Part 6. Anti-epileptic drugs and anticonvulsant drugs ( 抗癫痫药和抗惊厥药 )

(A) Antiepileptic drugs ( 抗癫痫药 ) 1. General concept of epilepsy: Epilepsy is a chronic disease of brain, there are abnormal focus in the brain of epileptic patients. The morbidity of epilepsy is 3‰ ～ 10‰ in the world. The morbidity is 4.8‰ in China, there are about 6 million epileptic patients now. 癫痫是慢性反复发作性短暂脑功能失调综合征。

There are abnormal focus in the brain of epileptic patients.

2.Classification of epileptic seizures: (1)Generalized seizures ( 全身性发作 ) (2)Partial seizures ( 局限性发作 ) (3)Unclassified seizures ( 未能分型的发作 )

3. Four types of the most common epileptic seizure: (1)Grand mal( 大发作 ): 2’~5’ Tonic-clonic seizures ( 强直阵挛性发作 ) Status epilepticus ( 癫痫持续状态 ) (2)Petit mal( 小发作 ): 5’’~30’’ Absence seizures ( 失神性发作 ) (3)Simple partial seizures: 20’’~60’’ ( 单纯局限性发作 ) (4)Complex partial seizures —— Psychomotor seizures: 30 ’’~ 2’ ( 精神运动性发作 )

Complex partial seizures —— Psychomotor seizures ( 精神运动性发作 )

4. Mechanisms of antiepileptic drugs: There are two general ways in which drugs might reduce seizures: (1)Action on lesion neurons of focus to inhibit production of abnormal discharge of focus; ( 抑制病灶区神经元异 常放电 ) (2)Action on normal neurons around the focus to inhibit diffusion of abnormal discharge from focus. ( 遏制异常放电向正 常组织扩散 )

5. Difficulty for treatment of epilepsy: (1)ADRs more: ADRs of antiepileptic drugs are more; (2)Compliance( 顺应性, 依从性 ) with medication is a major problem: Because of the need for long-term drug therapy together with unwanted effects.

6. Anti-epileptic drugs in commom use: (1)Sodium phenytoin( 苯妥英钠 ); (2)Phenobarbital( 苯巴比妥 ), Primidone( 扑米酮 ); (3)Ethosuximide( 乙琥胺 ); (4)Benzidiazepines( 苯二氮卓类 ); (5)Sodium valproate( 丙戊酸钠 ) ; (6)Carbamazepine( 卡马西平 ).

Sodium phenytoin ( 苯妥英钠, Dilantin, 大仑丁 ) 1. Pharmacological effects: (1)Membrane stabilization( 膜稳定 ): ① blocking voltage-dependent Na + channel ( 电压依赖性钠通道 ), to reduce Na + influx. Membrane stabilization of phenytoin is apparent on all excitable cell membrane, including cell membrane of central and peripheral nerve( 中枢和外 周神经 ), and myocardium( 心肌 ).

Blocking voltage-dependent Na + channel, to reduce Na + influx.

② blocking voltage-dependent Ca 2+ channel, to inhibit Ca 2+ influx. ③ inhibiting calmodulin kininase ( 钙调 素激酶 ). ④ selectively inhibiting PTP( 强直后增 强, post tetanic potentiation) 反复高频电刺激的后果 (2) Enhancing GABA function: To inhibit GABA re-uptake in terminal of central nerves, to lead to postsynaptic membrane super- polarization, enhancing GABAergic function.

2. Clinical uses: (1)Prevent & treat epileptic seizures ① effective for: grand mal ( 大发作 ), simple partial seizures ( 单纯局限性 发作 ), psychomotor seizures ( 精神运动性 发作 ) ② and effective for: status epilepticus ( 癫痫持续 ) but ineffective for petit mal ( 小发作 ).

(2)Cerebral neuralgia( 脑神经痛 ): Such as trigeminal neuralgia( 三叉神经 痛 ) & glosspharyngeal neuralgia ( 舌咽 神经痛 ) The curative effect is relative to stabilization of the cell membrane of those nerves. (3)Anti-arrhythmia( 抗心律失常 ): The curative effect is relative to stabilization of the myocardial cell membrane also.

3. Pharmacokinetics: (1)Absorption: po. Slowly, irregularly. Bioavailability vary in different preparation. im. Alkalinity is potent, irritant. ( 强碱性，刺激性大 ) (2)Plasma protein binding rate: about 90 %, ——Drug interaction !

(3)Metabolism: ● in liver, its ability of elimination is limited, Cp ＞ 10  g/ml,  zero kinetics, t 1/2 . Its effective Cp ( 血药浓度 ) is 10  g/ml, close to toxic concentration(20  g/ml). ——Dosage individualization ! ● Can induce hepatic microsomal enzymes ( 肝微粒体酶 ) ——Drug interaction !

