Transcript 第十六章抗癫痫和抗惊厥药

Antiepileptic and Anticonvulsive Drugs
Lou haiyan
Institute of Pharmacology
School of Medicine
Shandong University
[email protected]
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Section 1 Antiepileptic Drugs
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Epilepsy (癫痫)
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Definition of epilepsy
A seizure is the clinical manifestation of a
sudden, excessive and synchronous
discharge of focal neurons and diffusion to
normal neuronal tissues.
Epilepsy is characterized by recurrent,
sudden and transient seizures.
sensory disorder, behavior disorder, and
psychotic
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Classifications of seizure types
1. Partial seizures (局限性发作)
① Simple partial seizures (单纯性局限性发作)
② Complex partial seizures (复合性局限性发作)
Psychomotor seizures (精神运动性发作)
2. Generalized seizures (全身性发作)
① Absence (petit mal) seizures (失神性发作, 小发作)
② Myoclonic seizures (肌阵挛性发作)
③ Generalized tonic-clonic (grad mal) seizures
(强直-阵挛性发作, 大发作）
④ Status epilepticus (癫痫持续状态)
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Cause of epilepsy
 Idiopathic epilepsy
 Complicated
 Genetic
 Secondary epilepsy
 CNS infection
 Trauma
 Tumor
 Parasites etc
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Pathogenesis of epilepsy
 initiation and spread
 Imbalance function of neurotransmitters
and instable neuronal membrane
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EEG Records During Epileptic
Seizure
Epilepsy is characterized by
uncontrolled excessive activity of
either a part or all of the central
nervous system.
Grand mal epilepsy: characterized
by extreme neuronal discharges in
all areas of the brain, last from a
few seconds to 3 to 4 minutes.
Petit mal epilepsy: Characterized
by 3 to 30 seconds of
unconsciousness or diminished
consciousness during which the
person has several twitch-like
contractions of the muscle.
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Diagnosis of Epilepsy




Yes or No ?
History
Classification
Reason?
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Treatment of Epilepsy
 Aim: Keep the patient free of seizures,
with no adverse effects, not affecting the
life quality.
 Cause
 Drug treatment
 Surgery or physical therapy
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Mechanisms of antiepilepsy drugs
Action Patterns:
1. Block the initiation of abnormal of
abnormal discharge from the focal area.
2. Prevent the spread of abnormal
discharge to adjacent brain areas.
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Mechanisms of antiepileptic drugs
1. Decrease activity of voltage-dependent Na+ channels
2. Decrease activity of voltage-dependent Ca2+ channels
N-type (neuronal); L-type (long lasting)
T-type (transient)
3. Enhance GABAergic transmission
decrease the reuptake or metabolism of GABA
direct action on the GABAA-R
4. Diminish glutamate function
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Section 2
Commonly-used antiepileptic drugs
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phenytoin sodium (苯妥英钠)
barbiturates： phenbarbital (苯巴比妥)
primidone (扑米酮)
carbamazepine (卡马西平)
ethosuximide (乙琥胺)
sodium valproate (丙戊酸钠)
benzodiazepines: diazepam ( 地西泮)
nitrozepam ( 硝西泮)
clonazepam (氯硝西泮)
antiepilepsirine (抗痫灵)
newer drugs: flunarizine (氟桂利嗪)
lamotrigine (拉莫三嗪)
topiramate ( 托吡酯)
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1. Phenytoin Sodium
（苯妥英钠, Dilantin, 大仑丁）
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【Pharmacological actions】
 Can not inhibit the discharge of neuron in
focus
 Prevent the diffusion in normal neuron
inhibit posttetanic potentiation (PTP,强直后增强):
反复高频电刺激(强直刺激)突触前神经纤维，引起突触
传递易化，使突触后纤维反应增强的现象
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【 Mechanisms of action 】
Membrane-stabilizing function
1. block voltage-sensitive Na+ channel
2. block voltage-sensitive Ca2+ channel
(L type, N type)
3. inhibit the activity of calmodulin kinase
(钙调素激酶)


presynaptic membrane—Glu release↓
postsynaptic membrane—depolarization↓
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【clinical uses】
1. Epilepsy:
generalized tonic-clonic seizures (grad mal)
and partial seizures (first choice)
except absence seizures (petit mal)
(no effect, even exacerbate disease)
attention: slow onset
phenobabital → phenytoin sodium
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【clinical uses】
2. Neuralgias：
trigeminal neuralgia (三叉神经痛)
glossopharyngeal neuralgia(舌咽神经痛)
3. Ventricular arrhythmia (心律失常) ：
cardiac glycoside induced (强心苷中毒)
-first choice
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【 Pharmacokinetics 】
1. Absorption
strong irritation(alkaline,pH=10.4), not im.
