抗癫痫药AntiepilepticDrugs.ppt

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1、抗癫痫药AntiepilepticDrugs Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望Definitions in epilepsy:Definitions in epilepsy:nEpilepsy Epilepsy comprises comprises recurrent recurrent episodes episodes of of abnormal abnormal cerebral cerebral neuronal neuronal dis

2、charge.discharge.The The resulting resulting seizures seizures are are usually usually clinically clinically obvious obvious and and vary vary in in pattern pattern according according to to which which parts parts of of the brain are affected.the brain are affected.nEpilepsy Epilepsy can can be be

3、caused caused by by many many neurological neurological diseases,diseases,including including infection,infection,trauma,trauma,infarction infarction and neoplasia.and neoplasia.nHeredity Heredity has has an an important important role role(especially(especially in in the idiopathic generalised epil

4、epsies).the idiopathic generalised epilepsies).Normal brain cellNormal brain cellAbnormal high-Abnormal high-frequency frequency dischargedischargeFocusFocusDrug actionDrug actionInhibit dischargeInhibit dischargeStabilize membrane,inhibit the Stabilize membrane,inhibit the diffusion of discharge(pr

5、imary)diffusion of discharge(primary)Common seizure types of Common seizure types of Epilepsy:Epilepsy:nGeneralised seizures.Generalised seizures.nAbsence(petit mal).Absence(petit mal).nTonic/clonic(grand mal).Tonic/clonic(grand mal).nPartial seizures.Partial seizures.nSimple partial seizures.Simple

6、 partial seizures.nComplex Complex partial partial seizures seizures(temporal(temporal lobe epilepsy).lobe epilepsy).Generalised seizures:Generalised seizures:nAbsence Absence(petit(petit mal):mal):These These seizures seizures have have abrupt abrupt onset onset and and cessation,cessation,with wit

7、h impaired impaired consciousness,consciousness,but but with with normal normal posture posture often often retained.retained.The The EEG EEG shows shows a a typical typical spike spike and wave pattern.and wave pattern.nTonic/clonic Tonic/clonic(grand(grand mal):mal):Consciousness Consciousness is

8、is impaired impaired and and the the patient patient usually usually falls falls to to the the floor.floor.A A phase phase of of muscle muscle contraction contraction(tonic)(tonic)is is followed followed by by irregular irregular muscle muscle clonus and then by sleep.Injury may occur.clonus and the

9、n by sleep.Injury may occur.Partial seizures:Partial seizures:nSimple Simple partial partial seizures:seizures:features features depend depend on on the the part part of of the the brain brain affected,affected,result result from from discharge discharge in in the the precentral precentral gyrus.gyr

10、us.Consciousness is unimpaired.Consciousness is unimpaired.nComplex Complex partial partial seizures seizures(temporal(temporal lobe lobe epilepsy):epilepsy):Consciousness Consciousness is is impaired impaired with with complex,often repetitive,plex,often repetitive,action.The EEG in The EEG in seiz

11、ure of Epilepsyseizure of Epilepsy 3 Hz Paradoxical discharge3 Hz Paradoxical dischargeSpike waveSpike waveEpilepsyEpilepsy Pathogenesis:nThe The neuron neuron in in brain brain lesion lesion depolarizes depolarizes together together suddenly,suddenly,and and then then product product high-high-freq

12、uency frequency,out-break,out-break discharge.discharge.The The discharge discharge can can diffuse diffuse to to surrounding surrounding normal normal tissue tissue extensive extensive excitation excitation the the brain brain function function transient aberration.transient aberration.Normal brain

13、 cellNormal brain cellAbnormal high-Abnormal high-frequency frequency dischargedischargeFocusFocusDrug actionDrug actionInhibit dischargeInhibit dischargeStabilize membrane,inhibit the Stabilize membrane,inhibit the diffusion of discharge(primary)diffusion of discharge(primary)EpilepsyEpilepsyTherap

14、eutic principle:nChange the permeability of NaChange the permeability of Na+,CaCa2+2+and and K K+in nerve cell membrane,degrade in nerve cell membrane,degrade excitement stage,extend refractory excitement stage,extend refractory phase.phase.nDirectly or indirectly increase CNS levels Directly or ind