4. Adverse reaction: more ! ADRs of phenytoin ( 苯妥英钠 ) depend upon the route and duration of exposure as well as dosage. (1)Gastrointestinal reaction: po. nausea ( 恶心 ), vomiting, epigastric pain ( 腹痛 ), etc. because its alkalinity is potent, irritant. ( 强碱性、刺激性 ) (2)Allergy: skin rash, granulocytosis( 粒细胞减 少 ), thrombocytopenia( 血小板减少 ), aplastic anemia( 再生障碍性贫血 ), etc.

(3)Toxic reaction: ● Acute toxicity: iv: speed, inhibit heart, Bp  po: overdose  CNS symptoms, when Cp ≥ 20  g/ml: vertigo( 眩晕 ), headache, ataxia ( 共济 失调 ), and nystagmus( 眼球震颤 ), etc. when Cp ≥ 40  g/ml: Mental confusion( 精神错乱 ). when Cp ≥ 50  g/ml: Coma( 昏迷 )

● Chronic toxicity: ① Gingival hyperplasia( 齿龈增生 ); ② Hematological reactions: such as megaloblastic anemia( 巨幼红细胞贫血 ), should be treated with formyl- tetrahydrofolic acid( 甲酰四氢叶酸 ); ③ Hepatic damage( 肝脏损害 ); ④ Osteomalacia( 骨质软化 ); ⑤ Teratogenesis( 致畸作用 ).

(4)Drug interactions: ① Plasma protein binding rate is about 90%, drug interactions with oral anticoagulants( 口服抗凝血药 ), phenylbutazone( 保泰松 ), etc. ② Chloramphenicol( 氯霉素 ) and isoniazid( 异烟肼 ) can inhibit hepatic microsomal enzymes, to increase Cp of phenytoin.

③ Phenybarbital( 苯巴比妥 ) and carbamazepine( 卡马西平 ) can induce hepatic microsomal enzymes, to decrease Cp of Phenytoin ( 苯妥英钠 ). ④ Phenytoin can induce hepatic microsomal enzymes, to enhance the metabolism of corticosteroids ( 皮质类固 醇 ) and contraceptives.

Phenobarbital( 苯巴比妥 ) effective for: Grand mal ( 大发作 ), po Status epilepticus ( 持续癫痫 ), im or iv Primidone( 扑米酮, 去氧巴比妥, 扑痫酮 ) effective for: Grand mal Simple partial seizures ( 单纯性局限性发作 ) adjuvant treatment for: Psychomotor seizures( 神经运动性发作 )

Ethosuximide ( 乙琥胺 ) Effective for petit mal. Its toxicity is very small, the first-chosen drug( 首选药 ) for petit mal ( 小发作 ). Benzodiazepines ( 苯二氮卓类 ), BZ Diazepam ( 地西泮，安定 ) iv: Status epilepticus Nitrozepam ( 硝西泮，硝基安定 ) po: Clonic seizures ( 小发作、肌症挛性发作 ) Clonazepam ( 氯硝西泮 ) & clobazam( 氯巴占 ): petit mal. Sodium valproate ( 丙戊酸钠 ) Effective for all seizures, but its liver damage limited its clinical use.

Carbamazepine ( 卡马西平, 酰胺咪嗪 ) 1. Pharmacological effect: to inhibit Na + channel, decrease Na + influx, to reduce seizure foci excessive discharge, and enhancing GABAergic function also. 2. Clinical uses: ● Pschomotor seizures & grand mal. ● Cerebral neuralgia( 脑神经疼痛 ): The curative effect for trigeminal neuralgia ( 三叉神经痛 ) is better than phenytoin. ● Mania( 躁狂症 )

Choice of drugs to treat epilepsy: Grand mal: sodium phenytoin ( 苯妥英钠 ), phenobarbital ( 苯巴比妥 ), primidone ( 扑痫酮 ), carbamazepine ( 卡马西平 ) Petit mal: ethosuximide ( 乙琥胺 ), clonazepam ( 氯硝西泮 ), clobazam ( 氯巴占 ) Psychomotor seizures: sodium phenytoin ( 苯妥英钠 ), or + primidone ( 扑痫酮 ) Simple partial seizure: the same drugs as grand mal.

