Q3 LONG ANSWER 10M ★ High-yield

Classify antiepileptic drugs by mechanism. Describe the choice of drug by seizure type and compare phenytoin, carbamazepine and valproate.

Pharmacology · 2nd Professional — Para-Clinical

Mechanisms of Antiepileptic Action

Mechanism	Drugs
Sodium channel blockade (use-dependent)	Phenytoin, carbamazepine, oxcarbazepine, lamotrigine, valproate, lacosamide
T-type calcium channel blockade (thalamic)	Ethosuximide, valproate — the mechanism relevant to absence seizures
Enhancement of GABA	Benzodiazepines and barbiturates (at the GABAA receptor); vigabatrin (inhibits GABA transaminase); tiagabine (blocks GABA reuptake); valproate
Binding to synaptic vesicle protein SV2A	Levetiracetam, brivaracetam
Glutamate antagonism	Topiramate, perampanel, felbamate
Calcium channel alpha-2-delta subunit	Gabapentin, pregabalin
Multiple mechanisms	Valproate and topiramate — which is why both have broad spectrum

Choice of Drug BY Seizure Type

Seizure type	First-line	Alternatives	Avoid
Focal (partial), with or without secondary generalisation	Carbamazepine, lamotrigine, levetiracetam	Oxcarbazepine, valproate, topiramate	—
Generalised tonic-clonic	Sodium valproate	Lamotrigine, levetiracetam (preferred in women of childbearing potential)	—
Absence	Ethosuximide or valproate	Lamotrigine	Carbamazepine, phenytoin and gabapentin worsen absence seizures
Myoclonic	Valproate or levetiracetam	Clonazepam, topiramate	Carbamazepine and phenytoin worsen myoclonus
Juvenile myoclonic epilepsy	Valproate; levetiracetam in women	Lamotrigine	Carbamazepine
Status epilepticus	Intravenous lorazepam	Then phenytoin, fosphenytoin, valproate or levetiracetam	—
Infantile spasms	ACTH or vigabatrin	Steroids	—
Febrile convulsion	Control the fever; rectal or buccal benzodiazepine for a prolonged seizure	—	Long-term antiepileptics are not indicated

CLINICAL PEARL

Carbamazepine and phenytoin make absence and myoclonic seizures worse, which is why the seizure type must be established before treatment. A generalised epilepsy misdiagnosed as focal and treated with carbamazepine deteriorates, and the deterioration is then mistaken for worsening disease and treated with a higher dose. Getting the classification right matters more than the choice within a class.

Phenytoin, Carbamazepine and Valproate

Feature	Phenytoin	Carbamazepine	Valproate
Kinetics	Zero-order within the therapeutic range — small dose increments only	Autoinduction — its own metabolism increases over 2–3 weeks, so the dose often needs raising	Enzyme inhibitor — raises lamotrigine and phenobarbitone
Characteristic adverse effects	Gingival hyperplasia, hirsutism, coarse facies, acne, ataxia and nystagmus (dose-related), megaloblastic anaemia (folate), osteomalacia, peripheral neuropathy, lymphadenopathy	Hyponatraemia (SIADH-like), diplopia, ataxia, rash, agranulocytosis and aplastic anaemia, hepatitis	Weight gain, tremor, hair loss (regrows curly), hepatotoxicity (especially under 2 years), pancreatitis, hyperammonaemia, thrombocytopenia, polycystic ovaries
Teratogenicity	Fetal hydantoin syndrome — cleft lip and palate, digital hypoplasia	Neural tube defects	The worst — neural tube defects and marked neurodevelopmental impairment; contraindicated in women of childbearing potential unless there is no alternative
Severe cutaneous reaction	Stevens–Johnson syndrome	Stevens–Johnson syndrome; strongly predicted by HLA-B*15:02 in South-East Asian and Indian populations — testing is recommended before starting	Less common
Monitoring	Plasma levels genuinely useful because of zero-order kinetics	Blood count, sodium, liver function	Liver function, blood count, amylase if symptomatic

