Antiepileptic and Anticonvulsant Drugs Zhong Chen Department of Pharmacology

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. 8:00-8:45 抗癫痫药和抗惊厥药 1 陈忠 8:50-9:35 癫痫概念、分类与发病机制 1 临床 09:50-10:35 癫痫临床表现、诊断与鉴别诊断 1 临床 10:40-11:25 癫痫治疗 1 临床 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。

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

Classification of epilepsy

International Classification of Epileptic Seizures: Partial Onset Seizures （局限性发作） l Simple Partial （单纯局限性） l Complex Partial （复合性局 限性） l 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

International Classification of Epileptic Seizures: Primary Generalized Seizures l Absence (Petit Mal) （失神性发作 / 小发作） l Myoclonic （肌阵挛性发作） l Generalized Tonic+Clonic （全身强直阵挛性发作）

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

病因论 §Underlying causes: 遗传 1.Birth trauma 外伤 2.Head injury 脑损伤 3.Tumour 肿瘤 4.Infection 感染 5.Metabolic disorder 代谢性病症 6.Cerebrovascular accident 脑血管意外 7.Deteriorating brain disease 其它脑疾病恶化

CAUSES OF CONGENITAL EPILEPSY 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) （先天性的）

诱发的危险因素 1.Alcoholism 酒精中毒. 2.Withdrawal from alcohol (“hang-over period”) 酒精戒断症. 3.Physical debilitation (illness, lack of sleep, exhaustion). 过度疲劳 4.Emotional stress 情绪应激 5.Watching visual flicker 闪烁的视觉障碍 6.Unknown aetiology. 一些未知因素

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

Sodium Influx Calcium Influx Chloride Influx PDS Surface Spike K efflux §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.

Antiepilepticdrugs Focus formation and epileptic attack Focus shift Refractory epilepsy Imbalance of excitation and inhibitory Na + 、 Ca 2+ 、 NMDA 、 K + 、 Cl - 、 GABA Spreading

Mechanisms of antiepileptic drugs §Electrophysiological §Inhibiting excessive discharges §Inhibiting spread of discharges §Molecular §Potentiating GABA neuronal functions §Inhibiting excitatory neuronal functions （ NMDA ） §Modulating Na +, Ca 2+, K +, Cl - channel fuctions §Others???

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

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

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） 17

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

1. Pharmacological effects and the mechanism (1) Effects — Inhibiting spread ofabnormal discharges — Inhibiting spread of abnormal discharges — Not on the happening of abnormal discharge — Not on the happening of abnormal discharge — Inhibit Na + and Ca 2+ influx — Inhibit Na + and Ca 2+ influx A. Antiepileptic drugs

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

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

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) A. Antiepileptic drugs （巨幼红细胞性贫血）

(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 A. Antiepileptic drugs Hirsutism( 多毛 )

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 A. Antiepileptic drugs

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

§Sedative and hypnotic effect. §Inhibiting both formation and spread of discharges. §  Cl - influx and  Ca 2+ influx §Effective for grand mal, status epilepticus, partial simple seizures. Phenobarbital 苯巴比妥 A. Antiepileptic drugs

§Block T-type Ca 2+ channel §Block Na + -K + ATPase §Inhibit cerebral metabolism and GABA transaminase §Effective for peptit mal §Combined with phenobarbital Ethosuximide 乙琥胺 A. Antiepileptic drugs

Valproate sodium 丙戊酸钠 A. Antiepileptic drugs §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 Ca 2+ §Enhance K + ? §GI side effects §Tremor §Hepatitis §Pancreatitis §Serious neural tube and cardiac defects in fetus in 1%

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.

§Blocks Na + and Ca 2+ 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 l Dose dependence-double vision, ataxia l rash 5-10% l rare marrow suppression l rare hepatitis l frequent hyponatremia/Water intoxication l fetal malformations Carbamazepine 卡马西平 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 A. Antiepileptic drugs

§Other antiepileptic drugs §Oxarbazepine （奥卡西平）： similar as carbamazepine but weaker §Antiepilepsirine （抗痫灵） : broad spectrum, esp. §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 Ca 2+ channel. broad spectrum §Topiramate 托吡酯： Blocks AMPA+kainate receptors Also blocks Na + and Ca 2+ channels A. Antiepileptic drugs

卡马西平 苯妥英钠 丙戊酸钠 拉莫三嗪

丙戊酸钠 乙琥胺 二甲双酮

丙戊酸钠 苯二氮卓类 巴比妥类

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

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

Drugs which affect Kainate and AMPA receptors §Topiramate §Zonisamide

Topiramate 托吡酯 §Mechanisms -Multiple l Blocks AMPA+kainate receptors l Blocks Na+ and Ca2+ channels l Potentiates GABA transmission §Effective against both partial and generalized epilepsy §Excreted primarily in urine §Start at 25 mg/day, titrate to /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 % reductions in over 20% of refractory patients

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 ).

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

Initiation of Treatment  It depends on the level of risk and the patient ’ s situation §Consider all the facts. l After a first seizure, the risk of subsequent epilepsy is 35% within 1-2 years l 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.

§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.) A. Antiepileptic drugs

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

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） NATURE REVIEWS | DRUG DISCOVERY 2010 Excitability Inhibition？

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

Failure of GABA inhibitory function in epileptogenesis Loss of GABA neurons Decreased expression of GABA receptors Transformation from inhibitory to “excitatory” (due to Cl- balance potential, a change of transporter expression) However, the para-synaptic GABA-----

52 现状： 近 16 年来有 14 个抗癫痫新药上市。 挑战： 1 、缺少难治性癫痫的有效治疗药物 2 、缺少作用于癫痫形成过程的药物 3 、缺少预防高风险人群癫痫发作的药物 目标： 治疗的目标应该是完全控制惊厥，没有或只有轻微 的副作用, 保持正常生活方式。

手术治疗 抗癫痫药 1. 已有抗癫痫药只能控制症 状为主 2. 25~30% 左右的患者产生 耐药（尤其是颞叶癫痫） 3. 药物毒副作用明显 1. 多灶点、隐源性癫痫患 者并不适合手术 2. 30% 左右的患者术后依 旧复发 3. 并发症 迫切需要寻找新的安全有效的治疗方法！ Bialer M, et al. Nat Rev Drug Discov, 2010 Berg AT, et al. Nat Rev Neurol, 2011

Epilepsy Surgery is not always useful

致痫区定位困难的患者 多灶性癫痫 For example 发作起始区 SOZ 和重要功能运动区接近

药物新靶点和药物的开发 抗癫痫药物 靶向性亚细胞特异性 个性化给药 毒性小，耐药性小 神经环路特异性 有效预防和治疗

用光遗传学失活皮层谷氨酸能神经元兴奋性可以有效控制癫痫

§1. Effects ： central depression; § vasodilatation, BP  ; § relaxing skeletal muscles §2. Uses ： convulsion ； hypertension crisis §3. Adverse effects ： §depression of respiratory and vasomotor centers, antagonized by Ca 2+ preparations (i.v.) Magnesium Sulfate 硫酸镁 B. Anticonvulsant drugs

§Other anticovulsant drugs §Sedative-hypnotic drugs B. Anticonvulsant drugs