Antiepileptic Drugs
Antiepileptic Drugs
What Do You Need to Know?
- Mechanisms of action — Na channel blockers, Ca channel blockers (T-type), GABA enhancers, SV2A binding, AMPA antagonists, carbonic anhydrase inhibitors, and multi-mechanism agents
- AED selection by seizure type — focal vs. generalized vs. absence vs. specific syndromes (JME, Lennox-Gastaut, Dravet, infantile spasms)
- Drugs that worsen seizures — Na channel blockers (carbamazepine, phenytoin, oxcarbazepine) worsen absence and myoclonic seizures; AVOID Na channel blockers in Dravet syndrome
- Side effect profiles — SJS/TEN (HLA-B*1502), hyponatremia (carbamazepine/oxcarbazepine), cerebellar atrophy (phenytoin), hepatotoxicity (valproate), kidney stones (topiramate)
- Pregnancy — valproate is the worst teratogen (neural tube defects, cognitive impairment); topiramate causes cleft lip/palate; lamotrigine and levetiracetam are safest; all patients need folic acid
- Drug interactions — enzyme inducers (phenytoin, carbamazepine, phenobarbital) vs. inhibitors (valproate); valproate doubles lamotrigine levels → SJS risk
- HLA testing — HLA-B*1502 before carbamazepine/phenytoin in Southeast Asian patients; HLA-A*3101 for carbamazepine in European/Japanese patients
- Status epilepticus protocol — benzodiazepines → fosphenytoin/valproate/levetiracetam → continuous infusion (midazolam/propofol/pentobarbital)
Mechanisms of Action
| Mechanism | Drugs | Key Details |
|---|---|---|
| Na channel blockers | Phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide | Block voltage-gated Na channels → stabilize inactivated state → reduce repetitive firing. Lacosamide enhances slow inactivation (unique among Na blockers) |
| T-type Ca channel blocker | Ethosuximide | Blocks thalamic T-type (low-threshold) Ca channels that generate 3 Hz spike-and-wave in absence seizures |
| GABAA receptor enhancers | Benzodiazepines, barbiturates | Benzos increase frequency of Cl channel opening; barbiturates increase duration. Barbiturates can also directly activate the channel at high doses |
| GABA reuptake/metabolism | Tiagabine, vigabatrin | Tiagabine inhibits GAT-1 GABA reuptake transporter. Vigabatrin irreversibly inhibits GABA-transaminase → increases synaptic GABA |
| SV2A binding | Levetiracetam, brivaracetam | Bind synaptic vesicle protein 2A (SV2A) → modulate neurotransmitter release. Brivaracetam has higher SV2A affinity |
| AMPA receptor antagonist | Perampanel | Selective non-competitive AMPA (glutamate) receptor antagonist → reduces excitatory neurotransmission |
| Carbonic anhydrase inhibition + mixed | Topiramate, zonisamide | Multiple mechanisms: Na channel blockade, CA inhibition, GABA enhancement, glutamate antagonism. Topiramate also blocks kainate/AMPA receptors |
| Multiple mechanisms | Valproate | Na channel blockade + T-type Ca channel blockade + increased GABA + HDAC inhibition. Broadest-spectrum AED |
Board Pearl
Benzodiazepines increase FREQUENCY; barbiturates increase DURATION of GABAA Cl channel opening. This is one of the most commonly tested pharmacology distinctions. At supratherapeutic doses, barbiturates can directly open Cl channels independent of GABA — explaining their greater lethality in overdose compared to benzodiazepines.
