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Epilepsy
20 notes available
1 Last Minute Review 2 Seizure Semiology & Localization 3 Epilepsy Diagnostic Workup 4 Neonatal & Infantile Encephalopathies 5 Childhood Epileptic Encephalopathies 6 Self-Limited & Absence Epilepsies 7 Temporal Lobe & Focal Epilepsies 8 Idiopathic Generalized Epilepsies 9 Progressive Myoclonic & Reflex Epilepsies 10 First Seizure & Acute Symptomatic 11 Status Epilepticus 12 Autoimmune Epilepsy 13 ASM Selection & Treatment 14 Individual ASM Profiles & PK 15 Presurgical Evaluation 16 Epilepsy Surgery 17 Neuromodulation (VNS, RNS, DBS) 18 Special Populations & SUDEP 19 Driving Regulations 20 Epilepsy Mimics & DDx
Clinical › Epilepsy

Individual ASM Profiles & PK

Individual ASM Profiles & Pharmacokinetics

What You'll Learn

  • Know each ASM by: mechanism, half-life, metabolism route, enzyme effect (inducer/inhibitor/none), key side effect, teratogenicity, and weight effect — the board tests all of these
  • Phenytoin = zero-order kinetics: small dose changes cause disproportionately large level changes; always check free levels in low albumin, renal failure, or VPA co-administration
  • Lamotrigine: mandatory 6–8 week titration (SJS/TEN risk); half-life doubles with VPA, halves with enzyme inducers; clearance increases 50–100% in pregnancy
  • Cenobamate: most potent adjunctive ASM (21% seizure-free in drug-resistant focal epilepsy); mandatory slow titration (DRESS risk)
  • Valproate: highest teratogenicity (MCM 10.3%); per 2024 AAN guidance, avoid in PWECP whenever possible (use only when benefits clearly outweigh risks and alternatives are inadequate); screen for POLG when clinical suspicion exists (children <2 yr, suspected mitochondrial disease, unexplained liver disease, developmental regression)
  • No-interaction ASMs: LEV, GBP, PGB, LCM — ideal for polypharmacy, elderly, transplant, and oncology patients
  • Pregnancy: LTG clearance increases 50–100% (monthly levels); postpartum dose taper over 2–3 weeks to avoid toxicity
HighYield Pearls
  • Phenytoin = zero-order (saturable) kinetics: 300 → 400 mg/d can push levels 13 → 30+ μg/mL; adjust by 30–60 mg increments and check FREE PHT in low albumin, renal failure, pregnancy, or VPA co-admin; IV must run via central line or with fosphenytoin to avoid PURPLE GLOVE syndrome; long-term → gingival hyperplasia, cerebellar atrophy, megaloblastic anemia, osteopenia
  • Carbamazepine = autoinduction: levels fall over 2–4 wks → recheck 4 wk after any dose change; SIADH/hyponatremia; aplastic anemia (rare); worsens absence/myoclonus; HLA-B*15:02 mandatory screen in Asian descent for CBZ/OXC/PHT (SJS/TEN); HLA-A*31:01 in Europeans/Japanese
  • Oxcarbazepine > CBZ for hyponatremia: more frequent and more severe, especially in elderly on diuretics; same HLA-B*15:02 risk; eslicarbazepine is same Na-channel class with fewer interactions
  • Valproate = highest teratogen (MCM 10.3%): NTDs, cardiac, IQ ↓7–10 points (NEAD), autism risk — avoid in PWECP per 2024 AAN; fatal hepatotoxicity in children <2 yr with POLG/Alpers; pancreatitis, thrombocytopenia, hyperammonemia (esp + TPM — consider L-carnitine); PCOS, weight gain, tremor, alopecia; glucuronidation inhibitor → doubles LTG
  • Lamotrigine SJS/TEN risk: mandatory 6–8 wk titration; halve LTG dose when on VPA, double on inducers; clearance ↑ 50–100% in pregnancy (monthly levels, target ≥65% preconception); taper postpartum over 2–3 wk to avoid toxicity; may worsen JME myoclonus in 5–10%
  • Levetiracetam = SV2A, no interactions: renal dose; behavioral irritability/aggression/depression (10–15%, pyridoxine may help in peds); preferred in pregnancy, ICU, transplant, oncology; brivaracetam = higher-affinity SV2A replacement (not add-on) with fewer behavioral effects
  • Topiramate red flags: cognitive slowing ("Dopa-max"), kidney stones, metabolic acidosis (check HCO3−), oligohidrosis + hyperthermia in children, acute angle-closure glaucoma in first month (emergent stop), weight loss, oral clefts ~1.4% (RR ~9–11×); zonisamide is similar profile + sulfa cross-reactivity caution
  • Lacosamide = slow Na inactivation: PR prolongation → baseline ECG in elderly / structural heart disease; atrial arrhythmia risk; IV available; preferred in critically ill / minimal interactions
  • Perampanel: only AMPA antagonist; t½ ~105 h (nightly dosing); boxed warning for aggression/hostility (~12–20% at 12 mg/d) and suicidality; DEA Schedule III
  • Cenobamate — 21% seizure-free in drug-resistant focal (unprecedented), but DRESS risk requires mandatory slow REMS titration (~11 wk to 200 mg, ~17–20 wk to 400 mg); CYP2C19 inhibitor (raises PHT, PB, norclobazam) + CYP3A4/2B6 inducer (reduces OCP, bupropion, methadone, efavirenz)
