phenytoin

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phenytoin antiepileptic pharmacology

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Here is a comprehensive overview of phenytoin drawn from Goodman & Gilman's Pharmacological Basis of Therapeutics and Katzung's Basic & Clinical Pharmacology (16th ed.):

Phenytoin (Diphenylhydantoin)

Phenytoin and Fosphenytoin chemical structures

Chemistry

Phenytoin (5,5-diphenylhydantoin) is a hydantoin derivative - a 5-membered ring compound structurally related to barbiturates. It has a pKa of ~8.06-8.33 and is poorly water-soluble in its free-base form. Fosphenytoin is the water-soluble disodium phosphate ester prodrug, rapidly converted to phenytoin in plasma, used for IV/IM administration.

Mechanism of Action

Phenytoin is a voltage-gated sodium channel blocker. It slows the rate of recovery of Na+ channels from inactivation, reducing sustained repetitive firing of action potentials evoked by depolarization. The effect is:

Voltage-dependent - greater effect when the membrane is depolarized
Use-dependent - more pronounced during high-frequency firing

At therapeutic concentrations, phenytoin acts selectively on Na+ channels without affecting spontaneous neuronal activity or GABA/glutamate responses. At 5-10x therapeutic concentrations, it also suppresses spontaneous activity and enhances GABA responses - effects that underlie its toxic manifestations.

Clinical Uses

Indication	Notes
Focal (partial) seizures	First-line historically; now second-line
Generalized tonic-clonic seizures	Focal-to-bilateral or idiopathic generalized
Status epilepticus (IV)	Fosphenytoin preferred IV
NOT absence seizures	May worsen them
NOT juvenile myoclonic epilepsy	May worsen myoclonic seizures
NOT Dravet syndrome	May worsen

Due to adverse effects and drug interactions, phenytoin is no longer considered first-line for chronic epilepsy management.

Pharmacokinetics

Absorption

Nearly complete from the GI tract, but highly formulation-dependent
Extended-release capsule: peak at 4-12 hours (allows once-daily dosing)
Prompt-release capsule: peak at 1.5-3 hours
IM injection is NOT recommended - unpredictable absorption with muscle precipitation

Distribution

Protein binding: ~90% to serum albumin
Volume of distribution: 0.6-0.7 L/kg
Small changes in bound fraction dramatically alter free (active) drug levels
Situations increasing free phenytoin: hypoalbuminemia (liver disease, nephrotic syndrome), hyperbilirubinemia, neonates, elderly, drug displacement (warfarin, valproate)

Metabolism - KEY CONCEPT: Zero-Order / Saturation Kinetics

At low concentrations, phenytoin follows first-order kinetics. As concentrations rise into the therapeutic range, hepatic metabolic capacity becomes saturated, shifting to zero-order (Michaelis-Menten) kinetics - a constant amount (not fraction) is metabolized per unit time.

Clinical implication: Small dose increases can cause disproportionately large rises in plasma levels and rapid toxicity.

Metabolized by CYP2C9 and CYP2C19 to inactive hydroxylated metabolites
Half-life: 12-36 hours (average ~24 hours) at low-to-mid therapeutic range; much longer at high concentrations
Time to steady state: 5-7 days at low levels; up to 4-6 weeks at higher levels

Therapeutic Range

Parameter	Value
Therapeutic total level	10-20 mcg/mL
Nystagmus appears at	~20 mcg/mL
Free phenytoin therapeutic	0.75-1.25 mcg/mL

Correction for hypoalbuminemia: Measured total level underestimates free drug. Use the Sheiner-Tozer equation when albumin is low.

Drug Interactions (Extensive)

Phenytoin is both a substrate and inducer of CYP enzymes, creating complex bidirectional interactions:

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

Isoniazid (especially slow acetylators)
Fluoxetine, fluvoxamine
Metronidazole, miconazole
Fluorouracil
Valproate (dual effect: displaces from protein binding + inhibits metabolism)

Drugs that DECREASE phenytoin levels:

Carbamazepine (CYP induction)
Alcohol (chronic use)
Barbiturates

Drugs whose levels are DECREASED by phenytoin (CYP induction):

Oral contraceptives (risk of contraceptive failure)
Warfarin
Corticosteroids
Many other CYP substrates

Adverse Effects

CNS (dose-related, most common)

Nystagmus (first sign of toxicity, at ~20 mcg/mL)
Diplopia, ataxia, dysarthria
Sedation, cognitive impairment
At toxic doses: cerebellar atrophy (long-term), worsening seizures

Chronic use

Gingival hyperplasia - ~20% of chronic users; minimized by good oral hygiene
Hirsutism - particularly troublesome in females
Coarsening of facial features
Osteomalacia / osteoporosis - due to altered vitamin D and vitamin K metabolism; leads to hypocalcemia, elevated alkaline phosphatase
Megaloblastic anemia - folate-related
Hyperglycemia/glycosuria - inhibition of insulin secretion
SIADH suppression (inhibits ADH release)

Hypersensitivity / Idiosyncratic

Morbilliform rash: 2-5% of patients
Stevens-Johnson syndrome / toxic epidermal necrolysis (rare but serious)
Hepatic necrosis
Hematological: neutropenia, leukopenia, agranulocytosis, aplastic anemia, thrombocytopenia
Drug-induced SLE

IV Administration

Purple glove syndrome - purplish-black discoloration with edema/pain distal to IV site (due to propylene glycol vehicle and alkaline pH)
Cardiac arrhythmias and hypotension with rapid IV infusion
Maximum IV rate: <50 mg/min (phenytoin) or <150 mg phenytoin equivalents/min (fosphenytoin)

Teratogenicity

Fetal hydantoin syndrome - craniofacial abnormalities, digit/nail hypoplasia, growth restriction, cognitive impairment
Neonatal coagulopathy (reduced vitamin K-dependent clotting factors) - treat/prevent with vitamin K

Formulations Summary

Form	Route	Notes
Extended-release capsule	Oral	Once-daily dosing possible
Prompt-release capsule	Oral	2-3x daily dosing
Suspension / chewable tabs	Oral	Free-base form
IV solution	IV	Contains propylene glycol, pH 12; risk of purple glove syndrome
Fosphenytoin (Cerebyx)	IV / IM	Water-soluble prodrug; preferred for parenteral use

Clinical Monitoring

Monitor total phenytoin levels (therapeutic: 10-20 mcg/mL); correct for albumin when appropriate
Monitor free phenytoin when protein binding is altered (renal failure, hypoalbuminemia, pregnancy, drug interactions)
Check LFTs, CBC, and bone density in long-term users
Serum level monitoring is mandatory when switching formulations

Sources: - Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 20 | - Katzung's Basic & Clinical Pharmacology, 16th Ed., Chapter 24

Recent evidence note: A 2025 network meta-analysis (PMID 39808752) of antiseizure medications for post-stroke seizures suggests newer agents may outperform phenytoin in this setting, consistent with its declining role as a first-line agent.

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