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1AntiseizuredrugsDr.WangFangDepartmentofPharmacology2EpilepsyAheterogeneoussymptomcomplex——achronicdisordercharacterizedbyrecurrentseizuresSeizuresarefiniteepisodesofbraindysfunctionresultingfromabnormaldischargeofcerebralneurons,whichisassociatedwiththeepisodichigh-frequencydischargeofimpulsesbyagroupofneuronsinthebrain.Causes:infection,neoplasm,headinjuryandheredity3ClassificationofseizuretypesPartialseizuresSimplepartialseizures:withoutlossofconsciousnessComplexpartialseizuresPartialseizuressecondarilygeneralizedtonic-clonicseizureGeneralizedseizuresAbsence(petitmal)seizures:Abruptonsetofimpairedconsciousnessassociatedwithstaringandcessationofongoingactivitiestypicallylastinglessthan30seconds.Generalizedtonic-clonic(grandmal)seizureMyoclonicseizureInfantilespasms4Aninitialstrongcontractionofthewholemusculature,causingarigidextensorspasm.Respirationstopsanddefecation,micturitionandsalivationoftenoccur.Thistoniclasts1minandfollowedbyseriesofviolent,synchronousjerksthatgraduallydiesoutin2-4min,andthengraduallyrecovers,feelingillandconfused.Tonic-clonicseizure5MechanismofactionEnhancedGABA-mediatedsynapticinhibitionDiminishexcitatory(glutamatergic)transmissionModificationofionicconductance(Limitactivationofaparticularvoltage-activatedT-typeCa2+channelandNa+channels)6Phenytoinsodium(dilantin)ExertsantiseizureactivitywithoutcausinggeneraldepressionoftheCNS.ModifythepatternofmaximalelectroshockseizuresNotinhibitclonicseizuresevokedbypentylenetetrazol7MechanismSlowtherateofNa+channelsrecoveryfrominactivation——voltage-(greatereffectifmembraneisdepolarized)anduse-dependent.

InhibitthecalciumchannelInhibittheactivityofcalmodulinInhibittheposttetanicpotentiation(PTP)Themajoractionistoblocksodiumchannelsandinhibitthegenerationofrepetitiveactionpotential.8PharmacokineticsAbsorption:i.misnotrecommendedoralispreferableHighlyboundtoplasmaproteinsEliminationisdose-dependentbelow10mg/ml,first-orderkinetics,t1/2~20hhigherconcentrations:zero-orderkinetics,t1/2increasedMeasurementofdrugconcentrationsinplasmafacilitatesoptimizingantiseizuremedication

9ClinicalusesOneofthemostdrugsagainstpartialseizuresandgeneralizedtonic-clonicseizures,butnotabsenceseizures.Thetherapeuticplasmalevelformostpatientsisbetween10and20μg/ml.Trigeminalandrelatedneuralgias(carbamazepineispreferable)Cardiacarrhythmias10ToxicityGastrointestinalsymptomsGingivalhyperplasia:alteredcollagenmetabolism,minimizedbygoodoralhygieneCerebellar-vestibulareffects:Nystagmus,diplopiaandataxiaLowfolatelevelsandmegaloblasticanemiaDrugallergy:skin,bonemarrow,andliver

Osteomalacia:abnormalitiesofVit.DmetabolismHirsutisminyoungfemales11EthosuximideAprimaryagentforthetreatmentofabsenceseizures——a“purepetitmal”drugReducesT-typeCa2+currentsinthalamicneuronsToxicity:Gastrointestinalcomplaints(nausea,vomiting,andanorexia)CNSeffects(drowsiness,lethargy,euphoria,dizziness,headache,andhiccough)12PhenobarbitalExertmaximalantiseizureactionatdosesbelowthoserequiredforhypnosisAneffectiveagentforgeneralizedtonic-clonicandpartialseizures.Itsefficacy,lowtoxicity,andlowcostmakeitanimportantagentforthesetypesofepilepsy.However,itssedativeeffectsanditstendencytodisturbbehaviorinchildrenhavereduceditsuseasaprimaryagent.

13CarbamazepineClinicaluses:Epilepsy:

generalizedtonic-clonicandbothsimpleandcomplexpartialseizuresTrigeminalandglossopharyngealneuralgiasBipolaraffectivedisorders:

includingsomeinwhomlithiumcarbonateisnoteffective14ValproatesodiumInhibitseizuresinavarietyofmodelsMechanismofactionincreasetheamountofGABAinhibit(athighconcentration)Na+andL-typeCa2+channel.TherapeuticapplicationsAbsence,myoclonic,partial,andtonic-clonicseizures.Bipolardisorderandmigraineprophylaxis15ValproatesodiumAdversereactionsGastrointestinalsymptomsCNSeffects:sedation,ataxia,andtremorFulminanthepatitis:espeaciallyinchildrenbelow2yearsofage;carefulmonitoringofliverfunctionTeratogeniceffects:neuraltubedefects16BenzodiazepinesDiazepam:Givenintravenousorrectallyishighlyeffectiveforstoppingcontinuousseizureactivity,especiallygeneralizedtonic-clonicstatusepilepsy.Nitrazepam:EspeciallyforinfantilespasmsandmyoclonicseizuresClonazepam:Long-actingdrugAgainstabsenceseizures,myoclonicseizuresandinfantilespasms17Whethertoinitiate?Generalprinciplesandchoiceofdrugsforthetherapyoftheepilepsies

AsimilarseizureoccurringinanindividualwithApositivefamilyhistoryofepilepsyAnabnormalneurologicalexamAnabnormalEEGAnabnormalMRI——carriesariskofrecurrenceapproximating60%,oddsthatfavorinitiationoftherapy.18Whethertocombine?GeneralprinciplesandchoiceofdrugsforthetherapyoftheepilepsiesUnlessstatusepilepticusexist,onlymonotherapyshouldbeinitiated.Dosageisincreasedatappropriateintervals,asrequiredforcontrolofseizuresoraslimitedbytoxicityIfcompliancehasbeenconfirmedyetseizurespersist,anotherdrugshouldbesubstit