  • Vigabatrin = first-line infantile spasms in TSC: irreversible GABA-T inhibitor; permanent visual field constriction → mandatory VFA q3 mo; reversible T2 BG/thalamic MRI changes; worsens absence/myoclonus
  • Felbamate restricted — APLASTIC ANEMIA + HEPATIC FAILURE, last-resort for LGS; tiagabine can precipitate non-convulsive SE (avoid IGE); ethosuximide = T-type Ca, first-line CAE for pure absence only (no GTC coverage)
  • Cardiac/REMS triad: Lacosamide → PR prolongation; Rufinamide → QT shortening (contraindicated in familial short QT); Fenfluramine → valvulopathy + PAH (mandatory echo baseline + q6 mo REMS)
🔍 Quick ReferenceAdverse effects / "must-not-miss" · Mechanism / kinetics · Drug interactions / pregnancy / monitoring
Adverse effects / "must-not-miss" reactions
  • Purple glove syndrome → IV phenytoin extravasation
  • Gingival hyperplasia + coarsened facies + cerebellar atrophy → phenytoin (chronic)
  • SIADH / hyponatremia + autoinduction + aplastic anemia → carbamazepine
  • Marked hyponatremia (worse than CBZ) → oxcarbazepine
  • Fatal hepatotoxicity in child <2 yr → valproate in POLG/Alpers
  • Pancreatitis + thrombocytopenia + hyperammonemia + alopecia → valproate
  • SJS/TEN with rapid titration (esp on VPA) → lamotrigine
  • Behavioral irritability / aggression / depression → levetiracetam
  • Cognitive slowing ("Dopa-max") + word-finding difficulty + kidney stones + metabolic acidosis + oral clefts + acute angle-closure glaucoma + oligohidrosis → topiramate
  • Kidney stones + oligohidrosis + sulfa cross-reactivity caution → zonisamide
  • PR prolongation / atrial arrhythmia (ECG before starting in elderly) → lacosamide
  • Boxed warning for aggression/hostility + suicidality → perampanel
  • DRESS with rapid titration → cenobamate
  • Permanent visual field constriction → mandatory VFA q3 mo; reversible T2 BG/thalamic MRI changes → vigabatrin
  • Aplastic anemia + hepatic failure (restricted, last-resort LGS) → felbamate
  • QT shortening (contraindicated in familial short QT) → rufinamide
  • Valvulopathy + pulmonary arterial hypertension (REMS echo q6 mo) → fenfluramine
  • Non-convulsive status when used in IGE → tiagabine
  • SLE-like reaction → ethosuximide
  • DRESS (fever + rash + eosinophilia + hepatitis/nephritis, 2–8 wk after start) → aromatic ASMs (PHT, CBZ, PB, LTG)
Mechanism / kinetics buzzwords
  • Zero-order (saturable) kinetics → phenytoin
  • Autoinduction of own CYP3A4 → carbamazepine
  • SV2A binding → levetiracetam (and brivaracetam, ~20× higher affinity)
  • Irreversible GABA-transaminase inhibitor → vigabatrin
  • GAT-1 (GABA reuptake) inhibitor → tiagabine
  • Enhances slow Na+ inactivation (unique) → lacosamide
  • α2δ subunit of voltage-gated Ca2+ channel → gabapentin / pregabalin
  • Selective AMPA receptor antagonist → perampanel
  • T-type Ca2+ channel → ethosuximide (also ZNS partial)
  • Carbonic anhydrase inhibition + multi-mechanism → topiramate, zonisamide
  • Glucuronidation inhibitor → doubles LTG → valproate
  • Dual Na+ channel + GABA-A positive allosteric modulator → cenobamate
  • 1,5-benzodiazepine (less tolerance than clonazepam) → clobazam
  • Saturable absorption (60% at 300 mg → ~27% at 1600 mg) → gabapentin
  • 5-HT2C agonist + serotonin releaser → fenfluramine
Drug interactions / pregnancy / monitoring
  • VPA doubles LTG — halve LTG dose; 25 mg QOD start with VPA on board → VPA + lamotrigine
  • Enzyme inducers reduce OCP/DOAC/warfarin/many ASMs → use LNG-IUD or copper IUD → CBZ, PHT, phenobarbital, primidone
  • OCPs lower LTG 40–60% — continuous OCP or LNG-IUD preferred → lamotrigine + estrogen
  • LTG clearance ↑ 50–100% in pregnancy — monthly levels, target ≥65% preconception → lamotrigine in pregnancy
  • Safest in pregnancy → lamotrigine + levetiracetam
  • Folic acid ≥0.4 mg/d all PWECP; 4–5 mg/d on VPA or CBZ → preconception planning
  • Therapeutic levels routinely useful → PHT, VPA, CBZ, PB, ESM (less rigid: LTG, LEV, LCM, ZNS)
  • HLA-B*15:02 (Han Chinese, Thai, Malay, Filipino) → screen before CBZ/OXC/PHT
  • HLA-A*31:01 (European, Japanese) → CBZ SJS/TEN, DRESS, maculopapular rash
  • VFA every 3 months → vigabatrin (vision loss)
  • Baseline ECG before starting in elderly / structural heart disease → lacosamide (PR prolongation)
  • Baseline echo + q6 mo REMS → fenfluramine (valvulopathy / PAH)
  • Stiripentol + CBD + cenobamate raise norclobazam (CYP2C19) → reduce clobazam 25–50% → "norclobazam-raising trio"
  • Minimal interactions / no enzyme effect → LEV, LTG (mild), LCM, GBP, PGB, BRV
  • Take with food (doubles bioavailability) → rufinamide
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