antiepilepticdrugs-200411073319421presentation

Anti epileptic drugs

1. Antiepileptic Drugs Dr. Dilip Kumar Singh Junior Resident KGMU lucknow

2. Objectives Epilepsy introduction Classify antiepileptic drugs Describe pharmacology of antiepileptic drugs Pharmacokinetics Mechanism of action Indications Adverse drug reactions Important drug interactions • Pharmacological management of epilepsy

3. Epilepsy These are group of disorders of the CNS characterized by- Paroxysmal cerebral dysrhythmia Loss or disturbance of consciousness ± Characteristic body movements, sensory or psychiatric phenomena

4. Seizure : A paroxysmal abnormal discharge at high frequency from neurons in cerebral cortex Convulsions: Violent contractions of skeletal muscles Involuntary

5. Etiology Idiopathic Congenital defects Head injuries, trauma, hypoxia Infection (meningitis, brain abscess, encephalitis)

6. Brain tumors (including tuberculoma), vascular occlusion Drug withdrawal (CNS depressants) Fever in children (febrile convulsion) Hypoglycemia, hypocalcemia

7. Focal or partial seizure Simple partial: Electrical discharge is confined to the motor area Complex partial: Electrical discharge is confined in certain parts of the temporal lobe Concerned with mood as well as muscle

8. Generalized seizure Tonic- clonic Convulsion & may bite his tongue & may lose control of his bladder or bowel Tonic After dropping unconscious experience only the tonic phase of seizure Atonic Unconsciousness Relaxation of muscles & drops down

9. Myoclonic Sudden, brief shock like contraction May involve the entire body or be confined to the face, trunk or extremities Absence Momentary loss of consciousness without involving motor area Most common in children ( 4-12 yrs ) EEG- symmetric 3 Hz spikes and wave pattern

10. Status epilepticus Seizure occur repeatedly with no recovery of consciousness b/w attacks OR Seizure activity > 30 min

11. Pathophysiology

12. Treatment of Seizures Strategies: Modification of ion conductance ↑ inhibitory (GABAergic) transmission ↓ excitatory (glutamatergic) activity

13. Up to 80% of pts partial or complete control of seizures with appropriate treatment Antiepileptic drugs suppress but do not cure seizures Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m -1 y) An initial therapeutic aim is to use only one drug (monotherapy)

14. Antiepileptic drugs

15. Antiepileptic drugs Barbiturate: Phenobarbitone Deoxybarbiturate: Primidone Hydantoin: Phenytoin, Fosphenytoin Iminostilbene: Carbamazepine, Oxcarbazepine Succinimide: Ethosuximide

16. Aliphatic carboxylic acid: Valproic acid (sodium valproate) Benzodiazepines: Clonazepam, Diazepam Lorazepam, Clobazam Phenyl triazine: Lamotrigine Cyclic GABA analogues: Gabapentin, Pregabalin

17. Newer drugs: Topiramate Zonisamide Lacosamide Vigabatrin levetiracetam

18. Phenobarbitone First efficacious antiepileptic drug introduced in 1912 Enhances the GABAA receptor mediated inhibition Raises the seizure threshold as well as limits spread and suppresses kindled seizures Slow oral absorption Metabolized in liver and excreted unchanged by kidney

19. Uses: Generalized tonic- clonic seizures Simple partial seizures Complex partial seizures Side effects : Sedation : most common Behavioral abnormality Diminution of intelligence Impair learning and memory

20. Phenytoin Anticonvulsant activity was first tested in electroshock seizure model MOA: neuronal membrane stabilizing property prolonging the inactivated state of voltage sensitive Na⁺ channel It prevent repetitive detonation of normal brain cell High frequency discharge are inhibited with little effect on normal low frequency discharge

21. Pharmacokinetics: Poor aqueous solubility 80-90% bound to plasma proteins Metabolized in liver by hydroxylation Order changes from first order to zero order on increasing conc.

