Ns8 Anticonvulsants

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NS8
Lecture 8 of 63 in the Neuroscience Module

"Anticonvulsants" [Pharmacology]

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  • 1. Anticonvulsants 2nd Medical Year 2006/07 JC3-NS8 Prof John Waddington
  • 2.  
  • 3.  
  • 4.  
  • 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
  • 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
  • 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
  • 8.
    • (a) Absence (Petit mal):
      • 3 Hz discharge
      • Brief, sudden loss of consciousness
    • (b)Tonic-clonic (Grand mal):
      • Widespread, polyphasic
      • Repetitive contraction/ relaxation
      • Unconsciousness
    2. Generalised seizures Discharge from focus with rapid spread to other areas of brain
    • ( c) Myoclonus
      • Brief, jerking movements
    • (d) Status epilepticus
      • Repeated seizures
      • No recovery of consciousness
      • Potentially life threatening
  • 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 Ca 2+ channel entry
    • Enhance GABA A -mediated inhibition
    • Reduce glutamate-NMDA-mediated excitation
  • 10.  
  • 11.  
  • 12. 3. Enhance GABA A -mediated inhibition
    • Increase in Cl - channel opening through GABA A -benzodiazepine receptor complex
    • Inhibition of GABA-T [ T ransaminase]
    • Inhibition of GABA uptake
    • 4. Reduce glutamate-NMDA-mediated excitation
    • Reduction in release of glutamate
  • 13. Classical anticonvulsants
    • Phenobarbitone
    • Mechanism
    • Na + and Ca 2+ channels
    • Enhances GABA A
    •  glutamate release
    • Use
    • Gen. tonic-clonic>partial
    • Enzyme inducer
      • S/Es
      • Highly sedative
      • Behavioural changes
      • Enzyme inducer
      • No longer front-line agent
  • 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
  • 15.
    • Carbamazepine
    • Mechanism
    • Na + channels
    • Use
    • Partial-complex, gen. tonic-clonic
    • Mood stabiliser
    • S/Es
    • Occular, ataxia, GIT
    • Aplastic anaemia, agranulocytosis,
    • Enzyme inducer
    • Valproate
    • Mechanism
    • Na + channels [+Ca 2+ channels, enhances GABA A ]
    • Use
    • Gen. tonic-clonic, absence, myoclonus
    • Mood stabiliser
    • S/Es
    • GIT, tremor, hepatotoxicity
    • Enzyme inhibitor
    • Dysmorphogenic-spina bifida
  • 16.
    • Ethosuximide
    • Mechanism
    • T-type Ca 2+ channels [distinct from L-type Ca 2+ channel blockers]
    • Use
    • Absence seizures
    • S/Es
    • GIT
    • Benzodiazepines
    • Mechanism
    • Enhance GABA A
    • Use
    • Diazepam: status epilepticus
    • Clonazepam: absence, myoclonus
    • S/Es
    • Sedation, tolerance
  • 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
  • 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
  • 19. Newer agents
    • Vigabatrin
    • Mechanism
    • Inhibition of GABA-T, elevating brain GABA
    • Use
    • Add-on therapy for refractory partial seizures
    • Monotherapy?
    • S/Es
    • Sedation, occular, mental
    • Minimal drug interactions
    • Lamotrigine
    • Mechanism
    • Na + channels
    •  glutamate release
    • Use
    • Add-on therapy for refractory partial seizures
    • Monotherapy?
    • S/Es
    • Sedation, occular, GIT, rash
    • Minimal drug interactions