AntiepilepticandAnticonvulsiveDrugsLouhaiyanInstituteofPharmacologySchoolofMedicineShandongUniversitylouhaiyan@1Section1AntiepilepticDrugs

2Epilepsy(癲癇)3Aseizureistheclinicalmanifestationofasudden,excessiveandsynchronousdischargeoffocalneuronsanddiffusiontonormalneuronaltissues.Epilepsyischaracterizedby

recurrent,suddenandtransientseizures.Definitionofepilepsy

sensorydisorder,behaviordisorder,andpsychotic4Classificationsofseizuretypes1.Partialseizures(局限性發作)①Simplepartialseizures(單純性局限性發作)②Complexpartialseizures(復合性局限性發作)Psychomotorseizures(精神運動性發作)2.Generalizedseizures(全身性發作)①Absence(petitmal)seizures(失神性發作,小發作)②Myoclonicseizures(肌陣攣性發作)③Generalizedtonic-clonic(gradmal)seizures(強直-陣攣性發作,大發作）④Statusepilepticus

(癲癇持續狀態)5CauseofepilepsyIdiopathicepilepsyComplicatedGeneticSecondaryepilepsyCNSinfectionTraumaTumorParasitesetc6PathogenesisofepilepsyinitiationandspreadImbalancefunctionofneurotransmittersandinstableneuronalmembrane

7EEGRecordsDuringEpilepticSeizureEpilepsyischaracterizedbyuncontrolledexcessiveactivityofeitherapartorallofthecentralnervoussystem.Grandmalepilepsy:characterizedbyextremeneuronaldischargesinallareasofthebrain,lastfromafewsecondsto3to4minutes.Petitmalepilepsy:Characterizedby3to30secondsofunconsciousnessordiminishedconsciousnessduringwhichthepersonhasseveraltwitch-likecontractionsofthemuscle.8DiagnosisofEpilepsyYesorNo?HistoryClassificationReason?9TreatmentofEpilepsyAim:Keepthepatientfreeofseizures,withnoadverseeffects,notaffectingthelifequality.CauseDrugtreatmentSurgeryorphysicaltherapy101.Blocktheinitiationofabnormalofabnormaldischargefromthefocalarea.2.Preventthespreadofabnormaldischargetoadjacentbrainareas.Mechanismsofantiepilepsydrugs

ActionPatterns:11Mechanismsofantiepilepticdrugs

1.Decreaseactivityofvoltage-dependentNa+channels2.Decreaseactivityofvoltage-dependentCa2+channelsN-type(neuronal);L-type(longlasting)T-type(transient)3.EnhanceGABAergictransmissiondecreasethereuptakeormetabolismofGABAdirectactionontheGABAA-R4.

Diminishglutamatefunction

12

Section2

Commonly-usedantiepilepticdrugs13

phenytoinsodium(苯妥英鈉)

barbiturates：phenbarbital(苯巴比妥)

primidone(撲米酮)

carbamazepine(卡馬西平)

ethosuximide(乙琥胺)

sodiumvalproate(丙戊酸鈉)

benzodiazepines:

diazepam(地西泮)

nitrozepam(硝西泮)

clonazepam(氯硝西泮)

antiepilepsirine(抗癇靈)

newerdrugs:flunarizine(氟桂利嗪)

lamotrigine(拉莫三嗪)

topiramate(托吡酯)14

1.PhenytoinSodium

（苯妥英鈉,Dilantin,大侖丁）15

【Pharmacologicalactions】CannotinhibitthedischargeofneuroninfocusPreventthediffusioninnormalneuroninhibitposttetanic

potentiation(PTP,強直后增強):反復高頻電刺激(強直刺激)突觸前神經纖維，引起突觸傳遞易化，使突觸后纖維反應增強的現象16Membrane-stabilizingfunction1.

blockvoltage-sensitiveNa+channel2.

blockvoltage-sensitiveCa2+channel(Ltype,Ntype)

3.inhibittheactivityofcalmodulin

kinase

(鈣調素激酶)presynapticmembrane—Glurelease↓postsynapticmembrane—depolarization↓【Mechanismsofaction】171.Epilepsy:

generalizedtonic-clonicseizures(gradmal)

andpartialseizures

(firstchoice)

except

absenceseizures(petitmal)

(noeffect,evenexacerbatedisease)

【clinicaluses】attention:slowonsetphenobabital→phenytoinsodium183.

Ventriculararrhythmia(心律失常)：

cardiacglycosideinduced(強心苷中毒)-firstchoice2.Neuralgias：

trigeminalneuralgia(三叉神經痛)glossopharyngealneuralgia(舌咽神經痛)【clinicaluses】191.Absorptionstrongirritation(alkaline,pH=10.4),notim.Oral:unpredictable,slowonset

Css:6-10d(10-20ug/ml)iv.forstatusepilepticus

【Pharmacokinetics】20【Pharmacokinetics】2.Metabolism:mainlyinliver,hepaticenzymeinduction

≤10g/ml:first-ordereliminationkinetics,

t1/2=20h

≥10g/ml:zero-ordereliminationkinetics,t1/2=60hmonitorblooddrugconcentration(10-20g/ml)3.C=10g/ml(anti-epilepsy)

C=20g/ml(intoxication)211.Localstimulation①gastrointestinalirritation②phlebitis(靜脈炎)③gingivalhyperplasia20%AdverseReactions222.CNSsymptoms

