Antiepileptic and Antiepileptic and Anticonvulsant DrugsAnticonvulsant Drugs

Zhong ChenDepartment of Pharmacology

chenzhong@zju.edu.cn

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 陈忠8:50-9:35 癫痫概念、分类与发病机制 1

09:50-10:35 癫痫临床表现、诊断与鉴别诊断 1

10:40-11:25 癫痫治疗 1

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。

Definition of EpilepsyEpilepsy is a chronic neurological disorder

characterized by recurrent seizures, which are finite

episodes of brain dysfunction resulting from abnormal

discharge of cerebral neurons.

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Third most common neurologic disorder after AD and stroke in the US.

Annual incidence in developed countries 50-70/100,000, higher in developing countries, worldwide prevalence 0.5-1%.

Incidence varies with age, high in early childhood, low in early adult life, and second peak after 65 yo.

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Incidence and prevalence of epilepsy

Classification of epileptic seizures

Simple partial

Complex partial

(consciousness is affected)

Partial seizures with secondary

generalization

Source of seizure

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Partial onset seizures

Absence (Petit Mal) Generalized Tonic+Clonic

(Grand Mal) Tonic Atonic Clonic and myoclonic

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Primary generalized seizures

Classification of epileptic seizures

Epidemiology by seizure types

Hauser WA. Epilepsia. 1992;33(suppl 4):S10.

Complex Partial

Unclassified

Myoclonic

Absence

Partial Unknown

Other Generalized Simple Partial

Generalized TC

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Stereotypical complex partial seizures8

Tonic phase

Clonic phase

CyanosisCry

Salivary frothing

Jerking of the limbs

Post-ictal phase

Patient feels lethaargic and confused after seizuresOften sleeps

Loss of consciousness, Fall, crying, and generalized tonic stiffeningoften with bladder incontinence

Simultaneous bilateral cortical seizure attack (GTC)

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病因论病因论 Underlying causes: Underlying causes: 遗传遗传1.1. Birth trauma Birth trauma 外伤外伤2.2. Head injury Head injury 脑损伤脑损伤3.3. Tumour Tumour 肿瘤肿瘤4.4. Infection Infection 感染感染5.5. Metabolic disorder Metabolic disorder 代谢性病症代谢性病症6.6. Cerebrovascular accident Cerebrovascular accident 脑血管意外脑血管意外7.7. Deteriorating brain disease Deteriorating brain disease 其它脑疾病恶化其它脑疾病恶化

•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

Current status of epilepsy treatmentDrug treatment is the main approach. AEDs are

from the first generation to the third generation.

Refractory epilepsy: about 30% of patients do not

respond at all, about 10% of patients with good initial

AED response cease to respond.

Surgery, ketogenic diet, electrical stimulation are options

for intractable epilepsy.

New drugs and new approaches are needed.13

Epilepsy Surgery is not always useful

致痫区定位困难的患者

多灶性癫痫

For exampleFor example

发作起始区

SOZ 和重要功能运动区接近

神经兴奋性毒性引起病理学改变神经兴奋性毒性引起病理学改变 Neuronal lossNeuronal loss神经元细胞缺失神经元细胞缺失

Pyramidal cells Dentate granule cells Inhibitory interneurons

Neuronal damageNeuronal damage神经元损伤神经元损伤 Reduced arborization of dentritic tree Reduced GABA receptors Reduced NMDA receptors

NeuroplasticityNeuroplasticity神经可塑性改变神经可塑性改变 Upregulation of NMDA receptors Downregulation of GABA receptors Sprouting of dentate granule cell axon

HyperexcitabilityHyperexcitability

GlutamateNMDA Receptor

Activation of AMPA receptor-> postsynaptic depolarization potentials/action potentials-> removal of voltage-dependent Mg++ blockade-> opening both Na+ and Ca++ channels

Ca++ influx mediated by NMDA receptor-> downstream intracellular signaling events-> enhance synaptic strength and synaptic plasticity.-> uncontrolled neuronal excitability

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Meir Bialer NATURE REVIEWS| Drug Discovery 2010

Mechanisms of AEDs

Modification of ionic conductance.

