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Antiepileptics
- 2. 2 Objectives • Classify antiepileptic drugs • Describe pharmacology of antiepileptic drugs – Mechanism of action – Relevant pharmacokinetics – Indications – Adverse drug reactions – Important drug interactions • Explain pharmacological management of epilepsy
- 4. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS Three main mechanisms – • Enhancement of GABA action • Inhibition of sodium channel function • Inhibition of calcium channel function. Other mechanisms include - - Inhibition of glutamate release and - Block of glutamate receptors.
- 5. 5 Classification of Anticonvulsants Action on Ion Channels Enhance GABA Transmission Inhibit EAA Transmissi on Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca++: Ethosuximide Valproic acid Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate Felbamate Topiramate
- 6. Mechanism of action of antiepileptic drugs Phenytoin, Carbamazepine, felbamate, lamotrigine, valproic acid • Block voltage-dependent sodium channels at high firing frequencies
- 7. Mechanism of action of antiepileptic drugs Barbiturates • Prolong GABA-mediated chloride channel openings Benzodiazepines • Increase frequency of GABA- mediated chloride channel openings 7
- 8. Valproate May enhance GABA transmission in specific circuits Blocks voltage-dependent sodium channels Blocks T-type calcium currents Ethosuximide • Blocks slow, threshold, “transient” (T-type) calcium channels in thalamic neurons 8 Mechanism of action of antiepileptic drugs(AEDs)
- 9. Newer AEDs: mechanism of action Vigabatrin: Irreversibly inhibits GABA transaminase Tiagabine: Interferes with GABA re-uptake Topiramate: – Blocks voltage-dependent sodium channels at high firing frequencies – Increases frequency at which GABA opens Cl- channels (different site from benzodiazepines) – Antagonizes glutamate actions at receptor subtype Gabapentin: May modulate amino acid transport into brain & May interfere with GABA re-uptake 9
- 10. Phenobarbitone • GABA-facilitatory • GABA-mimetic • Adverse effects – sedative action. – Long term administration - behavioral abnormalities, impairment of learning and memory, hyperactivity in children, mental confusion in older people. – Rashes, megaloblastic anaemia and osteo- malacia on prolonged use.
- 11. Uses/indications • Generalized tonic-clonic (GTC), simple partial (SP) and complex partial (CP) seizures: 60 mg 1-3 times a day in adults; in children (3-6 mg/kg/ day). • Status epilepticus: may be injected i.m. or i.v. but response is slow to develop. • not effective in absence seizures.
- 12. Phenytoin (Diphenylhydantoin) • Most commonly used. • Phenytoin prolongs the inactivated state of voltage sensitive neuronal Na+ channel and reduces the neuronal excitability.
- 13. Pharmacokinetics • Absorption is formulation dependent • highly bound to plasma proteins • fosphenytoin is for IV, IM routes • The kinetics changes from first order to zero order over the therapeutic range(small increments in dose produce disproportionately high plasma concentrations.) • The t1/2 - 12-24 hours progressively ↑es upto 60 hr when plasma concentration rises above 10 ug/ml as metabolizing enzymes get saturated.
- 14. Adverse effect At therapeutic levels - • Gum hypertrophy: • Hirsutism: • Hypersensitivity reactions: • Megaloblastic anaemia: • Osteomalacia: • Hyper-glycaemia. • foetal hydantoin syndrome (hypoplastic phalanges, cleft palate, hare lip, microcephaly),due to its areneoxide metabolite.
- 15. Adverse effect At high plasma levels (dose related toxicity) • CNS- Cerebellar and vestibular manifestations: ataxia, vertigo, diplopia, nystagmus are the most characteristic features. Drowsiness, behavioral alterations, mental confusion and hallucinations. • GIT - Epigastric pain, nausea and vomiting: minimised by taking the drug with meals. • CVS – hypotension & arrhythmias.
- 16. Uses • Generalized tonic-clonic, simple and comp lex partial seizures. • It is ineffective in absence seizures. Dose: 100 mg BD, maximum 400 mg/day; Children 5-8 mg/kg/day, • Status epilepticus: occasionally used by slow i.v. injection. • Trigeminal neuralgia - second choice drug to carbamazepine.
