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Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
Ns8 Anticonvulsants
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Ns8 Anticonvulsants

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NS8 …

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

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