Anti-epileptics

1. Modern treatment of seizures started in 1850 with the introduction
of bromides, on the basis of the theory that epilepsy was caused by
an excessive sex drive. In 1910, phenobarbital, which then was
used to induce sleep, was found to have antiseizure activity and
became the drug of choice for many years. A number of
medications similar to phenobarbital were developed, including
primidone. Houston Merrit and Tracy Putnam introduced animal
models for screening multiple compounds for antiepileptic activity,
published in Journal of the American Medical Association in 1938.
In 1940, phenytoin (PHT) was found to be an effective drug for the
treatment of epilepsy, and since then it has become a major first-
line antiepileptic drug (AED) in the treatment of partial and
secondarily generalized seizures.
In 1968, carbamazepine (CBZ) was approved, initially for the
treatment of trigeminal neuralgia; later, in 1974, it was approved for
partial seizures. Ethosuximide has been used since 1958 as a first-
choice drug for the treatment of absence seizures without
generalized tonic-clonic seizures. Valproate was licensed in
Europe in 1960 and in the United States in 1978, and now is widely
available throughout the world. It became the drug of choice in
primary generalized epilepsies and in the mid 1990s was approved
for treatment of partial seizures. These anticonvulsants were the
mainstays of seizure treatment until the 1990s, when newer AEDs
with good efficacy, fewer toxic effects, better tolerability, and no
need for blood level monitoring were developed. The new AEDs
have been approved in the United States as add-on therapy only,
with the exception of lamotrigine, which is approved for conversion
to monotherapy.
The AEDs can be grouped according to their main mechanism of
action, although many of them have several actions and others
have unknown mechanisms of action. The main groups include
sodium channel blockers, calcium current inhibitors, gamma-
aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic
anhydrase inhibitors, hormones, and drugs with unknown
mechanisms of action.

2. Carbamazepine
The main mode of action
Block sodium channels during rapid, repetitive, sustained neuronal
firing and to prevent posttetanic potentiation.
Formulations that are available include suspension, syrup, tablets
(100 mg, 200 mg, 400 mg).
Antiepileptic effect and clinical use
Highly effective for partial onset seizures, including
cryptogenic and symptomatic partial seizures.
Treatment of generalized tonic-clonic seizures.
Side effects and toxicity
Dose-related adverse effects, which include dizziness,
diplopia, nausea, ataxia, and blurred vision.
Rare idiosyncratic adverse effects include aplastic
anemia, agranulocytosis, thrombocytopenia, and
Stevens-Johnson syndrome. Asymptomatic elevation of
liver enzymes in 5-10% of patients. Rarely, severe
hepatotoxic effects can occur.
Drug interactions
Several drugs, such as macrolide antibiotics (erythromycin and
clarithromycin), isoniazid, chloramphenicol, calcium channel
blockers, cimetidine, and propoxyphene, inhibit the hepatic
enzyme cytochrome P-4503A4 (CYP3A4), which is responsible
for the metabolic breakdown of CBZ, thereby raising its levels.
CBZ induces the metabolism of tricyclic antidepressants, oral
contraceptives, cyclosporin A, and warfarin by inducing the
hepatic enzyme CYP3A4.

3. Phenytoin
The main mode of action
It blocks movements of ions through the sodium channels during
propagation of the action potential, and therefore blocks and
prevents posttetanic potentiation, and reduces the spread of
seizures.
It also demonstrates an inhibiting effect on calcium channels and
the sequestration of calcium ions in nerve terminals, thereby
inhibiting voltage-dependent neurotransmission at the level of the
synapse.
Antiepileptic effect and clinical use
PHT is one of the most commonly used first-line or adjunctive
treatments for:
partial and generalized seizures
Lennox-Gastaut syndrome
status epilepticus
childhood epileptic syndromes.
It is not indicated for myoclonus and absence seizures.
Adverse effects and toxicity
One disadvantage of this drug is that it causes CNS and systemic
adverse effects. The long-term use is associated with osteoporosis.
CNS effects occur particularly in the cerebellum and the vestibular
system, causing ataxia and nystagmus. Some degree of
drowsiness and lethargy is present. Nausea and vomiting, rash,
blood dyscrasias, headaches, vitamin K and folate deficiencies,
loss of libido, hormonal dysfunction, and bone marrow hypoplasia
are among the most common adverse effects.
When given during pregnancy, PHT, like other AEDs, can cause
cleft palate, cleft lip, congenital heart disease, slowed growth rate,
and mental deficiency in the offspring.