Master AED Reference Table
| Drug | Mechanism | Seizure Types | Key Side Effects | Monitoring | Pregnancy |
|---|---|---|---|---|---|
| Phenytoin | Na channel | Focal, GTC | Gingival hyperplasia, hirsutism, coarsened facies, cerebellar atrophy, SJS/TEN, osteoporosis, megaloblastic anemia | Drug levels (zero-order kinetics!), CBC, LFTs, HLA-B*1502, vitamin D | Fetal hydantoin syndrome (craniofacial, digit hypoplasia) |
| Carbamazepine | Na channel | Focal, GTC | Hyponatremia (SIADH), SJS/TEN, aplastic anemia, agranulocytosis, diplopia, ataxia | Drug levels, CBC, Na, LFTs, HLA-B*1502, HLA-A*3101 | NTDs, craniofacial defects (less than VPA) |
| Oxcarbazepine | Na channel | Focal, GTC | Hyponatremia (more than CBZ), dizziness, diplopia | Na levels, HLA-B*1502 | Similar to CBZ but less data |
| Lacosamide | Na channel (slow inactivation) | Focal | PR prolongation, dizziness, diplopia | ECG (PR interval) | Limited data |
| Lamotrigine | Na channel + glutamate | Focal, GTC, absence, LGS | SJS/TEN (especially with rapid titration or VPA combo), insomnia, headache | Drug levels (especially pregnancy), rash monitoring | Safest; levels drop in pregnancy (increase dose) |
| Valproate | Multiple (Na, T-Ca, GABA) | Broad spectrum: GTC, absence, myoclonic, focal, LGS | Hepatotoxicity, pancreatitis, tremor, weight gain, alopecia, thrombocytopenia, PCOS, hyperammonemia | Drug levels, CBC, LFTs, ammonia, lipase | Worst teratogen — NTDs, cognitive impairment, autism. AVOID in women of childbearing age |
| Ethosuximide | T-type Ca channel | Absence only | GI upset, headache, hiccups, rarely SJS, blood dyscrasias | Drug levels, CBC | Relatively safe but limited data |
| Levetiracetam | SV2A | Focal, GTC, myoclonic | Behavioral: irritability, aggression, depression; somnolence | Minimal monitoring (renal dosing); no drug interactions | Safest (with lamotrigine); no dose adjustment needed |
| Brivaracetam | SV2A (high affinity) | Focal | Somnolence, dizziness; less behavioral than LEV | Minimal | Limited data |
| Topiramate | Mixed (Na, CA, GABA, glutamate) | Focal, GTC, LGS | Kidney stones, metabolic acidosis, cognitive slowing ("Dopamax"), weight loss, acute angle-closure glaucoma | Bicarbonate, renal function | Teratogen — cleft lip/palate (oral clefts) |
| Zonisamide | Mixed (Na, T-Ca, CA) | Focal, GTC | Kidney stones, oligohidrosis (children), weight loss, metabolic acidosis | Bicarbonate, renal function | Teratogenic in animals; limited human data |
| Vigabatrin | Irreversible GABA-T inhibitor | Infantile spasms (especially TSC), focal | Irreversible bilateral concentric visual field constriction (up to 30–40%); requires visual field monitoring | Visual field testing every 3 months (ERG in children) | Limited data; used when benefit outweighs risk |
| Perampanel | AMPA antagonist | Focal, GTC | Dizziness, aggression, somnolence; boxed warning for psychiatric effects | Behavior monitoring | Limited data |
| Clobazam | GABAA (1,5-benzodiazepine) | LGS, Dravet (adjunctive) | Sedation, drooling; less sedating than other benzodiazepines | CYP2C19 poor metabolizers (higher levels) | Risk of neonatal withdrawal |
| Phenobarbital | GABAA (duration) | Focal, GTC, neonatal seizures | Sedation, cognitive impairment, hyperactivity (children), Dupuytren contracture, osteoporosis | Drug levels, CBC, LFTs, vitamin D | Teratogenic (cardiac defects); enzyme inducer |
Board Pearl
Phenytoin follows zero-order (saturation) kinetics — small dose increases can cause disproportionately large increases in serum levels and toxicity. Signs of toxicity appear in a predictable order: nystagmus first (typically at levels >20), then ataxia, then confusion/lethargy, then coma. Chronic use causes irreversible cerebellar atrophy (Purkinje cell loss).
AED Selection by Seizure Type & Epilepsy Syndrome
| Seizure Type / Syndrome | First-Line AEDs | Key Notes |
|---|---|---|
| Focal (partial) seizures | Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, lacosamide | Most AEDs work for focal seizures; any of these are reasonable first-line |
| Generalized tonic-clonic | Valproate, lamotrigine, levetiracetam | Avoid Na channel blockers if uncertain whether focal vs. generalized (may worsen generalized) |
| Absence seizures | Ethosuximide, valproate | Ethosuximide = first-line for absence only (no GTC protection). Valproate if coexisting GTC. Lamotrigine less effective but an option |
| Juvenile myoclonic epilepsy (JME) | Valproate, levetiracetam, lamotrigine | Lifelong treatment usually required; high relapse with withdrawal. Avoid carbamazepine/phenytoin (worsen myoclonus) |
| Infantile spasms (West syndrome) | ACTH, vigabatrin | Vigabatrin is first-line if tuberous sclerosis complex (TSC). ACTH is first-line for all other etiologies. Hypsarrhythmia on EEG |
| Lennox-Gastaut syndrome | Valproate, lamotrigine, rufinamide, clobazam | Cannabidiol (Epidiolex) FDA-approved as adjunctive. Slow spike-and-wave (<2.5 Hz) on EEG |
| Dravet syndrome | Valproate + clobazam + stiripentol; fenfluramine | AVOID all Na channel blockers (phenytoin, carbamazepine, oxcarbazepine, lamotrigine) — they worsen seizures. SCN1A mutation |
Board Pearl
Dravet syndrome (SCN1A mutation) + Na channel blockers = disaster. Lamotrigine, carbamazepine, phenytoin, and oxcarbazepine all worsen seizures in Dravet. Treatment is valproate + clobazam + stiripentol (a CYP inhibitor that boosts clobazam levels). Fenfluramine (serotonin releaser) is FDA-approved for Dravet. Always think Dravet when a board question describes a child with refractory febrile seizures starting at age 6 months whose seizures worsen on Na channel blockers.
