Institute of Pharmacology Antiepileptic and Anticonvulsive Drugs Lou haiyan Institute of Pharmacology School of Medicine Shandong University louhaiyan@sdu.edu.cn

Section 1 Antiepileptic Drugs

Epilepsy (癫痫)

Definition of epilepsy A seizure is the clinical manifestation of a sudden, excessive and synchronous discharge of focal neurons and diffusion to normal neuronal tissues. Epilepsy is characterized by recurrent, sudden and transient seizures. 癫痫的两个基本特征：反复性/发作性 sensory disorder, behavior disorder, and psychotic

Classifications of seizure types 1. Partial seizures (局限性发作) ① Simple partial seizures (单纯性局限性发作) ② Complex partial seizures (复合性局限性发作) Psychomotor seizures (精神运动性发作) 2. Generalized seizures (全身性发作) 　 ① Absence (petit mal) seizures (失神性发作, 小发作) ② Myoclonic seizures (肌阵挛性发作) ③ Generalized tonic-clonic (grad mal) seizures (强直-阵挛性发作, 大发作） ④ Status epilepticus (癫痫持续状态)

Cause of epilepsy Idiopathic epilepsy Secondary epilepsy Complicated Genetic Secondary epilepsy CNS infection Trauma Tumor Parasites etc

Pathogenesis of epilepsy initiation and spread Imbalance function of neurotransmitters and instable neuronal membrane

EEG Records During Epileptic Seizure Epilepsy is characterized by uncontrolled excessive activity of either a part or all of the central nervous system. Grand mal epilepsy: characterized by extreme neuronal discharges in all areas of the brain, last from a few seconds to 3 to 4 minutes. Petit mal epilepsy: Characterized by 3 to 30 seconds of unconsciousness or diminished consciousness during which the person has several twitch-like contractions of the muscle.

Diagnosis of Epilepsy Yes or No ? History Classification Reason?

Treatment of Epilepsy Aim: Keep the patient free of seizures, with no adverse effects, not affecting the life quality. Cause Drug treatment Surgery or physical therapy

Mechanisms of antiepilepsy drugs Action Patterns: 1. Block the initiation of abnormal of abnormal discharge from the focal area. 2. Prevent the spread of abnormal discharge to adjacent brain areas.

Mechanisms of antiepileptic drugs 1. Decrease activity of voltage-dependent Na+ channels 2. Decrease activity of voltage-dependent Ca2+ channels N-type (neuronal); L-type (long lasting) T-type (transient) 3. Enhance GABAergic transmission decrease the reuptake or metabolism of GABA direct action on the GABAA-R 4. Diminish glutamate function

Section 2 Commonly-used antiepileptic drugs

phenytoin sodium (苯妥英钠) barbiturates： phenbarbital (苯巴比妥) primidone (扑米酮) carbamazepine (卡马西平) ethosuximide (乙琥胺) sodium valproate (丙戊酸钠) benzodiazepines: diazepam ( 地西泮) nitrozepam ( 硝西泮) clonazepam (氯硝西泮) antiepilepsirine (抗痫灵) newer drugs: flunarizine (氟桂利嗪) lamotrigine (拉莫三嗪) topiramate ( 托吡酯)

1. Phenytoin Sodium （苯妥英钠, Dilantin, 大仑丁）

【Pharmacological actions】 Can not inhibit the discharge of neuron in focus Prevent the diffusion in normal neuron inhibit posttetanic potentiation (PTP,强直后增强): 反复高频电刺激(强直刺激)突触前神经纤维，引起突触 传递易化，使突触后纤维反应增强的现象

【 Mechanisms of action 】 Membrane-stabilizing function 1. block voltage-sensitive Na+ channel 2. block voltage-sensitive Ca2+ channel (L type, N type) 3. inhibit the activity of calmodulin kinase (钙调素激酶) presynaptic membrane—Glu release↓ postsynaptic membrane—depolarization↓

【clinical uses】 1. Epilepsy: generalized tonic-clonic seizures (grad mal) and partial seizures (first choice) except absence seizures (petit mal) (no effect, even exacerbate disease) attention: slow onset phenobabital → phenytoin sodium

【clinical uses】 2. Neuralgias： trigeminal neuralgia (三叉神经痛) glossopharyngeal neuralgia(舌咽神经痛) 3. Ventricular arrhythmia (心律失常) ： cardiac glycoside induced (强心苷中毒) -first choice

【 Pharmacokinetics 】 1. Absorption strong irritation(alkaline,pH=10.4), not im. Oral: unpredictable, slow onset Css : 6-10d (10-20ug/ml) iv. for status epilepticus

【 Pharmacokinetics 】 2. Metabolism: mainly in liver, hepatic enzyme induction ≤ 10g/ml :first-order elimination kinetics, t1/2=20h ≥ 10g/ml : zero-order elimination kinetics, t1/2=60h monitor blood drug concentration (10-20g/ml) 3. C=10g/ml (anti- epilepsy) C=20g/ml (intoxication)

Adverse Reactions 1. Local stimulation ① gastrointestinal irritation ② phlebitis (静脉炎) ③ gingival hyperplasia 20%

2. CNS symptoms  20g/ml：dizziness, ataxia ﹥40g/ml: psychotic disiorder ﹥50g/ml: coma

rachitis(佝偻病): children 3. Megaloblastic anemia 防治：甲酰四氢叶酸 4. Hypocalcemia, osteomalacia(软骨症) rachitis(佝偻病): children 防治：Vit D

Adverse Reactions 5. Allergy skin rash agranulocytosis（粒细胞缺乏） thrombocytopenia（血小板减少） aplastic anemia（再生障碍性贫血） hepatic lesion

