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. 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:

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. Cl- Gabapentin Vigabatrin Valproate Gabapentin BenzodiazepinesGT
Succinic
Semialdehyde
Valproate
SSD
metabolites
Gabapentin
Tiagabine
Benzodiazepines
Barbiturates
Topiramate
Cl-
GT: GABA transaminase
SSD:Succinic 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. 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
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: