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Basic Science
Pharmacology
11 notes available
1 Last Minute Review 2 Neuropharmacology Principles 3 Antiepileptic Drugs 4 Movement Disorder Pharmacology 5 Neuromuscular Pharmacology 6 Headache Pharmacology 7 Pain & Anesthesia Pharmacology 8 Psychopharmacology 9 Stroke & Vascular Pharmacology 10 Immunotherapy & MS Pharmacology 11 Antimicrobials & CNS Infections
Basic Science › Pharmacology

Antiepileptic Drugs

Antiepileptic Drugs

What You'll Learn

  • 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 — in Dravet, AVOID chronic Na channel blockers (CBZ, OXC, PHT, LTG) — all can worsen seizures; in IGE/JME, AVOID narrow Na channel blockers (CBZ, OXC, PHT) — worsen absence/myoclonic; lamotrigine is a broad-spectrum IGE option but may worsen myoclonus in JME
  • 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 formally recommended before carbamazepine in Han Chinese/Thai/Malay/South Asian patients; avoid OXC and PHT in known carriers (formal testing not mandated); HLA-A*3101 for carbamazepine hypersensitivity in European/Japanese patients
  • Status epilepticus protocol — benzodiazepines → fosphenytoin/valproate/levetiracetam → continuous infusion (midazolam/propofol/pentobarbital)
HighYield Pearls
  • PURPLE GLOVE SYNDROME: IV phenytoin extravasation → limb discoloration/edema/ischemia — use fosphenytoin instead (water-soluble prodrug, less tissue toxicity).
  • Phenytoin zero-order kinetics: small dose change → disproportionate level rise; toxicity order = nystagmus → ataxia → confusion → coma; chronic use → irreversible cerebellar (Purkinje) atrophy.
  • Carbamazepine autoinduction (own CYP3A4 metabolism — levels fall over weeks) + HLA-B*1502 SJS/TEN in Han Chinese/Thai/Malay/South Asian; class-avoid OXC and PHT in known carriers.
  • Valproate HEPATOTOXICITY — fatal risk in children <2 on polytherapy and in POLG / Alpers syndrome (mitochondrial); also urea cycle disorders (fatal hyperammonemia). AVOID in women of childbearing age (worst teratogen — NTDs, autism, ↓IQ).
  • Lamotrigine SJS/TEN — risk explodes with rapid titration or VPA co-therapy (VPA doubles LTG); halve LTG dose and titrate over 6+ weeks when on VPA.
  • Levetiracetam behavioral adverse effects (irritability/aggression/depression — pyridoxine may mitigate); otherwise preferred in pregnancy and ICU (renal clearance, no CYP, levels ↓ in pregnancy — monitor monthly).
  • Topiramate — cognitive slowing ("Dopamax"), kidney stones (Ca-phosphate), non-anion-gap metabolic acidosis, acute angle-closure glaucoma, cleft lip/palate in pregnancy.
  • VIGABATRIN — PERMANENT bilateral concentric visual field constriction (up to 30–40%); requires counseling + periodic ophthalmologic monitoring — visual field testing (perimetry) when feasible; ERG ± OCT when perimetry is unreliable (infants, developmentally limited); first-line for infantile spasms in TSC (ACTH for non-TSC).
  • FELBAMATE — APLASTIC ANEMIA + fulminant HEPATIC FAILURE (boxed warnings); reserved for refractory Lennox-Gastaut.
  • Cenobamate — rapid titration → DRESS; must start 12.5 mg with 2-week intervals; QT shortening.
  • Zonisamide — sulfa allergy concern; kidney stones; oligohidrosis in children. Lacosamide — PR prolongation (baseline ECG). Perampanel — boxed warning: serious or life-threatening psychiatric & behavioral reactions (aggression, hostility, irritability, anger, homicidal ideation/threats).
  • Dravet pearls: stiripentol, cannabidiol, and fenfluramine (5-HT releaser/σ-1 agonist — valvulopathy/PAH risk → REMS echo monitoring) are syndrome-specific; in Dravet, AVOID chronic Na channel blockers (PHT, CBZ, OXC, LTG) — all can worsen seizures. In IGE/JME, AVOID narrow Na channel blockers (CBZ, OXC, PHT); lamotrigine is a broad-spectrum IGE option but may worsen myoclonus in JME.
  • Broad-spectrum (IGE coverage): VPA, LTG, LEV, TPM, ZNS — LTG is a broad-spectrum IGE option but may worsen myoclonus in JME. Ethosuximide = absence ONLY (no GTC protection — switch/add VPA if GTC coexist).
  • Pregnancy: AVOID VPA and TPM; prefer LEV and LTG; LTG levels DROP 50–65% (estrogen ↑ glucuronidation) — increase dose, monitor monthly, taper postpartum to avoid toxicity.
