抗癲癇藥專業(yè)知識講座抗癲癇藥專業(yè)知識講座第1頁Definitionsinepilepsy:Epilepsycomprisesrecurrentepisodesofabnormalcerebralneuronaldischarge.Theresultingseizuresareusuallyclinicallyobviousandvaryinpatternaccordingtowhichpartsofthebrainareaffected.Epilepsycanbecausedbymanyneurologicaldiseases,includinginfection,trauma,infarctionandneoplasia.Heredityhasanimportantrole(especiallyintheidiopathicgeneralisedepilepsies).抗癲癇藥專業(yè)知識講座第2頁NormalbraincellAbnormalhigh-frequencydischargeFocusDrugactionInhibitdischargeStabilizemembrane,inhibitthediffusionofdischarge(primary)抗癲癇藥專業(yè)知識講座第3頁CommonseizuretypesofEpilepsy:Generalisedseizures.Absence(petitmal).Tonic/clonic(grandmal).Partialseizures.Simplepartialseizures.Complexpartialseizures(temporallobeepilepsy).

抗癲癇藥專業(yè)知識講座第4頁Generalisedseizures:Absence(petitmal):Theseseizureshaveabruptonsetandcessation,withimpairedconsciousness,butwithnormalpostureoftenretained.TheEEGshowsatypical‘spikeandwave’pattern.Tonic/clonic(grandmal):Consciousnessisimpairedandthepatientusuallyfallstothefloor.Aphaseofmusclecontraction(‘tonic’)isfollowedbyirregularmuscleclonusandthenbysleep.Injurymayoccur.抗癲癇藥專業(yè)知識講座第5頁Partialseizures:Simplepartialseizures:featuresdependonthepartofthebrainaffected,resultfromdischargeintheprecentralgyrus.Consciousnessisunimpaired.Complexpartialseizures(temporallobeepilepsy):Consciousnessisimpairedwithcomplex,oftenrepetitive,action.抗癲癇藥專業(yè)知識講座第6頁TheEEGinseizureofEpilepsy

3HzParadoxicaldischargeSpikewave抗癲癇藥專業(yè)知識講座第7頁Epilepsy

Pathogenesis:Theneuroninbrainlesiondepolarizestogethersuddenly,andthenproducthigh-frequency,out-breakdischarge.Thedischargecandiffusetosurroundingnormaltissue→extensiveexcitation→thebrainfunctiontransientaberration.抗癲癇藥專業(yè)知識講座第8頁NormalbraincellAbnormalhigh-frequencydischargeFocusDrugactionInhibitdischargeStabilizemembrane,inhibitthediffusionofdischarge(primary)抗癲癇藥專業(yè)知識講座第9頁EpilepsyTherapeuticprinciple:ChangethepermeabilityofNa+,

Ca2+andK+innervecellmembrane,degradeexcitementstage,extendrefractoryphase.DirectlyorindirectlyincreaseCNSlevelsofGABA.抗癲癇藥專業(yè)知識講座第10頁Theprimary

animalmodels

usedinanti-epilepticdrugsresearchMaximalelectroshockseizure(MES)

model：screenthedrugswhichusedingrandmal.

Pentetrazole(PTZ)inducedconvulsionmodel:

screenthedrugswhichusedinpetitmal.

Kindlingseizuremodel:

screenthedrugswhichusedingrandmal.

Spontaneouslyepilepticrat(SER)model：

usedinanti-epilepticdrugsresearch.memo:將震顫大鼠與Zitter基因變異大鼠交配，于1986年培育出SER鼠。它也含有震顫，腦海綿狀變性等特點。是tm基因與Zitter（zi）基因共同突變結果。除了含有TRM大鼠重度失神發(fā)作之外，SER鼠還表現(xiàn)為高頻率強直性自發(fā)痙攣。在SER鼠大腦皮質及海馬用慢性統(tǒng)計電極作自發(fā)腦電波檢驗發(fā)覺，當SER失神發(fā)作時，出現(xiàn)與TRM鼠一樣5—7Hz多波峰波群放電；在其出現(xiàn)強直性痙攣時，出現(xiàn)兩個部位一致低振幅快速波。中樞神經(jīng)系統(tǒng)病理檢驗結果顯示，SER除含有TRM鼠重度腦海綿狀變性外，還出現(xiàn)了神經(jīng)細胞低形成或形成異常，生殖器萎縮，不育，胡須和體毛屈曲，視覺障礙，聽覺障礙，高級運動障礙等。抗癲癇藥專業(yè)知識講座第11頁ClassificationofAntiepilepticDrugsHydantoins：Sodium