- Na+

- K+

- Ca2+

Enhancement of GABAergic (inhibitory) transmission

Diminution of excitatory transmissionNetwork?

Bialer M et al., Nature Review, 2010

现有抗癫痫药物作用靶点

溴化物、硼砂

最终目标预防及治愈癫痫

正在研发的新型抗癫痫药

Shorvon SD et al., Epilepsia, 2009

抗癫痫药物发展历程

第一代 第二代 第三代

抗癫痫药物的分类抗癫痫药物的分类按化学结构分类：

巴比妥类（苯巴比妥）乙内酰脲类（苯妥英钠）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） 22

HNO

O

O

O

Na

AEDs Effective as Monotherapy (Single Agent)

Partial (Localization Related)

Phenytoin Carbamazepine Valproate Oxcarbazepine Lamotrigine Topiramate Gabapentin

Generalized

Phenytoin Carbamazepine Valproate

(GTC and absence) Ethosuximide - (absence) Topiramate

(GTC) Lamotrigine

(absence)

Bold= new generation AED

New AEDs effective as adjunctive treatment for refractory epilepsy

Partial

Topiramate Levetiracetam Pregabalin Zonisamide Oxcarbazepine

Lamotrigine Gabapentin Tiagabine

Generalized

Topiramate Levetiracetam Lamotrigine

Data from randomized placebo controlled trials

Drugs in red are generally considered high potency

Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by

cultured neurons.

Drugs that act on Na+ channel

PhenytoinCarbamazepineOxcarbazepineLamotrigine

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Mechanisms of action:Binding to and hence prolonging the status

of inactivated state of Na+ channels (main mechanism)

Blocking L- and N- type Ca2+ channels (inhibits release of transmitters, stabilizes membrane)

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Phenytoin

Phenytoin (Dilantin)

Non-linear kinetics Therapeutic range = 10-20 μg/ml

Levels above 20 cause ataxia and nystagmus ( 眼球震颤 )

Half life = 12-24 hours, slow effect

Oral Dose: about 5 mg / kg

www.boomer.org/c/p4/c21/c2103.html

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• Hepatic metabolism

- CYP2C enzyme pathway

- CYP3A/2C enzyme inducer

2. 2. Clinical uses*Clinical uses*

(1) Antiepilepsy(1) Antiepilepsy Effective against partial seizures and generalized tonic-

clonic seizures Grand mal, status epilepticus ; Grand mal, status epilepticus ; Partial seizures (simple and complex);Partial seizures (simple and complex); Ineffective for petit mal (absence seizures)Ineffective for petit mal (absence seizures)

(2) Trigeminal and related neuralgia(2) Trigeminal and related neuralgia sciatica ( 坐骨神经痛 ), glossopharyngeal neuralgia ( 舌咽神经痛 )

(3) Antiarrhythmia(3) Antiarrhythmia

Phenytoin

Side effects:

CNS: Particularly in the cerebellum and vestibular systemsParticularly in the cerebellum and vestibular systems （小脑（小脑前庭系统）前庭系统） : nystagmus: nystagmus（眼球震颤）（眼球震颤） , ataxia, ataxia（共济失调）（共济失调） .

Behavioral changes: confusion, hallucinationBehavioral changes: confusion, hallucination

Local irritating (alkaline): gingival hyperplasia, GI upset,

phlebiitis

Hematologic complications

- Megaloblastic anemia （巨幼红细胞性贫血）（巨幼红细胞性贫血）

(folic acid loss)

- Agranulocytosis

Phenytoin

Gingival hyperplasia

Side effects: (4) Allergic reactions(4) Allergic reactions Skin reactions; blood cell abnormality (including Skin reactions; blood cell abnormality (including

thrombocytopeniathrombocytopenia 血 小 板 减 少 症 , , agranulocytosisagranulocytosis 粒细胞缺乏 );hepatic toxicity; );hepatic toxicity; ect.ect.