Drugs That Worsen Seizures
A critical board-tested concept: certain AEDs can paradoxically worsen specific seizure types.
| Drug | Seizure Types Worsened | Mechanism / Notes |
|---|---|---|
| Carbamazepine | Absence, myoclonic | Na channel blockade paradoxically promotes thalamocortical oscillations in generalized epilepsies |
| Phenytoin | Absence, myoclonic | Same mechanism; avoid in idiopathic/genetic generalized epilepsies |
| Oxcarbazepine | Absence, myoclonic | Same class effect as carbamazepine |
| Lamotrigine | Myoclonic (in some patients) | Can worsen myoclonus in JME in some cases; still used cautiously |
| Vigabatrin | Absence, myoclonic, non-focal seizures | May worsen generalized seizure types; primarily used for infantile spasms and focal seizures |
| Tiagabine | Absence, non-focal seizures | GABAergic mechanism may promote absence-type discharges |
| Gabapentin / Pregabalin | Myoclonic, absence | May worsen generalized epilepsies; use only for focal seizures and neuropathic pain |
Clinical Pearl
When a patient with presumed focal epilepsy has seizures worsen after starting carbamazepine or phenytoin, reconsider the diagnosis — the patient may actually have idiopathic generalized epilepsy (IGE) with unrecognized absence or myoclonic seizures. Always get a good history for morning myoclonic jerks and absence spells before prescribing Na channel blockers.
Side Effects & Toxicity
High-Yield Side Effect Associations
| Drug | Signature Side Effects | Board-Yield Details |
|---|---|---|
| Phenytoin | Gingival hyperplasia, hirsutism, coarsened facies, cerebellar atrophy, SJS/TEN, megaloblastic anemia, osteoporosis | HLA-B*1502 testing in Southeast Asian patients before use. Zero-order kinetics — toxicity: nystagmus → ataxia → confusion. Purple glove syndrome with IV infiltration |
| Carbamazepine | Hyponatremia (SIADH), SJS/TEN, aplastic anemia, agranulocytosis, diplopia | HLA-B*1502 (Southeast Asian) and HLA-A*3101 (European/Japanese). Potent CYP3A4 inducer — autoinduction of own metabolism |
| Valproate | Hepatotoxicity, pancreatitis, tremor, weight gain, thrombocytopenia, PCOS, hyperammonemia, alopecia | Contraindicated in mitochondrial disease (especially POLG mutations — fatal hepatotoxicity) and urea cycle disorders (fatal hyperammonemia). Highest risk of hepatic failure in children <2 on polytherapy |
| Lamotrigine | SJS/TEN | Risk greatly increased with rapid titration or concurrent valproate (which doubles LTG levels). Must titrate slowly over 6+ weeks. If rash develops, stop immediately |
| Topiramate | Kidney stones (calcium phosphate), metabolic acidosis, cognitive slowing, weight loss, acute angle-closure glaucoma | "Dopamax" — word-finding difficulty is common. Causes non-anion-gap metabolic acidosis (carbonic anhydrase inhibition). Teratogenic — cleft lip/palate |
| Levetiracetam | Behavioral: irritability, aggression, depression, psychosis (rare) | Minimal drug interactions (renally cleared, no CYP metabolism). Considered one of the safest AEDs. Brivaracetam may have fewer behavioral effects |
| Vigabatrin | Irreversible bilateral concentric visual field constriction | Retinal toxicity (GABA accumulation in retina). Requires baseline and serial visual field testing (perimetry in adults, ERG in children). Risk up to 30–40% with chronic use |
Board Pearl
Valproate is contraindicated in POLG mutations (mitochondrial DNA polymerase gamma) — it causes fatal hepatotoxicity. Any child or young adult presenting with epilepsy + liver failure after starting valproate should raise suspicion for underlying mitochondrial disease. Similarly, valproate is contraindicated in urea cycle disorders where it can precipitate fatal hyperammonemic encephalopathy.
