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Ns8 Anticonvulsants


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Lecture 8 of 63 in the Neuroscience Module

"Anticonvulsants" [Pharmacology]

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Ns8 Anticonvulsants

  1. 1. Anticonvulsants 2nd Medical Year 2006/07 JC3-NS8 Prof John Waddington
  2. 5. Issues of selectivity <ul><li>Neuronal selectivity : drugs may act at more than one site; e.g. inhibition of reuptake and receptor antagonism </li></ul><ul><li>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 </li></ul>
  3. 6. Epilepsy <ul><li>2nd most common neurological disorder after stroke; 0.5-1.0% of population </li></ul><ul><li>Seizure : sudden abnormal discharge of impulses from a group of neurons </li></ul><ul><li>Symptoms determined by site [ focus ] and spread [ localised/generalised ] of discharge as well as amplitude </li></ul>
  4. 7. Classification of epilepsy <ul><li>1. Partial (focal) seizures </li></ul><ul><li>Discharge begins and remains localised, often in cortex; site determines symptoms </li></ul><ul><li>(a) Simple seizures </li></ul><ul><li> No loss of consciousness </li></ul><ul><li>(b) Complex seizures </li></ul><ul><li> Some loss of consciousness </li></ul>
  5. 8. <ul><li>(a) Absence (Petit mal): </li></ul><ul><ul><li>3 Hz discharge </li></ul></ul><ul><ul><li>Brief, sudden loss of consciousness </li></ul></ul><ul><li>(b)Tonic-clonic (Grand mal): </li></ul><ul><ul><li>Widespread, polyphasic </li></ul></ul><ul><ul><li>Repetitive contraction/ relaxation </li></ul></ul><ul><ul><li>Unconsciousness </li></ul></ul>2. Generalised seizures Discharge from focus with rapid spread to other areas of brain <ul><li>( c) Myoclonus </li></ul><ul><ul><li>Brief, jerking movements </li></ul></ul><ul><li>(d) Status epilepticus </li></ul><ul><ul><li>Repeated seizures </li></ul></ul><ul><ul><li>No recovery of consciousness </li></ul></ul><ul><ul><li>Potentially life threatening </li></ul></ul>
  6. 9. Anticonvulsants Mechanisms of anticonvulsant activity <ul><li>General </li></ul><ul><li>Action at focus to reduce discharge </li></ul><ul><li>Reduction of propagation from focus </li></ul><ul><li>Specific </li></ul><ul><li>Prolong inactivation state of Na + channels </li></ul><ul><li>Reduce Ca 2+ channel entry </li></ul><ul><li>Enhance GABA A -mediated inhibition </li></ul><ul><li>Reduce glutamate-NMDA-mediated excitation </li></ul>
  7. 12. 3. Enhance GABA A -mediated inhibition <ul><li>Increase in Cl - channel opening through GABA A -benzodiazepine receptor complex </li></ul><ul><li>Inhibition of GABA-T [ T ransaminase] </li></ul><ul><li>Inhibition of GABA uptake </li></ul><ul><li>4. Reduce glutamate-NMDA-mediated excitation </li></ul><ul><li>Reduction in release of glutamate </li></ul>
  8. 13. Classical anticonvulsants <ul><li>Phenobarbitone </li></ul><ul><li>Mechanism </li></ul><ul><li>Na + and Ca 2+ channels </li></ul><ul><li>Enhances GABA A </li></ul><ul><li> glutamate release </li></ul><ul><li>Use </li></ul><ul><li>Gen. tonic-clonic>partial </li></ul><ul><li>Enzyme inducer </li></ul><ul><ul><li>S/Es </li></ul></ul><ul><ul><li>Highly sedative </li></ul></ul><ul><ul><li>Behavioural changes </li></ul></ul><ul><ul><li>Enzyme inducer </li></ul></ul><ul><ul><li>No longer front-line agent </li></ul></ul>
