Phenytoin

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phenytoin antiepileptic pharmacology

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Here is a complete reference on Phenytoin, compiled from Katzung's Basic and Clinical Pharmacology (16th ed.) and Goodman & Gilman's Pharmacological Basis of Therapeutics.

Phenytoin (Diphenylhydantoin)

Chemistry & Formulations

Phenytoin is the 5,5-diphenyl-substituted analog of hydantoin - a five-membered ring structurally related to barbiturates (six-membered ring). Its prodrug, fosphenytoin, is a water-soluble phosphate ester that is rapidly converted to phenytoin in plasma and is preferred for IV use.

Phenytoin free base: pKa = 8.06-8.33; poorly water soluble
Phenytoin sodium: dissolves in water (17 mg/mL); the IV solution contains propylene glycol and alcohol at pH 12
Oral forms: extended-release capsules (peak 4-12 h), prompt-release capsules (peak 1.5-3 h), suspension, and chewable tablets
Intramuscular injection is not recommended - absorption is unpredictable and precipitation in muscle occurs

Mechanism of Action

Phenytoin limits the repetitive firing of action potentials evoked by sustained depolarization. It does this by slowing the rate of recovery of voltage-activated Na+ channels from inactivation - the effect is both:

Voltage-dependent: greater effect when membrane is depolarized
Use-dependent: frequency of firing determines how much drug binds

At therapeutic concentrations, effects are selective on Na+ channels with no change in spontaneous activity or GABA/glutamate responses. At 5-10x therapeutic levels, additional effects appear (reduced spontaneous activity, enhanced GABA responses) - these underlie toxicity.

Goodman & Gilman's, p. 392-394

Clinical Uses

Indication	Notes
Focal (partial) seizures	First-line (historically), now second-line
Generalized tonic-clonic seizures	Focal-to-bilateral and idiopathic
Status epilepticus (acute)	IV fosphenytoin preferred
NOT effective	Absence epilepsy
May worsen	Juvenile myoclonic epilepsy, Dravet syndrome, absence seizures

Phenytoin is no longer considered first-line for chronic therapy due to adverse effects and drug-drug interactions.

Katzung's, p. 651

Pharmacokinetics

Absorption

Highly formulation-dependent; nearly complete GI absorption but time to peak ranges 3-12 hours
Extensively (~90%) bound to serum albumin - displacement by other drugs (warfarin, valproate, sulfonamides) or hypoalbuminemia increases free (active) drug

Elimination - Saturation (Zero-Order) Kinetics

This is phenytoin's most clinically important pharmacokinetic feature:

Dose vs serum concentration for phenytoin vs other ASMs

At low levels: first-order kinetics (constant fraction eliminated per unit time)
As levels rise into the therapeutic range: hepatic metabolism (CYP2C9/CYP2C19) becomes saturated → shifts to zero-order kinetics (constant quantity per unit time)
A small dose increase can cause a disproportionately large rise in plasma level, leading to rapid toxicity
Half-life: 12-36 hours (average 24 h) at low-mid therapeutic range; much longer at higher levels
Steady-state after dose change: 5-7 days at low levels; up to 4-6 weeks at higher levels

Key Parameters

Parameter	Value
Protein binding	~90% (albumin)
Therapeutic range	10-20 mcg/mL (total); free level preferred in hypoalbuminemia
Metabolism	CYP2C9 (primary), CYP2C19
Kinetics	Zero-order at therapeutic doses
Elimination	Urine (inactive metabolites); minimal unchanged

Katzung's, p. 652

Correction for Hypoalbuminemia (Sheiner-Tozer formula)

Corrected level = measured total level / [(0.2 × albumin) + 0.1]

Drug Interactions

Phenytoin is a major enzyme inducer (CYP1A2, CYP2C, CYP3A4) and therefore reduces levels of many co-administered drugs.