Pregnancy & AEDs
Teratogenicity Hierarchy
- Valproate — HIGHEST teratogenic risk of all AEDs (6–10% major malformation rate)
- Neural tube defects (spina bifida) — dose-dependent, especially >700 mg/day
- Reduced IQ and increased risk of autism spectrum disorder in exposed children
- Avoid in all women of childbearing potential unless no alternative exists
- Topiramate — increased risk of oral clefts (cleft lip/palate); 2–3x background risk
- Phenytoin — fetal hydantoin syndrome (craniofacial anomalies, nail/digit hypoplasia, growth restriction)
- Carbamazepine — neural tube defects (lower risk than valproate, ~1%); craniofacial defects
- Phenobarbital — cardiac malformations, cleft palate
Safest AEDs in Pregnancy
- Lamotrigine and levetiracetam — lowest malformation rates in pregnancy registries
- Lamotrigine levels drop significantly in pregnancy (increased glucuronidation driven by estrogen) — monitor levels monthly and increase dose as needed; levels rebound postpartum — reduce dose after delivery
- Levetiracetam clearance also increases in pregnancy but levels are more stable
Folic Acid Supplementation
- All women of childbearing age on AEDs should take folic acid supplementation
- Standard recommendation: 0.4–4 mg/day (higher dose for women on valproate or carbamazepine, or with prior NTD history)
- Begin before conception — neural tube closes by day 28 of gestation
Clinical Pearl
Lamotrigine levels drop by 50–65% during pregnancy due to estrogen-induced upregulation of UGT glucuronidation. This often requires dose increases of 200–300% during pregnancy. Critically, levels rebound rapidly postpartum as estrogen falls — if the dose is not reduced after delivery, toxicity (including SJS) can occur. Monthly level monitoring is essential throughout pregnancy and the postpartum period.
Drug Interactions
Enzyme Inducers vs. Inhibitors
| Category | Drugs | Clinical Significance |
|---|---|---|
| CYP450 Inducers | Phenytoin, carbamazepine, phenobarbital, primidone, (oxcarbazepine — mild) | Reduce levels of: oral contraceptives (breakthrough pregnancy!), warfarin, statins, immunosuppressants, other AEDs. Carbamazepine induces its own metabolism (autoinduction) |
| CYP450 Inhibitor | Valproate | Inhibits glucuronidation of lamotrigine → doubles lamotrigine levels → increased SJS/TEN risk. Also inhibits metabolism of phenobarbital and ethosuximide |
| Minimal interactions | Levetiracetam, brivaracetam, lacosamide, gabapentin, pregabalin, vigabatrin | Renally cleared or non-CYP metabolism; preferred when polypharmacy is a concern |
Critical Interaction: Valproate + Lamotrigine
- Valproate inhibits UGT glucuronidation of lamotrigine → doubles lamotrigine half-life and serum levels
- Dramatically increases risk of SJS/TEN if lamotrigine is titrated at standard rates
- Solution: halve the lamotrigine titration rate and target dose when used with valproate (start 25 mg every other day, not daily)
HLA Testing Before AED Initiation
- HLA-B*1502: Screen before carbamazepine, oxcarbazepine, or phenytoin in patients of Southeast Asian descent (Han Chinese, Thai, Malaysian, Filipino, Indonesian). Positive → high risk of SJS/TEN
- HLA-A*3101: Screen before carbamazepine in European and Japanese patients — associated with drug reaction with eosinophilia and systemic symptoms (DRESS)
Board Pearl
Enzyme-inducing AEDs reduce oral contraceptive efficacy. Women on phenytoin, carbamazepine, or phenobarbital who rely on hormonal contraception are at risk of unplanned pregnancy. Non-enzyme-inducing options (levetiracetam, lamotrigine, lacosamide) are preferred. Note that lamotrigine and oral contraceptives have a bidirectional interaction — estrogen lowers lamotrigine levels, and lamotrigine may reduce contraceptive levels.
Status Epilepticus Management
Definition: ≥5 minutes of continuous seizure activity or ≥2 seizures without return to baseline. A neurological emergency with mortality of 10–30%.
