Antiepileptic and Anticonvulsant Drugs

Antiepileptic and Antiepileptic and Anticonvulsant DrugsAnticonvulsant Drugs

2012.4.25

Weiping ZhangDepartment of Pharmacology

[email protected]

Objectives * To review the classification of seizures* To review the classification of seizures * To discuss potential targets of antiepileptic drugs.* To discuss potential targets of antiepileptic drugs. To present an evidence-based review of the major To present an evidence-based review of the major

antiepileptic drugs.antiepileptic drugs.

8:00-8:45 抗癫痫药和抗惊厥药 1 张纬萍8:50-9:35 癫痫概念、分类与发病机制 1 王爽09:50-10:35 癫痫临床表现、诊断与鉴别诊断 1 王爽10:40-11:25 癫痫治疗 1

王爽

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

Abnormal high frequency discharging

Abnormal spreading

Brain malfunctionAccompanied with abnormal EEG

发病率高；

突发性，不可预测；

不可根治，需终身服药

Classification of epilepsyClassification of epilepsy

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）

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

Origin of a surface epileptic discharge

• EEG

• Populations of neurons (field potentials)

• Individual neurons

• Individual synapses

• Individual ion channels on individual neurons

Sodium InfluxCalcium Influx

Chloride Influx

PDS

Surface Spike

K efflux

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.

AntiepilepticAntiepilepticdrugsdrugs

Focus formation and epileptic attackFocus formation and epileptic attack

Focus shiftFocus shift

Refractory epilepsyRefractory epilepsy

Imbalance of excitation and inhibitoryImbalance of excitation and inhibitory NaNa++ 、、 CaCa2+2+ 、、 NMDANMDA 、、 KK+ + 、、 ClCl-- 、、 GABAGABA

SpreadingSpreading

Mechanisms of antiepileptic drugsMechanisms of antiepileptic drugs

ElectrophysiologicalElectrophysiological Inhibiting excessive dischargesInhibiting excessive discharges Inhibiting spread of dischargesInhibiting spread of discharges

MolecularMolecular Potentiating GABA neuronal functionsPotentiating GABA neuronal functions Inhibiting excitatory neuronal functionsInhibiting excitatory neuronal functions Modulating NaModulating Na++, Ca, Ca2+2+, K, K++, Cl, Cl- - channel fuctichannel fucti

onsons

A.A. Antiepileptic drugsAntiepileptic drugs

Special drugsSpecial drugs

Phenytoin Sodium Phenytoin Sodium 苯妥英钠，大仑丁苯妥英钠，大仑丁

CO

N

N

HC6H5

C6H5

NaO

1. 1. Pharmacological effects and the mechanismPharmacological effects and the mechanism

(1) Effects (1) Effects

— — Inhibiting spread ofInhibiting spread of abnormal discharges abnormal discharges

— — Not on the happening of abnormal dischargeNot on the happening of abnormal discharge

— — Inhibit NaInhibit Na++ and Ca and Ca2+2+ influx influx


1. 1. Pharmacological effects and the mechanismPharmacological effects and the mechanism

(2) Mechanism (2) Mechanism

— — blocking Nablocking Na++ channel in inactive state channel in inactive state

— — Inhibiting L- and N-type CaInhibiting L- and N-type Ca2+2+ channel channel

(but not T-type Ca(but not T-type Ca2+2+ channel ) channel )

— — Calmodulin Calmodulin neurotransmitter release neurotransmitter release

(NE, 5-HT, DA etc.)(NE, 5-HT, DA etc.)

— — block posttetanic potentiation (PTP) formationblock posttetanic potentiation (PTP) formation


2. 2. Clinical usesClinical uses

(1) Antiepilepsy(1) Antiepilepsy Grand mal, status epilepticus; Grand mal, status epilepticus; Partial seizures (simple and complex);Partial seizures (simple and complex); Ineffective for petit mal(Ineffective for petit mal( 小发作小发作 ) (absence seiz) (absence seiz

uresures ，失神性发作，失神性发作 ))

(2) Trigeminal and related neuralgia(2) Trigeminal and related neuralgia

(3) Antiarrhythmia(3) Antiarrhythmia


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 linearPsuedo first order

A.A. Antiepileptic drugsAntiepileptic drugs3. 3. ADMEADME

4. 4. Adverse effectsAdverse effects

(1) Local reactions(1) Local reactions GI reactions; gingival hyperplasiaGI reactions; gingival hyperplasia

(2) CNS reactions(2) CNS reactions Particularly in the cerebellum and vestibular systems: nParticularly in the cerebellum and vestibular systems: n

ystagmus (ystagmus ( 眼球震颤眼球震颤 ), ataxia (), ataxia ( 共济失调共济失调 ), ), etc.etc.

