1. Antiepileptic and Anticonvulsant Drugs
Zhong Chen
Department of Pharmacology

2. 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
09:50-10:35
癫痫临床表现、诊断与鉴别诊断
10:40-11:25
癫痫治疗
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。

3. Definition of Epilepsy
Epilepsy is a chronic neurological disorder characterized by recurrent seizures, which are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons.
Symptoms of epilepsy: abnormal motor control (seizures), cognition, sensation and consciousness
Epilepsy should not be understood as a single disorder, but rather as a group of vastly divergent symptoms but all involving episodic abnormal electrical activity in the brain.
Seizure symptoms vary. Some people with epilepsy simply stare blankly for a few seconds during a seizure, while others repeatedly twitch their arms or legs
Even mild seizures may require treatment because they can be dangerous during activities such as driving or swimming

4. Incidence and prevalence of epilepsy
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.

5. Classification of epileptic seizures
Source
of seizure
Partial onset seizures
Simple partial
Complex partial (consciousness is affected)
Partial seizures with secondary generalization
Seizure types are organized firstly according to whether the source of the seizure within the brain is localized (partial or focal onset seizures) or distributed (generalized seizures).
Partial seizures simple partial seizure and complex partial (psychomotor) seizure, depending on whether consciousness is affected. Complex partial seizures often result in blank staring and purposeless movements — such as hand rubbing, chewing, swallowing or walking in circles.
A partial seizure may spread within the brain - a process known as secondary generalization.

6. Classification of epileptic seizures
Primary generalized seizures
Absence (Petit Mal)
Generalized Tonic+Clonic (Grand Mal)
Tonic
Atonic
Clonic and myoclonic
Generalized seizures are divided according to the effect on the body but all involve loss of consciousness. May be accompanied with sensory and autonomic system dysfunction. Highly synchronous discharge in all recording channels.
Absence: brief loss of consciousness
Grand mal: unconsciousness, convulsions, muscle rigidity
Myoclonic: sporadic jerking movement
Clonic: repetitive rhythmic jerking movements
Tonic: muscle stiffness, rigidity
Atonic: loss of muscle tone

7. Epidemiology by seizure types
Complex Partial
Unclassified
Myoclonic
Absence
Partial Unknown
Other Generalized
Simple Partial
Generalized TC
Hauser WA. Epilepsia ;33(suppl 4):S10.

8. Stereotypical complex partial seizures
Stare, attention, scream, fear
Stereotypical complex partial seizures

9. Simultaneous bilateral cortical seizure attack (GTC)
Tonic phase
Simultaneous bilateral cortical seizure attack (GTC)
Cyanosis
Cry
Loss of consciousness,
Fall, crying, and
generalized tonic stiffening
often with bladder incontinence
Clonic phase
Salivary frothing
Jerking of the limbs
1    Aura may or may not be present. 2    Sudden loss of consciousness may occur. 3    In the tonic phase, the entire body becomes rigid. If standing or sitting, the client falls stiffly to the floor. A cry may be uttered. Respirations are interrupted temporarily, and the client may become cyanotic. The jaw is fixed and the hands are clenched. The eyes may be opened wide; the pupils are dilated and fixed. The tonic phase lasts 30 to 60 seconds. At the end of this phase the client breathes deeply.
4    The clonic phase begins next, with rhythmic, jerky contraction and relaxation of all body muscles, especially those of the extremities (see Figure 71-2, B). The client is usually incontinent and may bite the lips, tongue, or inside of the mouth. Excessive saliva is blown from the mouth, which creates frothing at the lips. 5    An entire tonic-clonic seizure may last from 2 to 5 minutes, after which the client enters the postictal phase, during which he or she relaxes and remains totally unresponsive for a time. The client may rouse briefly and then go into a postictal sleep lasting 30 minutes to several hours. This sleep may be followed by general fatigue, depression, confusion, or headache, all of which gradually resolve. The client has complete amnesia for the seizure episode and may feel nauseated, stiff, and sore. Bruising may occur as the result of falls. Petechial hemorrhages may develop on the face and chest due to the vasovagal responses. Falling during the seizure may cause other injury.
Tonic-clonic seizures vary in frequency from many times daily to once or twice a year. Tonic-only and clonic-only seizures may also occur.
Post-ictal phase
Patient feels lethargic and confused after seizures
Often sleeps

11. 病因论 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
AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE ASSOCIATED WITH EPILEPSY. MOST FORMS INVOLVE INHERITING MORE THAN ONE LOCUS. (EXAMPLES: JUVENILE MYOCLONIC, PETIT MAL)

