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