Anticonvulsant Drugs

A seizure is a brief, temporary disturbance in the electrical activity of

the brain.
Epilepsy is a disorder characterized by recurring seizures (also known
as seizure disorder).
International Classification of Seizures
1. Generalized Seizures which affect the entire brain.
A. Absence seizures (formerly called petit mal)
B. Myoclonic seizures
C. Clonic seizures
D. Tonic seizures
E. Tonic clonic seizures (formerly called grand mal)
F. Atonic seizures (drop attacks).
2. Partial Seizures which affect a part of the brain.
A. Simple partial seizures- jacksonian (consciousness not impaired)
B. Complex partial seizures-Psychomotor (with impaired consciousness)
C. Partial seizures evolving to secondarily generalized seizures
Status epilepticus: Continuous seizure activity for more than 30
minutes, or 2 or more seizures without recovery of consciousness.
Emergency: Recurrent tonic-clonic convulsions without recovery in
between.
Aura is the subjective sensation or phenomenon that precedes and
marks the onset of the epileptic seizure-it may localize the seizure origin
within the brain.
Ictus is the attack or seizure itself.
Postictal period is the time after the ictus during which the patient
may be drowsy, confused, and disoriented.
Aim of Therapy
-

Selection inhibition of the epileptogenic focus

Prevent spread of the abnormal impulse in the surrounding normal

tissue
Treatment is directed towards the cause and use minimal number
of drugs to avoid interactions.
Treatment should be continued for 2-3 years and should not be
stopped suddenly (abruptly), otherwise status epilepticus will be
precipitated.

Mechanism of action of antiepileptic drugs:

-

Block of Na+ channels and so prolong the inactive state

e.g. phenytoin, carbamazepine, Lamotrigine.

Block of T-type Ca++ channels e.g. ethosuximide and valproic

acid.
Increase inhibitory

barbiturates, vigabatrin.
Decrease excitatory effect of glutamic acid e.g. topiramate,

effect of

GABA e.g. benzodiazepines,

lamotrigine and felbamate.

-

Increase outward positive currentK+ e.g.

valproate&

Retiagabine
Many AEDs pleiotropicact via multiple mechanisms e.g.

Felbamate, Lamotrigine, Topiramate& Valproate.

1) Phenytoin: (Diphenyl-hydantion):
It has antiepileptic activity without causing general depression of
C.N.S. It has stabilizing effect on excitable membranes including
neurons and heart, through inhibiting Na+ influx.
Pharmacokinetics: Absorbed orally, highly bound to plasma
proteins, metabolized in liver by hydroxylation and conjugation (its
metabolism is saturated at therapeutic doses zero order
kinetic), excreted in urine.
Used in:
1- Grand mal and partial seizures (not in petit mal).
2- Treatment of arrhythmia especially induced by digitalis.
Adverse effects:
1- Gingival hyperplasia, hirsutism, osteomalacia (alter Vit. D
metabolism and inhibit Ca++ absorption).
2- Gastrointestinal irritation (so given with meals), hepatitis.

34567-

Ataxia, diplopia, vertigo, nystagmus.

Blood dyscrasias, hypersensitivity reaction.
Teratogenic effects.
Megaloblastic anaemia (due to decreased folic acid absorption).
Inhibit antidiuretic hormone(ADH) and insulin secretion,

increase metabolism of vitamin K.

Interactions:
1- Enzymes activators as carbamazepine decreased its effect while
enzyme inhibitors as cimetidine increased its effect.
2- It is enzyme inducer, so increase metabolism of corticosteroids,
digitoxin, oral contraceptives, theophylline.
3- Can displace thyroxin and tricyclic antidepressants from plasma
proteins, and is displaced by sodium valproate.
4- Enhance toxicity of methotrexate (it decreases folic acid).
1) Barbiturates:
Phenobarbitone and primidone (which is active and partly
metabolized into phenobarbitone). Metabolized by oxidation,
hydroxylation then conjugation, but phenobarbitone is eliminated
partly unchanged.
Uses: Grand mal and partial seizures.
Adverse effects: Sedation, drowsiness,