Behavioral changes: confusion, hallucination, comaBehavioral changes: confusion, hallucination, coma

(3) Hemological reactions(3) Hemological reactions Megaloblastic anemia (affect the metabolism of folic aciMegaloblastic anemia (affect the metabolism of folic aci

d)d)


(4) Allergic reactions(4) Allergic reactions Skin reactions; blood cell abnormality (including throSkin reactions; blood cell abnormality (including thro

mbocytopenia, agranulocytosis);mbocytopenia, agranulocytosis); hepatic toxicity; hepatic toxicity; ect.ect.

(5) Skeletal reactions(5) Skeletal reactions Osteomalacia by increase vitamin D metabolism and cOsteomalacia by increase vitamin D metabolism and c

alcium absorption (inducer)alcium absorption (inducer)

(6) Others(6) Others Birth defects, Birth defects, hirsutism, etchirsutism, etc


5.5. Drug interactions Drug interactions （蛋白结合、代谢）（蛋白结合、代谢）

(1) Increases plasma concentrations of drugs by displacem(1) Increases plasma concentrations of drugs by displacement of plasma protein binding ent of plasma protein binding (salicylates)(salicylates)

(2) Drug metabolizing enzyme (2) Drug metabolizing enzyme inhibitorinhibitor decrease the meta decrease the metabolismbolism of phenytoin of phenytoin (isoniazid(isoniazid 异烟肼异烟肼 , chloramphenic, chloramphenicolol 氯霉素氯霉素 ))

(3) Drug metabolizing enzyme (3) Drug metabolizing enzyme inducer inducer increase the metabincrease the metabolismolism of phenytoin of phenytoin (phenobarbital, carbamazepine)(phenobarbital, carbamazepine)

(4) Phenytoin enhances the metabolism of corticosteroids a(4) Phenytoin enhances the metabolism of corticosteroids and vitamin Dnd vitamin D


Drugs acting at the chloride channel

Benzodiazepines Binds to specific

receptors

Phenobarbital Binds to barbiturate

specific receptor

Valproate Decreases GABA

degradation in presynaptic terminal


Sedative and hypnoticSedative and hypnotic effect. effect. Inhibiting both formation and spread of discharges.Inhibiting both formation and spread of discharges. ClCl-- influx and influx and Ca Ca2+2+ influx influx Effective for grand mal , status epilepticus, partial simple seEffective for grand mal , status epilepticus, partial simple se

izures.izures.

Phenobarbital Phenobarbital 苯巴比妥苯巴比妥


C2H5

CO

NH

NH

CO

CO

C

C6H5

Block T-type CaBlock T-type Ca2+2+ channel channel Block NaBlock Na++-K-K++ ATPase ATPase Inhibit cerebral metabolism and GABA tInhibit cerebral metabolism and GABA transaminaseransaminase Effective forEffective for peptit malpeptit mal Combined with phenobarbitalCombined with phenobarbital

Ethosuximide Ethosuximide 乙琥胺乙琥胺


Valproate sodium Valproate sodium 丙戊酸钠丙戊酸钠


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 effectsTremorHepatitisPancreatitisSerious neural tube and

cardiac defects in fetus in 1%

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 v

ision, ataxia

rash 5-10%

rare marrow suppression

rare hepatitis

frequent hyponatremia/Water intoxication

fetal malformations

Carbamazepine Carbamazepine 卡马西平卡马西平


N

CONH2

Other antiepileptic drugsOther antiepileptic drugs

Primidone Primidone 扑米酮扑米酮：： analogues of phenobarbital, useanalogues of phenobarbital, used for phenobarbital- and phenytoin-ineffective patid for phenobarbital- and phenytoin-ineffective patientsents

Mephenytoin Mephenytoin 美芬妥英美芬妥英 ,, Ethotoin Ethotoin 乙苯妥英钠乙苯妥英钠：： analoganalogues of phenytoinues of phenytoin

Diazepam Diazepam 地西泮地西泮 : : status epilepticus (status epilepticus (i.v.i.v.))

