ANTI-EPILEPTICS

CLASSIFICATION
MECHANISM OF ACTION
PHENYTOIN
(DIPHENYLHYDANTOIN)
•Phenytoin is one of the most commonly used antiepileptic drugs. It has
a selective antiepileptic effect and does not produce significant
drowsiness.

•Mechanism of Action: Phenytoin acts by stabilizing neuronal

membrane and prevents spread of seizure discharges. The sodium
channels exist in three forms: resting, activated and inactivated states.

•Phenytoin delays recovery of Na channels from inactivated state,

thereby reduces neuronal excitability and inhibits high-frequency firing.
•Pharmacokinetics: Phenytoin is absorbed slowly through the GI
tract, widely distributed and highly (about 90%) bound to plasma
proteins. It is almost completely metabolized in liver by
hydroxylation and glucuronide conjugation.

•Repeated administration of phenytoin causes enzyme induction and

increases the rate of metabolism of co administered drugs.

•The plasma concentration increases markedly with slight increase in

dose resulting in toxicity. Hence, therapeutic monitoring of phenytoin
is essential for adjustment of dosage.
Adverse Effects
Phenytoin has dose-dependent toxicity. The adverse effects are as
follows:
1. Hypertrophy and Hyperplasia of gums
2. Hypersensitivity reactions
3. Hirsutism
4. Hyperglycaemia
5. Megaloblastic anaemia
6. Osteomalacia
7. Hypocalcaemia
8. Fetal Hydantoin syndrome
FOSPHENYTOIN
•It is a prodrug of phenytoin, which is converted to phenytoin by
phosphatases. Dose of fosphenytoin is expressed as phenytoin equivalents
(PE).
•It is available for i.m. and i.v. administration.
•Fosphenytoin can be administered in normal saline or glucose. It has
significantly less irritant effect on the veins than phenytoin.
•It is preferred to phenytoin in status epilepticus because of above
advantages. The rate of i.v. infusion should not exceed 150 mg PE/minute.
•Hypotension and cardiac arrhythmias may occur with rapid
administration.
CARBAMAZEPINE
(IMINOSTILBENE)
Mechanism of Action: Like phenytoin, carbamazepine slows the rate of
recovery of Na1 channels from inactivation, thereby reduces neuronal
excitability.
Pharmacokinetics Carbamazepine is absorbed slowly and erratically
from GI tract, binds to plasma proteins, is well distributed in the body
including the cerebrospinal fluid (CSF) and metabolized in liver.
One of its metabolites retains anticonvulsant activity. Repeated use causes
enzyme induction and reduces the effectiveness of the drug itself
(autoinduction) as well as that of valproate, phenytoin, lamotrigine,
topiramate, OC pills, etc.
•Adverse Effects: The common adverse effects of carbamazepine
include sedation, drowsiness, vertigo, ataxia, diplopia, blurred
vision, nausea, vomiting and confusion.

•Hypersensitivity reactions are skin rashes, eosinophilia,

lymphadenopathy and hepatitis.

•Rarely, it causes bone marrow depression with neutropenia,

aplastic anaemia and agranulocytosis. On chronic therapy, it may
cause water retention due to the release of antidiuretic hormone
(ADH).
OXCARBAZEPINE
Oxcarbazepine is an analogue of carbamazepine.

Mechanism of action and therapeutic uses are similar to carbamazepine. It

is a prodrug and is converted to active form after administration.

Its enzyme-inducing property is much less; hence, drug interactions are

few. It is less potent and less hepatotoxic than carbamazepine.

Eslicarbazepine It is similar in structure to carbamazepine. It is useful for

treatment of partial seizures
PHENOBARBITONE
(BARBITURATE)
•Phenobarbitone is a barbiturate and was widely used as an antiepileptic
drug. Its use has declined because of availability of safer drugs.

• It acts by potentiating GABA activity. Phenobarbitone is absorbed

slowly but completely after oral administration; about 50% is bound to
plasma proteins.

• Repeated administration causes enzyme induction and reduces the

effectiveness of co-administered drugs.
Adverse Effects: The most common side effect of phenobarbitone is sedation, but
tolerance develops gradually with continued administration. The other side effects
are nystagmus, ataxia, confusion, megaloblastic anaemia and skin rashes.

On chronic therapy, it may cause behavioural disturbances with impairment of

memory in children.

Uses. Phenobarbitone is effective in GTCS and partial seizures.

