Antiepileptic and Antiepileptic and Anticonvulsant DrugsAnticonvulsant Drugs
2012.4.25
Weiping ZhangDepartment of Pharmacology
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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)
A.A. Antiepileptic drugsAntiepileptic drugs
(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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic 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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
Valproate sodium Valproate sodium 丙戊酸钠丙戊酸钠
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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.)
A.A. Antiepileptic drugsAntiepileptic drugs
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