Antiepileptic Drugs & Recent Development

8. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzo-
diazepines, gabapentin, levetiracetam, tiagabine,
vigabatrin, topiramate, valproate; the result is increased
permeability to chloride ion,which reduces neuronal
excitability.
Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.

9. (2) Reducing cell membrane permeability to
voltage-dependent sodium channels:
carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to
calcium T-channels:
• valproate, ethosuximide; the result is diminishing
of the generation
• of action potential.
(4) Inhibiting excitory neurotransmitter glutamate:
lamotrigine.

10. Carbamazepine
Lamotrigine
Oxcarbazepine
Phenytoin
Topiramate
Valproate
Ethosuximide
Levetiracetam
Pregabalin
Valproate
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin
Na+ Ca2+
GABA

12. Antiseizure drugs
enhanced
GABA
synaptic
transmission

13. Antiseizure drugs, enhanced Na+ channel inactivation

14. Na Channels
• Voltage- gated sodium channels are critical for action potential (AP)
generation and propagation .
• The sodium channel exists in three principal conformational states:
1. the channel is in the resting closed state;
2. the channel opens and permits the conduction of sodium ions;
3. the channel then enters a nonconducting, inactivated state.
Phenytoin, lamotrigine, oxcarbazepine, and car- bamazepine bind
to and stabilize the inactivated state of the sodium channel

15. Calcium channels
Calcium channels are also targets for AEDs, as they
regulate not only neuronal excitability but also
neurotransmitter release
The voltage-gated calcium channels expressed in the
brain can be subdivi- ded into four main classes, L-,
P/Q-, N-, and T- type channels
N- and P/Q-type channels-Gabapentin, Pregabalin
 T- type –ethosuximide, zonisamide and valproate

16. • GABAergic system Gamma amino butyric acid
(GABA) is the major inhibitory
neurotransmitter in the brain.

17. Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels.

25. Clobazam
• synthesized in 1972 by modification of the
• retained 20% of the the anxiolytic activity of
diazepam,10-15 % of diazepam's sedative
effects
• introduced as an anti-anxiety agent about half
as potent as diazepam and producing less
psychomotor side-effects than diazepam.
• later found to have major antiepileptic effects

26. Mode of action
Clobazam exerts its anxiolytic and anticonvulsant
action at the benzodiazepine binding site of the
Gamma-aminobutyric acid A (GABA -A) receptor
complex by increasing the likelihood of opening of
the ligand-gated Cl~ ion channel in response to
given concentration of GABA.
Exact mechanism of action not fully understood:
thought to potentiate GABAergic neurotransmission
resulting from binding to GABA-A receptor

27. Pharmacokinetics
Bioavailability: 100%
Peak Plasma Time: 0.5-4 hr
Half-life: 36-42 hr (clobazam); 72-82 hr (N-
desmethylclobazam)
Excretion: 11% as metabolites feces (1%
unchanged drug), 82% as metabolites urine (2%
unchanged drug)

28. Administration
• Individualize weight-based dose according to
clinical efficacy and tolerability
• Doses above 5 mg/day should be administered
in divided doses twice daily (5 mg dose can be
administered as a single daily dose)
• May be taken without regard to food