Oral: unpredictable, slow onset
Css : 6-10d (10-20ug/ml)
iv. for status epilepticus
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【 Pharmacokinetics 】
2. Metabolism:
mainly in liver, hepatic enzyme induction
≤ 10g/ml :first-order elimination kinetics,
t1/2=20h
≥ 10g/ml : zero-order elimination kinetics,
t1/2=60h
monitor blood drug concentration (10-20g/ml)
3. C=10g/ml (anti- epilepsy)
C=20g/ml (intoxication)
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Adverse Reactions
 1. Local stimulation
 ① gastrointestinal irritation
 ② phlebitis (静脉炎)
 ③ gingival hyperplasia
20%
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 2. CNS symptoms
 20g/ml：dizziness, ataxia
﹥40g/ml: psychotic disiorder
﹥50g/ml: coma
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 3. Megaloblastic anemia
 防治：甲酰四氢叶酸
 4. Hypocalcemia,
osteomalacia(软骨症)
rachitis(佝偻病): children
 防治：Vit D
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Adverse Reactions
5. Allergy
skin rash
agranulocytosis（粒细胞缺乏）
thrombocytopenia（血小板减少）
aplastic anemia（再生障碍性贫血）
hepatic lesion
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【 Adverse Reactions 】
6.Teratogenesis
fetal hydantoin syndrome
(胎儿妥因综合征）
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芬兰 1980～1998年，研究人员追踪了一家
产科诊所中970位怀孕的癫痫妇女，其中有
740位在怀孕初期（前3个月）服用抗癫痫药
物，另外239位则无。结果在这些服用抗癫
痫药物的怀孕妇女中，共产下28个严重畸形
儿（3.8%），未服用抗癫痫药物组产下2个
严重畸形儿（0.8%；P=0.02）
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2. Phenobarbital (苯巴比妥)
【Pharmacological actions and clinical uses】
1. rapid onset
2. used for generalized tonic-clonic seizures and
status epilepticus (iv), but not first choice
Mechanisms: inhibit initiation and spread of abnormal
discharge
 increase GABA induced Cl-in (extend opening time)
 inhibit excitatory neurotransmitter-mediated effect
 high dose inhibit Na+ ,Ca2+ (L and N-type) channel
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3. Primidone (扑米酮)
active metabolites:
phenobarbital
phenylethylmalonamides
(PEMA, 苯乙基丙二酰胺)
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4. Ethosuximide (乙琥胺)
The only indication: absence epilepsy-first choice
Mechanisms:
inhibit the T-type Ca2+ current in thalamic
neurons
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5. Benzodiazepines
1. Diazepam: status epilepticus-first choice
(iv, slow)
2. Nitrazepam (硝西泮):
absence seizure, myoclonic seizure,
infantile spasm
3. Clonazepam (氯硝西泮): broad-spectrum
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6. Sodium Valproate (丙戊酸钠)
Uses: Broad-spectrum
 Less effective for grad mal than phenytoin and
phenobarbital
 Similar effective for partial mal with carbamazepine
 More effective than ethosuximide for absence seizure
but not the first choice due to hepatic toxicity.
