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AntiepilepticandAnticonvulsiveDrugsLouhaiyanInstituteofPharmacologySchoolofMedicineShandongUniversitylouhaiyan@1Section1AntiepilepticDrugs
2Epilepsy(癲癇)3Aseizureistheclinicalmanifestationofasudden,excessiveandsynchronousdischargeoffocalneuronsanddiffusiontonormalneuronaltissues.Epilepsyischaracterizedby
recurrent,suddenandtransientseizures.Definitionofepilepsy
sensorydisorder,behaviordisorder,andpsychotic4Classificationsofseizuretypes1.Partialseizures(局限性發(fā)作)①Simplepartialseizures(單純性局限性發(fā)作)②Complexpartialseizures(復(fù)合性局限性發(fā)作)Psychomotorseizures(精神運(yùn)動(dòng)性發(fā)作)2.Generalizedseizures(全身性發(fā)作)①Absence(petitmal)seizures(失神性發(fā)作,小發(fā)作)②Myoclonicseizures(肌陣攣性發(fā)作)③Generalizedtonic-clonic(gradmal)seizures(強(qiáng)直-陣攣性發(fā)作,大發(fā)作)④Statusepilepticus
(癲癇持續(xù)狀態(tài))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(qiáng)直后增強(qiáng)):反復(fù)高頻電刺激(強(qiáng)直刺激)突觸前神經(jīng)纖維,引起突觸傳遞易化,使突觸后纖維反應(yīng)增強(qiáng)的現(xiàn)象16Membrane-stabilizingfunction1.
blockvoltage-sensitiveNa+channel2.
blockvoltage-sensitiveCa2+channel(Ltype,Ntype)
3.inhibittheactivityofcalmodulin
kinase
(鈣調(diào)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(qiáng)心苷中毒)-firstchoice2.Neuralgias:
trigeminalneuralgia(三叉神經(jīng)痛)glossopharyngealneuralgia(舌咽神經(jīng)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(xì)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(chǎn)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(gè)月)服用抗癲癇藥物,另外239位則無(wú)。結(jié)果在這些服用抗癲癇藥物的懷孕婦女中,共產(chǎn)下28個(gè)嚴(yán)重畸形兒(3.8%),未服用抗癲癇藥物組產(chǎn)下2個(gè)嚴(yán)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(zhuǎn)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(jìn)ADH分泌病因:下丘腦-神經(jīng)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(duì)癥選藥原則癲癇類(lèi)型首選藥物大發(fā)作和局限性發(fā)作苯妥英鈉小發(fā)作乙琥胺大發(fā)作和精神運(yùn)動(dòng)型性發(fā)作卡馬西平癲癇持續(xù)狀態(tài)地西泮iv大發(fā)作合并小發(fā)作丙戊酸鈉40++++++++++41Principles1.對(duì)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(dǎo)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
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