Antiepileptics
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This document discusses antiepileptic drugs, including their mechanisms of action, classifications, pharmacokinetics, indications, and adverse effects. It classifies antiepileptic drugs based on their actions on ion channels and neurotransmitter systems. The main mechanisms of action are enhancement of GABA transmission, inhibition of sodium channels, and inhibition of calcium channels. Common antiepileptic drugs like phenytoin, carbamazepine, valproic acid, lamotrigine, ethosuximide, gabapentin, vigabatrin, and tiagabine are described in terms of their pharmacological properties and clinical uses.
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
- #10: Live
- #14: metabolized in liver by hydroxylation and glucuronide conjugation.
- #15: 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.
- #18: worsening of seizures with higher doses.