4. Fosphenytoin
Fosphenytoin sodium injection is a prodrug intended for parenteral
administration. Its active metabolite is PHT. It is safer and better
tolerated than PHT and can be infused 3 times faster than
intravenous (IV) PHT.
Antiepileptic effect and clinical use
The antiepileptic effect of fosphenytoin is attributable to PHT.
Fosphenytoin is indicated for treatment of status epilepticus.
Adverse effects and toxicity
Cardiovascular depression and hypotension may occur but less
than with PHT.
Severe burning, itching, and/or paresthesia, mainly in the groin
area, have been associated with rapid infusion. The discomfort
may be improved by lowering the infusion rate .
Oxcarbazepine
The main mode of action
Like CBZ, OXC blocks the neuronal sodium channel during
sustained rapid repetitive firing.
Antiepileptic effects and clinical use
OXC is approved for monotherapy or adjunctive therapy in partial
and secondary generalized seizures.
OXC is better tolerated and has fewer drug interactions than CBZ.
In adults, the dose is 600 mg/d up to a maximum of 2400 mg/d.
Adverse effects and toxicity
Somnolence, headache, dizziness, rash, hyponatremia,
weight gain, GI disturbances, and alopecia are the most
commonly reported adverse effects.
Dose-related adverse effects include fatigue, headache,
dizziness, and ataxia. Hyponatremia is mild and can be

5. corrected by fluid restriction. Idiosyncratic reactions appear to
be less common than with CBZ.
Lamotrigine
The main mode of action
Inhibit depolarization of the glutaminergic presynaptic membrane,
thus inhibiting release of glutamate.
Antiepileptic effect and clinical use
It is effective in:
partial seizures
secondarily generalized tonic-clonic seizures
primary generalized seizures
atypical absence seizures
tonic/atonic seizures
Lennox-Gastaut syndrome
myoclonic seizures, but can worsen "in some patients"
juvenile myoclonic epilepsy or myoclonic epilepsy of infancy.
In children on valproate, the starting dose of LTG is 0.15 mg/kg,
with increments every 1-2 weeks up to a maximum of 1-5 mg/kg.
Adverse effects and toxicity
LTG produces few CNS side effects.
Rash is the main concern associated with this drug. Severe
rash (more common in children taking valproate) may develop
and lead to Stevens-Johnson syndrome, which may be fatal,
but this is rare (0.1%).
Other adverse reactions are headache, blood dyscrasias,
ataxia, diplopia, GI disturbance, psychosis, tremor,
hypersensitivity reactions, somnolence, and insomnia.
Zonisamide
The main mode of action
Reduction of neuronal repetitive firing by blocking sodium channels
and preventing neurotransmitter release.

6. Antiepileptic effect and clinical use
Adjunctive therapy for patients with partial seizures who are
12 years or older.
Treatment of myoclonus, esp., in juvenile myoclonic epilepsy.
Adverse effects and toxicity
Dizziness, anorexia, headache, ataxia, confusion, speech
abnormalities, mental slowing, irritability, tremor, and weight
gain. Somnolence and fatigue have been reported frequently.
ZNS is associated with renal stones in 1.5% of patients.
Idiosyncratic skin reactions (eg, Stevens-Johnson syndrome,
toxic epidermal necrolysis) have been reported.
Clobazam
The main mode of action
In addition to its agonist action at the GABA-A receptor, clobazam
may affect voltage-sensitive conductance of calcium ions and the
function of sodium channels.
Antiepileptic effect and clinical use
Clobazam is a potent anticonvulsant for partial epilepsy.
Adverse effects and toxicity
The most common effect is sedation. Others include dizziness,
ataxia, blurred vision, diplopia, irritability, depression, muscle
fatigue, and weakness. Idiosyncratic reactions are very rare.
Clonazepam
The main mode of action
Clonazepam has higher affinity for the GABA-A receptor site .
Antiepileptic effect and clinical use
The drug of choice for myoclonic seizures and subcortical
myoclonus.

