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

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 ): ①blocking 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.

②blocking voltage-dependent Ca2+

channel, to inhibit Ca2+ influx. ③inhibiting calmodulin kininase (钙调素激酶 ). ④selectively 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 ①effective 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 )

②and 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, t1/2 .

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: ①Gingival hyperplasia(齿龈增生 ); ②Hematological 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 ); ③Hepatic damage(肝脏损害 ); ④Osteomalacia(骨质软化 ); ⑤Teratogenesis(致畸作用 ).

(4)Drug interactions: ①Plasma protein binding rate is about 90%, drug interactions with oral anticoagulants(口服抗凝血药 ), phenylbutazone(保泰松 ), etc.

②Chloramphenicol(氯霉素 ) and isoniazid(异烟肼 ) can inhibit hepatic microsomal enzymes, to increase Cp of phenytoin.

③Phenybarbital(苯巴比妥 ) and carbamazepine(卡马西平 ) can induce hepatic microsomal enzymes, to decrease Cp of Phenytoin (苯妥英钠 ).

④Phenytoin 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 ) anddrugs 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%; Cmax: 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: ①After po 2-3 weeks, the curative effect takes place; ②The 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 D2 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: B6, 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:

①can decrease the effective dose of L-dopa and enhance the curative effects of L-dopa;

②significantly 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 drugsAmantadine(金刚烷胺 )

It is an antiviral agent used for the prevention and treatment of influenza A2, it has anti-PD actions too.

The mechanism of action is not clear: ①It might alter DA release or re-uptake; ②Anticholinergic 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.

应颂敏应颂敏yings@zju.edu.cnyings@zju.edu.cn 4141

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