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抗癫痫药专业知识讲座抗癫痫药专业知识讲座第1页Definitionsinepilepsy:Epilepsycomprisesrecurrentepisodesofabnormalcerebralneuronaldischarge.Theresultingseizuresareusuallyclinicallyobviousandvaryinpatternaccordingtowhichpartsofthebrainareaffected.Epilepsycanbecausedbymanyneurologicaldiseases,includinginfection,trauma,infarctionandneoplasia.Heredityhasanimportantrole(especiallyintheidiopathicgeneralisedepilepsies).抗癫痫药专业知识讲座第2页NormalbraincellAbnormalhigh-frequencydischargeFocusDrugactionInhibitdischargeStabilizemembrane,inhibitthediffusionofdischarge(primary)抗癫痫药专业知识讲座第3页CommonseizuretypesofEpilepsy:Generalisedseizures.Absence(petitmal).Tonic/clonic(grandmal).Partialseizures.Simplepartialseizures.Complexpartialseizures(temporallobeepilepsy).
抗癫痫药专业知识讲座第4页Generalisedseizures:Absence(petitmal):Theseseizureshaveabruptonsetandcessation,withimpairedconsciousness,butwithnormalpostureoftenretained.TheEEGshowsatypical‘spikeandwave’pattern.Tonic/clonic(grandmal):Consciousnessisimpairedandthepatientusuallyfallstothefloor.Aphaseofmusclecontraction(‘tonic’)isfollowedbyirregularmuscleclonusandthenbysleep.Injurymayoccur.抗癫痫药专业知识讲座第5页Partialseizures:Simplepartialseizures:featuresdependonthepartofthebrainaffected,resultfromdischargeintheprecentralgyrus.Consciousnessisunimpaired.Complexpartialseizures(temporallobeepilepsy):Consciousnessisimpairedwithcomplex,oftenrepetitive,action.抗癫痫药专业知识讲座第6页TheEEGinseizureofEpilepsy
3HzParadoxicaldischargeSpikewave抗癫痫药专业知识讲座第7页Epilepsy
Pathogenesis:Theneuroninbrainlesiondepolarizestogethersuddenly,andthenproducthigh-frequency,out-breakdischarge.Thedischargecandiffusetosurroundingnormaltissue→extensiveexcitation→thebrainfunctiontransientaberration.抗癫痫药专业知识讲座第8页NormalbraincellAbnormalhigh-frequencydischargeFocusDrugactionInhibitdischargeStabilizemembrane,inhibitthediffusionofdischarge(primary)抗癫痫药专业知识讲座第9页EpilepsyTherapeuticprinciple:ChangethepermeabilityofNa+,
Ca2+andK+innervecellmembrane,degradeexcitementstage,extendrefractoryphase.DirectlyorindirectlyincreaseCNSlevelsofGABA.抗癫痫药专业知识讲座第10页Theprimary
animalmodels
usedinanti-epilepticdrugsresearchMaximalelectroshockseizure(MES)
model:screenthedrugswhichusedingrandmal.
Pentetrazole(PTZ)inducedconvulsionmodel:
screenthedrugswhichusedinpetitmal.
Kindlingseizuremodel:
screenthedrugswhichusedingrandmal.