  9. 14. Typical agents <ul><li>Phenytoin </li></ul><ul><li>Mechanism </li></ul><ul><ul><li>Prolongs inactivation state of Na + channels, reducing likelihood of repetitive discharge </li></ul></ul><ul><li>Use </li></ul><ul><ul><li>Gen. tonic-clonic, partial [status epilepticus] </li></ul></ul><ul><li>S/Es </li></ul><ul><ul><li>Occular, ataxia [sedation], gingival hyperplasia, hirsuitism </li></ul></ul><ul><ul><li>dysmorphogenic-cleft palate </li></ul></ul>
  10. 15. <ul><li>Carbamazepine </li></ul><ul><li>Mechanism </li></ul><ul><li>Na + channels </li></ul><ul><li>Use </li></ul><ul><li>Partial-complex, gen. tonic-clonic </li></ul><ul><li>Mood stabiliser </li></ul><ul><li>S/Es </li></ul><ul><li>Occular, ataxia, GIT </li></ul><ul><li>Aplastic anaemia, agranulocytosis, </li></ul><ul><li>Enzyme inducer </li></ul><ul><li>Valproate </li></ul><ul><li>Mechanism </li></ul><ul><li>Na + channels [+Ca 2+ channels, enhances GABA A ] </li></ul><ul><li>Use </li></ul><ul><li>Gen. tonic-clonic, absence, myoclonus </li></ul><ul><li>Mood stabiliser </li></ul><ul><li>S/Es </li></ul><ul><li>GIT, tremor, hepatotoxicity </li></ul><ul><li>Enzyme inhibitor </li></ul><ul><li>Dysmorphogenic-spina bifida </li></ul>
  11. 16. <ul><li>Ethosuximide </li></ul><ul><li>Mechanism </li></ul><ul><li>T-type Ca 2+ channels [distinct from L-type Ca 2+ channel blockers] </li></ul><ul><li>Use </li></ul><ul><li>Absence seizures </li></ul><ul><li>S/Es </li></ul><ul><li>GIT </li></ul><ul><li>Benzodiazepines </li></ul><ul><li>Mechanism </li></ul><ul><li>Enhance GABA A </li></ul><ul><li>Use </li></ul><ul><li>Diazepam: status epilepticus </li></ul><ul><li>Clonazepam: absence, myoclonus </li></ul><ul><li>S/Es </li></ul><ul><li>Sedation, tolerance </li></ul>
  12. 17. Drug interactions <ul><li>1. Induction of hepatic microsomal enzymes </li></ul><ul><li>E.g. by phenobarbitone, carbamazepine: increases clearance of itself, phenytoin [and other drugs] </li></ul><ul><li>2. Inhibition of hepatic microsomal enzymes </li></ul><ul><li>E.g. by valproate: decreases clearance of phenytoin, phenobarbitone, to give toxicity </li></ul><ul><li>3. Interactions with other drugs </li></ul><ul><li>E.g. enzyme inhibitors such as cimetidine decrease clearance of phenytoin to give toxicity </li></ul>
  13. 18. Pharmacokinetics <ul><li>Phenytoin </li></ul><ul><li>Lower doses: normal, 1st order kinetics , i.e. constant fraction cleared/unit time </li></ul><ul><li>Higher doses: elimination mechanisms saturated; change to zero order kinetics , i.e. constant amount cleared/unit time - </li></ul><ul><li> small increase in dose gives large increase in concentration, hence toxicity </li></ul>
  14. 19. Newer agents <ul><li>Vigabatrin </li></ul><ul><li>Mechanism </li></ul><ul><li>Inhibition of GABA-T, elevating brain GABA </li></ul><ul><li>Use </li></ul><ul><li>Add-on therapy for refractory partial seizures </li></ul><ul><li>Monotherapy? </li></ul><ul><li>S/Es </li></ul><ul><li>Sedation, occular, mental </li></ul><ul><li>Minimal drug interactions </li></ul><ul><li>Lamotrigine </li></ul><ul><li>Mechanism </li></ul><ul><li>Na + channels </li></ul><ul><li> glutamate release </li></ul><ul><li>Use </li></ul><ul><li>Add-on therapy for refractory partial seizures </li></ul><ul><li>Monotherapy? </li></ul><ul><li>S/Es </li></ul><ul><li>Sedation, occular, GIT, rash </li></ul><ul><li>Minimal drug interactions </li></ul>