 Grad mal combined with absence seizure -first choice
 Refractory epilepsy(顽固性癫痫)
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 Mechanisms:
inhibit discharge spread
 enhance GABA function：
 inhibit Na+ , T-type Ca2+ channel
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6. Sodium Valproate (丙戊酸钠)
Sodium Valproate
+
glutamic acid
GAD
-
GABA
GABA-T succinic acid
GAD:谷氨酸脱羧酶
semialdehyde
琥珀酸半醛
GABA-T：谷氨酸转氨酶
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Adverse Reactions
 Gastrointestinal reactions and CNS
reactions
 Liver injury: 25% routine examination
 Teratogenesis
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7. Carbamazepine (卡马西平)
【Pharmacological actions and clinical uses】
1. Epilepsy: broad spectrum
grad mal, complex partial seizures -first choice
no good for absence epilepsy
2. Neuralgias: more effective than phenytoin
Mechanisms
 inhibit Na+ 、Ca2+ channel
 enhance GABA inhibitory function
3. Diabetes insipidus (尿崩症)
4. Mania and depression (躁狂抑郁症)
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尿崩症
病因: 下丘脑-神经垂体部位的病变
↓ADH (AVP), 肾小管重吸收功能障碍
多尿、烦渴、多饮与低比重尿
AVP (arginine vasopressin): 精氨酸加压素
ADH (antidiuretic hormone): 抗利尿激素
卡马西平：促进ADH分泌
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Others
 Antiepilepsirin (抗痫灵)
 flunarizine (氟桂利嗪)
 Lamotrigine (拉莫三嗪)
newer
 Topiramate (托吡酯，妥泰)
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Principles
1. Select drug according to epilepsy classification
2. Increase dose gradually
3. Transitional drug change: add a second drug
before stop the first one
4. Withdraw slowly (half year)
5. Monitor hemogram(血象) and liver function
6. Pregnant woman should take caution
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对症选药原则
癫痫类型
首选药物
大发作和局限性发作
小发作
大发作和精神运动型性发作
癫痫持续状态
大发作合并小发作
苯妥英钠
乙琥胺
卡马西平
地西泮 iv
丙戊酸钠
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Principles
1. 对症选药
2. 剂量渐增
3. 先加后撤
4. 久用慢停
5. 肝功血象
6. 孕妇慎用
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Section 3 Anticonvulsants
 Barbiturates
 Benzodiazepines
 Chloral hydrate
 Magnesium Sulfate
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Magnesium Sulfate
different administration routes →different effects
1. oral — catharsis, cholagogue (导泻、利胆)
2. external — dephlogisticate (消炎)
3. iv or im —
anticonvulsive: relaxant of skeletal muscle
BP lowering: inhibit cardiac muscle, dilate VSM
Mechanism: calcium antagonism
Uses: hypertensive crisis, convulsion
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Magnesium Sulfate
Overdose:
respiratory inhibition
and hypotension
tendon reflex（腱反射）
Treatment:
 artificial breathing
 iv calcium chloride or
calcium gluconate
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Case history
 Gaby is a 22-year old student who is studying to becoming a
teacher. She has no previous serious medical history.One day,as
she relaxes with her fellow students after an examination, she feels
strange, with butterfly in her stomach and a sensation of fear and
anxiety. She then collapses rigidly onto the floor. She has strong
convulsions for about 2 min, during which she knocks against a
chair. Her body then relaxes, and for the next 3min she can not be
roused. When she wakes up she is confused and tired, and also
bruised from hitting the chair. She is taken to hospital by her
colleagues, where the doctor tells her she has a seizure, there is no
family history of seizure. She undergoes a series of test, including
an EEG and a brain scan. A few weeks later she has a second
seizure at home and following a consultation with the hospital
specialist, she starts taking sodium valproate. She is advised to
change her type of contraceptive pill. She is very concerned about
the implications of having this disease for her career choice as
teacher.
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