7. Effective in generalized convulsions and, to a lesser extent, in
partial epilepsies.
Very effective in the emergency treatment of status
epilepticus, like diazepam, and can be given IV or rectally.
Withdrawal from clonazepam may induce status epilepticus or
exacerbation of seizures. Psychiatric withdrawal also may occur,
manifested as insomnia, anxiety, psychosis, and tremor.
Adverse effects and toxicity
The major adverse effect is sedation, even at low doses.
Clonazepam has the typical adverse effects of
benzodiazepines (eg, ataxia, hyperactivity, restlessness,
irritability, depression, cardiovascular or respiratory
depression).
Children and infants may have hypersalivation. Occasionally.
Phenobarbital
The main mode of action
1) It has a direct action on GABA-A receptors prolonging the
duration of chloride channel opening.
2) It also reduces sodium and potassium conductance and
calcium influx and depresses glutamate excitability.
Antiepileptic effect and clinical use
As effective as PHT and CBZ in the treatment of partial
and secondarily generalized seizures.
It is a second-line drug because of its adverse effects
such as sedation and cognitive slowing.
Physical dependence and withdrawal seizures occur with long-term
use.
Adverse effects and toxicity
The most important adverse effects are cognitive and behavior
alterations. Sedation is prominent. Psychomotor slowing, poor
concentration, depression, irritability, ataxia, and decreased libido

8. are other effects. Coarsening of facial features, osteomalacia, and
Dupuytren contractures. Folate deficiency, megaloblastic anemia,
and idiosyncratic skin reaction are rare.
Primidone
The main mode of action
This drug is metabolized to PHB and phenylethylmalonamide
(PEMA). The main action is through the derived PHB.
Antiepileptic effect and clinical use
Primidone has the same indications as PHB.
Adverse effects and toxicity
The major adverse effects are intense sedation, dizziness, and
nausea. Other effects are the same as those of PHB.
Tiagabine
The main mode of action
Inhibition of the GABA transporter-1 (GAT-1).
Antiepileptic effect and clinical use
Add-on therapy in patients with partial or secondarily generalized
seizures refractory to treatment.
Adverse effects and toxicity
The adverse effects include dizziness, asthenia,
nervousness, tremor, depressed mood, and emotional lability.
Others included somnolence, headaches, abnormal thinking,
abdominal pain, pharyngitis, ataxia, confusion, psychosis, and
skin rash.
A few clinical trials have reported the occurrence of
convulsive and nonconvulsive status epilepticus with TGB.
TGB therapy should be used cautiously in patients with a
history of status epilepticus.
TGB is contraindicated in severe hepatic impairment, pregnancy,
and lactation.

9. Vigabatrin
The main mode of action
It is a close structural analog of GABA, binding irreversibly to the
active site of GABA-T.
Antiepileptic effect and clinical use
Very effective in the treatment of infantile spasms; therefore, it is
the drug of choice for this indication in many countries.
The usual starting dose for adults is 500 mg twice daily, to a
maximum dose of 4000 mg/d.
Adverse effects and toxicity
The most common adverse effect is drowsiness.
Others include neuropsychiatric symptoms, such as
depression (5%), agitation (7%), confusion and, rarely,
psychosis.
Recent studies showed visual field changes, characterized
by concentric constriction, with preservation of central vision.
Gabapentin
The main mode of action
Gabapentin (GBP) was developed to have a structure similar to
that of GABA.
Antiepileptic effect and clinical use
Useful in the treatment of partial and secondarily generalized tonic-
clonic seizures but is ineffective in myoclonus and in most
generalized seizure disorders.
Adverse effects and toxicity
GBP is relatively well tolerated. No significant serious idiosyncratic
or systemic adverse effects have been reported.

