Antiepiletpic Drugs (AEDs)

1. Antiepiletpic Drugs (AEDs) -----Epilepsy is a chronic disorder characterized by recurrent seizures, which are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons Dept of Pharmacology Shi-Hong Zhang (张世红) shzhang713@zju.edu.cn

2. International Classification of Epileptic Seizures:Partial Onset Seizures Source of seizure • Simple Partial • Complex Partial (consciousness is affected) • Partial Seizures with secondary generalization

3. International Classification of Epileptic Seizures: Primary Generalized Seizures • Absence (Petit Mal) • Generalized Tonic+Clonic (Grand Mal) • Tonic • Atonic • Clonic and myoclonic

4. Stereotypical complex partial seizures

5. Tonic phase Simultaneous bilateral cortical seizure attack Cyanosis Cry Loss of consciousness, Fall, crying, and generalized tonic stiffening often with bladder incontinence Clonic phase Salivary frothing Jerking of the limbs Post-ictal phase Patient feels lethargic and confused after seizures Often sleeps

6. Partial (Localization Related) Phenytoin Carbamazepine Valproate Oxcarbazepine Lamotrigine Topiramate Gabapentin Generalized Phenytoin Carbamazepine Valproate (GTC and absence) Ethosuximide - (absence) Topiramate (GTC) Lamotrigine (absence) AEDs Effective as Monotherapy (Single Agent) Bold= new generation AED

7. Partial Topiramate Levetiracetam Pregabalin Zonisamide Oxcarbazepine Lamotrigine Gabapentin Tiagabine Generalized Topiramate Levetiracetam Lamotrigine Data from randomized placebo controlled trials New AEDs effective as adjunctive treatment for refractory epilepsy • Drugs in red are generally considered high potency

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

9. Mechanisms of AEDs • Modification of ionic conductance. - Na+ - K+ - Ca2+ • Enhancement of GABAergic (inhibitory) transmission • Diminutionof excitatory transmission

10. Drugs which act on Na+ channel • Phenytoin • Carbamazepine • Oxcarbazepine • Lamotrigine

11. Phenytoin • Effective against partial seizures and generalized tonic-clonic seizures • Non-linear kinetics • Therapeutic range = 10-20 ug/ml • Levels above 20 cause ataxia and nystagmus (眼球震颤) • Half life = 12-24 hours, slow effect • Hepatic metabolism • CYP3A enzyme pathway www.boomer.org/c/p4/c21/c2103.html Oral Dose: about 5 mg / kg

12. 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)

13. Phenytoin ---Other uses • Chronic neuropathic pain: trigeminal neuralgia (三叉神经痛), sciatica (坐骨神经痛), glossopharyngeal neuralgia (舌咽神经痛) • Arrhythmia--b anti-arrhythmia drug

14. Phenytoin side effects • CNS: nystagmus, diplopia, ataxia, depression • Local irritating: gingival hyperplasia, GI upset, phlebitis • Hematologic complications - Megaloblastic anemia: folic acid loss - Agranulocytosis • Idiosyncratic or allergic reactions - Rash, up to 10%, can be very serious - stop drug - Fever - Hepatitis • Skeleton: osteomalacia (骨软化, Vit D degradation↑) • Others: birth defects (fetal malformations, class D), hirsutism

15. Phenytoin side effects Gingival hyperplasia hirsutism

16. Mephenytoin: more severe adverse effectsEthotoin: Less effective

17. Blocks Na+ channels and presynaptically decrease synaptic 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) Carbamazepine

18. Carbamazepine • Mechanisms: blockade of Na+ and Ca2+ channels, potentiation of GABA transmission • 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!

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

20. 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 rash Dizziness, headache, diplopia, nausea, somnolence Class C in pregnancy, but significantly lower than other Lamotrigine

21. Drugs acting at the chloride channel • 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

24. 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) Valproate

25. 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.

26. 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

27. Levetiracetam Effective for partial epilepsy 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 primarily affect potassium channel

28. Drugs which affect Kainate and AMPA receptors • Topiramate • Zonisamide

29. 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 Relatively safe, Class C? in pregnancy High Potency ----75% reductions in over 20% of refractory patients Topiramate

30. Drugs which affect calcium channels Ethosuximide • 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)

31. Teratogenicity • 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 (Class D drugs) • Folate supplementation prevents neural tube defects (split spine, 脊柱裂).

33. When to initiate treatment?

34. 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 Case Study: Initiation of Treatment

35. 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

36. 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

37. Initiation of Treatment Decreased risk • Idiopathic cause • Generalized seizure • No family history of epilepsy • Normal electroencephalogram • Normal findings on neurologic examination

38. Initiation of Treatment • the risk-benefit ratio of the anticonvulsant treatment must be carefully assessed in patients after a single seizure • Avoid valproic acid in a woman of childbearing potential. Answer 4 is clearly a poor choice.

39. Initiation of Treatment