Antiepileptic and Anticonvulsant Drugs Xiangnan Zhang Department of Pharmacology Xiangnan_zhang@zju.edu.cn 2016.5.11

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 临床 09:50-10:35 癫痫临床表现、诊断与鉴别诊断 10:40-11:25 癫痫治疗 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  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

Epilepsy 在我国大概有900多万患者 Nature outlook 2014 癫痫表现为脑电异常兴奋和同步化，可以是局灶性也可是全脑的泛化。癫痫发作主要表现为抽搐和意识丧失，因此严重影响患者生活，极易导致意外发生。根据WTO的数据统计，癫痫发病呈现青少年和老年人发病较高，发展中国家发病高于发达国际这样一种态势，在我国大概有900多万患者 在我国大概有900多万患者

Classification of epilepsy

Simple Partial（单纯局限性） Complex Partial （复合性局限性） 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

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

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

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

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)

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

Origin of a surface epileptic discharge EEG Populations of neurons (field potentials) Individual neurons Individual synapses Individual ion channels on individual neurons Such studies support the idea that pharmacological regulation of synaptic function can regulate the propensity for seizures and provide a framework for electrophysiological analyses aimed at elucidating the role of both synaptic and nonsynaptic mechanisms in expression of seizures and epilepsy. Progress in techniques of electrophysiology has fostered the progressive refinement of the level of analysis of seizure mechanisms from the EEG to populations of neurons (field potentials) to individual neurons to individual synapses and individual ion channels on individual neurons. Cellular electrophysiological studies of epilepsy over roughly two decades beginning in the mid-1960s were focused on elucidating the mechanisms underlying the depolarization shift (DS), the intracellular correlate of the "interictal spike" (Figure 19-1). The interictal (or between-seizures) spike is a sharp waveform recorded in the EEG of patients with epilepsy; it is asymptomatic in that it is accompanied by no detectable change in the patient's behavior. The location of the interictal spike helps localize the brain region from which seizures originate in a given patient. The DS consists of a large depolarization of the neuronal membrane associated with a burst of action potentials. In most cortical neurons, the DS is generated by a large excitatory synaptic current that can be enhanced by activation of voltage-regulated intrinsic membrane currents. Although the mechanisms generating the DS are increasingly understood, it remains unclear whether the interictal spike triggers a seizure, inhibits a seizure, or is an epiphenomenon with respect to seizure occurrence in an epileptic brain. While these questions remain unanswered, study of the mechanisms of DS generation set the stage for inquiry into the cellular mechanisms of a seizure.

Epileptic neurons generate Paroxysmal Depolarizing Shift (PDS) 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. Surface Spike PDS Sodium Influx Calcium Influx Chloride Influx K efflux A paroxysmal depolarizing shift (PDS) is a cellular manifestation of epilepsy. First, there is a Ca2+ mediated depolarization, which causes voltage gated Na+ to open, resulting in action potentials. This depolarization is followed by a period of hyper-polarization mediated by Ca2+-dependent K+ channels or GABA-activated Cl- influx.

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

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???

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

抗癫痫药物发展历程 第一代 第二代 第三代 正在研发的新型抗癫痫药 最终目标 预防及治愈癫痫 溴化物、硼砂 目前癫痫的临床治疗是以药物控制症状为主，从19世纪中期的溴化物、硼砂的发现到20世纪苯妥因纳、丙戊酸钠等直至最新发现的药物左乙拉西坦、瑞替加滨经历了一个半世纪的发展，尽管目前已经有20多种不同类型不同作用靶点的抗癫痫药物可供选择，但是仍旧30%左右的患者出现耐药。而且，距离我们临床用药的最终目标（预防及治愈癫痫发作）仍相去甚远。 可能的原因：1 癫痫发病的确切机制不清。2 临床用药没有很好的针对不同发作类型去针对性的给药。 3 药物靶点相对单一 Shorvon SD et al., Epilepsia, 2009

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）

A. Antiepileptic drugs 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 www.boomer.org/c/p4/c21/c2103.html Oral Dose: about 5 mg / kg

A. Antiepileptic drugs 1. Pharmacological effects and the mechanism — Inhibiting spread of abnormal discharges — Not on the happening of abnormal discharge — Inhibit Na+ and Ca2+ influx “but not T-type Ca2+ channel”可能与治疗失神发作无效有关；