Treatment Protocol
| Stage | Time | Treatment | Details |
|---|---|---|---|
| First-line | 0–5 min | Benzodiazepines | IV lorazepam 0.1 mg/kg (max 4 mg/dose, repeat once) OR IM midazolam 10 mg (RAMPART trial — IM midazolam non-inferior to IV lorazepam in prehospital setting) |
| Second-line | 5–20 min | Fosphenytoin, valproate, or levetiracetam | ESETT trial: all three are equally effective (~45% response rate). Fosphenytoin 20 mg PE/kg IV; valproate 40 mg/kg IV; levetiracetam 60 mg/kg IV (max 4500 mg) |
| Refractory SE | >20–40 min | Continuous IV infusion | Midazolam drip, propofol drip, or pentobarbital drip; requires intubation, continuous EEG monitoring; goal = burst suppression |
| Super-refractory SE | >24 h on anesthetics | Ketamine, additional anesthetics, immunotherapy if autoimmune | Consider autoimmune etiology (anti-NMDAR, anti-LGI1); may need prolonged coma; high mortality |
Board Pearl
The ESETT trial (2019) demonstrated that fosphenytoin, valproate, and levetiracetam are equally effective as second-line agents for benzodiazepine-refractory status epilepticus (~45% success rate each). The RAMPART trial showed IM midazolam is non-inferior to IV lorazepam in the prehospital setting, making it the preferred first-line agent when IV access is not available.
Clinical Pearl
In super-refractory status epilepticus (persisting ≥24 hours despite anesthetic agents), always consider autoimmune encephalitis as the underlying etiology — particularly anti-NMDA receptor encephalitis in young women. These patients may require immunotherapy (IV steroids, IVIG, plasma exchange, rituximab) rather than escalating antiepileptic drugs. Check for ovarian teratoma and send autoimmune antibody panels early.
Quick Reference Table
Antiepileptic Drugs — At a Glance
| Clinical Scenario | Key Association | Board-Yield Detail |
|---|---|---|
| Absence seizures | Ethosuximide (if absence-only) or valproate | Carbamazepine/phenytoin WORSEN absence |
| JME | Valproate, levetiracetam | Lifelong therapy; avoid Na channel blockers |
| Infantile spasms + TSC | Vigabatrin | First-line specifically for TSC; visual field monitoring |
| Dravet syndrome | VPA + clobazam + stiripentol; fenfluramine | AVOID all Na channel blockers (including lamotrigine) |
| Lennox-Gastaut | VPA, lamotrigine, rufinamide, clobazam, CBD | Slow spike-and-wave <2.5 Hz on EEG |
| Pregnancy (safest) | Lamotrigine, levetiracetam | LTG levels drop in pregnancy; VPA is worst teratogen |
| Worst teratogen | Valproate | NTDs, cognitive impairment, autism; avoid in women of childbearing age |
| Cleft lip/palate risk | Topiramate | Also causes kidney stones, metabolic acidosis, cognitive slowing |
| SJS/TEN risk (HLA-B*1502) | Carbamazepine, phenytoin, oxcarbazepine | Test Southeast Asian patients before prescribing |
| SJS from drug interaction | Lamotrigine + valproate | VPA doubles LTG levels; slow titration mandatory |
| Zero-order kinetics | Phenytoin | Small dose change → large level change; nystagmus is first sign of toxicity |
| Minimal drug interactions | Levetiracetam | Renally cleared; no CYP metabolism; behavioral side effects main limitation |
| Contraindicated in mito/POLG | Valproate | Fatal hepatotoxicity; also avoid in urea cycle disorders |
| Status epilepticus first-line | Benzodiazepines (lorazepam IV or midazolam IM) | RAMPART trial: IM midazolam non-inferior to IV lorazepam |
| SE second-line (ESETT trial) | Fosphenytoin = valproate = levetiracetam | All equally effective (~45%); choose based on clinical context |
| Irreversible visual field loss | Vigabatrin | Bilateral concentric constriction; serial visual field testing required |
| Enzyme inducers | Phenytoin, carbamazepine, phenobarbital | Reduce OCP, warfarin, statin, immunosuppressant levels |
References
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- Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus (RAMPART). N Engl J Med. 2012;366(7):591-600.
- Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17(6):530-538.
- Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study). N Engl J Med. 2009;360(16):1597-1605.
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- Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563.
- Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs — best practice guidelines for therapeutic drug monitoring. Epilepsia. 2008;49(7):1239-1276.