PhenytoinBarbiturates：Phenobarbital,PrimidoneSuccinimide：EthosuximideBenzodiazepine:Diazepam,NitrazepamOthers:SodiumValproate抗癲癇藥專業(yè)知識講座第12頁SodiumPhenytoin(苯妥英鈉)

【Physiologicaldisposition】SodiumPhenytoinisabsorbedslowlyafteroraladministration.→After6-10days,itsplasmaconcentrationcanachieveeffectlevels.Thisdrughasvariableinterpatientplasmaconcentration.抗癲癇藥專業(yè)知識講座第13頁SodiumPhenytoinMechanismofaction:①Itcanblocksodiumchannels(voltage-,frequency-,andtimedependentfashion)andinhibitthegenerationofactionpotentials.②ItcanincreasethefunctionofinhibitorytransmitterGABA,inhibitnerveterminaltouptakeGABAandinducetheincreasingofGABAreceptor,therebyenhanceGABA-mediatedpostsynapticinhibition.抗癲癇藥專業(yè)知識講座第14頁SodiumPhenytoin【Pharmacologicpropertiesandclinicalapplication】Anti-epileptic：Itcanbeusedforpartialseizuresandtonic/clonicseizures,butnotforothergeneralisedseizuretypes.Peripheralneuralgia：cranialnerve,ischiadicnerveandcranialnerve.

Arrhythmia:

membrane-stabilizingaction.抗癲癇藥專業(yè)知識講座第15頁SodiumPhenytoinDigestivesystemGingivalhyperplasiaNervoussystemHematologicalsystemSkeletalsystemAllergicresponseOthers【Adverseeffects】抗癲癇藥專業(yè)知識講座第16頁SodiumPhenytoin【Adverseeffects】Digestivesystem:anorexia,nausea,vomitingandabdominalpain(recommendtotakeitaftermeal).ItmaycausephlebitisafterIV.Gingivalhyperplasia:Itcommonoccursinchildrenandteenagersafterlongtermuse,theincidencerateisabout20%.Generally,thiseffectcanresolveafterdrugwithdraw3to6months.抗癲癇藥專業(yè)知識講座第17頁SodiumPhenytoin【Adverseeffects】

Nervoussystem:nystagmus,diplopia,vertigo,ataxia(usuallyonlyatveryhighconcentration).Severepatientoccurslanguagedisorder,mentalconfusionandcataphora.Hematologicalsystem:Becauseitcaninhibittheabsorptionoffolinicacidandaccelerateitsmetabolism.Thisdrugalsocaninhibitfolicacidreductase.Soitmaycausemegaloblasticanemiaafterlong-termuse(recommendtopretreatwithfolinicacid).抗癲癇藥專業(yè)知識講座第18頁SodiumPhenytoin【Adverseeffects】

Skeletalsystem:ItcanenhancevitaminDmetabolism,soPhenytoinmayincreasetheriskofhypocalcemia,ricketsandosteomalaciaafterlong-termtreatment(pretreatwithvitaminDifnecessary).Allergicresponse:

rash,thrombocytopenia

,agranulocytosisandaplasticanemia.Others:

rarelyappearmalebarymastia,female

hirsutismandlymphadenectasis.抗癲癇藥專業(yè)知識講座第19頁Phenobarbital(苯巴比妥)Mechanismofaction:Phenobarbitalcaninhibittheparadoxicaldischargeofepilepsyfocusselectively,enhancestimulationofsurroundingtissuesandblockdischargediffusetonormaltissues.PhenobarbitalfacilitateGABA-mediatedinhibitionofneuronalactivity.抗癲癇藥專業(yè)知識講座第20頁PhenobarbitalPharmacologicproperties:Phenobarbitalcanbeusedforalltypesofepilepsy.Theeffectsbyturnsare:grandmalandstatusepileptics＞localpsychomotorseizure＞petitmal.Takeeffectrapidly（1～2hr),thefirstchoiceofgrandmal.Preventconvulsiveandeliminateprecursorysymptom.抗癲癇藥專業(yè)知識講座第21頁Phenobarbital【Adverseeffects】Somnolence、depression.Tolerancedevelopsafterlong-termtreatment.抗癲癇藥專業(yè)知識講座第22頁Primidone(去氧苯比妥)

