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Mechanism of action of Antiepileptic Drugs
B. Gitanjali Gitanjali-1:
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Cellular Mechanisms of Seizure Generation
Excitation (too much) • Ionic-inward Na+, Ca++ currents • Neurotransmitter: glutamate, aspartate Inhibition (too little) • Ionic-inward Cl; outward K+ currents • Neurotransmitter: GABA Gitanjali-5:
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AEDs: Molecular and Cellular Mechanisms
Phenytoin, Carbamazepine • Block voltage-dependent sodium channels at high firing frequencies Gitanjali-6:
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Na+ Open Activation gate Na+ Inactivation gate Na+ Gitanjali-7:
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Block channels firing at high frequencies
Na+ Block channels firing at high frequencies Inactivated channel Na+ Na+ Na+ Carbamazepine Phenytoin Felbamate Lamotrigine Barbiturates Topiramate Gitanjali-8:
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AEDs: Molecular and Cellular Mechanisms
Barbiturates • Prolong GABA-mediated chloride channel openings • Some blockade of voltage- dependent sodium channels Gitanjali-9:
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AEDs: Molecular and Cellular Mechanisms
Benzodiazepines • Increase frequency of GABA- mediated chloride channel openings Gitanjali-10:
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AEDs: Molecular and Cellular Mechanisms
Valproate May enhance GABA transmission in specific circuits Blocks voltage-dependent sodium channels Blocks T-type calcium currents Gitanjali-11:
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Cl- Gabapentin Vigabatrin Valproate Gabapentin Benzodiazepines
GT Succinic Semialdehyde Valproate SSD metabolites Gabapentin Tiagabine Benzodiazepines Barbiturates Topiramate Cl- GT: GABA transaminase SSD:Succinic semialdehyde dehydrogenase Gitanjali-12:
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AEDs: Molecular and Cellular Mechanisms
Ethosuximide •Blocks slow, threshold, “transient” (T-type) calcium channels in thalamic neurons Gitanjali-13:
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Voltage regulated Ca++ current, low threshold “T” current in
thalamus Involved in 3 per second spike and wave rhythm Ca++ Gitanjali-14:
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Ca++ Ethosuximide Valproate
Reduction in the flow of Ca++ through T - type Ca++ channels in thalamus Gitanjali-15:
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Newer AEDs: Molecular and cellular Mechanisms
Vigabatrin • Irreversibly inhibits GABA- transaminase Tiagabine • Interferes with GABA re-uptake Gitanjali-16:
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Newer AEDs: Molecular and cellular Mechanisms
Topiramate Blocks voltage-dependent sodium channels at high firing frequencies Increases frequency at which GABA opens Cl- channels (different site from benzodiazepines) Antagonizes glutamate actions at receptor subtype Gitanjali-17:
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Newer AEDs: Molecular and Cellular Mechanisms
Felbamate • May block voltage-dependent sodium channel at high firing frequencies • May modulate NMDA receptor via strychnine insensitive glycine receptor Gitanjali-18:
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AEDs: Molecular and Cellular Mechanisms
Gabapentin • May modulate amino acid transport into brain • May interfere with GABA re-uptake Gitanjali-19:
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Newer AEDs: Molecular and Cellular Mechanisms
Lamotrigine • Blocks voltage-dependent sodium channels at high firing frequencies • May interfere with pathologic glutamate release Gitanjali-20:
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