10. Valproate
The main mode of action
The mechanism of action is uncertain. VPA enhances GABA
function, but this effect is observed only at high concentrations. It
may increase the synthesis of GABA by stimulating GAD.
Antiepileptic effect and clinical use
It is the drug of choice in:
• Idiopathic generalized epilepsy
• Juvenile myoclonic epilepsy and can be used in other types of
myoclonus
a first-line drug in photosensitive epilepsy and Lennox-Gastaut
syndrome.
a second choice in the treatment of infantile spasms.
In focal epilepsy, VPA is effective as other first-line agents.
Adverse effects and toxicity
Dose-related adverse effects include nausea, vomiting,
tremor, sedation, confusion or irritability, and weight gain.
Metabolic effects from interference in mitochondrial
metabolism include hypocarnitinemia, hyperglycinemia, and
hyperammonemia.
Severe sedation or even coma may result from
hyperammonemia, typically with normal liver function tests.
Hair loss or curling of hair may occur.
VPA has adverse endocrine effects, including insulin
resistance and change in sex hormone levels causing
anovulatory cycles, amenorrhea, and polycystic ovary
syndrome.
Bone marrow suppression with neutropenia and allergic
rashes are rare.
Acute pancreatitis is rare but potentially fatal and usually
reverses after withdrawal of VPA.
The most serious idiosyncratic adverse effect is
hepatotoxicity.

11. Felbamate
The main mode of action
Blocks the NMDA receptors and voltage-gated calcium channels
and also modulates sodium-channel conductance, but has no
effect on GABA receptors.
Antiepileptic effect and clinical use
Felbamate is restricted to patients with severe partial epilepsy or
Lennox-Gastaut syndrome who do not respond to other
medications.
This limited usage is because of the small but definitive risk of
aplastic anemia and hepatic failure.
Adverse effects and toxicity
Common adverse effects include insomnia, weight loss, nausea,
decreased appetite, dizziness, fatigue, ataxia, and lethargy.
Topiramate
The main mode of action
Exerts an inhibitory effect on sodium conductance.
Enhances GABA by unknown mechanisms.
Inhibits the AMPA subtype glutamate receptor.
Weak inhibitor of carbonic anhydrase.
Antiepileptic effect and clinical use
It also has been effective in drug-resistant generalized epilepsies
as adjunctive therapy, including:
Juvenile myoclonic epilepsy,
Absence seizures
Generalized tonic-clonic seizures
Lennox-Gastaut syndrome.
Adverse effects and toxicity
1) The most common adverse effects of topiramate include ataxia,
impairment of concentration, confusion, dizziness, fatigue,

12. paresthesia in the extremities, somnolence, disturbance of
memory, depression, agitation, and slowness of speech.
2) The most common adverse effects in children are somnolence,
anorexia, fatigue, and nervousness.
3) The drug causes weight loss in many patients, sometimes
more than 10 kg, an effect that may lead to discontinuation.
The weight loss appears to be related to appetite suppression.
4) No idiosyncratic severe reactions or allergic rashes have been
reported. No hepatotoxicity, hematologic toxicity, serious GI
toxicity, or cardiotoxicity have been documented.
5) Recently, acute myopia with angle-closure glaucoma has been
reported as a rare adverse event associated with topiramate.
Levetiracetam
The main mode of action
Levetiracetam (LEV) is a piracetam derivative.
The mechanism of action is unknown. However, LEV inhibits Ca2+
release from the IP3-sensitive stores which could explain some of
LEV's antiepileptic properties.
Antiepileptic effect and clinical use
The results suggest that LEV might have a significant effect in
generalized epilepsies. In March, 2007 it was approved by the
FDA for primary generalized tonic-clonic seizures in adults and
children aged 6 years and older.
Adverse effects and toxicity
The most significant adverse effects are somnolence, asthenia,
and dizziness.
LEV has no strong tendency to exacerbate seizures, unlike this
paradoxical effect recorded in some patients treated with other
AEDs.