General Principles of Treatment

Treatment is usually started after a second unprovoked seizure, or after a first if the risk of recurrence is high (abnormal EEG or imaging, focal deficit)
Monotherapy wherever possible — start low, increase slowly to the maximum tolerated dose before adding a second drug; about 70% are controlled on one drug
If the first drug fails, substitute rather than add, unless it produced partial benefit
Never stop abruptly — withdrawal seizures and status epilepticus may follow; taper over months
Withdrawal may be considered after 2 to 3 seizure-free years, weighing the recurrence risk against the burden of treatment and the implications for driving
Adherence is the commonest cause of breakthrough seizures, and should be asked about before the dose is increased

Newer Antiepileptic Drugs

Drug	Mechanism	Place and cautions
Levetiracetam	SV2A binding	Broad spectrum; renally excreted; almost NO interactions, so it is preferred in the elderly, in liver disease and alongside chemotherapy or antiretrovirals. Causes irritability and behavioural change
Lamotrigine	Sodium channel blockade	Broad spectrum; the safest in pregnancy; but the dose must be escalated very slowly because of stevens–johnson syndrome, and halved if valproate is co-prescribed
Topiramate	Multiple	Also for migraine prophylaxis; causes weight loss, paraesthesiae, renal stones, glaucoma and cognitive slowing ("dopamax")
Oxcarbazepine	Sodium channel	Like carbamazepine but less enzyme induction; more hyponatraemia
Gabapentin, pregabalin	Calcium channel alpha-2-delta subunit	Weak antiepileptics; their main use is neuropathic pain; both are now recognised as drugs of misuse
Vigabatrin	GABA transaminase inhibition	Infantile spasms; causes irreversible visual field constriction, so use is tightly restricted

Applied Aspects

Valproate must not be given to women who could become pregnant unless no alternative exists, with a pregnancy prevention programme; this is now an absolute restriction in most jurisdictions and is a major change in practice
Folic acid 5 mg daily before conception for every woman with epilepsy planning pregnancy
Enzyme-inducing antiepileptics reduce oral contraceptive efficacy — phenytoin, carbamazepine, phenobarbitone, topiramate; alternative contraception is essential. Valproate, levetiracetam and lamotrigine do not induce (though oestrogen lowers lamotrigine levels)
Test for HLA-B*15:02 before carbamazepine where available; the association with Stevens–Johnson syndrome is strong in Indian and South-East Asian populations
Epilepsy carries great social stigma in India, affecting marriage, employment and schooling; counselling the family and correcting misconceptions is as much a part of treatment as the drug
Advise on safety — swimming alone, cooking over open fires, working at heights, and driving regulations; and on sleep, alcohol and adherence as seizure triggers
Phenytoin is a poor choice for long-term use in the young because of gingival hyperplasia, hirsutism and coarsening of the features, which matter greatly to adolescents and drive non-adherence
Neurocysticercosis is the commonest cause of new-onset focal seizures in India, and imaging should be arranged rather than treating empirically
Antiepileptics interact widely — with each other, with warfarin, with antiretrovirals and with chemotherapy; levetiracetam is notably free of interactions and is often preferred for that reason
Bone health is affected by enzyme-inducing antiepileptics through vitamin D metabolism; calcium and vitamin D supplementation is worth considering with long-term use
Sudden unexpected death in epilepsy (SUDEP) is a real risk, greatest with poorly controlled generalised tonic-clonic seizures, and is a further reason to pursue full control rather than accept partial improvement
Generic substitution of antiepileptics is discouraged for patients who are stable, since small differences in bioavailability can precipitate seizures or toxicity in a narrow-index drug
The treatment gap for epilepsy in India exceeds 50% — most of it from cost, distance and stigma rather than from any lack of effective drugs; phenobarbitone remains cheap, effective and appropriate where resources are limited

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