Antiepileptic Drugs
Pharmacology · CNS · lean revision notes
title: "Antiepileptic Drugs" subject: "Pharmacology" group: "CNS" difficulty: "Hard" highYield: true
Antiepileptic Drugs
Antiepileptic drugs (AEDs) are among the most heavily tested topics in NEET PG Pharmacology because every drug carries a signature mechanism, a drug-of-choice (DOC) tag, a teratogenic flag, and a unique toxicity. This note organises them by mechanism, locks in the DOC for each seizure type, and walks through status epilepticus stepwise — the three angles examiners love most.
Definition & basic concepts
Epilepsy is a tendency to recurrent, unprovoked seizures arising from abnormal, synchronous neuronal discharge. AEDs do not cure epilepsy; they raise the seizure threshold or suppress propagation. The pharmacological goal is to enhance inhibition (GABA) or reduce excitation (Na+/Ca2+ influx, glutamate).
Seizures are broadly classified (ILAE) into:
- Focal (partial) — onset in one hemisphere; may be focal aware (simple partial) or focal impaired-awareness (complex partial), with or without secondary generalisation.
- Generalised — bilateral from onset: tonic-clonic (grand mal), absence (petit mal), myoclonic, atonic, tonic.
- Status epilepticus — continuous seizure activity ≥5 min or recurrent seizures without recovery of consciousness between them.
High-yield: A seizure ≥5 minutes is now defined operationally as status epilepticus (older texts said 30 min). Treat at 5 minutes.
Classification by mechanism of action
| Mechanism | Drugs | Typical use |
|---|---|---|
| Na+ channel blockade (prolong inactivated state) | Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Lacosamide, Zonisamide, Topiramate | Focal & GTCS |
| T-type Ca2+ channel block (thalamic) | Ethosuximide, Valproate (partly) | Absence |
| GABA enhancement | Benzodiazepines & barbiturates (GABA-A), Tiagabine (GAT-1 reuptake block), Vigabatrin (GABA-transaminase inhibitor) | Broad / focal |
| SV2A vesicle binding | Levetiracetam, Brivaracetam | Broad spectrum |
| Multiple / broad spectrum | Valproate, Topiramate, Felbamate | Broad spectrum |
| α2δ Ca2+ subunit binding | Gabapentin, Pregabalin | Focal, neuropathic pain |
| AMPA receptor antagonist | Perampanel | Focal & GTCS |
High-yield: Benzodiazepines increase frequency of Cl⁻ channel opening; barbiturates increase duration of opening. Both act on GABA-A. (Mnemonic: Frequency = Benzodiazepines is wrong order — remember "Benzo–Frequency, Barb–Duration".)
Drug of choice by seizure type
This is the single most exam-relevant table.
| Seizure type | First-line / DOC | Alternatives / notes |
|---|---|---|
| Focal (partial) | Carbamazepine / Lamotrigine / Levetiracetam | Oxcarbazepine, lacosamide; levetiracetam favoured in elderly |
| Generalised tonic-clonic (GTCS) | Valproate (males), Lamotrigine/Levetiracetam (women of childbearing age) | Topiramate |
| Absence (petit mal) | Ethosuximide (pure absence) | Valproate if absence + GTCS coexist |
| Myoclonic / Juvenile myoclonic epilepsy | Valproate | Levetiracetam, topiramate; avoid carbamazepine/phenytoin (worsen) |
| Atonic | Valproate | Lamotrigine |
| Status epilepticus (initial) | IV Lorazepam (or buccal/IM midazolam) | Diazepam |
| Status — 2nd line | IV Fosphenytoin / Valproate / Levetiracetam | — |
| Lennox-Gastaut syndrome | Valproate ± lamotrigine | Rufinamide, clobazam, felbamate |
| Infantile spasms (West syndrome) | ACTH / Vigabatrin (vigabatrin first if tuberous sclerosis) | Prednisolone |
| Trigeminal neuralgia | Carbamazepine | Oxcarbazepine, baclofen |
| Neonatal seizures | Phenobarbitone | Phenytoin |
High-yield: Carbamazepine, phenytoin, oxcarbazepine, gabapentin and vigabatrin can worsen absence and myoclonic seizures. Never give carbamazepine in juvenile myoclonic epilepsy.