Spontaneouslyepilepticrat(SER)model:
usedinanti-epilepticdrugsresearch.memo:将震颤大鼠与Zitter基因变异大鼠交配,于1986年培育出SER鼠。它也含有震颤,脑海绵状变性等特点。是tm基因与Zitter(zi)基因共同突变结果。除了含有TRM大鼠重度失神发作之外,SER鼠还表现为高频率强直性自发痉挛。在SER鼠大脑皮质及海马用慢性统计电极作自发脑电波检验发觉,当SER失神发作时,出现与TRM鼠一样5—7Hz多波峰波群放电;在其出现强直性痉挛时,出现两个部位一致低振幅快速波。中枢神经系统病理检验结果显示,SER除含有TRM鼠重度脑海绵状变性外,还出现了神经细胞低形成或形成异常,生殖器萎缩,不育,胡须和体毛屈曲,视觉障碍,听觉障碍,高级运动障碍等。抗癫痫药专业知识讲座第11页ClassificationofAntiepilepticDrugsHydantoins:Sodium
PhenytoinBarbiturates:Phenobarbital,PrimidoneSuccinimide:EthosuximideBenzodiazepine:Diazepam,NitrazepamOthers:SodiumValproate抗癫痫药专业知识讲座第12页SodiumPhenytoin(苯妥英钠)
【Physiologicaldisposition】SodiumPhenytoinisabsorbedslowlyafteroraladministration.→After6-10days,itsplasmaconcentrationcanachieveeffectlevels.Thisdrughasvariableinterpatientplasmaconcentration.抗癫痫药专业知识讲座第13页SodiumPhenytoinMechanismofaction:①Itcanblocksodiumchannels(voltage-,frequency-,andtimedependentfashion)andinhibitthegenerationofactionpotentials.②ItcanincreasethefunctionofinhibitorytransmitterGABA,inhibitnerveterminaltouptakeGABAandinducetheincreasingofGABAreceptor,therebyenhanceGABA-mediatedpostsynapticinhibition.抗癫痫药专业知识讲座第14页SodiumPhenytoin【Pharmacologicpropertiesandclinicalapplication】Anti-epileptic:Itcanbeusedforpartialseizuresandtonic/clonicseizures,butnotforothergeneralisedseizuretypes.Peripheralneuralgia:cranialnerve,ischiadicnerveandcranialnerve.
Arrhythmia:
membrane-stabilizingaction.抗癫痫药专业知识讲座第15页SodiumPhenytoinDigestivesystemGingivalhyperplasiaNervoussystemHematologicalsystemSkeletalsystemAllergicresponseOthers【Adverseeffects】抗癫痫药专业知识讲座第16页SodiumPhenytoin【Adverseeffects】Digestivesystem:anorexia,nausea,vomitingandabdominalpain(recommendtotakeitaftermeal).ItmaycausephlebitisafterIV.Gingivalhyperplasia:Itcommonoccursinchildrenandteenagersafterlongtermuse,theincidencerateisabout20%.Generally,thiseffectcanresolveafterdrugwithdraw3to6months.抗癫痫药专业知识讲座第17页SodiumPhenytoin【Adverseeffects】
Nervoussystem:nystagmus,diplopia,vertigo,ataxia(usuallyonlyatveryhighconcentration).Severepatientoccurslanguagedisorder,mentalconfusionandcataphora.Hematologicalsystem:Becauseitcaninhibittheabsorptionoffolinicacidandaccelerateitsmetabolism.Thisdrugalsocaninhibitfolicacidreductase.Soitmaycausemegaloblasticanemiaafterlong-termuse(recommendtopretreatwithfolinicacid).抗癫痫药专业知识讲座第18页SodiumPhenytoin【Adverseeffects】
Skeletalsystem:ItcanenhancevitaminDmetabolism,soPhenytoinmayincreasetheriskofhypocalcemia,ricketsandosteomalaciaafterlong-termtreatment(pretreatwithvitaminDifnecessary).Allergicresponse:
rash,thrombocytopenia
,agranulocytosisandaplasticanemia.Others:
rarelyappearmalebarymastia,female
