Antiepileptic Drugs

1. By: Muhammad Usman Khalid
DPT,MS-NMPT
*

2. *
*The term epilepsy refers to disorder of brain
function characterized by periodic and
unpredictable occurrence of seizures, resulting
from neuronal discharges. The form of seizure
depends on the part of the brain affected.
Seizures are thought to arise from the cerebral
cortex, not from other CNS structures.

3. *Mechanisms of Action
of Antiepileptic Drugs:
Antiepileptic drugs are sometime called
anticonvulsants because the drugs are used to treat or
prevent convulsions caused by other brain
diseases(e.g. trauma, infection, tumour, stroke etc.).
The main mechanisms of actions of antiepileptic drugs
are as under:
1- Inhibition of sodium channel function.
2- Inhibition of calcium channel function.
3- Enhancement of GABA action.

4. *1- Inhibition of Sodium
Channel Function:
*Many drugs act by blocking voltage-dependent
sodium channels, which carry the inward membrane
current necessary for generation of action potential.
These drugs inhibit preferentially the cells that are
firing repetitively, higher the frequency of firing,
greater the block produced. Antiepileptic drugs bind
to sodium channels in inactivated state and prevent
them from returning to resting state and thus reduce
the number of functional neurons available for
generation of action potential.

6. *Enhancement of
GABA action:
*A large number of antiepileptic drugs act by
enhancing the activation of GABAA receptors
(Neuroinhibitory).

9. *Inhibition of Calcium
Channel Function:
*T-type low-voltage calcium channels are
important in determining the rhythmic discharge
of thalamic neurons concerned with absence
seizures. Thus, the drugs (valproates,
clonazepam etc.) effective for controlling
absence seizures, appear to block T- type low-
voltage calcium channels.

11. *I- Hydantoins:
*I- Phenytoin: is effective against all types of
partial and tonic-clonic seizures but ineffective
against absence seizures, which may even get
worse. It exerts its anti-seizure effect without
causing general CNS depression. Its effect is
mediated by slowing of rate of recovery of
voltage-activated sodium channels from
inactivated state. At therapeutic dose, its effect
on sodium channels is selective.

12. *I- Hydantoins:
Pharmacokinetics:
Phenytoin is absorbed well when given orally. It is
extensively bound (~ 90%) to plasma protein
mainly albumin.

13. *
* Toxicity:
*Headache, ataxia and vertigo without sedation.
At higher doses confusion and intellectual
deterioration occurs.
*Hyperplasia of gums develops gradually,
hirsutism occurs in young females due to
increased androgen secretion.
* Fetal malformations in children born to
phenytoin-treated mothers are also reported

14. Therapeutic Uses:
Phenytoin is one of the more widely used
antiepileptic agent. It is effective in partial (simple
& complex) and tonic-clonic seizure but
ineffective in absence seizures.

15. *Phenobarbitone ( Phenobarbital):
*Phenobarbital acts by potentiating synaptic
inhibition through an action on GABA receptors.
*Pharmacokinetics: The drug is absorbed well
following oral administration. Its plasma half-
life is 50-140 hours.
* Toxicity: Sedation, megaloblastic anemia,
hypersensitivity and osteomalacia.

16. *Ethosuximide:
*The main effect of the drug is inhibition of T- type
calcium channels that play role in generating the
3/second firing rhythm in thalamic relay neurons that
is characteristic of absence seizures.
*The drug is absorbed completely from GIT. It is
metabolized and excreted like phenobarbital.
*Commonly occurring side effects are nausea,
vomiting and anorexia. CNS side-effects include
lethargy, drowsiness, headache and hiccough.

17. *Valproic Acid:
i- It inhibits sodium channels
ii- It inhibit T-type calcium channels.
iii- It increases GABA contents of brain by inhibiting two
enzymes, GABA transaminase and succinic semi aldehyde
dehydrogenase, that inactivate GABA.
Valproate is absorbed rapidly from GIT and completely
after oral administration.
Toxic effects include GIT disturbance, thinning and curling
of hair.
Hepatotoxicity is the sever toxic effect. Valporic acid is
teratogenic causing spina bifida and other neural defect.

19. *Gabapentin and
Pregabalin:
*. Both these drugs act by binding to α2δ-1 subunit of
voltage-gated calcium channels. This leads to
decreased Ca++ entry, with a predominant effect on
presynaptic N-type channels.
* Both drugs are absorbed after oral administration.
The drugs are excreted un-metabolized in urine.
* Pregabalin is effective in neuropathic pain. Toxic
effects include somnolence, ataxia and fatigue.

20. *Vigabatrin:
*It binds with Gaba-metabolizing enzyme
GABA-transaminase irreversibly and hence
increases the brain content of GABA.
*The drug may cause depression and psychotic
disturbances.

21. *Lamotrigine:
*. It acts by inhibiting sodium and calcium
channels and also inhibiting synaptic release of
glutamate.
* It is completely absorbed from GIT and its half-
life is 24-30 hours.
*Main side effects are nausea, dizziness and
ataxia and sensitivity reactions.

22. *Carbamazepine:
*It is one of the most widely used anti seizure
drug, chemically derived from tricyclic
antidepressants.
*Carbamazepine is absorbed slowly from GIT. Its
half-life is 30 hours when given as single dose.
*It is strong inducer of hepatic enzymes and its
half-life shortens to 15 hours when given
repeatedly.

23. *Zonisamide:
*It is thought to act by inhibiting sodium and
calcium channels and enhancing GABA
function.
*It is an adjunt therapy of partial and generalized
seizures but may be effective as mono-therapy.