医学课件抗癫痫药_1

抗癫痫药 Antiepileptic Drugs 北京协和医学院基础医学院药理学系 叶菜英 Definitions in epilepsy: nEpilepsy comprises recurrent episodes of abnormal cerebral neuronal discharge. The resulting seizures are usually clinically obvious and vary in pattern according to which parts of the brain are affected. nEpilepsy can be caused by many neurological diseases, including infection, trauma, infarction and neoplasia. nHeredity has an important role (especially in the idiopathic generalised epilepsies). Normal brain cell Abnormal high- frequency discharge Focus Drug action Inhibit discharge Stabilize membrane, inhibit the diffusion of discharge (primary) Common seizure types of Epilepsy: nGeneralised seizures. nAbsence (petit mal). nTonic/clonic (grand mal). nPartial seizures. nSimple partial seizures. nComplex partial seizures (temporal lobe epilepsy). Generalised seizures: nAbsence (petit mal): These seizures have abrupt onset and cessation, with impaired consciousness, but with normal posture often retained. The EEG shows a typical spike and wave pattern. nTonic/clonic (grand mal): Consciousness is impaired and the patient usually falls to the floor. A phase of muscle contraction (tonic) is followed by irregular muscle clonus and then by sleep. Injury may occur. Partial seizures: nSimple partial seizures: features depend on the part of the brain affected, result from discharge in the precentral gyrus. Consciousness is unimpaired. nComplex partial seizures (temporal lobe epilepsy): Consciousness is impaired with complex, often repetitive, action. The EEG in seizure of Epilepsy 3 Hz Paradoxical discharge Spike wave Epilepsy Pathogenesis: nThe neuron in brain lesion depolarizes together suddenly, and then product high- frequency ,out-break discharge. The discharge can diffuse to surrounding normal tissue extensive excitation the brain function transient aberration. Normal brain cell Abnormal high- frequency discharge Focus Drug action Inhibit discharge Stabilize membrane, inhibit the diffusion of discharge (primary) Epilepsy Therapeutic principle: nChange the permeability of Na+, Ca2+and K+ in nerve cell membrane, degrade excitement stage, extend refractory phase. nDirectly or indirectly increase CNS levels of GABA. The The primaryprimary animal animal modelsmodels used used in in anti-anti-epileptic drugs research drugs research Maximal electroshock seizure (MES )Maximal electroshock seizure (MES ) modelmodel：screen the screen the drugs which used in drugs which used in grand mal. PentetrazolePentetrazole (PTZ) induced (PTZ) induced convulsion model: screen screen the drugs which used in the drugs which used in petit mal. Kindling seizure model:Kindling seizure model: screen the drugs which used in screen the drugs which used in grand mal. Spontaneously 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 Drugs nHydantoins：Sodium Phenytoin nBarbiturates：Phenobarbital, Primidone nSuccinimide：Ethosuximide nBenzodiazepine: Diazepam, Nitrazepam nOthers: Sodium Valproate Sodium Phenytoin (苯妥英钠) 【Physiological disposition】 nSodium Phenytoin is absorbed slowly after oral administration.After 6-10 days, its plasma concentration can achieve effect levels. This drug has variable interpatient plasma concentration. Sodium Phenytoin Mechanism of action: It can block sodium channels (voltage- ,frequency-,and time dependent fashion) and inhibit the generation of action potentials. It can increase the function of inhibitory transmitter GABA, inhibit nerve terminal to uptake GABA and induce the increasing of GABA receptor, thereby enhance GABA- mediated postsynaptic inhibition. Sodium Phenytoin 【Pharmacologic properties and clinical application】 nAnti-epileptic：It can be used for partial seizures and tonic/clonic seizures, but not for other generalised seizure types. nPeripheral neuralgia：cranial nerve, ischiadic nerve and cranial nerve. nArrhythmia : membrane-stabilizing action. Sodium Phenytoin nDigestive system nGingival hyperplasia nNervous system nHematological system nSkeletal system nAllergic response nOthers 【Adverse effects】 Sodium Phenytoin 【Adverse effects】 nDigestive system: anorexia, nausea, vomiting and abdominal pain (recommend to take it after meal). It may cause phlebitis after IV. nGingival hyperplasia: It common occurs in children and