12. 诱发的危险因素 Alcoholism酒精中毒.
Withdrawal from alcohol (“hang-over period”)酒精戒断症.
Physical debilitation (illness, lack of sleep, exhaustion).过度疲劳
Emotional stress情绪应激
Watching visual flicker闪烁的视觉障碍
Unknown aetiology.一些未知因素

13. Current status of epilepsy treatment
Drug 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.
About 20~30% of patients with epilepsy continue to have breakthrough epileptic seizures despite best anticonvulsant treatment.
Most AEDs only can control seizures, but can not inhibit epileptogenesis. Symptom control vs antiepileptogenesis. Little is known about the generation of epilepsy.

14. Epilepsy Surgery is not always useful

15. For example 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 发作起始区 举例癫痫手术困难的患者
例1：无灶的癫痫患者，定位困难
例2：多灶性癫痫
例3：患者的致痫区和运动区重叠
SOZ 和重要功能运动区接近
多灶性癫痫

16. 神经兴奋性毒性引起病理学改变 Neuronal loss神经元细胞缺失 Neuronal damage神经元损伤
Pyramidal cells
Dentate granule cells
Inhibitory interneurons
Neuronal damage神经元损伤
Reduced arborization of dentritic tree
Reduced GABA receptors
Reduced NMDA receptors
Neuroplasticity神经可塑性改变
Upregulation of NMDA receptors
Downregulation of GABA receptors
Sprouting of dentate granule cell axon

17. Glutamate NMDA Receptor Hyperexcitability 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

18. Meir Bialer NATURE REVIEWS| Drug Discovery 201018

19. Mechanisms of AEDs Modification of ionic conductance. - Na+ - K+
Enhancement of GABAergic (inhibitory) transmission
Diminution of excitatory transmission
Network? 19

20. 现有抗癫痫药物作用靶点
Bialer M et al., Nature Review, 2010

21. 抗癫痫药物发展历程 第一代 第二代 第三代 正在研发的新型抗癫痫药 最终目标 预防及治愈癫痫 溴化物、硼砂
目前癫痫的临床治疗是以药物控制症状为主，从19世纪中期的溴化物、硼砂的发现到20世纪苯妥因纳、丙戊酸钠等直至最新发现的药物左乙拉西坦、瑞替加滨经历了一个半世纪的发展，尽管目前已经有20多种不同类型不同作用靶点的抗癫痫药物可供选择，但是仍旧30%左右的患者出现耐药。而且，距离我们临床用药的最终目标（预防及治愈癫痫发作）仍相去甚远。
可能的原因：1 癫痫发病的确切机制不清。2 临床用药没有很好的针对不同发作类型去针对性的给药。 3 药物靶点相对单一
最终目标
预防及治愈癫痫
Shorvon SD et al., Epilepsia, 2009

22. 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）

23. 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)
FDA-approval usually requires that 50% of the patient treatment group had at least a 50% improvement in the rate of epileptic seizures. About 20~30% of patients with epilepsy continue to have breakthrough epileptic seizures despite best anticonvulsant treatment.
Most AEDs only can control seizures, but can not inhibit epileptogenesis. Symptom control vs antiepileptogenesis. Little is known about the generation of epilepsy.
Bold= new generation AED 23

24. 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 24

25. Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by cultured neurons.

26. Drugs that act on Na+ channel
Phenytoin
Carbamazepine
Oxcarbazepine
Lamotrigine

27. Phenytoin 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)

28. Phenytoin (Dilantin) Non-linear kinetics
Oral Dose: about 5 mg / kg
Non-linear kinetics
Therapeutic range = μg/ml
Levels above 20 cause ataxia and nystagmus (眼球震颤)
Half life = hours, slow effect
Blow 20ug/ml: first order kinetics
Above 20ug/ml: zero order kinetics
Be effective slowly, control acute symptom using other fast-acting drugs, eg. phenobarbital first
Dosing every 20 hours, the normal half-life, could rapidly lead to dangerous accumulation. There is considerable individual variation in the plasma concentration achieved with a given dose.
Acute oral overdosage results primarily in signs referable to the cerebellum and vestibular system.
Hepatic metabolism
CYP2C enzyme pathway
- CYP3A/2C enzyme inducer

29. Phenytoin 2. Clinical uses* (1) Antiepilepsy
Effective against partial seizures and generalized tonic-clonic seizures
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

