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Mechanism of action of Antiepileptic Drugs

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Succinic. Semialdehyde. Gabapentin. GT: GABA transaminase. SSD:Succinic semialdehyde dehydrogenase. GT. SSD. Vigabatrin. Valproate. Benzodiazepines ... – PowerPoint PPT presentation

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Title: Mechanism of action of Antiepileptic Drugs


1
Mechanism of action of Antiepileptic Drugs
B. Gitanjali
Gitanjali-1
2
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
3
AEDs Molecular and Cellular Mechanisms
  • Phenytoin, Carbamazepine
  • Block voltage-dependent sodium
  • channels at high firing frequencies

Gitanjali-6
4
Na
Open
Activation gate
Na
Inactivation gate
Na
Gitanjali-7
5
Na
Block channels firing at high frequencies
Inactivated channel
Na
Na
Na
Carbamazepine Phenytoin Felbamate Lamotrigine
Barbiturates Topiramate
Gitanjali-8
6
AEDs Molecular and Cellular Mechanisms
  • Barbiturates
  • Prolong GABA-mediated chloride
  • channel openings
  • Some blockade of voltage-
  • dependent sodium channels

Gitanjali-9
7
AEDs Molecular and Cellular Mechanisms
  • Benzodiazepines
  • Increase frequency of GABA-
  • mediated chloride channel
    openings

Gitanjali-10
8
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
9
Gabapentin
GABA
Vigabatrin
GT
Succinic Semialdehyde
Valproate
SSD
metabolites
Gabapentin Tiagabine
Benzodiazepines
Barbiturates
Topiramate
Cl-
GT GABA transaminase
SSDSuccinic semialdehyde dehydrogenase
Gitanjali-12
10
AEDs Molecular and Cellular Mechanisms
  • Ethosuximide
  • Blocks slow, threshold, transient
  • (T-type) calcium channels in
  • thalamic neurons

Gitanjali-13
11
Ca
Voltage regulated Ca current, low threshold
T current in thalamus
Involved in 3 per second spike and wave rhythm
Ca
Gitanjali-14
12
Ca
Ethosuximide Valproate
Ca
Reduction in the flow of Ca through T
- type Ca channels in thalamus
Gitanjali-15
13
Newer AEDs Molecular and cellular Mechanisms
  • Vigabatrin
  • Irreversibly inhibits GABA-
  • transaminase
  • Tiagabine
  • Interferes with GABA re-uptake

Gitanjali-16
14
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
15
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
16
AEDs Molecular and Cellular Mechanisms
  • Gabapentin
  • May modulate amino acid
  • transport into brain
  • May interfere with GABA
  • re-uptake

Gitanjali-19
17
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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