15、irectly increase CNS levels of GABA.of GABA.The The primaryprimary animal animal modelsmodels used used in in anti-anti-epilepticepileptic drugs research drugs researchMaximal electroshock seizure(MES)Maximal electroshock seizure(MES)Maximal electroshock seizure(MES)Maximal electroshock seizure(MES)

16、modelmodelmodelmodel：screen the screen the screen the screen the drugs which used in drugs which used in drugs which used in drugs which used in grand mal.grand mal.Pentetrazole(PTZ)induced Pentetrazole(PTZ)induced Pentetrazole(PTZ)induced Pentetrazole(PTZ)induced convulsion model:convulsion model:s

17、creen screen screen screen the drugs which used in the drugs which used in the drugs which used in the drugs which used in petit mal.petit mal.Kindling seizure model:Kindling seizure model:Kindling seizure model:Kindling seizure model:screen the drugs which used in screen the drugs which used in gra

18、nd mal.S Spontaneously epileptic rat(SER)modelpontaneously epileptic rat(SER)model：used in anti-used in anti-epileptic drugs research.drugs research.memo:将震颤大鼠与Zitter基因变异大鼠交配，于1986年培育出SER鼠。它也具有震颤，脑海绵状变性等特点。是tm基因与Zitter（zi）基因共同突变的结果。除了具有TRM大鼠的重度失神发作之外，SER鼠还表现为高频率的强直性自发痉挛。在SER鼠的大脑皮质及海马用慢性记录电极作自发的脑电波检查

19、发现，当SER失神发作时，出现与TRM鼠同样的57Hz的多波峰波群放电；在其出现强直性痉挛时，出现两个部位一致的低振幅快速波。中枢神经系统病理检查结果显示，SER除具有TRM鼠的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。Classification of Antiepileptic DrugsClassification of Antiepileptic DrugsnHydantoinsHydantoins：SodiumSodium PhenytoinPhenytoinnBarbituratesBarbitura

20、tes：Phenobarbital,PrimidonePhenobarbital,PrimidonenSuccinimideSuccinimide：EthosuximideEthosuximidenBenzodiazepine:Benzodiazepine:Diazepam,NitrazepamDiazepam,NitrazepamnOthers:Others:Sodium ValproateSodium ValproateSodium Phenytoin(Sodium Phenytoin(苯妥英钠苯妥英钠)【Physiological dispositionPhysiological dis

21、position】nSodium Phenytoin is absorbed slowly Sodium Phenytoin is absorbed slowly after oral administration.After 6-10 after oral administration.After 6-10 days,its plasma concentration can days,its plasma concentration can achieve effect levels.This drug has achieve effect levels.This drug has vari

22、able interpatient plasma variable interpatient plasma concentration.concentration.Sodium Phenytoin Sodium PhenytoinMechanism of action:Mechanism of action:It can block sodium channels(voltage-It can block sodium channels(voltage-,frequency-,and time dependent fashion)and,frequency-,and time dependen

23、t fashion)and inhibit the generation of action potentials.inhibit the generation of action potentials.It can increase the function of inhibitory It can increase the function of inhibitory transmitter GABA,inhibit nerve terminal to transmitter GABA,inhibit nerve terminal to uptake GABA and induce the

24、 increasing of uptake GABA and induce the increasing of GABA receptor,thereby enhance GABA-GABA receptor,thereby enhance GABA-mediated postsynaptic inhibition.mediated postsynaptic inhibition.Sodium PhenytoinSodium Phenytoin【Pharmacologic properties and clinical Pharmacologic properties and clinical

25、 applicationapplication】nAnti-epilepticAnti-epileptic：It can be used for partial It can be used for partial seizures and tonic/clonic seizures,but not for seizures and tonic/clonic seizures,but not for other generalised seizure types.other generalised seizure types.nPeripheral neuralgiaPeripheral ne