(5) Skeletal reactions(5) Skeletal reactions OsteomalaciaOsteomalacia 骨质软化症 by abnormal vitamin D by abnormal vitamin D

metabolism and calcium absorptionmetabolism and calcium absorption 低血钙症低血钙症 (6)(6) Teratism 畸胎畸胎

Others: birth defects (fetal malformations,

class D), hirsutism

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Phenytoin

hirsutism

Necessary to monitor plasma concentrationsNecessary to monitor plasma concentrations

4.4. Drug interactions Drug interactions

(1) Increases plasma concentrations of drugs by (1) Increases plasma concentrations of drugs by displacement of plasma protein binding (salicylates)displacement of plasma protein binding (salicylates) ， ， and inhibition of P450 inactivation (isoniazidand inhibition of P450 inactivation (isoniazid 异烟肼 , , chloramphenicolchloramphenicol 氯霉素 ))

(2) Decreases plasma concentrations of drugs (2) Decreases plasma concentrations of drugs (phenobarbital, carbamazepine) by by enhancing (phenobarbital, carbamazepine) by by enhancing metabolismmetabolism

(3) Phenytoin enhances the metabolism of corticosteroids (3) Phenytoin enhances the metabolism of corticosteroids and vitamin Dand vitamin D

A.A. Antiepileptic drugsAntiepileptic drugs

Carbamazepine卡马西平

Mechanisms: blockade of Na+ and Ca2+ channels, potentiation of GABA transmission

Half life = 8-12 hours (steady state)

Like phenytoin, metabolized by CYP3A pathway (inducer itself)

Effective against partial and generalized tonic-clonic seizures, trigeminal neuralgia and mania

Safety and Toxicitypeak effect- diplopia, ataxiarash 5-10%rare marrow suppression

aplastic anemia and

agranulocytosisrare hepatitisfrequent hyponatremia at high dosefetal malformations (class D)

Dose in Adults 200 mg once a day After several days, 200 mg twice

a day Slowly titrate to 10 mg/kg

• Therapeutic = 6 -12 ug/ml

Watch for Rash!

Carbamazepine

Oxcarbazepine

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--- less effective

--- improved toxicity profile

(fewer hypersensitivity reactions

less hepatic enzyme induction)

Lamotrigine拉莫三嗪

Na+ channel blocker Ca2+ channel blocker Moderate effective against both partial

and generalized epilepsy (absence/myoclonic) as add-on or monotherapy

Hepatic metabolism, significant drug interactions with valproate (CYP inhibitor) leads to twofold increase in half-life time (level and side-effects increase)

Linear clearance Half life -24 hours Start 25 mg/day, titrate slowly to 300-

500 mg/day

10% risk of rashDizziness,

headache, diplopia, nausea, somnolence

Class C in pregnancy, significantly lower than other

Side effects

Benzodiazepines Binds to BZD specific receptors

Phenobarbital Binds to barbiturate specific receptors

Gabapentin GABA analogue, alters GABA metabolism, release and

reuptake, effective as an adjunct against partial seizures and generalized tonic-clonic seizures

Valproate Decreases GABA degradation in presynaptic terminal

Drugs acting at the chloride channels

Valproate丙戊酸

Broad spectrum: - absence: ethosuximide first

choice - generalized tonic-clonic - partial Blocks Na+ channels and

NMDA receptors Increases GABA levels

Facilitates GAD Inhibits GAT-1 Inhibits degradation of

GABA dose = 15-20 mg/kg to start

using a TID schedule

GI side effects (abdominal pain and heartburn)

Obesity + Metabolic syndrome (weight gain, increased appetite, and hair loss)

Hepatotoxicity, elevates ammonia (liver function monitoring required)

Fine tremor Serious neural tube (spina bifida,

split spine) and cardiac defects in fetus in 1% (Pregnancy Category D)

Side effects:

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.