hirsutismandlymphadenectasis.抗癫痫药专业知识讲座第19页Phenobarbital(苯巴比妥)Mechanismofaction:Phenobarbitalcaninhibittheparadoxicaldischargeofepilepsyfocusselectively,enhancestimulationofsurroundingtissuesandblockdischargediffusetonormaltissues.PhenobarbitalfacilitateGABA-mediatedinhibitionofneuronalactivity.抗癫痫药专业知识讲座第20页PhenobarbitalPharmacologicproperties:Phenobarbitalcanbeusedforalltypesofepilepsy.Theeffectsbyturnsare:grandmalandstatusepileptics>localpsychomotorseizure>petitmal.Takeeffectrapidly(1~2hr),thefirstchoiceofgrandmal.Preventconvulsiveandeliminateprecursorysymptom.抗癫痫药专业知识讲座第21页Phenobarbital【Adverseeffects】Somnolence、depression.Tolerancedevelopsafterlong-termtreatment.抗癫痫药专业知识讲座第22页Primidone(去氧苯比妥)
Primidone(扑米酮)Pharmacologicproperties:Absorptionafteroraladministrationisrapid,andtheplasmapeakconcentrationisapproximately3hoursattherapeuticdoses.Itcanbeusedforalltypesofepilepsyexceptpetitmal.It’sbettertousethisdrugwithsodiumphenytoin.Withregardtograndmal,theeffectofprimidoneisbetterthanphenobarbital,thisdrugisuselesstopetitmal.抗癫痫药专业知识讲座第23页Primidone(Primidone)【Adverseeffects】Common:somnolence,vertigo,nauseaandvomiting.Rare:
megaloblasticanemia,leucopeniaandthrombocytopenia.抗癫痫药专业知识讲座第24页Ethosuximide(乙琥胺)Petitmal(firstchoice),uselesstoothertypesofseizure.
[Commonadverseeffect]Gastrointestinaltract:anorexia,nausea,vomiting.CNS:headache,dizzinessandsomnolence.Rarelyappearagranulemiaandaplasticanemia.
抗癫痫药专业知识讲座第25页Diazepem(安定)&Nitrazepem(硝基安定)Diazepem
:Diazepemisindicatedforstatusepilepticus.Nitrazepem:It’shighlyeffectiveincontrollingpetitmalandmyoclonusepilepsy.Suddenwithdrawalofnitrazepemislikelytoaggravateseizureandinducedsymptom.抗癫痫药专业知识讲座第26页SodiumValproate(丙戊酸钠
)Pharmacologicproperties:
Enhancetheenzymaticactivityofglutamatedecarboxylase.→GABA↑InhibitGABAreuptakeandsynapseinactivation→synapsefrontalmembraneGABA↑→enhanceGABApostsynapticinhibitionBroadspectrumantiepilepticdrug,usetoalltypesofepilepsy.CNS:
somnolence,disequilibrium,acratiaandtremor.Hepaticlesion(20%patients).Gastrointestinaltract:nausea,vomitingandanorexia.抗癫痫药专业知识讲座第27页Carbamzepine(卡马西平)Pharmacologicproperties:
Carbamazepinecanblocksodiumchannel,inhibitparadoxicaldischargeanddischargediffusion.ItmayrelatetothepostsynapticinhibitionofGABA.Broadspectrumantiepilepticdrug,usetoalltypesofepilepsy.
Trigeminalneuralgia(therapeuticeffectisgood).Antidiuresis-diabetesinsipidus.抗癫痫药专业知识讲座第28页Carbamzepine【Adverseeffects】CNS:
somnolence,disequilibriumGastrointestinaltract:nausea,vomitingandanorexia.Rash,leucopenia,thrombocytopenia,aplasticanemiaandhepaticlesion.
抗癫痫药专业知识讲座第29页PrincipleofMedication
1~2times/year,nodrugsareneededGrandpit(firstchoice):Sodiumphenytoinorphenobarbital,carbamzepine,Primidone.Petitmal(firstchoice):Ethosuximide,clonazepamandsodiumvalproate.Statusepilepticus:Diazepamorsodiumphenytoin(IV),phenobarbital,diazepam,clonazepam.Psychomotor:Sodiumphenytoinorcombinewithdesoxybarbitalorcarbamazepine.抗癫痫药专业知识讲座第30页PrincipleofMedication(I)Thedosecanbegraduallyincreasedfromalowstartingdoseuntilreachthebesteffect.Intheinitialstage,thepatientsshouldonlybetreatedwithasingleantiepilepticdrug,if
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