26、uralgia：cranial nerve,ischiadic cranial nerve,ischiadic nerve and cranial nerve.nerve and cranial nerve.nArrhythmia:Arrhythmia:membrane-stabilizing action.membrane-stabilizing action.Sodium PhenytoinSodium PhenytoinnDigestive system Digestive system nGingival hyperplasiaGingival hyperplasianNervous

27、systemNervous systemnHematological systemHematological systemnSkeletal systemSkeletal systemnAllergic responseAllergic responsenOthersOthers【Adverse effectsAdverse effects】Sodium PhenytoinSodium Phenytoin【Adverse effects】nDigestive system:Digestive system:anorexia,nausea,vomiting and anorexia,nausea

28、,vomiting and abdominal pain(recommend to take it after meal).abdominal pain(recommend to take it after meal).It may cause phlebitis after IV.It may cause phlebitis after IV.nGingival hyperplasia:Gingival hyperplasia:It common occurs in It common occurs in children and teenagers after long term use,

29、the children and teenagers after long term use,the incidence rate is about 20%.Generally,this effect incidence rate is about 20%.Generally,this effect can resolve after drug withdraw 3 to 6 months.can resolve after drug withdraw 3 to 6 months.Sodium PhenytoinSodium Phenytoin【Adverse effects】nNervous

30、 system:Nervous system:nystagmus,diplopia,vertigo,nystagmus,diplopia,vertigo,ataxia(usually only at very high ataxia(usually only at very high concentration).Severe patient occurs language concentration).Severe patient occurs language disorder,mental confusion and cataphora.disorder,mental confusion

31、 and cataphora.nHematological Hematological system:system:Because Because it it can can inhibit inhibit the the absorption absorption of of folinic folinic acid acid and and accelerate accelerate its its metabolism.metabolism.This This drug drug also also can can inhibit inhibit folic folic acid aci

32、d reductase.reductase.So So it it may may cause cause megaloblastic megaloblastic anemia anemia after after long-term long-term use use(recommend(recommend to to pretreat with folinic acid).pretreat with folinic acid).Sodium PhenytoinSodium Phenytoin【Adverse effects】nSkeletal system:Skeletal system:

33、It can enhance vitamin D It can enhance vitamin D metabolism,so Phenytoin may increase the risk metabolism,so Phenytoin may increase the risk of hypocalcemia,rickets and osteomalacia after of hypocalcemia,rickets and osteomalacia after long-term treatment(pretreat with vitamin D if long-term treatme

34、nt(pretreat with vitamin D if necessary).necessary).nAllergic response:Allergic response:rash,rash,thrombocytopenia thrombocytopenia,agranulocytosis and aplastic anemia.,agranulocytosis and aplastic anemia.nOthers:Others:rarely appear rarely appear male male barymastia,female barymastia,female hirsu

35、tism and lymphadenectasis.hirsutism and lymphadenectasis.Phenobarbital(Phenobarbital(苯巴比妥苯巴比妥)Mechanism of action:Mechanism of action:nPhenobarbital Phenobarbital can can inhibit inhibit the the paradoxical paradoxical discharge discharge of of epilepsy epilepsy focus focus selectively,selectively,e

36、nhance enhance stimulation stimulation of of surrounding surrounding tissues tissues and and block block discharge discharge diffuse diffuse to to normal tissues.normal tissues.nPhenobarbital facilitate GABA-mediated inhibition of Phenobarbital facilitate GABA-mediated inhibition of neuronal activit

37、y.neuronal activity.PhenobarbitalPhenobarbitalPharmacologic properties:Pharmacologic properties:nPhenobarbital can be used for all types of Phenobarbital can be used for all types of epilepsy.The effects by turns are:grand epilepsy.The effects by turns are:grand mal and status epilepticsmal and stat

38、us epilepticslocal local psychomotor seizurepsychomotor seizurepetit mal.petit mal.nTake effect rapidlyTake effect rapidly（1 12 hr),the first 2 hr),the first choice of grand mal.choice of grand mal.nPrevent convulsive and eliminate Prevent convulsive and eliminate precursory symptom.precursory sympt

