Antiepileptic Drugs
A Step 1 high-yield tour of antiepileptic drugs organized by mechanism (use-dependent Na+ channel block, thalamic T-type and alpha-2-delta Ca2+ modulation, GABA-A enhancement, and SV2A binding), with seizure-type first-lines, a drug-comparison table, toxicity vignettes, legitimate mnemonics, and pharmacokinetic/pregnancy pearls.
Framework: how AEDs stop a seizure
Antiepileptic drugs (AEDs) quiet hypersynchronous neuronal firing through a handful of mechanisms the boards test relentlessly:
- Na+ channel blockers (use-dependent, prolong the inactivated state): phenytoin, carbamazepine, oxcarbazepine, lamotrigine; valproate and topiramate also contribute Na+ block among multiple actions.
- Ca2+ current reducers: ethosuximide and valproate block thalamic T-type Ca2+ channels (the pacemaker of 3-Hz absence spike-and-wave); gabapentin and pregabalin bind the alpha-2-delta subunit of voltage-gated Ca2+ channels.
- GABA enhancers: benzodiazepines (increase frequency of Cl- channel opening), barbiturates (increase duration of opening), vigabatrin (irreversibly inhibits GABA transaminase), topiramate/valproate (raise GABA among other effects).
- SV2A binder: levetiracetam.
Match the drug to the seizure: focal -> carbamazepine / lamotrigine / levetiracetam; generalized tonic-clonic -> valproate / lamotrigine / levetiracetam; absence -> ethosuximide; status epilepticus -> a benzodiazepine first.
- Ethosuximide = 1st-line absence (blocks thalamic T-type Ca2+); valproate is the broad-spectrum alternative. Signature tox: GI upset, fatigue, headache (EFGH).
- Status epilepticus: benzodiazepine (lorazepam) to abort, then a longer-acting agent (fosphenytoin, valproate, or levetiracetam) for maintenance.
- Valproate = broadest spectrum; also treats bipolar disorder and migraine prophylaxis. Signature tox: hepatotoxicity, pancreatitis, tremor, weight gain; it is an enzyme INHIBITOR.
- Carbamazepine = 1st-line trigeminal neuralgia. Signature tox: agranulocytosis / aplastic anemia and SIADH (hyponatremia); P450 inducer.
- Phenytoin: signature tox = gingival hyperplasia, hirsutism, megaloblastic anemia (folate antagonism), dose-dependent nystagmus/ataxia; zero-order (nonlinear) kinetics near therapeutic levels; P450 inducer.
- Topiramate: kidney stones, weight loss, cognitive/word-finding slowing, acute angle-closure glaucoma, metabolic acidosis.
- Vigabatrin: permanent (irreversible) visual field loss.
- Enzyme inducers (phenytoin, carbamazepine, phenobarbital) lower OCP and warfarin levels; valproate inhibits.
- Most teratogenic AED = valproate (neural tube defects, lowest offspring IQ).
- SJS/TEN: lamotrigine (titrate slowly; risk worse when combined with valproate) and carbamazepine (screen HLA-B*1502 in patients of Asian ancestry).