A. Antiepileptic drugs 1. Pharmacological effects and the 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 “but not T-type Ca2+ channel”可能与治疗失神发作无效有关；

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 起效慢

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 呈碱性，有刺激性，不宜肌注，口服吸收不规则，剂型、颗粒大小及添加剂均可影响吸收的速率和程度，血浆蛋白结合率高达85-90%，经肝脏羟化再加葡萄糖醛酸结合后经肾脏排出

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）

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

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

Drugs acting at the chloride channel 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

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. Cl- influx (突触前) and  Ca2+ influx（突触后，导致NE、Ach和谷氨酸释放减少） 对小发作和婴儿痉挛效果差 起效快，疗效好，价格低、毒性低（嗜睡、精神萎靡、共济失调，偶见巨幼细胞贫血、血小板减少、白细胞减少等）

A. Antiepileptic drugs Ethosuximide 乙琥胺 Block T-type Ca2+ channel Block Na+-K+ ATPase Inhibit cerebral metabolism and GABA transaminase Effective for peptit mal Combined with phenobarbital 疗效不及氯硝西泮，但副作用及耐受性的产生也较少。 GI responses， CNS（头疼、头晕、嗜睡等）、精神异常（精神病史患者）、贫血、可导致癫痫大发作。

A. Antiepileptic drugs Valproate sodium 丙戊酸钠 GI side effects Tremor 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% GABA合成增加，抑制降解、摄取，增强对GABA的反应性 对小发作的作用优于乙琥胺，但由于其肝脏毒性作用，不做首选。

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

A. Antiepileptic drugs Carbamazepine 卡马西平 Safety and Toxicity 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 Rash、marrow suppression为特异质反应

Other antiepileptic drugs 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 扑米酮：体内转化为苯巴比妥和苯乙基丙二酰胺，用药期间定期查血象，肝肾功能不全者禁用； 美芬妥英：体内容易蓄积、不良反应重，仅用于其他药物不能控制的患者。 乙苯妥英钠：作用和毒性均弱，仅用于辅助用药。 氯硝西泮:对小发作的疗效较地西泮强

Other antiepileptic drugs 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 奥卡西平：过敏反应少，对肝药酶的诱导作用弱。 抗痫灵：桂皮酰胺类药，系我国合成的抗癫痫药物，厌食、恶心头晕嗜睡等，无肝毒性、造血系统损伤； 氟桂利嗪:对电惊厥引起的癫痫有效，但对戊四唑引起的癫痫无效，安全，主要有困倦、镇静、体重增加

卡马西平 拉莫三嗪 丙戊酸钠 苯妥英钠

丙戊酸钠 二甲双酮 乙琥胺

丙戊酸钠 苯二氮卓类 巴比妥类

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 Levetiracetam: 左乙拉西坦 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 Category 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

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.

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.)

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

？ × 抗癫痫药物 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） 癫痫的形成和发作 癫痫扩散 癫痫灶点转移 NATURE REVIEWS | DRUG DISCOVERY 2010 Excitability Inhibition ？ 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） 相应的药物研发主要针对单基因，单离子通道，单神经递质等策略，这些药物大多作用全脑毒副作用大，停药困难，并且有30%左右的患者多已有抗癫痫耐受。并且对于癫痫形成过程目前尚无药可用。

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？

Decreased expression of GABA receptors 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----- Failure of GABA inhibitory function in epileptogenesis

现状： 挑战： 目标： 近16年来有14个抗癫痫新药上市。 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。

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

Epilepsy Surgery is not always useful

For example 致痫区定位困难的患者 SOZ 和重要功能运动区接近 多灶性癫痫 发作起始区 举例癫痫手术困难的患者 例1：无灶的癫痫患者，定位困难 例2：多灶性癫痫 例3：患者的致痫区和运动区重叠 多灶性癫痫

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

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 最近science translational medicine文章先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（左a、b、c）。作者认为由于光遗传学的临床应用性，还有待确证，比如光毒性和光纤设备的研发等，他们进而开发出基于Kv 1.1钾离子通道基因治疗策略（右图）。 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

B. Anticonvulsant drugs Magnesium Sulfate 硫酸镁 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 Ca2+ preparations (i.v.)

B. Anticonvulsant drugs Other anticovulsant drugs Sedative-hypnotic drugs