Nitrozepam Nitrozepam 硝西泮硝西泮 :: peptit malpeptit mal

Clonazepam Clonazepam 氯硝西泮氯硝西泮：： broad-spectrumbroad-spectrum


Other antiepileptic drugsOther antiepileptic drugs

OxarbazepineOxarbazepine （奥卡西平）：（奥卡西平）： similar as carbamazepine but similar as carbamazepine but weakerweaker

AntiepilepsirineAntiepilepsirine （抗痫灵）（抗痫灵） : : broad spectrum, esp.broad spectrum, esp. grand mal

Lamotrigine Lamotrigine 拉莫三嗪：拉莫三嗪： NaNa++ channel antagonist. Effective a channel antagonist. Effective against both partial and generalized epilepsygainst both partial and generalized epilepsy

FlunarizineFlunarizine 氟桂利嗪氟桂利嗪 : Inhibit L- and T-type Ca: Inhibit L- and T-type Ca2+2+ channel. br channel. broad spectrumoad spectrum

TopiramateTopiramate 托吡酯：托吡酯： Blocks AMPA+kainate receptorsBlocks AMPA+kainate receptors

Also blocks Also blocks NaNa++ and Ca and Ca2+2+ channelschannels


卡马西平

苯妥英钠丙戊酸钠

拉莫三嗪

丙戊酸钠

乙琥胺

二甲双酮

丙戊酸钠

苯二氮卓类

巴比妥类

Increasing expression of ABC transporter after epilepsyIncreasing expression of ABC transporter after epilepsy

Anti-epileptic drug Anti-epileptic drug sensitive ratsensitive rat

P-gp P-gp

Anti-epileptic drug Anti-epileptic drug insensitive ratinsensitive rat

P-gpP-gp 抑制剂增强抗癫痫药抑制剂增强抗癫痫药 (( 奥卡西平奥卡西平 , oxcarbazepine, oxcarbazepine ，， OXC)OXC) 作用及作用及延长癫痫病人入院间隔时间延长癫痫病人入院间隔时间

P-gpP-gp 基因敲除及其抑制剂增加脑内抗癫痫药浓度基因敲除及其抑制剂增加脑内抗癫痫药浓度

Common toxicity of antiepileptic drugs:Common toxicity of antiepileptic drugs:

CNS reactionsCNS reactions

Hemological reactionsHemological reactions

Hepatic toxicityHepatic 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.

Principals of antiepileptic drug usesPrincipals of antiepileptic drug uses1. Choice of drugs1. Choice of drugs

(1) Grand mal / Partial(1) Grand mal / Partial ：： Phenytoin, Carbamazepine, PhenobarbitalPhenytoin, Carbamazepine, Phenobarbital Primidone, Valproate sodiumPrimidone, Valproate sodium

(2) Peptit mal:(2) Peptit mal: EthosuximideEthosuximide

Clonazepam, Valproate sodiumClonazepam, Valproate sodium

(3) Psychomotor(3) Psychomotor ：： Carbamazepine, PhenytoinCarbamazepine, Phenytoin

(4) Status epilepticus(4) Status epilepticus ：： Diazepan (i.v.)Diazepan (i.v.)

Phenytoin (i.v.), Phenobrbital (i.m.)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

1. 1. EffectsEffects ：： central depression;central depression; vasodilatation, BP vasodilatation, BP ; ; relaxing skeletal musclesrelaxing skeletal muscles

2. 2. UsesUses ：： convulsionconvulsion ；； hypertension crisishypertension crisis

3. 3. Adverse effectsAdverse effects ：： depression of respiratory and vasomotor centers, depression of respiratory and vasomotor centers,

antagonized by Caantagonized by Ca2+2+ preparations ( preparations (i.v.i.v.))

Magnesium Sulfate Magnesium Sulfate 硫酸镁硫酸镁

B.B. Anticonvulsant drugsAnticonvulsant drugs

Other anticovulsant drugsOther anticovulsant drugs

Sedative-hypnotic drugsSedative-hypnotic drugs

B.B. Anticonvulsant drugsAnticonvulsant drugs

Antiepileptic and Anticonvulsant Drugs

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