1. Antiepileptic and Anticonvulsant Drugs Zhong Chen Department of Pharmacology chenzhong@zju.edu.cn 2012.5.14

2. Objectives • * To review the classification of seizures • * To discuss potential targets of antiepileptic drugs. • To present an evidence-based review of the major antiepileptic drugs. 掌握苯妥英钠的药理作用，临床应用，不良反应及药物相互作用；熟悉苯巴比妥、乙琥胺、卡马西平、丙戊酸钠、硫酸镁的临床应用；了解其他抗癫痫和抗惊厥的药物。

3. Local excitatory  发病率高； 突发性，不可预测； 很难根治，常需终身服药 Abnormal high frequency discharging Abnormal spreading Brain malfunction Accompanied with abnormal EEG

4. Classification of epilepsy

5. International Classification of Epileptic Seizures:Partial Onset Seizures（局限性发作） • Simple Partial（单纯局限性） • Complex Partial （复合性局限性） • Partial Seizures with secondary generalization （局限性发作继发全身强直阵挛性发作） • Partial seizures with dyscognitive features • Partial seizures without dyscognitive features

6. International Classification of Epileptic Seizures: Primary Generalized Seizures • Absence (Petit Mal) （失神性发作/小发作） • Myoclonic （肌阵挛性发作） • Generalized Tonic+Clonic （全身强直阵挛性发作） http://www.uwo.ca/cns/resident/pocketbook/pictures/3-hz-s-w.jpg

7. The pathways for seizure propagation in partial seizures and primary generalized seizures

8. 病因论 • Underlying causes: 遗传 • Birth trauma 外伤 • Head injury 脑损伤 • Tumour 肿瘤 • Infection 感染 • Metabolic disorder 代谢性病症 • Cerebrovascular accident 脑血管意外 • Deteriorating brain disease 其它脑疾病恶化

9. CAUSES OF CONGENITAL EPILEPSY （先天性的） • DYSGENESIS (生殖障碍，FAILURE OF CORTEX TO GROW PROPERLY) • VASCULAR MALFORMATIONS（畸形） • AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE ASSOCIATED WITH EPILEPSY. MOST FORMS INVOLVE INHERITING MORE THAN ONE LOCUS. (EXAMPLES: JUVENILE MYOCLONIC, PETIT MAL)

10. 诱发的危险因素 • Alcoholism酒精中毒. • Withdrawal from alcohol (“hang-over period”)酒精戒断症. • Physical debilitation (illness, lack of sleep, exhaustion).过度疲劳 • Emotional stress情绪应激 • Watching visual flicker闪烁的视觉障碍 • Unknown aetiology.一些未知因素

11. Origin of a surface epileptic discharge • EEG • Populations of neurons (field potentials) • Individual neurons • Individual synapses • Individual ion channels on individual neurons

12. Surface Spike • Seizures are generated by groups of neurons which depolarizing synchronously • Epileptic neurons generate Paroxysmal Depolarizing Shift (PDS) • During a PDS, there is the repetitive activation of key ion channels. • These ion channels represent opportunities to prevent or terminate seizures. PDS Sodium Influx Calcium Influx Chloride Influx K efflux

13. Imbalance of excitation and inhibitory Na+、Ca2+、NMDA、K+ 、Cl-、GABA Antiepileptic drugs Focus formation and epileptic attack Focus shift Spreading Refractory epilepsy

14. Mechanisms of antiepileptic drugs • Electrophysiological • Inhibiting excessive discharges • Inhibiting spread of discharges • Molecular • Potentiating GABA neuronal functions • Inhibiting excitatory neuronal functions（NMDA） • Modulating Na+, Ca2+, K+, Cl- channel fuctions • Others???

15. 现有抗癫痫药物作用靶点 Bialer M et al., Nature Review, 2010

16. 抗癫痫药物发展历程 第一代 第二代 第三代 溴化物、硼砂 正在研发的新型抗癫痫药 最终目标 预防及治愈癫痫 Shorvon SD et al., Epilepsia, 2009

17. 抗癫痫药物的分类 • 按化学结构分类： • 巴比妥类（苯巴比妥） • 乙内酰脲类（苯妥英钠） • 丁二酰亚胺类（乙琥胺） • 苯二氮卓类（地西泮） • 二苯并氮杂卓类（卡马西平、奥卡西平） • 脂肪羧酸类（丙戊酸钠） • 氨基酸类（加巴喷丁） • 新型AEDs（拉莫三嗪、托吡酯、LEV等）