Drugs that affect KA and AMPA receptors

Topiramate (Topamax)

Zonisamide (Zonegran)

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Topiramate (Topamax)

Mechanisms

Blocks AMPA+kainate receptors

Blocks Na+ and Ca2+ channels

Potentiates GABA transmission

Effective against both partial and generalized epilepsy as

add-on or monotherapy

High Potency

---75% reductions in over 20% of refractory patients

Excreted primarily in urine

Start at 25 mg/day, titrate to 300-500/day 41

Topiramate

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)

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Side effects:

Drugs that affect calcium channels

Levetiracetam ( 左乙拉西

坦 ) Binds synaptic vesicle

glycoprotein 2A and inhibits

presynaptic Ca2+ channels

Blocks kainate receptors

Affects GABA receptors43

Effective for partial

epilepsy with or without

generalization as add-

on therapy

High Potency

--75% reduction in

seizures in over 20% of

refractory patients

Few side effects except:

Somnolence,

asthenia, and

dizziness

Pregnancy category C

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Levetiracetam

Drugs which affect calcium channels

Ethosuximide 乙琥胺 *

• Mechanism– Blocks T-Ca2+ channels in thalamic neurons (T-type

calcium currents are thought to provide a pacemaker current in thalaamic neurons responsible for generating the rhythmic cortical discharge of an absence attack)

• Effective against absence seizures• Long half life time 40~50h• Effective dose range 750–1500 mg/d

• Adverse effects: gastric distress (stomachache, nausea, vomiting), CNS response (fatigue, dizziness, headache, euphoria, sleepiness, hiccup)

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 ).

When to initiate treatment?

Case Study: Initiation of Treatment

A 22 year old female sustains a head injury with loss of consciousness

Two years later she develops a single secondarily generalized tonic-clonic seizure

MRI and EEG are normal You should

1. Instruct her not to drive. Report the event to the department of public health or DMV

2. Wait until a second seizure, and then initiate an AED

3. Initiate a pregnancy class C AED now.

4. Initiate, phenytoin, valproic acid, phenobarbital, or carbamazepine now

Initiation of Treatment

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%

It depends on the level of risk and the patient’s situation

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Consider treatment Do not treat

Abnormal EEG Normal EEG

Known cause (tumor, stroke) Unknown cause

Generalized tonic-clonic seizure Simple partial seizure

High-risk occupation (driver, pilot, etc)

Seizure during sleep

No disease interfering with drugs

Blood, liver kidney disease

Alcohol- or drug-related seizure

Factors for determining whether to start treatment after a first seizure

the risk-benefit ratio of the antiepileptic treatment must be carefully assessed in patients after a single seizure

Avoid class D AEDs like valproic acid in a woman of childbearing potential.

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Initiation of treatment

Initiation of Treatment

Increased risk• Known symptomatic cause• Partial seizures• Family history of epilepsy• Abnormal electroencephalogram (particularly generalized spike-and-slow wave)• Abnormal findings on neurologic examination• Abnormal imaging findings

Decreased riskIdiopathic causeGeneralized seizureNo family history of epilepsyNormal electroencephalogramNormal findings on neurologic examination

Initiation of Treatment

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Box Box Common toxicityCommon toxicity of antiepileptic drugs: of antiepileptic drugs:

CNS reactionsCNS reactions

Hemological reactionsHemological reactions

Hepatic toxicityHepatic toxicity

A.A. Antiepileptic drugsAntiepileptic drugs

2. Dosage2. Dosage ：： small – larger doses; small – larger doses; dose individualization; dose individualization; plasma concentration monitoring if necessaryplasma concentration monitoring if necessary

3. Usage3. Usage ：： drug combinationdrug combination

4. Withdrawal4. Withdrawal ：： gradually and slowlygradually and slowly

A.A. Antiepileptic drugsAntiepileptic drugs

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 centersdepression of respiratory and vasomotor centers

血管运动中枢 , , antagonized by calcium antagonized by calcium preparations (preparations (i.v.i.v.))

Magnesium Sulfate Magnesium Sulfate 硫酸镁硫酸镁B.B. Antiseizure drugsAntiseizure drugs

Other anticovulsant drugsOther anticovulsant drugs

Sedative-hypnotic drugsSedative-hypnotic drugs

B.B. Anticonvulsant drugsAnticonvulsant drugs