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Antiepileptic and Anticonvulsant Drugs

Antiepileptic and Anticonvulsant Drugs. Weiping Zhang Department of Pharmacology weiping601@zju.edu.cn. 2012.4.25. Objectives. * To review the classification of seizures * To discuss potential targets of antiepileptic drugs.

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Antiepileptic and Anticonvulsant Drugs

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  1. Antiepileptic and Anticonvulsant Drugs Weiping Zhang Department of Pharmacology weiping601@zju.edu.cn 2012.4.25

  2. 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. 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。

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

  4. Classification of epilepsy

  5. 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

  6. 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

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

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

  9. Surface Spike • 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. PDS Sodium Influx Calcium Influx Chloride Influx K efflux

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

  11. Mechanisms of antiepileptic drugs • Electrophysiological • Inhibiting excessive discharges • Inhibiting spread of discharges • Molecular • Potentiating GABA neuronal functions • Inhibiting excitatory neuronal functions • Modulating Na+, Ca2+, K+, Cl- channel fuctions

  12. A.Antiepileptic drugs • Special drugs Phenytoin Sodium 苯妥英钠，大仑丁

  13. A.Antiepileptic drugs 1. Pharmacological effects and the mechanism (1) Effects — Inhibiting spread ofabnormal discharges — Not on the happening of abnormal discharge — Inhibit Na+ and Ca2+ influx

  14. A.Antiepileptic drugs 1. Pharmacological effects and the mechanism (2) 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

  15. A.Antiepileptic drugs 2. Clinical uses (1) Antiepilepsy • Grand mal, status epilepticus; • Partial seizures (simple and complex); • Ineffective for petit mal(小发作) (absence seizures，失神性发作) (2) Trigeminal and related neuralgia (3) Antiarrhythmia

  16. 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

  17. A.Antiepileptic drugs 4. Adverse effects (1) Local reactions • GI reactions; gingival hyperplasia (2) CNS reactions • Particularly in the cerebellum and vestibular systems: 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)

  18. A.Antiepileptic drugs (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

  19. 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

  20. 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

  21. 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.

  22. A.Antiepileptic drugs Ethosuximide 乙琥胺 • Block T-type Ca2+ channel • Block Na+-K+ ATPase • Inhibit cerebral metabolism and GABA transaminase • Effective forpeptit mal • Combined with phenobarbital

  23. A.Antiepileptic drugs Valproate sodium 丙戊酸钠 • 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%

  24. 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 A.Antiepileptic drugs Carbamazepine 卡马西平

  25. 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

  26. 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

  27. 拉莫三嗪 卡马西平 丙戊酸钠 苯妥英钠

  28. 丙戊酸钠 二甲双酮 乙琥胺

  29. 丙戊酸钠 苯二氮卓类 巴比妥类

  30. Increasing expression of ABC transporter after epilepsy Anti-epileptic drug sensitive rat Anti-epileptic drug insensitive rat P-gp

  31. P-gp基因敲除及其抑制剂增加脑内抗癫痫药浓度P-gp基因敲除及其抑制剂增加脑内抗癫痫药浓度 P-gp抑制剂增强抗癫痫药(奥卡西平, oxcarbazepine，OXC)作用及延长癫痫病人入院间隔时间

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

  33. 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.

  34. 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.)

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

  36. 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.)

  37. B.Anticonvulsant drugs • Other anticovulsant drugs • Sedative-hypnotic drugs

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