医学课件抗癫痫药_1

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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:,Epilepsy 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. Epilepsy can be caused b

2、y many neurological diseases, including infection, trauma, infarction and neoplasia. Heredity 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

3、 of discharge (primary),Common seizure types of Epilepsy:,Generalised seizures. Absence (petit mal). Tonic/clonic (grand mal). Partial seizures. Simple partial seizures. Complex partial seizures (temporal lobe epilepsy).,Generalised seizures:,Absence (petit mal): These seizures have abrupt onset and

4、 cessation, with impaired consciousness, but with normal posture often retained. The EEG shows a typical spike and wave pattern. Tonic/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 clonu

5、s and then by sleep. Injury may occur.,Partial seizures:,Simple partial seizures: features depend on the part of the brain affected, result from discharge in the precentral gyrus. Consciousness is unimpaired. Complex partial seizures (temporal lobe epilepsy): Consciousness is impaired with complex,

6、often repetitive, action.,The EEG in seizure of Epilepsy,3 Hz Paradoxical discharge,Spike wave,Epilepsy,Pathogenesis: The neuron in brain lesion depolarizes together suddenly, and then product high-frequency ,out-break discharge. The discharge can diffuse to surrounding normal tissue extensive excit

7、ation 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: Change the permeability of Na+, Ca2+and K+ in nerve cell membrane, d

8、egrade excitement stage, extend refractory phase. Directly or indirectly increase CNS levels of GABA.,The primary animal models used in anti-epileptic drugs research,Maximal electroshock seizure (MES ) model:screen the drugs which used in grand mal.,Pentetrazole (PTZ) induced convulsion model: scree

9、n the drugs which used in petit mal.,Kindling seizure model: screen the drugs which used in grand mal.,Spontaneously epileptic rat (SER) model: used in anti-epileptic 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

10、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,Hydantoins:Sodium Phenytoin Barbiturates:Phenobarbital, Primidone Succinimi

11、de:Ethosuximide Benzodiazepine: Diazepam, Nitrazepam Others: Sodium Valproate,Sodium Phenytoin (苯妥英钠),【Physiological disposition】 Sodium Phenytoin is absorbed slowly after oral administration.After 6-10 days, its plasma concentration can achieve effect levels. This drug has variable interpatient pla

12、sma 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 in

13、creasing of GABA receptor, thereby enhance GABA-mediated postsynaptic inhibition.,Sodium Phenytoin,【Pharmacologic properties and clinical application】 Anti-epileptic:It can be used for partial seizures and tonic/clonic seizures, but not for other generalised seizure types. Peripheral neuralgia:crani

14、al nerve, ischiadic nerve and cranial nerve. Arrhythmia : membrane-stabilizing action.,Sodium Phenytoin,Digestive system Gingival hyperplasia Nervous system Hematological system,Skeletal system Allergic response Others,【Adverse effects】,Sodium Phenytoin,【Adverse effects】 Digestive system: anorexia,

15、nausea, vomiting and abdominal pain (recommend to take it after meal). It may cause phlebitis after IV. Gingival 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

16、Phenytoin,【Adverse effects】 Nervous system: nystagmus, diplopia, vertigo, ataxia (usually only at very high concentration). Severe patient occurs language disorder, mental confusion and cataphora. Hematological 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,

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