  • Enzyme INDUCERS (PHT, CBZ, PB, primidone) → reduce OCP / DOAC / warfarin / statins → use copper IUD or progestin-only depot; enzyme INHIBITOR VPA → ↑LTG & ↑PB levels.
🔍 Quick ReferenceMechanism · Adverse effects · Interactions / pregnancy
Mechanism of action
  • "Slow inactivation of Na channel" → Lacosamide (unique among Na blockers)
  • "Irreversible GABA-transaminase inhibitor" → Vigabatrin
  • "SV2A binding" → Levetiracetam & Brivaracetam (BRV = higher affinity)
  • "Selective non-competitive AMPA antagonist" → Perampanel
  • "Blocks thalamic T-type Ca channels → 3-Hz spike-and-wave" → Ethosuximide
  • "α2δ subunit of voltage-gated Ca channel" → Gabapentin / Pregabalin
  • "Benzos ↑ FREQUENCY; Barbiturates ↑ DURATION" of GABA-A Cl channel opening
  • "Dual Na inactivation + GABA-A PAM" → Cenobamate
  • "Neurosteroid GABA-A PAM (synaptic + extrasynaptic δ)" → Ganaxolone (CDKL5)
  • "5-HT releaser + sigma-1 agonist" → Fenfluramine (Dravet, LGS)
  • "Prodrug of S-licarbazepine" → Eslicarbazepine acetate
Adverse effects / "must-not-miss"
  • "Purple glove syndrome" → IV Phenytoin extravasation
  • "Gingival hyperplasia + hirsutism + coarsened facies + cerebellar atrophy" → Phenytoin
  • "SJS/TEN with HLA-B*1502 in Asians" → Carbamazepine (class: OXC, PHT)
  • "Hyponatremia / SIADH" → Oxcarbazepine > Carbamazepine (also eslicarbazepine)
  • "Aplastic anemia + fulminant hepatic failure" → Felbamate
  • "Fatal hepatotoxicity in child <2 / POLG / Alpers" → Valproate
  • "Irreversible bilateral concentric visual field constriction" → Vigabatrin
  • "Dopamax — word-finding difficulty + kidney stones + cleft lip + acute angle-closure glaucoma" → Topiramate
  • "Behavioral aggression / irritability / depression" → Levetiracetam (pyridoxine may help)
  • "DRESS with rapid titration" → Cenobamate; also QT shortening → Cenobamate & Rufinamide
  • "PR interval prolongation" → Lacosamide
  • "Boxed warning — serious psychiatric & behavioral reactions (aggression, hostility, anger, homicidal ideation)" → Perampanel
  • "Valvulopathy / PAH — REMS echo monitoring" → Fenfluramine
  • "Sulfa allergy + oligohidrosis in children" → Zonisamide
  • "Retinal pigmentation + blue skin discoloration (withdrawn)" → Ezogabine/Retigabine
Interactions / pregnancy / monitoring
  • "Valproate doubles lamotrigine levels → SJS" → halve LTG titration when combined
  • "Autoinduction — own CYP3A4 metabolism" → Carbamazepine
  • "Worst teratogen — NTDs, autism, ↓IQ" → Valproate (avoid in women of childbearing age)
  • "Cleft lip/palate in pregnancy" → Topiramate (& Phenobarbital)
  • "Safest AEDs in pregnancy" → Lamotrigine & Levetiracetam (monitor levels — both fall in pregnancy)
  • "Enzyme inducers reduce OCP/DOAC/warfarin" → PHT, CBZ, PB, primidone → use copper IUD or POP/depot
  • "Zero-order kinetics — check Sheiner-Tozer in hypoalbuminemia/uremia" → Phenytoin
  • "Periodic visual field testing; ERG ± OCT when perimetry is unreliable (infants/devo-limited)" → Vigabatrin
  • "Baseline + serial ECG (PR & QT)" → Lacosamide (PR), Cenobamate / Rufinamide (QT)
  • "Folic acid 4 mg/day preconception" → women on enzyme-inducing AEDs or valproate
  • "CBD & stiripentol raise N-desmethylclobazam" → reduce clobazam dose 25–50% (anticipate sedation/ataxia)
  • "First-line infantile spasms with TSC" → Vigabatrin (ACTH for non-TSC etiologies)
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
Dual: Na inactivation + GABA-A PAM Cenobamate Enhances Na channel inactivation + positive allosteric modulator of GABAA; focal-onset seizures (adjunct/monotherapy); DRESS risk — slow titration mandatory (2-week intervals starting at 12.5 mg); QT shortening
Na channel (prodrug) Eslicarbazepine acetate Prodrug of S-licarbazepine (active metabolite of oxcarbazepine); once-daily; hyponatremia (similar to OXC/CBZ)
Neurosteroid GABA-A PAM Ganaxolone Positive allosteric modulator at synaptic and extrasynaptic (δ-subunit) GABAA receptors. FDA-approved 2022 for CDKL5 deficiency disorder
KCNQ2/3 K-channel opener Ezogabine / Retigabine (withdrawn) Opened neuronal Kv7 (KCNQ2/3) K channels → hyperpolarization. Withdrawn from market due to retinal pigmentation and blue skin discoloration
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.

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