Download 抗癫痫药

Antiepileptic and
Anticonvulsant Drugs
Zhong Chen
Department of Pharmacology
[email protected]
2012.5.14
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.
8:00-8:45
抗癫痫药和抗惊厥药
1
陈忠
8:50-9:35
癫痫概念、分类与发病机制
1
临床
09:50-10:35
癫痫临床表现、诊断与鉴别诊断
1
临床
10:40-11:25
癫痫治疗
1
临床
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 malfunction
Accompanied with abnormal EEG
发病率高；
突发性，不可预测；
很难根治，常需终身服药
Classification 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
•
Partial seizures with
dyscognitive features
Partial Seizures with
secondary generalization
•
Partial seizures
without dyscognitive
features
限性）

（局限性发作继发全身强直阵挛性
发作）
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
The pathways for
seizure propagation in
partial seizures and
primary generalized
seizures
病因论

1.
2.
3.
4.
5.
6.
7.
Underlying causes: 遗传
Birth trauma 外伤
Head injury 脑损伤
Tumour 肿瘤
Infection 感染
Metabolic disorder 代谢性病症
Cerebrovascular accident 脑血管意外
Deteriorating brain disease 其它脑疾病恶化
CAUSES OF CONGENITAL EPILEPSY
（先天性的）
• DYSGENESIS (生殖障碍，FAILURE OF
CORTEX TO GROW PROPERLY)
• VASCULAR MALFORMATIONS（畸形）
• AT LEAST EIGHT SINGLE LOCUS GENETIC
DEFECTS ARE ASSOCIATED WITH
EPILEPSY. MOST FORMS INVOLVE
INHERITING MORE THAN ONE LOCUS.
(EXAMPLES: JUVENILE MYOCLONIC,
PETIT MAL)
诱发的危险因素
1. Alcoholism酒精中毒.
2. Withdrawal from alcohol (“hang-over
period”)酒精戒断症.
3. Physical debilitation (illness, lack of sleep,
exhaustion).过度疲劳
4. Emotional stress情绪应激
5. Watching visual flicker闪烁的视觉障碍
6. Unknown aetiology.一些未知因素
Origin of a surface epileptic discharge
•
EEG
•
Populations of
neurons (field
potentials)
•
Individual
neurons
•
Individual
synapses
•
Individual ion
channels on
individual
neurons
 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.
Surface Spike
PDS
Sodium Influx
Calcium Influx
Chloride Influx
K efflux
Imbalance of excitation and inhibitory
Na+、Ca2+、NMDA 、K+ 、Cl-、GABA
Antiepileptic
drugs
Focus formation and epileptic attack
Focus shift
Spreading
Refractory epilepsy
Mechanisms of antiepileptic drugs
 Electrophysiological
 Inhibiting excessive discharges
 Inhibiting spread of discharges





Molecular
Potentiating GABA neuronal functions
Inhibiting excitatory neuronal functions（NMDA）
Modulating Na+, Ca2+, K+, Cl- channel fuctions
Others???
现有抗癫痫药物作用靶点
Bialer M et al., Nature Review, 2010
抗癫痫药物发展历程
第一代
第二代
第三代
溴化物、硼砂
正在研发的新型抗癫痫药
最终目标
预防及治愈癫痫
Shorvon SD et al., Epilepsia, 2009
抗癫痫药物的分类
按化学结构分类：
O
H
N
巴比妥类（苯巴比妥）
O
乙内酰脲类（苯妥英钠）
O
丁二酰亚胺类（乙琥胺）
苯二氮卓类（地西泮）
二苯并氮杂卓类（卡马西平、奥卡西平）
脂肪羧酸类（丙戊酸钠）
氨基酸类（加巴喷丁）
新型AEDs（拉莫三嗪、托吡酯、LEV等）
17
O
Na
A. Antiepileptic drugs
Phenytoin*
 Blocks sodium channels
 Effective against partial
seizures and generalized
tonic-clonic seizures
 Non-linear kinetics
 Half life = 24 hours
 Therapeutic range = 10-20
ug/ml

Levels above 20 cause ataxia
and nystagmus
 Hepatic metabolism


20ug/ml
CYP3A enzyme pathway
CYP3A antagonists will raise
phenytoin levels
www.boomer.org/c/p4/c21/c2103.html
Oral Dose: about 5 mg / kg
A. Antiepileptic drugs
1. Pharmacological effects and the mechanism
(1) Effects
— Inhibiting spread of abnormal discharges
— Not on the happening of abnormal discharge
— Inhibit Na+ and Ca2+ influx
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
A. Antiepileptic drugs
2. Clinical uses
(1) Antiepilepsy
 Grand mal, status epilepticus;
 Partial seizures (simple and complex);
 Ineffective for petit mal (absence seizures)
(2) Trigeminal and related neuralgia
sciatica (坐骨神经痛), glossopharyngeal neuralgia
(舌咽神经痛)
(3) Antiarrhythmia
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
A. Antiepileptic drugs
4. Adverse effects
(1) Local reactions
 GI reactions; gingival hyperplasia（齿龈增生）
(2) CNS reactions
 Particularly in the cerebellum and vestibular systems （小
脑前庭系统） : 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)
（巨幼红细胞性贫血）
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
Hirsutism(多毛)
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
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
A. Antiepileptic drugs
Phenobarbital
NH
O
CO
C
C2H5
C
NH