22. Drug Interactions Potent inducer of CYP2C8/9, CYP3A4/5 Competitively inhibits CYP2C9/l 9 Phenobarbitone competitively inhibits phenytoin metabolism Carbamazepine and phenytoin induce each other's metabolism Competitively inhibits warfarin metabolism Sucralfate binds phenytoin and decreases its absorption

23. Valproate : Displaces protein bound phenytoin ↓ metabolism Plasma level of unbound phenytoin ↑ Chloramphenicol, isoniazid, cimetidine and warfarin Inhibit phenytoin metabolism Can precipitate toxicity

24. Adverse effect : At therapeutic levels Gum hypertrophy Hypersensitivity reactions Megaloblastic anaemia Osteomalacia Foetal hydantoin syndrome Hypoplastic phalanges Cleft palate Microcephaly

25. Dose related toxicity: At high plasma levels Cerebellar and vestibular manifestations: Ataxia, vertigo, diplopia Epigastric pain, nausea and vomiting Thrombophlebitis

26. Uses: Generalized tonic clonic seizures (GTCS) Partial seizures Less used due to side effect Status epilepticus Only when fosphenytoin is not available Trigeminal neuralgia Second choice drug to carbamazepine

27. Fosphenytoin Prodrug of phenytoin Introduced to overcome the difficulties in i.v . administration of phenytoin Less thrombophlebitis Can be injected in both saline & glucose

28. Carbamazepine Introduced for trigeminal neuralgia Chemically related to imipramine Na + channels prolongation of inactivated state Raise threshold of PTZ induced convulsions and electroshock convulsions

29. Pharmacokinetics: Poor water solubility 75% bound to plasma proteins Metabolized in liver by oxidation to an active metabolite (10-11 epoxy carbamazepine) Excreted in urine as glucuronide conjugate Plasma t 1/2 approx. 30 hours Therapeutic index narrow (6-12 µg/ml)

30. Drug Interactions Enzyme inducer; can reduce efficacy- Haloperidol, oral contraceptives Lamotrigine, valproate and topiramate Metabolism of carbamazepine is induced by phenobarbitone, phenytoin, and vice versa Erythromycin , fluoxetine, isoniazid inhibit metabolism of carbamazepine

31. Adverse effects: Neurotoxicity Vomiting, diarrhoea Hypersensitivity reactions Hyponatremia & water intoxication Craniofacial anomalies & neural tube defects Uses: Most effective drug for partial seizures Generalized tonic clonic seizures Trigeminal neuralgia

32. Oxcarbazepine Closely related to carbamazepine Active metabolite With improved toxicity profile MOA: Similar to carbamazepine Alters Na+ conductance Inhibits high frequency repetitive firing

33. Uses: Same as Carbamazepine Adverse effects: Less than Carbamazepine

34. Valproic acid (sodium valproate) Branched chain aliphatic carboxylic acid MOA : Multiple mechanism Prolong Na⁺ channel inactivation Weak attenuation of Ca 2+ mediated ‘T’ current Augmentation of release of inhibitory transmitter GABA

35. Pharmacokinetics : Oral absorption is good 90% bound to plasma protein t 1/2 = 10 -15 hours Excreted in urine ( glucuronide ) Uses: Absence seizures Generalized tonic clonic seizures Myoclonic seizures Atonic seizures Bipolar disorder

36. Drug Interactions Phenobarbitone and lamotrigine: Inhibiting their metabolism ↑ plasma levels Phenytoin: displaces phenytoin from protein binding site ↓ metabolism

37. Carbamazepine: Valproate inhibits hydrolysis of active epoxide metabolite Concurrent administration of clonazepam and valproate is contraindicated (Absence status may be precipitated)

38. Adverse effect : Nausea, Drowsiness ( MC) V : Vomiting A : Alopecia L : Liver damage P : PCOD R : Rash O : Obesity A : Agranulocytosis T : Tremors E : Epigastric pain Neural Tube defect (Spina bifida)

39. Diazepam , lorazepam Benzodiazepines Lorazepam longer acting MOA: Allosteric modulators of GABA receptors Potentiate GABA function by ↑ frequency of Cl - channel opening Muscle relaxant activity Uses: Status epilepticus (IV) Febrile Sz ( rectal diazepam)