It is the cheapest antiepileptic drug. It is also useful in the prophylactic treatment
of febrile convulsions.
In status epilepticus, phenobarbitone is injected intravenously when convulsions
are not controlled with diazepam and phenytoin.
ETHOSUXIMIDE
(SUCCINIMIDE)
• It acts by inhibiting T-type Ca current in thalamic neurons.

•It is completely absorbed after oral administration.

• The common side effects are GI disturbances like nausea, vomiting and
anorexia. The other side effects are headache, hiccough, eosinophilia,
neutropenia, thrombocytopenia with bone marrow depression and rarely skin
rashes.

•It is effective for the treatment of absence seizures.

 VALPROATE / VALPROIC ACID
Sodium valproate is a broad-spectrum antiepileptic drug.
Mechanism of Action
1. Like phenytoin and carbamazepine, valproate delays the recovery of Na1 channels
from inactivation.
2. Like ethosuximide, it blocks T-type Ca21 current in thalamic neurons.
3. Increases the activity of GABA in the brain by: (a) Increased synthesis of GABA by
stimulating GAD (glutamic acid decarboxylase) enzyme. (b) Decreased degradation of
GABA by inhibiting GABA-T (GABA-transaminase) enzyme. Pharmacokinetics.
Valproate is rapidly and almost completely absorbed from the GI tract, highly (about
90%) bound to plasma proteins, metabolized in liver and excreted in urine
Adverse Effects (Note the Mnemonic VALPROATE)
1. The common side effects related to GI tract are nausea, Vomiting, Anorexia and
abdominal discomfort.
2. CNS side effects include sedation, ataxia and tremor.

3. A rare but serious complication is fulminant hepatitis (Liver), hence avoided in

children younger than 3 years. Monitoring of hepatic function is essential during
valproate therapy; Elevation of liver enzymes occurs.

4. Teratogenicity: Orofacial and digital abnormalities; neural tube defects with

increased incidence of spina bifida, so it should not be given during pregnancy.

5. The other adverse effects include skin Rashes, Alopecia and curling of hair; acute
Pancreatitis may occur rarely.
Uses. Sodium valproate is highly effective in absence, myoclonic,
partial (SPS and CPS) and generalized tonic–clonic seizures.
Other uses of valproate are mania, bipolar disorder and migraine
prophylaxis.

Divalproex: It contains valproic acid and sodium valproate in 1:1

ratio. It is administered orally. It causes less GI side effects than
valproic acid.
 DIAZEPAM, LORAZEPAM,
CLONAZEPAM
(BENZODIAZEPINES)
•Diazepam and lorazepam are effective in controlling status epilepticus.
Intravenous diazepam is used in the emergency treatment of status
epilepticus, tetanus, eclamptic convulsions, febrile convulsions, drug-
induced convulsions, etc.
•Diazepam has a rapid onset but short duration of action; hence, repeated
doses are required. Diazepam can be administered rectally in children
during emergency.
•Lorazepam is preferred in status epilepticus because: 1. It has a rapid onset
and long duration of action. 2. It has less damaging effect on injected vein.
•Clonazepam, a long-acting BZD, is used in absence and myoclonic
seizures.
Sites of Action Midbrain (ascending reticular formation), limbic
system, brain stem, etc.

Mechanism of Action
BZDs facilitate action of GABA – they potentiate inhibitory
effects of GABA. Benzodiazepines
Bind to specific site on GABAA receptor (different from GABA-
binding site)
Increase in frequency of opening of Cl− channels Increase in
GABA-mediated chloride current
Adverse Effects.
Intravenous diazepam and lorazepam may cause hypotension and
respiratory depression.
The main side effects of clonazepam are sedation and lethargy, but
tolerance develops on chronic therapy.
Other side effects are hypotonia, dysarthria, dizziness and
behavorial disturbances like irritability, hyperactivity and lack of
concentration.
NEWER ANTI-EPILEPTICS
STATUS EPILEPTICUS
STATUS EPILEPTICUS It is a medical emergency and should be treated
immediately. It is characterized by recurrent attacks of tonic–clonic
seizures without the recovery of consciousness in between or a single
episode lasts longer than 30 minutes.
Treatment
1. Hospitalize the patient.
2. Maintain airway and establish a proper i.v. line.
3. Administer oxygen.
4. Collect blood for estimation of glucose, calcium, electrolytes and urea.
5. Maintain fluid and electrolyte balance