vertigo,

ataxia,

headache, irritability, dependence, megaloblastic anemia and

osteomalacia.
Interactions: Enzyme induction of oral anticoagulants, oral
contraceptives, oral hypoglycemic and other anticonvulsants.
Contraindications: In petit mal epilepsy and porphyria.
2) Carbamazepine (Tegretol):
- It blocks Na+ channels as phenytoin.
- Effective in grand mal epilepsy and in simple and complex partial
seizures, also in trigeminal neuralgia and diabetes insipidus.
- Given orally and is enzyme inducer.
Adverse effects: Nausea, vomiting, diarrhea, dizziness, ataxia,
diplopia, antidiuretic effects, skin rashes, hepatitis, and bone
marrow depression.
3) Valproic acid = sodium valproate (Epilim-Depakene):
- Acts by increasing level of GABA by inhibiting GABA transaminase
which is responsible for breakdown of GABA. It blocks also Na + and
Ca++ channels.
- It is effective in all types of epilepsy.
- Absorbed orally, highly bound to plasma proteins, metabolized in
liver.

Adverse effects: Sedation, ataxia, nausea, gastric irritation,

thrombocytopenia,

drug

hepatitis,

transient

hair

loss

and

teratogenic effect (may produce spina bifida).

Interactions: It is enzyme inhibitor so increases Phenobarbitone
in plasma and may increase phenytoin level.
4) Benzodiazepines:
They act on benzodiazepines receptors so potentiate the action of
GABA.
- Diazepam and lorazepam are given I.V. in status epilepticus,
diazepam is also effective in other types of epilepsy, but long-term
use is limited by the development of tolerance.
- Clonazepam is used orally in absence seizures and myoclonic
seizures.
5) Ethosuximide (Zarontin):
Succinamide derivative which blocks Ca++ channels T-type.
It given orally, 75% is metabolized in liver and 25% excreted
unchanged in urine. Used in petit mal epilepsy (drug of choice).
Side effects: Gastrointestinal intolerance, drowsiness mood
changes, blood dyscrasias and allergy.
6) Trimethadione and paramethadione:
- Used in petit mal epilepsy, but produce sedation, hemeralopia or
glare effect (blurred vision in bright light), nephrotic syndrome,
exacerbate grand mal epilepsy, hepatitis and bone marrow
depression.
7) Acetazolamide (Diamox):
Carbonic anhydrase inhibitor, used in petit mal.

New Anticonvulsant Drugs

1. Lamotrigine: blocks Na+ channels and glutamate receptors

and it used in partial seizures.
Side Effects: sedation, ataxia, diplopia and stevens-Johnson
syndrome.
2. Vigabatrin: Is irreversible inhibitor of GABA transaminase
which is responsible for degradation of GABA and is used in
partial

seizures.

Side effects: depression, psychosis and visual dysfunction.

3. Gabapentin: acts by promoting GABA release. Used in partial
seizures, migraine and neuropathic pain.
Side effects: sedation ataxia and cognitive changes.

4. Felbamate: Blocks Na+ and Ca++ channels and glutamate

Seizure types

1st choice

2nd choice

Generalized tonicclonic or simple

partial seizure

Carbamazepine,
Phenytoin and
Valproic acid

Phenobarbitone
and Valproate

Absence seizure

Ethosuximide

Valproate

Complex partial
seizure with or
without
generalization
Myoclonic

Phenytoin,
Carbamazepine
and Valproate

Gabapentin
Lamotrigine

Valproate

Lamotrigine
Topiramate

Status epilepticus

Diazepam
Lorazepam

Phenytoin IV
Phosphenytoin IV

Febrile convulsions

Diazepam rectal
0.5mg/kg

receptors and used in partial seizures.

5. Tigabine: blocks GABA transporter and used in partial
seizures.
Side effects: Sedation, dizziness and flu like symptoms.
6. Topiramate: blocks glutamate receptors and increase GABA
effects and used in partial seizures.
Side effects: Sedation, ataxia, weight loss and renal stones.
Treatment of Epilepsies Drug choices