18. A.Antiepileptic drugs www.boomer.org/c/p4/c21/c2103.html Phenytoin* • Blocks sodium channels • Effective against partial seizures and generalized tonic-clonic seizures • Non-linear kinetics • Half life = 24 hours • Therapeutic range = 10-20 ug/ml • Levels above 20 cause ataxia and nystagmus • Hepatic metabolism • CYP3A enzyme pathway • CYP3A antagonists will raise phenytoin levels 20ug/ml Oral Dose: about 5 mg / kg

19. A.Antiepileptic drugs 1. Pharmacological effects and the mechanism (1) Effects — Inhibiting spread ofabnormal discharges — Not on the happening of abnormal discharge — Inhibit Na+ and Ca2+ influx

20. A.Antiepileptic drugs 1. Pharmacological effects and the mechanism (2) Mechanism — blocking Na+ channel in inactive state — Inhibiting L- and N-type Ca2+ channel (but not T-type Ca2+ channel ) —  Calmodulin  neurotransmitter release (NE, 5-HT, DA etc.) — block posttetanic potentiation (PTP) formation

22. A.Antiepileptic drugs 2. Clinical uses (1) Antiepilepsy • Grand mal, status epilepticus; • Partial seizures (simple and complex); • Ineffective for petit mal (absence seizures) (2) Trigeminal and related neuralgia • sciatica (坐骨神经痛), glossopharyngeal neuralgia (舌咽神经痛) (3) Antiarrhythmia

23. A.Antiepileptic drugs 3. ADME • Non-linear kinetics • Half life = 24 hours • Therapeutic range = 10-20 ug/ml • Levels above 20 cause ataxia and nystagmus • Hepatic metabolism • CYP3A enzyme pathway • CYP3A antagonists will raise phenytoin levels Initially linear Psuedo first order

25. A.Antiepileptic drugs 4. Adverse effects (1) Local reactions • GI reactions; gingival hyperplasia（齿龈增生） (2) CNS reactions • Particularly in the cerebellum and vestibular systems（小脑前庭系统） : nystagmus (眼球震颤), ataxia (共济失调), etc. • Behavioral changes: confusion, hallucination, coma (3) Hemological reactions • Megaloblastic anemia (affect the metabolism of folic acid) （巨幼红细胞性贫血）

26. A.Antiepileptic drugs (4) Allergic reactions • Skin reactions; blood cell abnormality (including thrombocytopenia, agranulocytosis); • hepatic toxicity; ect. (5) Skeletal reactions • Osteomalacia by increase vitamin D metabolism and calcium absorption (inducer) (6) Others • Birth defects, hirsutism, etc Hirsutism(多毛)

27. A.Antiepileptic drugs 5. Drug interactions（蛋白结合、代谢） (1) Increases plasma concentrations of drugs by displacement of plasma protein binding (salicylates) (2) Drug metabolizing enzyme inhibitor decrease the metabolism of phenytoin (isoniazid异烟肼, chloramphenicol氯霉素) (3) Drug metabolizing enzyme inducer increase the metabolism of phenytoin (phenobarbital, carbamazepine) (4) Phenytoin enhances the metabolism of corticosteroids and vitamin D

28. A.Antiepileptic drugs Drugs acting at the chloride channel Benzodiazepines • Binds to specific receptors Phenobarbital • Binds to barbiturate specific receptor Valproate • Decreases GABA degradation in presynaptic terminal

29. A.Antiepileptic drugs Phenobarbital 苯巴比妥 • Sedative and hypnotic effect. • Inhibiting both formation and spread of discharges. • Cl- influx and  Ca2+ influx • Effective for grand mal , status epilepticus, partial simple seizures.

30. A.Antiepileptic drugs Ethosuximide 乙琥胺 • Block T-type Ca2+ channel • Block Na+-K+ ATPase • Inhibit cerebral metabolism and GABA transaminase • Effective forpeptit mal • Combined with phenobarbital

31. A.Antiepileptic drugs Valproate sodium 丙戊酸钠 • Broad spectrum • Inhibiting both spread of discharges but not formation • Increases GABA levels inhibits degradation of GABA in presynaptic terminal • Inhibit Na+ and L-type Ca2+ • Enhance K+ ? • GI side effects • Tremor • Hepatitis • Pancreatitis • Serious neural tube and cardiac defects in fetus in 1%

32. During and After Valproate Therapy It should be noted that valproate is an effective and popular antiseizure drug and that only a very small number of patients have had severe toxic effects from its use.

