人體結(jié)構(gòu)與功能 21-Sedative-hypnotics and anti-epileptic,anti-seizure drugs（2）學習資料

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(復合性局限性發(fā)作)Psychomotorseizures(精神運動性發(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?。?5

【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(jīng)纖維，引起突觸傳遞易化，使突觸后纖維反應(yīng)增強的現(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個月）服用抗癲癇藥物，另外239位則無。結(jié)果在這些服用抗癲癇藥物的懷孕婦女中，共產(chǎn)下28個嚴重畸形兒（3.8%），未服用抗癲癇藥物組產(chǎn)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(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對癥選藥原則癲癇類型首選藥物大發(fā)作和局限性發(fā)作苯妥英鈉小發(fā)作乙琥胺大發(fā)作和精神運動型性發(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