teenagers after long term use, the incidence rate is about 20%. Generally, this effect can resolve after drug withdraw 3 to 6 months. Sodium Phenytoin 【Adverse effects】 nNervous system: nystagmus, diplopia, vertigo, ataxia (usually only at very high concentration). Severe patient occurs language disorder, mental confusion and cataphora. nHematological system: Because it can inhibit the absorption of folinic acid and accelerate its metabolism. This drug also can inhibit folic acid reductase. So it may cause megaloblastic anemia after long-term use (recommend to pretreat with folinic acid). Sodium Phenytoin 【Adverse effects】 nSkeletal system: It can enhance vitamin D metabolism, so Phenytoin may increase the risk of hypocalcemia, rickets and osteomalacia after long-term treatment(pretreat with vitamin D if necessary). nAllergic response: rash, thrombocytopenia , agranulocytosis and aplastic anemia. nOthers: rarely appear male barymastia, female hirsutism and lymphadenectasis. Phenobarbital (苯巴比妥) Mechanism of action: nPhenobarbital can inhibit the paradoxical discharge of epilepsy focus selectively, enhance stimulation of surrounding tissues and block discharge diffuse to normal tissues. nPhenobarbital facilitate GABA-mediated inhibition of neuronal activity. Phenobarbital Pharmacologic properties: nPhenobarbital can be used for all types of epilepsy. The effects by turns are: grand mal and status epilepticslocal psychomotor seizurepetit mal. nTake effect rapidly（12 hr), the first choice of grand mal. nPrevent convulsive and eliminate precursory symptom. Phenobarbital 【Adverse effects】 nSomnolence、depression. nTolerance develops after long-term treatment. Primidone(去氧苯比妥) Primidone(扑米酮) nPharmacologic properties: Absorption after oral administration is rapid, and the plasma peak concentration is approximately 3 hours at therapeutic doses. It can be used for all types of epilepsy except petit mal. Its better to use this drug with sodium phenytoin. With regard to grand mal, the effect of primidone is better than phenobarbital,this drug is useless to petit mal. Primidone (Primidone) 【Adverse effects】 nCommon: somnolence, vertigo, nausea and vomiting. n Rare: megaloblastic anemia, leucopenia and thrombocytopenia. Ethosuximide (乙琥胺 ) nPetit mal (first choice), useless to other types of seizure. Common adverse effect nGastrointestinal tract: anorexia, nausea, vomiting. nCNS: headache, dizziness and somnolence. nRarely appear agranulemia and aplastic anemia. Diazepem(安定) & Nitrazepem(硝基安定) Diazepem ： nDiazepem is indicated for status epilepticus. Nitrazepem : nIts highly effective in controlling petit mal and myoclonus epilepsy. nSudden withdrawal of nitrazepem is likely to aggravate seizure and induced symptom. Sodium Valproate (丙戊酸钠 ) Pharmacologic properties: nEnhance the enzymatic activity of glutamate decarboxylase.GABA nInhibit GABA reuptake and synapse inactivationsynapse frontal membrane GABA enhance GABA postsynaptic inhibition nBroad spectrum antiepileptic drug, use to all types of epilepsy. nCNS: somnolence, disequilibrium, acratia and tremor. nHepatic lesion (20% patients). nGastrointestinal tract: nausea, vomiting and anorexia. Carbamzepine (卡马西平) Pharmacologic properties: nCarbamazepine can block sodium channel, inhibit paradoxical discharge and discharge diffusion. It may relate to the postsynaptic inhibition of GABA. nBroad spectrum antiepileptic drug, use to all types of epilepsy. nTrigeminal neuralgia (therapeutic effect is good). nAntidiuresisdiabetes insipidus. Carbamzepine 【Adverse effects】 nCNS: somnolence, disequilibrium nGastrointestinal tract: nausea, vomiting and anorexia. nRash，leucopenia ，thrombocytopenia， aplastic anemia and hepatic lesion. Principle of Medication n12 times/year，no drugs are needed nGrand pit (first choice): Sodium phenytoin or phenobarbital, carbamzepine, Primidone. nPetit mal (first choice): Ethosuximide, clonazepam and sodium valproate. nStatus epilepticus:Diazepam or sodium phenytoin (IV), phenobarbital, diazepam, clonazepam. nPsychomotor: Sodium phenytoin or combine with desoxybarbital or carbamazepine. Principle of Medication (I) nThe dose can be gradually increased from a low starting dose until reach the best effect. nIn the initial stage, the patients should only be treated with