Choice of drugs to treat epilepsy: Status epilepticus: iv.diazepam ( 地西泮 ), or im phenobarbital ( 苯巴比妥 ), or iv sodium phenytoin ( 苯妥英钠 )

(B) Anticonvulsant drugs ( 抗惊厥药物 ) ▲ iv. Diazepam; ▲ im. or iv. Phenobarbital; ▲ pr. Chloral hydrate ( 水合氯醛 ). Magnesium sulfate( 硫酸镁 ) 1. Pharmacological effects po: can not be absorption, —— catharsis( 导泻作用 ). iv, im: ● CNS depression ● muscle relaxation ● vasodilatation

2. Clinical Uses: ● Anti-convulsion: im, or iv gtt.; ● Treatment of hypertensive crisis ( 高血 压危象 ): im, or iv gtt. 3. Adverse reactions: ● Respiratory depression; ● Hypotension. Those ADRs can be antagonized by iv. calcium preparation.

Part 7. Drugs of anti-Parkinson’s disease( 抗帕金森病药 ) and drugs of treatment of senile dementia( 治疗老年性痴呆药 )

(A)Drugs of anti-Parkinson’s disease( 抗帕金森病药 ) (B)Drugs of treatment of senile dementia( 治疗老年性痴呆药 )

进行性的锥体外系功能障碍的中枢神经系统退行 性疾病。

1. Clinical symptoms of PD: (1)resting tremor( 静止震颤 ), (2)rigidity( 肌肉僵直 ), (3)bradykinesia( 运动迟缓 ), (4)dysmnesia( 记忆障碍 ), (5)dementia( 痴呆 ), etc. (A)Drugs of anti-Parkinson’s disease( 抗帕金森病药 ) Parkinson’s disease = PD

2. Neural mechanism of PD: There are two kinds of neuron in striatum( 纹状体 ): Dopaminergic neuron, Cholinergic neuron. Insufficiency of the function of dopaminergic nerves the function of cholinergic nerve is relatively dominant.

3. The drugs of anti-PD: Ⅰ. Dopamine mimetics ( 拟多巴胺药类 ) Ⅱ. Central anti-choline drugs ( 中枢抗胆碱药类 ) Ⅲ. Others( 其他类 )

Ⅰ. Dopamine mimetics ( 拟多巴胺药 ) Levedopa ( 左旋多巴, L-dopa ) 1. Pharmacokinetics (1)Absorption po: absorbed fast in intestine, Bioavailability: 41±16%; C max : 0.5~2 hr; (2)Elimination t ½ : 1.4±0.4 (1~3) hr; In blood, 95% L-dopa is transformed to DA by DOPA decarboxylase ( 多巴脱羧酶 ), DA is destroyed by MAO ( 单胺氧化酶 ) and COMT ( 儿茶酚胺 -O- 甲基转移酶 ), less than 1% L- dopa penetrates the CNS.

2. Effects and clinical use: CNS L-dopa Dopamine(DA) L-dopa is the single most effective agent in the treatment of PD. Characteristics of its effect: ① After po 2-3 weeks, the curative effect takes place; ② The curative effect for younger and low-grade patient is well.

3. Adverse reaction The most ADR are caused by DA. (1)GI reactions nausea, vomiting, etc. Owing to DA activating D 2 receptor of CTZ. (2)Cardiovascular reactions DA activating  2 receptor of heart. (3)Undesirable on/off fluctuations ( 不随意摇动 ): in 2~4 months. (4)Psychonosema( 精神障碍 ) isomnia( 失眠 ), hallucination( 幻觉 ), delusion( 妄想 ), mania( 躁狂 ), etc. (5)Drug interaction: B 6, Mao inhibitor ( 单 胺氧化酶抑制剂 ), chlorpromazine ( 氯丙嗪 ), reserpine ( 利血平 ), etc.

Carbidopa( 卡比多巴 ) It is an inhibitor of DOPA decarboxylase ( 脱羧酶抑制剂 ) and cannot cross blood-brain barrier. Merits of combined treatment of Carbidopa and L-dopa: ① can decrease the effective dose of L-dopa and enhance the curative effects of L-dopa; ② significantly decrease cardiac toxicity of L-dopa; proportion of Carbidopa and L-dopa is 1 : 10.

Ⅱ. Central anti-choline drugs ( 中枢抗胆碱药 ) Trihexyphenide( 苯海索, Artane, 安坦 ) Artane can enter CNS and block M receptor of nigro-striatal ( 黑质 - 纹状体 ) pathway, to reduce the effects of ACh. Peripheral effects of anticholine of Antane is weaker than Atropine, about 1/3 ~ 1/10. The curative effect of Antane to PD is lower than L-dopa.

Ⅲ. Other drugs Amantadine ( 金刚烷胺 ) It is an antiviral agent used for the prevention and treatment of influenza A 2, it has anti-PD actions too. The mechanism of action is not clear: ① It might alter DA release or re-uptake; ② Anticholinergic properties also may contribute to its therapeutic action. Its curative effect is weaker than L-dopa and stronger than Artane. It is used as initial therapy of mild PD.

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