- 17. Carbamazepine • Adverse effects – Dose related neurotoxicity—sedation, dizziness, vertigo, diplopia and ataxia. – Vomiting, diarrhea – Acute intoxication - coma, convulsions and cardiovascular collapse. – Hypersensitivity reactions:rashes,photosensitivity hepatitis, lupus like syndrome – Water retention and hyponatremia in the elderly as it enhances ADH action. – Teratogenic
- 18. Uses • It is the most effective drug for CPS • First choice drug with phenytoin for GTC and SPS . • Trigeminal and related neuralgias - is the drug of choice. • Manic depressive illness and acute mania - as an alternative to lithium
- 19. ETHOSUXIMIDE • Inhibit T type Ca+2 current in thalamic neurons. • Adverse effects – GI intolerance, tiredness, mood changes, agitation, headache, drowsiness and inability to concentrate • Uses – Only in ABSENCE SEIZURES but Use has now declined as many consider valproic acid to be superior to it.
- 20. VALPROIC ACID (Sodium Valproate) Multiple mechanisms of action : • Phenytoin like frequency dependent prolongation of Na* channel inactivation. • Attenuation of Ca2+ mediated 'T' current (ethosuximide like) • Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation (by GABA-transaminase) & by increasing its synthesis.
- 21. Uses • Highly effective in absence seizure. • Alternative /adjuvant drug for GTCS, SPS and CPS. • Myoclonic and atonic seizures—control is often incomplete, but it is the drug of choice. • Mania and bipolar illness: as alternative to lithium.
- 22. Adverse effects • anorexia, vomiting, loose motions, heart burn • Drowsiness, ataxia, tremors • Alopecia, curling of hair, increased bleeding tendency • Fulminant hepatitis (very rare0 • Pancreatitis • High incidence of PCOD in young girls • Teraotogenic 22
- 23. LAMOTRIGINE Blocks sodium as well as high voltage dependent calcium channels Uses • Broad spectrum antiepileptic. • Refractory cases of partial seizures and GTCS • Absence and myoclonic or akinetic epilepsy . • Lennox-gastaut syndrome Adverse effects • sleepiness, dizziness, diplopia,ataxia and vomiting. • better tolerated than carbamazepine or phenytoin. • Rash may be a severe
- 24. GABAPENTIN • Enhances GABA release in brain. • does not act as agonist at GABAA receptor. • Reduces seizure frequency in refractory partial seizures with or without generalization. • Effective in SPS and CPS • Manic depressive illness and migraine • first line drug for pain - diabetic neuropathy and postherpetic neuralgia, • Adverse effects - mild sedation, tiredness, dizziness and unsteadiness.
- 25. VIGABATRIN • Inhibitor of GABA-transaminase which degrades GABA • Effective in refractory epilepsy, specially partial seizures with or without generalization. • Adverse effects- behavioral changes, depression and psychosis . drowsiness, amnesia, visual field contraction, motor disturbances, agitation in children.
- 26. TIAGABINE • Recently developed anticonvulsant - potentiates GABA mediated neuronal inhibition by depressing GABA transporter GAT-1 which removes synaptically released GABA into neurons & glial cells. • Uses – add on therapy of partial seizures with or without secondary generalization. • Adverse effects- mild sedation, nervousness, asthenia, amnesia & abdominal pain.
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- 30. Reference • Lippincots illustrated pharmacology 6th edition page 157-168 • Essentials of Medical Pharmacology 7th edition by KD tripathi 30
Editor's Notes
- Live
- metabolized in liver by hydroxylation and glucuronide conjugation.
- Commonest , more in younger patients. coarsening of facial features, acne. Megaloblastic anaemia: phenytoin decreases folate absorption and increases its excretion. Hypersensitivity reactions: Rashes, DLE, lymphadenopathv; neutropenia is rare but requires discontinuation of therapy Osteomalacia: increase metaboism of vit. D and interferes with calcium metabolism. inhibit insulin release and cause hyper-glycaemia. Used during pregnancy—can produce foetal hydantoin syndrome (hypoplastic phalanges, cleft palate, hare lip, microcephaly),due to its areneoxide metabolite.
- worsening of seizures with higher doses.