33. Blocks Na+ and Ca2+ channels Enhance GABA Like phenytoin, metabolized by CYP3A pathway (an inducer) Need titration up! Effective against psychomotor seizures, and grand mal Effective for mania, depression, and neuralgia Safety and Toxicity Dose dependence-double vision, ataxia rash 5-10% rare marrow suppression rare hepatitis frequent hyponatremia/Water intoxication fetal malformations A.Antiepileptic drugs Carbamazepine 卡马西平

35. A.Antiepileptic drugs • Other antiepileptic drugs • Primidone 扑米酮：analogues of phenobarbital, used for phenobarbital- and phenytoin-ineffective patients • Mephenytoin 美芬妥英, Ethotoin 乙苯妥英钠： analogues of phenytoin • Diazepam 地西泮: status epilepticus (i.v.) • Nitrozepam 硝西泮:peptit mal • Clonazepam 氯硝西泮：broad-spectrum

36. A.Antiepileptic drugs • Other antiepileptic drugs • Oxarbazepine（奥卡西平）：similar as carbamazepine but weaker • Antiepilepsirine（抗痫灵）: broad spectrum, esp.grand mal • Lamotrigine 拉莫三嗪： Na+ channel antagonist. Effective against both partial and generalized epilepsy • Flunarizine氟桂利嗪: Inhibit L- and T-type Ca2+ channel. broad spectrum • Topiramate托吡酯： Blocks AMPA+kainate receptors Also blocks Na+ and Ca2+channels

37. 拉莫三嗪 卡马西平 丙戊酸钠 苯妥英钠

38. 丙戊酸钠 二甲双酮 乙琥胺

39. 丙戊酸钠 苯二氮卓类 巴比妥类

40. Drugs which primarily affect potassium channel Levetiracetam Blocks voltage gated K+ channels in hippocampus neurons Blocks kainate receptors Affects GABA receptors Blocks action potentials, and paroxysmal depolarizing shifts Madeja et al Neuropharamacology 2003

41. Drugs which primarily affect potassium channel Levetiracetam Effective for partial epilepsy with or without generalization High Potency -----75% reduction in seizures in over 20% of refractory patients Few side effects except: Somnolence, asthenia, and dizziness Pregnancy category C

42. Drugs which affect Kainate and AMPA receptors Topiramate Zonisamide

43. Topiramate托吡酯 Mechanisms -Multiple Blocks AMPA+kainate receptors Blocks Na+ and Ca2+ channels Potentiates GABA transmission Effective against both partial and generalized epilepsy Excreted primarily in urine Start at 25 mg/day, titrate to 300-500/day Behavioral /Cognitive problems common (somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion) Low risk of rash Causes weight loss Class D in pregnancy (oral clefts) High Potency ----75% reductions in over 20% of refractory patients

44. Teratogenicity 致畸作用 All AEDs cause fetal malformations in at least 6% of infants, such as neural tube defects, mouth malformation, cardiopathy. Highest risk with phenytoin, valproate, phenobarbital, and carbamazepine, etc (Class D drugs) Folate supplementation prevents neural tube defects (split spine, 脊柱裂).

45. A.Antiepileptic drugs Common toxicity of antiepileptic drugs: CNS reactions Hemological reactions Hepatic toxicity

46. Initiation of Treatment • It depends on the level of risk and the patient’s situation • Consider all the facts. • After a first seizure, the risk of subsequent epilepsy is 35% within 1-2 years • After a second seizure, the risk is over 90% • Abnormal MRI and/or EEG substantially increase the risk • Avoid valproic acid in a woman of childbearing potential.

47. A.Antiepileptic drugs • Principals of antiepileptic drug uses • 1. Choice of drugs • (1) Grand mal / Partial： • Phenytoin, Carbamazepine, Phenobarbital • Primidone, Valproate sodium • (2) Peptit mal:Ethosuximide • Clonazepam, Valproate sodium • (3) Psychomotor：Carbamazepine, Phenytoin • (4) Status epilepticus：Diazepan (i.v.) • Phenytoin (i.v.), Phenobrbital (i.m.)

48. During Treatment • Start from mono-therapy • Dose individualization and titration up • No frequent changing and stop slowly • Monitor frequently

49. NATURE REVIEWS | DRUG DISCOVERY 2010 ？ Inhibition Excitability • 抗癫痫药物 • 单基因 • 单离子通道 • 单神经递质 癫痫的形成和发作 × 癫痫灶点转移 癫痫扩散 • 毒性较大 • 停药困难 • 耐药性癫痫 难治性癫痫（以颞叶癫痫最常见）

50. Modulation of the NMDA receptor in epileptogenesis • Expression of subunit proteins • NR1-NR2 co-assembly • Anchoring of the NMDA receptor at the postsynaptic membranes • NMDA receptor phosphorylation • However？