抗癫痫药 Antiepileptic Drugs

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

2. 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 by many neurological diseases, including infection, trauma, infarction and neoplasia. • Heredity has an important role (especially in the idiopathic generalised epilepsies).

3. Normal brain cell Abnormal high-frequency discharge Focus Inhibit discharge Drug action Stabilize membrane, inhibit the diffusion of discharge (primary)

4. 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).

5. Generalised seizures: • Absence (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. • 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 clonus and then by sleep. Injury may occur.

6. 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, often repetitive, action.

7. The EEG in seizure of Epilepsy Spike wave 3 Hz Paradoxical discharge

8. 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 excitation →the brain function transient aberration.

9. Normal brain cell Abnormal high-frequency discharge Focus Inhibit discharge Drug action Stabilize membrane, inhibit the diffusion of discharge (primary)

10. Epilepsy Therapeutic principle: • Change the permeability of Na+,Ca2+and K+ in nerve cell membrane, degrade excitement stage, extend refractory phase. • Directly or indirectly increase CNS levels of GABA.

11. 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5—7Hz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。 • Maximal electroshock seizure (MES )model： • screen the drugs which used in grand mal. The primaryanimal modelsused in anti-epileptic drugs research • Pentetrazole (PTZ) induced convulsion model: screen 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.

12. Classification of Antiepileptic Drugs • Hydantoins：SodiumPhenytoin • Barbiturates：Phenobarbital, Primidone • Succinimide：Ethosuximide • Benzodiazepine: Diazepam, Nitrazepam • Others: Sodium Valproate

13. 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 plasma concentration.

14. Sodium Phenytoin 【 Mechanism of action 】 ①It can block sodium channels (voltage-, frequency-, and time dependent fashion) and inhibit the generation of action potentials. ②It 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.

15. 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：cranial nerve, ischiadic nerve and cranial nerve. • Arrhythmia :membrane-stabilizing action.

16. Digestive system Gingival hyperplasia Nervous system Hematological system Skeletal system Allergic response Others Sodium Phenytoin 【Adverse effects】

17. Sodium Phenytoin 【Adverse effects】 • Digestive system: anorexia, 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.

18. 【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

19. Sodium Phenytoin 【Adverse effects】 • Skeletal 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). • Allergic response:rash, thrombocytopenia, agranulocytosis and aplastic anemia. • Others:rarely appear male barymastia, femalehirsutism and lymphadenectasis.

20. Phenobarbital (苯巴比妥) 【 Mechanism of action 】 • Phenobarbital can inhibit the paradoxical discharge of epilepsy focus selectively, enhance stimulation of surrounding tissues and block discharge diffuse to normal tissues. • Phenobarbital facilitate GABA-mediated inhibition of neuronal activity.

21. Phenobarbital 【Pharmacologic properties 】 • Phenobarbital can be used for all types of epilepsy. The effects by turns are: grand mal and status epileptics＞local psychomotor seizure＞petit mal. • Take effect rapidly（1～2 hr), the first choice of grand mal. • Prevent convulsive and eliminate precursory symptom.

22. Phenobarbital 【Adverse effects】 • Somnolence、depression. • Tolerance develops after long-term treatment.

23. Primidone(去氧苯比妥) Primidone(扑米酮) 【Pharmacologic 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. It’s 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.

24. Primidone (Primidone) 【Adverse effects】 • Common: somnolence, vertigo, nausea and vomiting. • Rare:megaloblastic anemia, leucopenia and thrombocytopenia.

25. Ethosuximide (乙琥胺 ) • Petit mal (first choice), useless to other types of seizure. 【 Common adverse effect 】 • Gastrointestinal tract: anorexia, nausea, vomiting. • CNS: headache, dizziness and somnolence. • Rarely appear agranulemia and aplastic anemia.

26. Diazepem(安定) & Nitrazepem(硝基安定) Diazepem : • Diazepem is indicated for status epilepticus. Nitrazepem : • It’s highly effective in controlling petit mal and myoclonus epilepsy. • Sudden withdrawal of nitrazepem is likely to aggravate seizure and induced symptom.

27. Sodium Valproate (丙戊酸钠 ) 【Pharmacologic properties 】 Enhance the enzymatic activity of glutamate decarboxylase.→GABA↑ Inhibit GABA reuptake and synapse inactivation→synapse frontal membrane GABA↑→ enhance GABA postsynaptic inhibition Broad spectrum antiepileptic drug, use to all types of epilepsy. CNS:somnolence, disequilibrium, acratia and tremor. Hepatic lesion (20% patients). Gastrointestinal tract: nausea, vomiting and anorexia.

28. Carbamzepine (卡马西平) 【Pharmacologic properties 】 • Carbamazepine can block sodium channel, inhibit paradoxical discharge and discharge diffusion. It may relate to the postsynaptic inhibition of GABA. • Broad spectrum antiepileptic drug, use to all types of epilepsy. • Trigeminal neuralgia (therapeutic effect is good). • Antidiuresis－diabetes insipidus.

29. Carbamzepine 【Adverse effects】 • CNS:somnolence, disequilibrium • Gastrointestinal tract: nausea, vomiting and anorexia. • Rash，leucopenia ，thrombocytopenia，aplastic anemia and hepatic lesion.

30. Principle of Medication • 1～2 times/year，no drugs are needed • Grand pit (first choice): Sodium phenytoin or phenobarbital, carbamzepine, Primidone. • Petit mal (first choice): Ethosuximide, clonazepam and sodium valproate. • Status epilepticus:Diazepam or sodium phenytoin (IV), phenobarbital, diazepam, clonazepam. • Psychomotor: Sodium phenytoin or combine with desoxybarbital or carbamazepine.

31. Principle of Medication (I) • The dose can be gradually increased from a low starting dose until reach the best effect. • In the initial stage, the patients should only be treated with a single antiepileptic drug, if the drug is useless, then it can be changed. When drug changing is necessary, it should be gradually withdrawn after the effect of new drug occurs. • After the symptom is fully controlled, the patients should continuing be treated for 2 or 3 years. Sudden withdrawal of drugs are likely to precipitate relapse.

32. Principle of Medication (II) • Enhance therapeutic effect: dosing individually, monitoring drug plasma concentration, examining regularly. • Evaluating efficacy and safety. • Adjusting drug dosage: the therapeutic index of antiepileptic drug is low→easy to be poisoning Therapeutic dose is get close to toxic dose.

33. Anticonvulsant Drugs • Convulsions are involuntary skeletal muscular contractions. Convulsions can arise from pathological processes within or outside the brain, toxins, drug overdose, or withdrawal from drug dependence. • Commonly used anticonvulsant drugs are sedative and hypnotic drugs. Magnesium Sulfate is also used on this disease.

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