High-yield: In women of childbearing potential, prefer lamotrigine or levetiracetam; valproate is contraindicated unless no alternative (highest teratogenicity).
Phenytoin — the classic exam drug
Mechanism: Blocks voltage-gated Na+ channels, prolonging the inactivated state and limiting high-frequency repetitive firing.
Pharmacokinetics — zero-order (saturation/Michaelis-Menten) kinetics: Above therapeutic levels, metabolising enzymes saturate, so a small dose increase causes a disproportionate rise in plasma level. This narrow therapeutic window is heavily tested.
- Therapeutic level: 10–20 µg/mL.
- ~90% protein-bound → measure free phenytoin in hypoalbuminaemia/renal failure/pregnancy.
- Potent CYP450 inducer.
Adverse effects (mnemonic for chronic toxicity):
"PHENYTOIN" — Pseudolymphoma/lymphadenopathy, Hirsutism + coarsening of facies, Enlarged gums (gingival hyperplasia), Nystagmus, Y (megaloblastic anaemia — folate↓), Teratogenicity (fetal hydantoin syndrome), Osteomalacia (vitamin D metabolism↑), Inhibition reversed (enzyme inducer), Neuropathy / cerebellar (ataxia, diplopia).
High-yield: Gingival hyperplasia is classic for phenytoin (also seen with ciclosporin and nifedipine). Megaloblastic anaemia from folate deficiency. Cerebellar atrophy with chronic use.
- Dose-related CNS toxicity progression: Nystagmus (~20 µg/mL) → ataxia/diplopia (~30) → confusion/lethargy (~40).
- IV phenytoin hazards: cardiac arrhythmia and hypotension (give ≤50 mg/min), and purple glove syndrome (tissue necrosis) on extravasation — fosphenytoin (water-soluble prodrug) is safer for IV/IM use.
- Fetal hydantoin syndrome: microcephaly, cleft lip/palate, hypoplastic distal phalanges/nails, growth retardation.
Carbamazepine
Mechanism: Na+ channel blockade (like phenytoin). DOC for trigeminal neuralgia and a first-line for focal seizures and GTCS.
- Autoinduction: induces its own metabolism (CYP3A4) → dose may need upward revision after 2–4 weeks.
- Active metabolite: carbamazepine-10,11-epoxide.
High-yield: SIADH → hyponatraemia is the classic metabolic adverse effect of carbamazepine (and oxcarbazepine, more so). Watch for confusion/seizure worsening due to low sodium.
- Haematological: aplastic anaemia, agranulocytosis, leukopenia.
- Skin: Stevens-Johnson syndrome / toxic epidermal necrolysis — strongly linked to HLA-B*1502 allele (screen in Han Chinese/Southeast Asian patients before starting).
- Teratogenic: neural tube defects (spina bifida).
Oxcarbazepine — keto-analogue, fewer drug interactions, less enzyme induction, but more hyponatraemia.
Valproate (sodium valproate / valproic acid)
The broadest-spectrum AED — effective in absence, myoclonic, atonic, GTCS, and focal seizures.
Mechanism (multiple): Na+ channel block + T-type Ca2+ modulation + ↑GABA (inhibits GABA transaminase) + reduces NMDA.
High-yield: Valproate is the most teratogenic AED — neural tube defects (spina bifida ~1–2%), plus reduced child IQ and autism risk. Avoid in pregnancy/women of childbearing age.
Adverse effects — mnemonic "VALPROATE":
- Hepatotoxicity (idiosyncratic, fatal in <2 yr children on polytherapy) — check LFTs.
- Pancreatitis (acute haemorrhagic).
- Weight gain, alopecia, tremor.
- Thrombocytopenia.
- Hyperammonaemic encephalopathy (treat with L-carnitine).
- Enzyme INHIBITOR (unlike phenytoin/carbamazepine/phenobarbitone which induce).