Drug -> mechanism -> use -> key toxicity
| Drug | Mechanism | Primary use | Key toxicity |
|---|---|---|---|
| Phenytoin / fosphenytoin | Blocks Na+ channels | Focal, generalized tonic-clonic, status | Gingival hyperplasia, hirsutism, ataxia/nystagmus, fetal hydantoin syndrome, megaloblastic anemia, osteopenia, DRESS/SJS; P450 inducer; zero-order kinetics |
| Carbamazepine | Blocks Na+ channels | Focal; trigeminal neuralgia | Agranulocytosis/aplastic anemia, SIADH (hyponatremia), SJS (HLA-B*1502), teratogen (neural tube defects); P450 inducer; auto-induction |
| Valproate | Na+ block, raises GABA, blocks T-type Ca2+ | Broad-spectrum; bipolar, migraine ppx | Hepatotoxicity, pancreatitis, neural tube defects, tremor, weight gain, hyperammonemia; P450 inhibitor |
| Ethosuximide | Blocks thalamic T-type Ca2+ | Absence (1st-line) | GI distress, fatigue, headache; SJS (rare) |
| Lamotrigine | Blocks Na+ channels | Focal, generalized, absence; bipolar | Stevens-Johnson syndrome (slow titration; worse with valproate) |
| Levetiracetam | Binds SV2A | Focal, generalized, myoclonic | Neuropsychiatric/mood changes; few drug interactions |
| Gabapentin / pregabalin | Bind alpha-2-delta Ca2+ subunit | Focal adjunct; neuropathic pain | Sedation, ataxia, weight gain, peripheral edema |
| Topiramate | Na+ block, raises GABA, carbonic anhydrase inhibition | Focal/generalized; migraine ppx | Weight loss, kidney stones, cognitive slowing, acute angle-closure glaucoma, metabolic acidosis |
| Phenobarbital | Increases duration of GABA-A Cl- opening | Neonatal seizures (classic 1st-line) | Sedation, dependence, respiratory depression; P450 inducer |
| Benzodiazepines | Increase frequency of GABA-A Cl- opening | Status epilepticus (acute abort) | Sedation, dependence, respiratory depression |
| Vigabatrin | Inhibits GABA transaminase | Refractory focal; infantile spasms | Permanent visual field loss |
- A 9-year-old with brief staring spells and a 3-Hz spike-and-wave EEG; first-line drug blocks thalamic T-type Ca2+ channels. -> Ethosuximide
- A teen on a seizure drug develops fever, sore throat, neutropenia, and hyponatremia. -> Carbamazepine (agranulocytosis + SIADH)
- Chronic therapy causes gum overgrowth, hirsutism, coarse facies, and nystagmus. -> Phenytoin
- A blistering, sloughing mucocutaneous rash two weeks after a rapidly titrated AED co-prescribed with valproate. -> Lamotrigine (SJS)
- A migraine patient develops kidney stones, weight loss, and word-finding difficulty. -> Topiramate
- Progressive loss of peripheral (visual field) vision on adjunctive therapy. -> Vigabatrin
- GABA-A channel kinetics — barbiDURates vs benzodiazepines: barbiDURates increase the DURation of Cl- channel opening; benzodiazepines increase the frequency of opening. High-yield twist: at high doses barbiturates can open the channel even without GABA (directly GABA-mimetic), whereas benzodiazepines cannot -> barbiturate overdose is more dangerous.
- EthoSUXimide -> absence: the drug that sux-fixes absence seizures. Its adverse effects follow EFGH: Fatigue, GI distress, Headache (plus rare SJS).
- Phenytoin toxicity cluster: cosmetic (gingival hyperplasia, hirsutism, coarse facies), hematologic (megaloblastic anemia from folate antagonism), cerebellar and dose-dependent (nystagmus -> ataxia -> sedation), plus P450 induction, osteopenia, and fetal hydantoin syndrome.
Pharmacokinetic and pregnancy pearls
Phenytoin shows zero-order (saturable) kinetics: once metabolizing enzymes saturate, a small dose increase produces a disproportionately large toxic rise (nystagmus -> ataxia -> sedation). It is highly protein-bound, so in hypoalbuminemia or renal failure the free (active) fraction rises even when the measured total level looks normal. Fosphenytoin is preferred for IV loading because IV phenytoin's propylene glycol diluent risks hypotension and arrhythmia.
In pregnancy, avoid valproate (neural tube defects, lowest offspring IQ) and minimize carbamazepine/phenytoin; favor lamotrigine or levetiracetam, supplement folate, and keep seizures controlled since uncontrolled generalized seizures also endanger the fetus. Remember that valproate inhibits metabolism and raises lamotrigine levels (increasing SJS risk), while carbamazepine auto-induces its own metabolism, so its levels fall over the first weeks of therapy.
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