苯巴比妥
CO
C6H5
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.
A. Antiepileptic drugs
Ethosuximide





乙琥胺
Block T-type Ca2+ channel
Block Na+-K+ ATPase
Inhibit cerebral metabolism and GABA transaminase
Effective for peptit mal
Combined with phenobarbital
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%
During and After Valproate Therapy
It should be noted that valproate is an effective and popular
antiseizure drug and that only a very small number of patients have
had severe toxic effects from its use.
A. Antiepileptic drugs
Carbamazepine
 Blocks
and
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
Na+
Ca2+
卡马西平
N
CONH 2
 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
 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
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
卡马西平
苯妥英钠
拉莫三嗪
丙戊酸钠
丙戊酸钠
二甲双酮
乙琥胺
丙戊酸钠
苯二氮卓类
巴比妥类
Drugs which primarily affect
potassium channel
 Levetiracetam




Blocks voltage gated K+
channels in hippocampus
neurons
Blocks kainate receptors
Affects GABA receptors
Blocks action potentials,
and paroxysmal
depolarizing shifts
Madeja et al Neuropharamacology 2003
Drugs which primarily affect
potassium channel
Levetiracetam
 Effective for partial
epilepsy with or without
generalization
 High Potency
-----75% reduction in
seizures in over 20% of
refractory patients
 Few side effects except:


Somnolence, asthenia, and
dizziness
Pregnancy category C
Drugs which affect Kainate and AMPA receptors
 Topiramate
 Zonisamide
Topiramate
托吡酯
 Mechanisms -Multiple
 Blocks AMPA+kainate
receptors
 Blocks Na+ and Ca2+
channels
 Potentiates GABA
transmission
 Effective against both partial
and generalized epilepsy
 Excreted primarily in urine
 Start at 25 mg/day, titrate to
300-500/day
 Behavioral /Cognitive problems
common (somnolence, fatigue,
dizziness, cognitive slowing,
paresthesias, nervousness, and
confusion)
 Low risk of rash
 Causes weight loss
 Class D in pregnancy (oral
clefts)
 High Potency
----75% reductions in over 20% of
refractory patients
Teratogenicity 致畸作用
 All AEDs cause fetal
malformations in at least 6% of
infants, such as neural tube
defects, mouth malformation,
cardiopathy.
 Highest risk with phenytoin,
valproate, phenobarbital, and
carbamazepine, etc (Class D
drugs)
 Folate supplementation prevents
neural tube defects (split spine, 脊
柱裂).
A. Antiepileptic drugs
Common toxicity of antiepileptic drugs:
CNS reactions
Hemological reactions
Hepatic 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.
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.)
During Treatment
 Start from mono-therapy
 Dose individualization and titration up
 No frequent changing and stop slowly
 Monitor frequently
NATURE REVIEWS | DRUG DISCOVERY
2010
Excitability
？
癫痫的形成和发作
癫痫扩散
Inhibition
抗癫痫药物
×
癫痫灶点转移
•单基因
•单离子通道
•单神经递质
•毒性较大
•停药困难
难治性癫痫（以颞叶癫痫最常见） •耐药性癫痫
Modulation of the NMDA receptor in
epileptogenesis
• Expression of subunit proteins
• NR1-NR2 co-assembly
• Anchoring of the NMDA receptor at the
•
postsynaptic membranes
NMDA receptor phosphorylation
• However？
• Loss of GABA neurons
• Decreased expression of GABA receptors
• Transformation from inhibitory to “excitatory”
(due to Cl- balance potential, a change of
transporter expression)
• However, the para-synaptic GABA-----
Failure of GABA inhibitory function in epileptogenesis
现状：
近16年来有14个抗癫痫新药上市。
挑战：
1、缺少难治性癫痫的有效治疗药物
2、缺少作用于癫痫形成过程的药物
3、缺少预防高风险人群癫痫发作的药物
目标：
治疗的目标应该是完全控制惊厥，没有或只有轻微
的副作用,保持正常生活方式。
52
抗癫痫药
手术治疗
迫切需要寻找新的安全有效的治疗方法！
1. 已有抗癫痫药只能控制症
状为主
2. 25~30%左右的患者产生耐
药（尤其是颞叶癫痫）
Bialer M, et al. Nat Rev Drug Discov, 2010
3. 药物毒副作用明显
1. 多灶点、隐源性癫痫患
者并不适合手术
2. 30%左右的患者术后依
旧复发
Berg
AT, et al. Nat Rev Neurol, 2011
3. 并发症
Epilepsy Surgery is not always useful
For example
发作起始区
致痫区定位困难的患者
SOZ 和重要功能运动区接近
多灶性癫痫
药物新靶点和药物的开发
亚细胞特异性
神经环路特异性
靶向性
抗癫痫药物
毒性小，耐药性小
个性化给药
有效预防和治疗
用光遗传学失活皮层谷氨酸能神经元兴奋性可以有效控制癫痫
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.)
B. Anticonvulsant drugs
 Other anticovulsant drugs
 Sedative-hypnotic drugs