Ns8 Anticonvulsants

Slide 1: Anticonvulsants 2nd Medical Year 2006/07 JC3-NS8 Prof John Waddington

Slide 5: Issues of selectivity • Neuronal selectivity: drugs may act at more than one site; e.g. inhibition of reuptake and receptor antagonism • CNS selectivity: drugs act in the periphery as well as in the brain; e.g. action on brain function may give therapeutic effects, while these same actions peripherally may cause side effects

Slide 6: Epilepsy • 2nd most common neurological disorder after stroke; 0.5-1.0% of population • Seizure: sudden abnormal discharge of impulses from a group of neurons • Symptoms determined by site [focus] and spread [localised/generalised] of discharge as well as amplitude

Slide 7: Classification of epilepsy 1. Partial (focal) seizures Discharge begins and remains localised, often in cortex; site determines symptoms (a) Simple seizures No loss of consciousness (b) Complex seizures Some loss of consciousness

Slide 8: 2. Generalised seizures Discharge from focus with rapid spread to other areas of brain (c) Myoclonus (a) Absence (Petit mal): - Brief, jerking - 3 Hz discharge movements - Brief, sudden loss of (d) Status epilepticus consciousness - Repeated seizures (b)Tonic-clonic (Grand mal): - No recovery of - Widespread, polyphasic consciousness - Repetitive contraction/ - Potentially life relaxation threatening - Unconsciousness

Slide 9: Anticonvulsants Mechanisms of anticonvulsant activity General - Action at focus to reduce discharge - Reduction of propagation from focus Specific - Prolong inactivation state of Na+ channels - Reduce Ca2+ channel entry - Enhance GABAA-mediated inhibition - Reduce glutamate-NMDA-mediated excitation

Slide 12: 3. Enhance GABAA-mediated inhibition - Increase in Cl- channel opening through GABAA-benzodiazepine receptor complex - Inhibition of GABA-T [Transaminase] - Inhibition of GABA uptake 4. Reduce glutamate-NMDA-mediated excitation - Reduction in release of glutamate

Slide 13: Classical anticonvulsants Phenobarbitone S/Es Mechanism - Highly sedative - Na+ and Ca2+ channels - Behavioural - Enhances GABAA changes   glutamate release - Enzyme inducer Use - Gen. tonic-clonic>partial No longer front-line - Enzyme inducer agent

Slide 14: Typical agents Phenytoin Mechanism - Prolongs inactivation state of Na+ channels, reducing likelihood of repetitive discharge Use - Gen. tonic-clonic, partial [status epilepticus] S/Es - Occular, ataxia [sedation], gingival hyperplasia, hirsuitism - dysmorphogenic-cleft palate

Slide 15: Carbamazepine Valproate Mechanism Mechanism - Na+ channels - Na+ channels [+Ca2+ channels, enhances GABAA] Use Use - Partial-complex, gen. tonic-clonic - Gen. tonic-clonic, absence, myoclonus - Mood stabiliser - Mood stabiliser S/Es S/Es - Occular, ataxia, GIT - GIT, tremor, hepatotoxicity - Aplastic anaemia, agranulocytosis, - Enzyme inhibitor - Dysmorphogenic-spina bifida - Enzyme inducer

Slide 16: Ethosuximide Benzodiazepines Mechanism Mechanism - T-type Ca2+ channels - Enhance GABAA [distinct from L-type Use 2+ Ca channel blockers] - Diazepam: status Use epilepticus - Absence seizures - Clonazepam: absence, S/Es myoclonus - GIT S/Es - Sedation, tolerance

Slide 17: Drug interactions 1. Induction of hepatic microsomal enzymes E.g. by phenobarbitone, carbamazepine: increases clearance of itself, phenytoin [and other drugs] 2. Inhibition of hepatic microsomal enzymes E.g. by valproate: decreases clearance of phenytoin, phenobarbitone, to give toxicity 3. Interactions with other drugs E.g. enzyme inhibitors such as cimetidine decrease clearance of phenytoin to give toxicity

Slide 18: Pharmacokinetics Phenytoin • Lower doses: normal, 1st order kinetics, i.e. constant fraction cleared/unit time • Higher doses: elimination mechanisms saturated; change to zero order kinetics, i.e. constant amount cleared/unit time -  small increase in dose gives large increase in concentration, hence toxicity

Slide 19: Newer agents Lamotrigine Vigabatrin Mechanism Mechanism - Na+ channels - Inhibition of GABA-T,   glutamate release elevating brain GABA Use Use - Add-on therapy for - Add-on therapy for refractory partial seizures refractory partial seizures - Monotherapy? - Monotherapy? S/Es S/Es - Sedation, occular, GIT, rash - Sedation, occular, mental - Minimal drug interactions - Minimal drug interactions