Antiepileptics

Antiepileptics by Dr. Pramod P Bhalerao

1. Antiepileptics Dr. Pramod P Bhalerao

2. Epilepsy Brief episodes (seizures) of loss or disturbance of consciousness, with or without characteristic body movements (convulsions).

3. Classification I. Generalised seizures 1. Generalised tonic- clonic seizures 2. Absence seizures 3. Atonic seizures 4. Myoclonic seizures 5. Infantile spasms ( Hypsarrhythmia ) II. Partial seizures 1. Simple partial seizures 2. Complex partial seizures 3. Simple partial or complex partial seizures secondarily generalized

4. Generalised tonic- clonic seizures (Grand mal) Commonest, lasts 1–2 min. The usual sequence is aura—cry—unconsciousness—tonic spasm of all body muscles— clonic jerking followed by prolonged sleep and depression of all CNS functions.

5. Absence seizures(Petit Mal) prevalent in children, lasts about 1/2 min. Momentary loss of consciousness, patient apparently freezes and stares in one direction, no muscular component.

6. Atonic seizures ( Akinetic epilepsy): Unconsciousness with relaxation of all muscles due to excessive inhibitory discharges. Patient may fall. Myoclonic seizures Shock-like momentary contraction of muscles of a limb or the whole body.

7. Partial seizures Simple partial seizures lasts 1/2–1 min. Often secondary. Convulsions are confined to a group of muscles or localized sensory disturbance depending on the area of cortex involved in the seizure, without loss of consciousness.

8. Complex partial seizures attacks of bizarre and confused behaviour and purposeless movements, emotional changes lasting 1–2 min along with impairment of consciousness. An aura often precedes. The seizure focus is located in the temporal lobe.

9. Simple partial or complex partial seizures secondarily generalized The partial seizure occurs first and evolves into generalized tonic- clonic seizures with loss of consciousness.

10. Most of the cases of epilepsy are primary (idiopathic), Some may be secondary to trauma/ surgery on the head, intracranial tumour , tuberculoma , cysticercosis , cerebral ischaemia , etc.

11. Phenobarbitone The first efficacious antiepileptic introduced in 1912. Enhancement of GABA A receptor mediated synaptic inhibition. Adverse effect- sedative action. Long term administration (as needed in epilepsy) may produce additional side effects like—behavioral abnormalities, diminution of intelligence, impairment of learning and memory, hyperactivity in children, mental confusion in older people.

12. Phenobarbitone : Mechanism of action

13. Phenobarbitone is one of the cheapest drug. It has broad spectrum efficacy in generalized tonic- clonic (GTC), simple partial (SP) and complex partial (CP) seizures in a dose of 60 mg 1–3 times a day in adults. It has become less popular than carbamazepine , phenytoin or valproate because of its dulling and behavioural side effects.

14. Phenytoin Prolonging the inactivated state of voltage sensitive neuronal Na+ channel.

15. Adverse effects of Phenytoin At therapeutic levels Gum hypertrophy Hirsutism Hypersensitivity reactions Megaloblastic anaemia Osteomalacia foetal hydantoin syndrome( hypoplastic phalanges, cleft palate, hare lip, microcephaly ) At high plasma levels (dose related toxicity) (a) Cerebellar and vestibular manifestations:ataxia , vertigo, diplopia , nystagmus .

16. Uses of Phenytoin Phenytoin is a first line antiepileptic drug, but less commonly used now because side effects are frequent. Indications are: 1. Generalized tonic- clonic , simple and complex partial seizures. It is ineffective in absence seizures. 2. Status epilepticus : occasionally used by slow i.v . injection ( fosphenytoin has replaced it). 3. Trigeminal neuralgia: second choice drug to carbamazepine .

17. Fosphenytoin Water soluble prodrug of phenytoin . On i.v . injection it is less damaging to the intima . it can be injected at a faster rate.

18. Carbamazepine it is a first line antiepileptic drug. Its pharmacological actions resemble phenytoin . Adverse effects Carbamazepine produces dose-related neurotoxicity—sedation, dizziness, vertigo, diplopia and ataxia.

19. Carbamazepine Uses CPS GTCS SPS Trigeminal and related neuralgias.

20. Ethosuximide Ethosuximide selectively suppresses T current. Thalamic neurones exhibit prominent ‘T’ (transient) current which is low threshold Ca2+ current (due to inward flow of Ca2+ through T type Ca2+ channels). Use: Absence seizures;

21. Valproic acid (Sodium valproate ) Valproate appears to act by multiple mechanisms: ( i ) A phenytoin -like frequency-dependent prolongation of Na+ channel inactivation. ii)Weak attenuation of Ca2+ mediated ‘T’ current ( ethosuximide like). (iii) Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation (by GABA- transaminase ) as well as probably by increasing its synthesis from glutamic acid.

22. Adverse effects of valproate Alopecia, curling of hair, weight gain Asymptomatic rise in serum transaminase Used during pregnancy, it has produced spina bifida and other neural tube defects in the offspring; should be avoided.

23. Uses of Valproate Drug of choice for absence seizures. Alternative/adjuvant drug for GTCS, SPS and CPS. Myoclonic and atonic seizures—control is often incomplete, but valproate is the drug of choice.

24. Diazepam(Benzodiazepines)

25. Diazepam(Benzodiazepines) A first line drug for emergency control of convulsions, e.g. status epilepticus . Rectal instillation of diazepam is now the preferred therapy for febrile convulsions in children. Adverse effects: sedation Thrombophlebitis of injected vein Limitation: Development of tolerance.

26. Gabapentin Enhances GABA release

27. Gabapentin Gabapentin is considered to be a first line drug for neuralgic pain due to diabetic neuropathy and postherpetic neuralgia.

28. Vigabatrin Inhibitor of GABA- transaminase , the enzyme which degrades GABA. Anticonvulsant action may be due to increase in synaptic GABA concentration.

29. Tiagabine This newer anticonvulsant potentiates GABA mediated neuronal inhibition by depressing GABA transporter GAT-1 which removes synaptically released GABA into neurones and glial cells.

30. Status epilepticus When seizure activity occurs for >5 min, or Two or more seizures occur without recovery of consciousness, Lorazepam 4 mg (0.1 mg/kg in children) injected i.v . at the rate of 2 mg/min, repeated once after 10 min if required, is the first choice drug now.