Primidone(撲米酮)Pharmacologicproperties:Absorptionafteroraladministrationisrapid,andtheplasmapeakconcentrationisapproximately3hoursattherapeuticdoses.Itcanbeusedforalltypesofepilepsyexceptpetitmal.It’sbettertousethisdrugwithsodiumphenytoin.Withregardtograndmal,theeffectofprimidoneisbetterthanphenobarbital,thisdrugisuselesstopetitmal.抗癲癇藥專業(yè)知識講座第23頁Primidone(Primidone)【Adverseeffects】Common:somnolence,vertigo,nauseaandvomiting.Rare:

megaloblasticanemia,leucopeniaandthrombocytopenia.抗癲癇藥專業(yè)知識講座第24頁Ethosuximide(乙琥胺)Petitmal(firstchoice),uselesstoothertypesofseizure.

[Commonadverseeffect]Gastrointestinaltract:anorexia,nausea,vomiting.CNS:headache,dizzinessandsomnolence.Rarelyappearagranulemiaandaplasticanemia.

抗癲癇藥專業(yè)知識講座第25頁Diazepem(安定)&Nitrazepem(硝基安定)Diazepem

：Diazepemisindicatedforstatusepilepticus.Nitrazepem:It’shighlyeffectiveincontrollingpetitmalandmyoclonusepilepsy.Suddenwithdrawalofnitrazepemislikelytoaggravateseizureandinducedsymptom.抗癲癇藥專業(yè)知識講座第26頁SodiumValproate(丙戊酸鈉

)Pharmacologicproperties:

Enhancetheenzymaticactivityofglutamatedecarboxylase.→GABA↑InhibitGABAreuptakeandsynapseinactivation→synapsefrontalmembraneGABA↑→enhanceGABApostsynapticinhibitionBroadspectrumantiepilepticdrug,usetoalltypesofepilepsy.CNS:

somnolence,disequilibrium,acratiaandtremor.Hepaticlesion(20%patients).Gastrointestinaltract:nausea,vomitingandanorexia.抗癲癇藥專業(yè)知識講座第27頁Carbamzepine(卡馬西平)Pharmacologicproperties:

Carbamazepinecanblocksodiumchannel,inhibitparadoxicaldischargeanddischargediffusion.ItmayrelatetothepostsynapticinhibitionofGABA.Broadspectrumantiepilepticdrug,usetoalltypesofepilepsy.

Trigeminalneuralgia(therapeuticeffectisgood).Antidiuresis－diabetesinsipidus.抗癲癇藥專業(yè)知識講座第28頁Carbamzepine【Adverseeffects】CNS:

somnolence,disequilibriumGastrointestinaltract:nausea,vomitingandanorexia.Rash，leucopenia，thrombocytopenia，aplasticanemiaandhepaticlesion.

抗癲癇藥專業(yè)知識講座第29頁PrincipleofMedication

1～2times/year，nodrugsareneededGrandpit(firstchoice):Sodiumphenytoinorphenobarbital,carbamzepine,Primidone.Petitmal(firstchoice):Ethosuximide,clonazepamandsodiumvalproate.Statusepilepticus:Diazepamorsodiumphenytoin(IV),phenobarbital,diazepam,clonazepam.Psychomotor:Sodiumphenytoinorcombinewithdesoxybarbitalorcarbamazepine.抗癲癇藥專業(yè)知識講座第30頁PrincipleofMedication(I)Thedosecanbegraduallyincreasedfromalowstartingdoseuntilreachthebesteffect.Intheinitialstage,thepatientsshouldonlybetreatedwithasingleantiepilepticdrug,if