High-yield: Valproate is an enzyme inhibitor; it raises lamotrigine levels (↑ risk of SJS) → halve lamotrigine starting dose when co-prescribed.
Ethosuximide
- Mechanism: blocks T-type Ca2+ channels in thalamic neurons.
- DOC for pure absence seizures (no effect on GTCS — so valproate preferred if both coexist).
- Adverse effects: GI upset, hiccups, and rarely SLE-like syndrome.
Newer / broad-spectrum agents
Levetiracetam — binds synaptic vesicle protein SV2A; broad spectrum, renally excreted, minimal interactions, no enzyme effect → favoured in elderly, hepatic disease, and women. Main adverse effect: behavioural/psychiatric (irritability, depression, psychosis).
Lamotrigine — Na+ channel blocker; broad spectrum, mood-stabilising, safe in pregnancy. Risk: Stevens-Johnson syndrome, worsened by rapid titration or co-administration with valproate → titrate slowly.
Topiramate — multiple mechanisms; adverse effects: weight loss, word-finding difficulty/cognitive slowing, renal stones, acute angle-closure glaucoma, metabolic acidosis (carbonic anhydrase inhibition), oligohidrosis. Also used for migraine prophylaxis.
Vigabatrin — irreversible GABA-transaminase inhibitor; DOC-tier for infantile spasms in tuberous sclerosis. Toxicity: irreversible visual field constriction (concentric) → mandatory perimetry.
Gabapentin / Pregabalin — bind α2δ subunit of voltage-gated Ca2+ channels; weak AEDs, mainly used for neuropathic pain, fibromyalgia, and anxiety.
Lacosamide — enhances slow inactivation of Na+ channels; risk of PR prolongation.
Perampanel — non-competitive AMPA receptor antagonist; psychiatric/aggression warning.
Phenobarbitone — oldest; GABA-A (↑duration of Cl⁻ opening), potent enzyme inducer; DOC for neonatal seizures; sedation limits adult use.
Enzyme induction vs inhibition — a favourite MCQ
| Enzyme INDUCERS | Enzyme INHIBITOR |
|---|---|
| Phenytoin | Valproate |
| Carbamazepine (auto-induces) | (also valproate inhibits epoxide hydrolase) |
| Phenobarbitone | — |
| Primidone | — |
High-yield: Inducers (phenytoin, carbamazepine, phenobarbitone, primidone — "PCPP") reduce efficacy of oral contraceptives, warfarin, and each other. Counsel on backup contraception.
Teratogenicity profile
| Drug | Signature defect |
|---|---|
| Valproate | Neural tube defects (spina bifida), ↓IQ, autism — worst |
| Carbamazepine | Neural tube defects |
| Phenytoin | Fetal hydantoin syndrome (cleft lip/palate, digit hypoplasia) |
| Phenobarbitone | Cardiac defects, cleft |
| Lamotrigine, Levetiracetam | Lowest risk — preferred in pregnancy |
High-yield: All women on AEDs planning pregnancy should take folic acid 5 mg/day (high-dose) periconceptionally to reduce neural tube defect risk.
Status epilepticus — stepwise management
A guaranteed exam flow. Memorise the sequence and timings.
Step 1 (0–5 min): Stabilise → ABC, oxygen, IV access, check glucose (give dextrose + thiamine if hypoglycaemic), monitor.
Step 2 (5–20 min): First-line benzodiazepine → IV Lorazepam 0.1 mg/kg (DOC; longer CNS duration than diazepam). If no IV access → IM midazolam or buccal/intranasal midazolam, or rectal diazepam.
Step 3 (20–40 min): Second-line → IV Fosphenytoin/Phenytoin OR IV Valproate OR IV Levetiracetam (any one; ESETT trial showed equivalent efficacy).
Step 4 (40–60 min): Refractory status → intubate + anaesthetic infusion: Midazolam, Propofol, or Thiopentone, with continuous EEG monitoring.