【 Adverse Reactions 】 6.Teratogenesis fetal hydantoin syndrome (胎儿妥因综合征）

芬兰 1980～1998年，研究人员追踪了一家产科诊所中970位怀孕的癫痫妇女，其中有740位在怀孕初期（前3个月）服用抗癫痫药物，另外239位则无。结果在这些服用抗癫痫药物的怀孕妇女中，共产下28个严重畸形儿（3.8%），未服用抗癫痫药物组产下2个严重畸形儿（0.8%；P=0.02）

2. Phenobarbital (苯巴比妥) 【Pharmacological actions and clinical uses】 1. rapid onset 2. used for generalized tonic-clonic seizures and 　 　status epilepticus (iv), but not first choice Mechanisms: inhibit initiation and spread of abnormal discharge increase GABA induced Cl-in (extend opening time) inhibit excitatory neurotransmitter-mediated effect high dose inhibit Na+ ,Ca2+ (L and N-type) channel

3. Primidone (扑米酮) active metabolites: phenobarbital phenylethylmalonamides (PEMA, 苯乙基丙二酰胺)

4. Ethosuximide (乙琥胺) The only indication: absence epilepsy-first choice Mechanisms: inhibit the T-type Ca2+ current in thalamic neurons

5. Benzodiazepines 1. Diazepam: status epilepticus-first choice (iv, slow) 2. Nitrazepam (硝西泮): absence seizure, myoclonic seizure, infantile spasm 3. Clonazepam (氯硝西泮): broad-spectrum

6. Sodium Valproate (丙戊酸钠) Uses: Broad-spectrum Less effective for grad mal than phenytoin and phenobarbital Similar effective for partial mal with carbamazepine More effective than ethosuximide for absence seizure but not the first choice due to hepatic toxicity. Grad mal combined with absence seizure -first choice Refractory epilepsy(顽固性癫痫)

inhibit discharge spread Mechanisms: inhibit discharge spread enhance GABA function： inhibit Na+ , T-type Ca2+ channel

6. Sodium Valproate (丙戊酸钠) + - GAD GABA-T succinic acid semialdehyde glutamic acid GABA 琥珀酸半醛 GAD:谷氨酸脱羧酶 GABA-T：谷氨酸转氨酶

Adverse Reactions Gastrointestinal reactions and CNS reactions Liver injury: 25% routine examination Teratogenesis

7. Carbamazepine (卡马西平) 【Pharmacological actions and clinical uses】 1. Epilepsy: broad spectrum grad mal, complex partial seizures -first choice no good for absence epilepsy 2. Neuralgias: more effective than phenytoin Mechanisms inhibit Na+ 、Ca2+ channel enhance GABA inhibitory function 3. Diabetes insipidus (尿崩症) 4. Mania and depression (躁狂抑郁症)

尿崩症 ↓ADH (AVP), 肾小管重吸收功能障碍 病因: 下丘脑-神经垂体部位的病变 多尿、烦渴、多饮与低比重尿 AVP (arginine vasopressin): 精氨酸加压素 ADH (antidiuretic hormone): 抗利尿激素 卡马西平：促进ADH分泌

Others Antiepilepsirin (抗痫灵) flunarizine (氟桂利嗪) Lamotrigine (拉莫三嗪) Topiramate (托吡酯，妥泰) newer

Principles 1. Select drug according to epilepsy classification 2. Increase dose gradually 3. Transitional drug change: add a second drug before stop the first one 4. Withdraw slowly (half year) 5. Monitor hemogram(血象) and liver function 6. Pregnant woman should take caution

对症选药原则 癫痫类型 首选药物 大发作和局限性发作 苯妥英钠 小发作 乙琥胺 大发作和精神运动型性发作 卡马西平 癫痫类型 　　　首选药物 大发作和局限性发作　 苯妥英钠 小发作 　　　　　乙琥胺 大发作和精神运动型性发作 卡马西平 癫痫持续状态 　　　　　地西泮 iv 大发作合并小发作 　　　　　 丙戊酸钠

+ + + + + + + + + +

Principles 1. 对症选药 2. 剂量渐增 3. 先加后撤 4. 久用慢停 5. 肝功血象 6. 孕妇慎用

Section 3 Anticonvulsants Barbiturates Benzodiazepines Chloral hydrate Magnesium Sulfate

Magnesium Sulfate different administration routes →different effects 1. oral — catharsis, cholagogue (导泻、利胆) 2. external — dephlogisticate (消炎) 3. iv or im — anticonvulsive: relaxant of skeletal muscle BP lowering: inhibit cardiac muscle, dilate VSM Mechanism: calcium antagonism Uses: hypertensive crisis, convulsion

Magnesium Sulfate Overdose: respiratory inhibition tendon reflex（腱反射） and hypotension Treatment: artificial breathing iv calcium chloride or calcium gluconate tendon reflex（腱反射）

Case history Gaby is a 22-year old student who is studying to becoming a teacher. She has no previous serious medical history.One day,as she relaxes with her fellow students after an examination, she feels strange, with butterfly in her stomach and a sensation of fear and anxiety. She then collapses rigidly onto the floor. She has strong convulsions for about 2 min, during which she knocks against a chair. Her body then relaxes, and for the next 3min she can not be roused. When she wakes up she is confused and tired, and also bruised from hitting the chair. She is taken to hospital by her colleagues, where the doctor tells her she has a seizure, there is no family history of seizure. She undergoes a series of test, including an EEG and a brain scan. A few weeks later she has a second seizure at home and following a consultation with the hospital specialist, she starts taking sodium valproate. She is advised to change her type of contraceptive pill. She is very concerned about the implications of having this disease for her career choice as teacher.