Phenytoin

Dilantin · Phenytek

Hydantoin sodium-channel-blocking antiepileptic

Use-dependent block of voltage-gated neuronal Na⁺ channels — stabilizes the inactivated state, raising the seizure threshold without affecting normal neuronal firing. Also blocks cardiac fast Na⁺ channels (class Ib antiarrhythmic activity).

Indications

•Status epilepticus (alternative second-line after benzo)
•Generalized tonic-clonic + focal seizures (chronic)
•Digoxin-induced ventricular arrhythmias (historical)
•Trigeminal neuralgia (occasional second-line)

Dosing

Context	Adult	Pediatric
Status epilepticus loading	20 mg/kg IV at ≤50 mg/min (≤25 mg/min in elderly/cardiac disease)	20 mg/kg IV at ≤1 mg/kg/min
Maintenance	100 mg IV/PO q8 h; titrate to level 10–20 mcg/mL (free 1–2 mcg/mL)	—
Fosphenytoin (preferred IV form)	20 mg PE/kg IV at ≤150 mg PE/min — equivalent to 1.5× phenytoin dose in PE units; less infusion reaction	—

Pharmacokinetics

Onset 0.5–1 h IV; peak 0.5–1 h. Half-life 7–42 h (zero-order kinetics — small dose change can produce large concentration change). 90% protein-bound (albumin); free fraction matters in hypoalbuminemia. Hepatic CYP2C9/CYP2C19 metabolism; potent CYP3A4 inducer.

Hemodynamic effects

Hypotension and bradycardia with rapid IV — limited by infusion rate and propylene-glycol vehicle (parenteral phenytoin only). Fosphenytoin lacks the propylene glycol and is hemodynamically safer.

Respiratory effects

Minimal direct effect; respiratory depression possible at toxic levels.

Side effects

!Cardiovascular collapse with rapid IV (the propylene glycol vehicle, not the drug — fosphenytoin avoids this)
!'Purple glove syndrome' — limb ischemia from extravasation; central line preferred
!Nystagmus → ataxia → drowsiness → confusion as level rises (>20, >30, >40 mcg/mL respectively)
!Gingival hyperplasia, hirsutism, coarsening of facies (chronic)
!Stevens-Johnson syndrome / TEN — increased risk in HLA-B*1502 carriers (Asian ancestry — screen)
!Hepatitis, lymphadenopathy (DRESS syndrome)
!Megaloblastic anemia (folate deficiency), osteomalacia (vitamin D metabolism)
!Fetal hydantoin syndrome (cleft palate, cardiac defects, microcephaly, hypoplastic nails)

Contraindications

×Sinus bradycardia, second/third-degree AV block, sinoatrial block
×Adams-Stokes syndrome
×Hypersensitivity to hydantoins

Clinical pearls

★FOSPHENYTOIN (Cerebyx) is the preferred parenteral form: water-soluble prodrug, faster infusion (150 mg PE/min vs 50), no propylene glycol → no cardiovascular collapse, can give IM, no purple-glove. Dose in 'phenytoin equivalents' (PE).
★FREE LEVEL IN LOW-ALBUMIN: corrected level = measured / (0.2 × albumin + 0.1) [Sheiner-Tozer]. In ICU patients with albumin 2.0, a measured 10 mcg/mL is actually a free fraction equivalent to 20 — at the toxic threshold.
★ENZYME INDUCTION: cuts warfarin, OCP, immunosuppressant (cyclosporine, tacrolimus), corticosteroid, NMB (rocuronium, vecuronium) levels. SRNAs see this clinically as paradoxically resistant non-depolarizing block in chronic phenytoin patients.
★ZERO-ORDER KINETICS: a 100 mg dose increase can move a level from 15 → 25 mcg/mL. Always recheck level 5–7 days after any change.
★ESETT (NEJM 2019): fosphenytoin equivalent to levetiracetam and valproate as benzo-refractory status second-line; choice driven by patient comorbidities.

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Education only — confirm against current package inserts and institutional protocols. Doses assume normal organ function unless otherwise noted.

Dosing

Context	Adult	Pediatric
Status epilepticus loading	20 mg/kg IV at ≤50 mg/min (≤25 mg/min in elderly/cardiac disease)	20 mg/kg IV at ≤1 mg/kg/min
Maintenance	100 mg IV/PO q8 h; titrate to level 10–20 mcg/mL (free 1–2 mcg/mL)	—
Fosphenytoin (preferred IV form)	20 mg PE/kg IV at ≤150 mg PE/min — equivalent to 1.5× phenytoin dose in PE units; less infusion reaction	—

Side effects

!Cardiovascular collapse with rapid IV (the propylene glycol vehicle, not the drug — fosphenytoin avoids this)
!'Purple glove syndrome' — limb ischemia from extravasation; central line preferred
!Nystagmus → ataxia → drowsiness → confusion as level rises (>20, >30, >40 mcg/mL respectively)
!Gingival hyperplasia, hirsutism, coarsening of facies (chronic)
!Stevens-Johnson syndrome / TEN — increased risk in HLA-B*1502 carriers (Asian ancestry — screen)
!Hepatitis, lymphadenopathy (DRESS syndrome)
!Megaloblastic anemia (folate deficiency), osteomalacia (vitamin D metabolism)
!Fetal hydantoin syndrome (cleft palate, cardiac defects, microcephaly, hypoplastic nails)

Clinical pearls

★FOSPHENYTOIN (Cerebyx) is the preferred parenteral form: water-soluble prodrug, faster infusion (150 mg PE/min vs 50), no propylene glycol → no cardiovascular collapse, can give IM, no purple-glove. Dose in 'phenytoin equivalents' (PE).
★FREE LEVEL IN LOW-ALBUMIN: corrected level = measured / (0.2 × albumin + 0.1) [Sheiner-Tozer]. In ICU patients with albumin 2.0, a measured 10 mcg/mL is actually a free fraction equivalent to 20 — at the toxic threshold.
★ENZYME INDUCTION: cuts warfarin, OCP, immunosuppressant (cyclosporine, tacrolimus), corticosteroid, NMB (rocuronium, vecuronium) levels. SRNAs see this clinically as paradoxically resistant non-depolarizing block in chronic phenytoin patients.
★ZERO-ORDER KINETICS: a 100 mg dose increase can move a level from 15 → 25 mcg/mL. Always recheck level 5–7 days after any change.
★ESETT (NEJM 2019): fosphenytoin equivalent to levetiracetam and valproate as benzo-refractory status second-line; choice driven by patient comorbidities.