40. Newer agents Differ from older drugs: Simple pharmacokinetic profile Relatively lack of drug-drug interaction Improved tolerability Costly with limited clinical experience

41. Lamotrigine Pharmacological effects: Well absorbed from GIT Metabolized primarily by glucuronidation Plasma t 1/2 approx. 24 hrs Mechanism of Action: Like phenytoin Inhibits excitatory amino acid release (glutamate & aspartate ) Blockade of Na channels

42. Uses : Add-on therapy or as monotherapy Side effects: Skin rash, blurred vision, diplopia Ataxia, headache, aggression Influenza – like syndrome

43. Gabapentin Structural analogue of GABA May increase the activity of GABA or inhibits its re-uptake Pharmacokinetics: Not bound to proteins Not metabolized and excreted unchanged in urine Does not induce or inhibit hepatic enzymes ( Plasma t ½ 5-7 hours

44. Side effects: Somnolence, dizziness Ataxia, fatigue and nystagmus Uses: As an adjunct with other antiepileptics Diabetic neuropathy Postherpetic neuralgia

45. Topiramate Pharmacological Effects: Well absorbed orally ( 80 % ) No effect on microsomal enzymes 9-17 % protein bound ( minimal ) Mostly excreted unchanged in urine Plasma t1l2 18-24 hrs.

46. Mechanism of Action: Blocks sodium channels (membrane stabilization) Potentiates the inhibitory effect of GABA Side effects: Psychological or cognitive dysfunction Weight loss Sedation, Dizziness Urolithiasis Paresthesia's (abnormal sensation ) Teratogenicity (in animal but not in human)

47. Vigabatrin Not bound to proteins ,Not metabolized Excreted unchanged in urine Plasma t1/2 4-7 hrs. Mechanism of action: Inhibits GABA metabolizing enzyme increase GAB content in the brain( similar to valproate).

48. Side effects: Visual field defects psychosis and depression Use: Drug of choice for infantile spasms

49. Zonisamide Pharmacokinetics: Well absorbed from GIT (100 %) Protein binding 40% Extensively metabolized in the liver No effect on liver enzymes Plasma t ½ 50 -68 hrs Mech of action: Prolongation of sodium channel inactivation

50. Uses: Add-on therapy for partial seizures Adverse effects: Drowsiness, ataxia , headache, loss of appetite, nausea & vomiting Somnolence

51. Vigabatrin MOA: Inhibit GABA transaminase Use : Refractory epilepsy CPS with or without generalization

52. Lacosamide MOA: Na + channel inactivation Suppressing repetitive firing of neurons Use: In adults only for add-on therapy ofpartial seizures with or without generalization Adverse effects: Ataxia, vertigo, diplopia

53. During pregnancy Safer antiepileptics Carbamazepine Oxcarbazepine Lamotrigine Ethosuximide Folic acid supplement

54. Common Causes of Failure of antiepileptics Improper diagnosis of the type of seizures Incorrect choice of drug Inadequate or excessive dosage Poor compliance

55. Guidelines for Anticonvulsant Therapy Start with one first line drugs Start with low dose: Gradually increase to effective dose or until side effects Check compliance If first drug fails due to side effects or continue seizures, start second line drugs, gradually withdrawing first

56. Try Three AED singly before using combinations Beware about drug interactions Do not use more than two drugs in combination at any one time If above fails consider occult structural or metabolic lesion and whether seizures are truly epileptic

57. Famous Persons with Epilepsy Socrates Aristotle Julius Caesar Alfred Nobel Napoleon Bonaparte Vladimir Ilyich Lenin Tony Greig

58. Summary Epilepsy is a neurological disorder Mainly of two types : Generalized and partial Anti epileptic drug act by- Modification of ion conductance ↑inhibitory (GABAergic) transmission ↓ excitatory (glutamatergic) activity Most of the anti epileptics are enzyme inducer

59. Valproate is first line drug for GTCS, myoclonic seizures, atonic seizures, absence seizures Carbamazepine is first line drug for partial seizures Rectal diazepam is given in febrile seizures Newer antiepileptics are : Topiramate, Zonisamide, Lacosamide Vigabatrin, levetiracetam

60. Thank You