So the line is: Benzodiazepine → Fosphenytoin/Valproate/Levetiracetam → Anaesthetic (midazolam/propofol/thiopentone) infusion.
High-yield: IV lorazepam is preferred over diazepam for status because diazepam redistributes rapidly out of brain (short anticonvulsant duration despite long plasma half-life).
Important drug interactions & monitoring
- Therapeutic drug monitoring is standard for phenytoin, carbamazepine, valproate, phenobarbitone (narrow index / nonlinear kinetics).
- Valproate + lamotrigine → ↑lamotrigine (SJS risk).
- Valproate + carbamapine → ↑epoxide (toxicity).
- Inducers ↓ levels of co-administered AEDs, OCPs, warfarin, ciclosporin.
Complications of therapy (general)
- Idiosyncratic: SJS/TEN (carbamazepine, lamotrigine, phenytoin, phenobarbitone), aplastic anaemia (carbamazepine, felbamate), hepatic failure (valproate, felbamate).
- Chronic: osteomalacia/osteoporosis (enzyme inducers ↑ vitamin D catabolism), folate deficiency, cerebellar degeneration (phenytoin).
- Withdrawal: abrupt stoppage can precipitate status epilepticus — taper slowly.
Key differentials / look-alike facts
- Absence vs complex partial: absence has no aura/post-ictal confusion, 3 Hz spike-wave EEG; complex partial has aura and post-ictal state.
- Gingival hyperplasia trio: Phenytoin, ciclosporin, nifedipine (amlodipine).
- Renal stones AEDs: Topiramate and zonisamide (carbonic anhydrase inhibition).
- Hyponatraemia AEDs: Carbamazepine > oxcarbazepine (SIADH).
- Visual field loss: Vigabatrin.
Recently asked / exam angle
- DOC for trigeminal neuralgia → carbamazepine (repeatedly asked).
- Which AED is an enzyme inhibitor → valproate (vs the PCPP inducers).
- AED causing gingival hyperplasia / zero-order kinetics → phenytoin.
- Most teratogenic AED / AED causing neural tube defects → valproate.
- AED safest in pregnancy → lamotrigine / levetiracetam.
- First drug in status epilepticus → IV lorazepam; IV alternative when no access → IM midazolam.
- AED causing SIADH/hyponatraemia → carbamazepine.
- AED causing irreversible visual field defects → vigabatrin.
- AED that worsens absence/myoclonic seizures → carbamazepine / phenytoin.
- Mechanism of levetiracetam → SV2A binding (newer, frequently asked single-best).
- AED causing renal stones + glaucoma + weight loss → topiramate.
- DOC for neonatal seizures → phenobarbitone.
Rapid revision
- Phenytoin = zero-order kinetics, gingival hyperplasia, megaloblastic anaemia, cerebellar atrophy, enzyme inducer.
- Fosphenytoin is the safer IV prodrug; phenytoin extravasation → purple glove syndrome.
- Carbamazepine = DOC trigeminal neuralgia; causes SIADH/hyponatraemia, aplastic anaemia, SJS (HLA-B*1502).
- Valproate = broadest spectrum, enzyme INHIBITOR, most teratogenic (neural tube defects), hepatotoxic, hyperammonaemia.
- Ethosuximide = T-type Ca2+ block, DOC pure absence, no GTCS cover.
- Levetiracetam = SV2A binding, behavioural side effects, safe in elderly/pregnancy.
- Lamotrigine = SJS (worse with valproate), mood stabiliser, pregnancy-safe.
- Topiramate = renal stones, glaucoma, cognitive slowing, weight loss, metabolic acidosis.
- Vigabatrin = GABA-transaminase inhibitor, irreversible visual field loss, infantile spasms (tuberous sclerosis).
- Status epilepticus: Lorazepam IV → Fosphenytoin/Valproate/Levetiracetam → anaesthetic infusion.
- Enzyme inducers = PCPP (Phenytoin, Carbamazepine, Phenobarbitone, Primidone) → ↓OCP/warfarin efficacy.
- All women on AEDs planning pregnancy → folic acid 5 mg/day; avoid valproate.