39、om.PhenobarbitalPhenobarbital【Adverse effects】nSomnolenceSomnolence、depression.depression.nTolerance develops after long-term Tolerance develops after long-term treatment.treatment.Primidone(Primidone(去氧苯比妥去氧苯比妥)Primidone(Primidone(扑米酮扑米酮)nPharmacologic properties:Pharmacologic properties:Absorption

40、 Absorption after after oral oral administration administration is is rapid,rapid,and and the the plasma plasma peak peak concentration concentration is is approximately approximately 3 3 hours hours at at therapeutic therapeutic doses.doses.It It can can be be used used for for all all types types

41、of of epilepsy epilepsy except except petit petit mal.mal.Its Its better better to to use use this this drug drug with with sodium sodium phenytoin.phenytoin.With With regard regard to to grand grand mal,mal,the the effect effect of of primidone primidone is is better better than than phenobarbital,

42、this phenobarbital,this drug is useless to petit mal.drug is useless to petit mal.Primidone(Primidone(Primidone)Primidone)【Adverse effects】nCommon:Common:somnolence,vertigo,nausea somnolence,vertigo,nausea and vomiting.and vomiting.n Rare:Rare:megaloblastic anemia,leucopenia megaloblastic anemia,leu

43、copenia and thrombocytopenia.and thrombocytopenia.Ethosuximide(Ethosuximide(乙琥胺乙琥胺)nPetit Petit mal mal(first(first choice),choice),useless useless to to other other types types of of seizure.seizure.Common adverse effect Common adverse effectnGastrointestinal tract:Gastrointestinal tract:anorexia,n

44、ausea,anorexia,nausea,vomiting.vomiting.nCNS:CNS:headache,headache,dizziness and somnolence.dizziness and somnolence.nRarely appear Rarely appear agranulemia and aplastic agranulemia and aplastic anemia.anemia.Diazepem(Diazepem(安定安定)&)&Nitrazepem(Nitrazepem(硝基安定硝基安定)DiazepemDiazepem：nDiazepem is ind

45、icated for status epilepticus.Diazepem is indicated for status epilepticus.NitrazepemNitrazepem:nIts Its highly highly effective effective in in controlling controlling petit petit mal mal and myoclonus epilepsy.and myoclonus epilepsy.nSudden Sudden withdrawal withdrawal of of nitrazepem nitrazepem

46、is is likely likely to to aggravate seizure and induced symptom.aggravate seizure and induced symptom.Sodium Valproate(丙戊酸钠丙戊酸钠)Pharmacologic propertiesPharmacologic properties:nEnhance Enhance the the enzymatic enzymatic activity activity of of glutamate glutamate decarboxylase.GABAdecarboxylase.GA

47、BAnInhibit Inhibit GABA GABA reuptake reuptake and and synapse synapse inactivationsynapse inactivationsynapse frontal frontal membrane membrane GABA GABA enhance enhance GABA GABA postsynaptic postsynaptic inhibitioninhibitionnBroad Broad spectrum spectrum antiepileptic antiepileptic drug,drug,use

48、use to to all all types types of of epilepsy.epilepsy.nCNS:CNS:somnolence,disequilibrium,acratia and tremor.somnolence,disequilibrium,acratia and tremor.nHepatic lesionHepatic lesion(20%patients).(20%patients).nGastrointestinal tract:Gastrointestinal tract:nausea,vomiting and anorexia.nausea,vomitin

49、g and anorexia.Carbamzepine(Carbamzepine(卡马西平卡马西平)Pharmacologic propertiesPharmacologic properties:nCarbamazepine can block sodium channel,inhibit paradoxical discharge and discharge diffusion.It may relate to the postsynaptic inhibition of GABA.postsynaptic inhibition of GABA.nBroad Broad spectrum

50、spectrum antiepileptic antiepileptic drug,drug,use use to to all all types types of epilepsy.of epilepsy.nTrigeminal neuralgia(therapeutic effect is good).nAntidiuresisdiabetes insipidus.Carbamzepine Carbamzepine【Adverse effectsAdverse effects】nCNS:CNS:somnolence,disequilibrium somnolence,disequilib