For education purpose only

1. Antiepileptic Drugs
DR. DILIP KUMAR SINGH
JUNIOR RESIDENT
KGMU LUCKNOW

2. Objectives
 Epilepsy introduction
 Classify antiepileptic drugs
 Describe pharmacology of antiepileptic drugs
o Pharmacokinetics
o Mechanism of action
o Indications
o Adverse drug reactions
o 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

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

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

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

11. 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

12. 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

13. 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

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

16. Pathophysiology

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

21.  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)

22. Antiepileptic drugs

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

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

27. Newer drugs:
 Topiramate
 Zonisamide
 Lacosamide
 Vigabatrin
 levetiracetam

28. 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

29. 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

30. 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

31. 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.

32. 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

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

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

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

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

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

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

40. 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 t1/2 approx. 30 hours
 Therapeutic index narrow (6-12 µg/ml)

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

42. 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

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

44. Uses:
 Same as Carbamazepine
Adverse effects:
 Less than Carbamazepine

45. Valproic acid (sodium valproate)
 Branched chain aliphatic carboxylic acid
MOA:
Multiple mechanism
o Prolong Na⁺ channel inactivation
o Weak attenuation of Ca2+ mediated ‘T’ current
o Augmentation of release of inhibitory transmitter
GABA

46. Pharmacokinetics :
 Oral absorption is good
 90% bound to plasma protein
 t1/2 = 10 -15 hours
 Excreted in urine ( glucuronide )
Uses:
 Absence seizures
 Generalized tonic clonic seizures
 Myoclonic seizures
 Atonic seizures
 Bipolar disorder

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

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

49. 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)

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

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

52. 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

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

54. 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

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

56. 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.

57. 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)

58. 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).

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

60. 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

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

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

63. 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

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

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

66. 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

67.  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

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

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

73.  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:
o Topiramate, Zonisamide, Lacosamide
o Vigabatrin, levetiracetam

75. Thank You