30. Phenytoin Side effects:
CNS: Particularly in the cerebellum and vestibular systems（小脑前庭系统）: nystagmus（眼球震颤）, ataxia（共济失调）. Behavioral changes: confusion, hallucination
Local irritating (alkaline): gingival hyperplasia, GI upset, phlebitis
Hematologic complications
- Megaloblastic anemia（巨幼红细胞性贫血）
(folic acid loss)
- Agranulocytosis
Gingival hyperplasia
The milder side effects include vertigo, ataxia, headache and nystagmus, but not sedation. At higher plasma concentrations, marked confusion with intellectual deterioration occurs; a paradoxical increase in seizure frequency is a particular trap for the unwary prescriber.
Gingival hyperplasia is the most common toxicity in children and adolescents. Oral hygiene (kneading the gum or frequen.t gargle) may be helpful

31. Phenytoin Side effects: (4) Allergic reactions (5) Skeletal reactions
Skin reactions; blood cell abnormality (including thrombocytopenia血小板减少症, agranulocytosis粒细胞缺乏);hepatic toxicity; ect.
(5) Skeletal reactions
Osteomalacia骨质软化症by abnormal vitamin D metabolism and calcium absorption低血钙症
(6) Teratism畸胎
Others: birth defects (fetal malformations, class D), hirsutism
hirsutism
Necessary to monitor plasma concentrations

32. A. Antiepileptic drugs 4. Drug interactions
(1) Increases plasma concentrations of drugs by displacement of plasma protein binding (salicylates)， and inhibition of P450 inactivation (isoniazid异烟肼, chloramphenicol氯霉素)
(2) Decreases plasma concentrations of drugs (phenobarbital, carbamazepine) by by enhancing metabolism
(3) Phenytoin enhances the metabolism of corticosteroids and vitamin D

33. 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 Toxicity
peak effect- diplopia, ataxia
rash 5-10%
rare marrow suppression
aplastic anemia and
agranulocytosis
rare hepatitis
frequent hyponatremia at high dose
fetal malformations (class D)
Phenytoin and phenobarbital induce CYP3A and decrease the stable plasma level of carbamazepine 33

34. Carbamazepine Dose in Adults 200 mg once a day
After several days, 200 mg twice a day
Slowly titrate to 10 mg/kg
Therapeutic = ug/ml
Watch for Rash! 34

35. Oxcarbazepine --- less effective
--- improved toxicity profile (fewer hypersensitivity reactions less hepatic enzyme induction)

36. Lamotrigine 拉莫三嗪 Side effects 10% risk of rash
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 mg/day
Side effects
10% risk of rash
Dizziness, headache, diplopia, nausea, somnolence
Class C in pregnancy, significantly lower than other
Caution: drug interaction with other AEDs. 36

37. Drugs acting at the chloride channels
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 37

38. Valproate 丙戊酸 Side effects: 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 = 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) 38

39. 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. 39

40. Drugs that affect KA and AMPA receptors
Topiramate (Topamax)
Zonisamide (Zonegran)

41. 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 /day
appears to do a little of everything, Its spectrum of action resembles that of phenytoin, and it is claimed to produce less severe side effects, as well as being devoid of the pharmacokinetic properties that cause trouble with phenytoin

42. Topiramate Side effects:
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)

43. 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 receptors
Levetiracetam: 左乙拉西坦

44. Levetiracetam
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

45. 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 thalamic 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)
GI distress: stomachache, nausea, vomiting
CNS response: fatigue, dizziness, headache, euphoria, sleepiness, hiccup 45

46. 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). 46

47. When to initiate treatment?

48. 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
Instruct her not to drive. Report the event to the department of public health or DMV
Wait until a second seizure, and then initiate an AED
Initiate a pregnancy class C AED now.
Initiate, phenytoin, valproic acid, phenobarbital, or carbamazepine now 48

49. 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 49

50. Factors for determining whether to
start treatment after a first seizure
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
electroencephalogram

51. Initiation of treatment
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.

52. 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 52

53. Initiation of Treatment
Decreased risk
Idiopathic cause
Generalized seizure
No family history of epilepsy
Normal electroencephalogram
Normal findings on neurologic examination
The EEG is a powerful predictor of recurrence after a single seizure.

55. A. Antiepileptic drugs Box Common toxicity of antiepileptic drugs:
CNS reactions
Hemological reactions
Hepatic toxicity

56. A. Antiepileptic drugs 2. Dosage： small – larger doses;
dose individualization;
plasma concentration monitoring if necessary
3. Usage： drug combination
4. Withdrawal：gradually and slowly

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

58. B. Anticonvulsant drugs
Other anticovulsant drugs
Sedative-hypnotic drugs