ttype)Ca2+current.TheT-typecalciumcurrentsprovideapacemakercurrentinthalamic(丘脑)

neuronsresponsibleforgeneratingtherhythmiccorticaldischargeofanabsenceattack.Inhibitionofthiscurrentcouldthereforeaccountforthespecifictherapeuticactionofethosuximide.2.ClinicalUseEthosuximideisparticularlyeffectiveagainstabsenceseizures.Clonazepamandvalproicacidwasplishedbycomparisonwithethosuximide.(1)

Absorptioniscompletefollowingadministrationoftheoraldosageforms.Peaklevelsareobserved3-7hoursafteroraladministrationofthecapsules.Thevolumeofdistributionapproximatesthatoftotalbodywater,ie,0.7L/kg.3.Pharmacokinetics(2)Ethosuximideisnotprotein-bound,andspinalfluidconcentrationsarethereforeequaltoplasmaconcentrations.(3)Ethosuximideiscompletelymetabolized,principallybyhydroxylation.Ethosuximidehasaverylowtotalbodyclearance(0.25L/kg/d).Thiscorrespondstoahalf-lifeofapproximately40hours.4.ToxicityThemostcommonadverseeffectisgastricdistress,nausea,andvomiting.Thiscanoftenbeavoidedbys