20g/ml：dizziness,ataxia﹥40g/ml:psychoticdisiorder﹥50g/ml:coma

233.Megaloblasticanemia防治：甲酰四氫葉酸4.Hypocalcemia,

osteomalacia(軟骨癥)

rachitis(佝僂病):children防治：VitD24AdverseReactions5.Allergyskinrash

agranulocytosis（粒細胞缺乏）

thrombocytopenia（血小板減少）

aplasticanemia（再生障礙性貧血）

hepaticlesion

256.Teratogenesis

【AdverseReactions】fetalhydantoinsyndrome(胎兒妥因綜合征）26

芬蘭1980～1998年，研究人員追蹤了一家產科診所中970位懷孕的癲癇婦女，其中有740位在懷孕初期（前3個月）服用抗癲癇藥物，另外239位則無。結果在這些服用抗癲癇藥物的懷孕婦女中，共產下28個嚴重畸形兒（3.8%），未服用抗癲癇藥物組產下2個嚴重畸形兒（0.8%；P=0.02）27

2.Phenobarbital(苯巴比妥)【Pharmacologicalactionsandclinicaluses】1.rapidonset2.usedforgeneralizedtonic-clonicseizuresand

statusepilepticus(iv),butnotfirstchoice

Mechanisms:inhibitinitiationandspreadofabnormaldischarge

increaseGABAinducedCl-in(extendopeningtime)inhibitexcitatoryneurotransmitter-mediatedeffecthighdoseinhibitNa+,Ca2+(LandN-type)channel28

3.Primidone(撲米酮)activemetabolites:

phenobarbital

phenylethylmalonamides(PEMA,苯乙基丙二酰胺)294.Ethosuximide(乙琥胺)Theonlyindication:

absenceepilepsy-firstchoiceMechanisms:inhibittheT-typeCa2+currentin

thalamicneurons

301.Diazepam:statusepilepticus-firstchoice

(iv,slow)2.Nitrazepam(硝西泮):absenceseizure,myoclonicseizure,infantilespasm3.Clonazepam(氯硝西泮):broad-spectrum5.Benzodiazepines316.SodiumValproate

(丙戊酸鈉)Uses:Broad-spectrumLesseffectiveforgradmalthanphenytoinand

phenobarbital

Similareffectiveforpartialmalwithcarbamazepine

Moreeffectivethanethosuximideforabsenceseizurebutnotthefirstchoiceduetohepatictoxicity.Gradmalcombinedwithabsenceseizure-firstchoice

Refractoryepilepsy(頑固性癲癇)32

Mechanisms:inhibitdischargespreadenhanceGABAfunction：

inhibitNa+,T-typeCa2+channel33SodiumValproateGADGABA-TglutamicacidsuccinicacidsemialdehydeGABA+-6.SodiumValproate

(丙戊酸鈉)GAD:谷氨酸脫羧酶GABA-T：谷氨酸轉氨酶琥珀酸半醛34AdverseReactionsGastrointestinalreactionsandCNSreactionsLiverinjury:25%routineexaminationTeratogenesis357.Carbamazepine(卡馬西平)【Pharmacologicalactionsandclinicaluses】1.Epilepsy:broadspectrum

gradmal,complexpartialseizures-firstchoice

nogoodforabsenceepilepsy2.Neuralgias:moreeffectivethanphenytoinMechanismsinhibitNa+、Ca2+channelenhanceGABAinhibitoryfunction3.Diabetesinsipidus

(尿崩癥)

4.Maniaanddepression(躁狂抑郁癥)36尿崩癥AVP(argininevasopressin):精氨酸加壓素ADH(antidiuretichormone):抗利尿激素卡馬西平：促進ADH分泌病因:下丘腦-神經垂體部位的病變↓ADH(AVP),

腎小管重吸收功能障礙多尿、煩渴、多飲與低比重尿37OthersAntiepilepsirin(抗癇靈)flunarizine(氟桂利嗪)Lamotrigine(拉莫三嗪)Topiramate(托吡酯，妥泰)newer38Principles1.Selectdrugaccordingtoepilepsyclassification2.Increasedosegradually3.Transitionaldrugchange:addaseconddrugbeforestopthefirstone4.Withdrawslowly(halfyear)5.Monitorhemogram(血象)andliverfunction6.Pregnantwomanshouldtakecaution39對癥選藥原則癲癇類型首選藥物大發作和局限性發作苯妥英鈉小發作乙琥胺大發作和精神運動型性發作卡馬西平癲癇持續狀態地西泮iv大發作合并小發作丙戊酸鈉40++++++++++41Principles1.對癥選藥2.劑量漸增3.先加后撤4.久用慢停5.肝功血象6.孕婦慎用42Section3Anticonvulsants

BarbituratesBenzodiazepinesChloralhydrateMagnesiumSulfate43MagnesiumSulfatedifferentadministrationroutes→differenteffects1.oral—catharsis,cholagogue(導瀉、利膽)2.external—dephlogisticate(消炎)3.ivorim—

anticonvulsive:relaxantofskeletalmuscle

BPlowering:inhibitcardiacmuscle,dilateVSM

Mechanism:calciumantagonismUses:

hypertensivecrisis,convulsion44MagnesiumSulfatetendonreflex（腱反射）Overdose:respiratoryinhibitionandhypotensionTreatment:artificialbreathingivcalciumchlorideorcalciumgluconate4546CasehistoryGabyisa22