Drugs that INCREASE phenytoin levels (inhibit CYP2C9/2C19):

Isoniazid (primarily in slow acetylators)
Fluoxetine, fluvoxamine
Fluorouracil
Metronidazole, miconazole
Valproate (also displaces from protein binding - dual effect, most significant)
Amiodarone, cimetidine, omeprazole

Drugs that DECREASE phenytoin levels (enzyme inducers):

Alcohol (chronic), barbiturates, carbamazepine

Drugs whose levels are REDUCED by phenytoin (induces their metabolism):

Oral contraceptives (CYP3A4) - risk of contraceptive failure
Valproate, tiagabine, ethosuximide, lamotrigine, topiramate, zonisamide, felbamate
Many benzodiazepines, warfarin, cyclosporine

Adverse Effects

Dose-Related (Concentration-Dependent)

These appear in a stepwise fashion as levels rise:

Plasma Level	Effects
10-20 mcg/mL	Therapeutic range; nystagmus may appear at upper end
>20 mcg/mL	Nystagmus (horizontal), mild diplopia
>30 mcg/mL	Ataxia, incoordination
>40 mcg/mL	Mental changes, lethargy, encephalopathy
Very high	Paradoxical seizure worsening, decerebrate posturing

Chronic/Long-Term Effects (Dose-Independent)

These are the classic adverse effects associated with long-term use:

Gingival hyperplasia: occurs in ~20% of patients; due to altered collagen metabolism; more common in younger patients; not related to plasma level
Hirsutism: coarsening of facial hair, especially troublesome in women/girls
Coarsening of facial features
Peripheral neuropathy: reduced deep tendon reflexes with chronic use
Osteomalacia / rickets: increased vitamin D catabolism (CYP induction); bone mineral density loss
Megaloblastic anemia: impaired folate absorption/metabolism

Idiosyncratic / Hypersensitivity

Morbilliform rash: most common (~5-10%); may progress to Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN) - rare
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): serious multi-organ hypersensitivity
Hepatotoxicity: rare but potentially severe
Hematologic: leukopenia, aplastic anemia (rare)
Lupus-like syndrome

IV/Infusion Complications

Purple glove syndrome: purplish-black discoloration + edema + pain distal to IV site; related to propylene glycol vehicle and high pH. Risk is lower with fosphenytoin
Cardiovascular: hypotension and cardiac arrhythmias (AV block, bradycardia) if infused too rapidly - maximum IV rate is 50 mg/min (25 mg/min in elderly or cardiac patients); fosphenytoin can be infused faster (150 mg PE/min)

Teratogenicity - "Fetal Hydantoin Syndrome"

Phenytoin is Category D / FDA-X equivalent in pregnancy:

Cleft lip/palate, cardiac defects
Digital hypoplasia, nail dysplasia
Growth restriction, dysmorphic facial features
Cognitive impairment
Risk is increased with polytherapy

Dosing

Adults oral: Start at 300 mg/day; increase in increments of no more than 25-30 mg/day due to saturation kinetics
Loading dose (status epilepticus): IV fosphenytoin 15-20 mg PE/kg at ≤150 mg PE/min
Monitoring: measure free phenytoin in hypoalbuminemia, renal failure, or when protein displacement interactions are suspected
Pediatric dosing: weight-based; different formulations have different bioavailability

Summary: Key High-Yield Points

Mechanism: Na+ channel blocker - slows recovery from inactivation (voltage- and use-dependent)
Kinetics: Zero-order (Michaelis-Menten / saturation kinetics) at therapeutic doses - small dose increase → large level increase
Therapeutic range: 10-20 mcg/mL (total); adjust for albumin
Classic ADRs: gingival hyperplasia, hirsutism, nystagmus, ataxia, fetal hydantoin syndrome
Enzyme inducer: reduces levels of OCP, warfarin, other ASMs
IV risk: purple glove syndrome; cardiac toxicity if infused too fast; fosphenytoin preferred
Not for absence seizures; may worsen JME and Dravet syndrome
No longer first-line for chronic epilepsy management

Sources: Katzung's Basic and Clinical Pharmacology, 16th ed., pp. 651-654; Goodman & Gilman's Pharmacological Basis of Therapeutics, pp. 392-430

Note on recent evidence: A 2025 network meta-analysis (PMID 39808752) on antiseizure medications in post-stroke seizures and a 2025 Neurocritical Care Society guideline (PMID 39707127) suggest newer agents (levetiracetam, lacosamide) are preferred over phenytoin in acute symptomatic settings, consistent with phenytoin's demotion from first-line status in current practice.

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