Ns8 Anticonvulsants

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    Ns8 Anticonvulsants - Presentation Transcript

    1. Anticonvulsants 2nd Medical Year 2006/07 JC3-NS8 Prof John Waddington
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    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
      • (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
    8. 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
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    11. 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
    12. 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
    13. 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
      • 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
      • 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
    14. 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
    15. 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
    16. 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

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