Phenytoin

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Phenytoin is a classic antiepileptic drug (hydantoin class) that works by blocking voltage-gated sodium channels, stabilizing neuronal membranes and preventing seizure propagation. It's used for tonic-clonic and focal seizures, and also for status epilepticus (IV form). It has a narrow therapeutic index, nonlinear (zero-order) pharmacokinetics, and a wide range of drug interactions and adverse effects.

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phenytoin antiepileptic

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Phenytoin

Class: Hydantoin antiseizure medication (ASM) Also known as: Diphenylhydantoin (DPH) First identified: 1938 - the oldest non-sedating antiseizure drug

Structure & Formulations

Phenytoin and Fosphenytoin chemical structures

Phenytoin is the 5,5-diphenyl-substituted analog of hydantoin - a five-membered ring structurally similar to barbiturates (six-membered ring). The free base (pKa 8.06-8.33) is poorly water-soluble; phenytoin sodium dissolves in water at 17 mg/mL.

Available formulations:

Form	Absorption characteristics
Extended-release capsule (phenytoin sodium)	Peak level 4-12 h; allows once-daily dosing
Prompt capsule (phenytoin sodium)	Peak level 1.5-3 h; requires more frequent dosing
Suspension & chewable tablets (free base)	Immediate-release
IV solution (pH 12, propylene glycol + alcohol)	Risk of purple glove syndrome; rate ≤50 mg/min
Fosphenytoin (IV/IM prodrug)	Water-soluble; converted by phosphatases in liver/RBCs; t½ conversion = 8-15 min; preferred over IV phenytoin

IM administration of phenytoin (not fosphenytoin) is not recommended - absorption is unpredictable and precipitation in muscle occurs.

Mechanism of Action

Phenytoin is a voltage-gated sodium channel blocker. It slows the rate of recovery of Na⁺ channels from inactivation, making it both:

Voltage-dependent - greater effect when the membrane is depolarized
Use-dependent - greater effect with repetitive firing

At therapeutic concentrations, phenytoin selectively limits repetitive high-frequency action potential firing without affecting basal neuronal activity or responses to GABA/glutamate. At 5-10x therapeutic concentrations, additional effects emerge (GABA enhancement, reduced spontaneous activity), which underlie phenytoin toxicity.

"Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization... This effect is mediated by a slowing of the rate of recovery of voltage-activated Na⁺ channels from inactivation." - Goodman & Gilman's, p. 411

Clinical Uses

Effective for:

Focal (partial) onset seizures
Focal-to-bilateral tonic-clonic seizures
Generalized tonic-clonic seizures (including in idiopathic generalized epilepsy)
Acute treatment of status epilepticus (IV/fosphenytoin)

May worsen:

Absence seizures
Juvenile myoclonic epilepsy (JME)
Dravet syndrome
Myoclonic seizures

Due to its adverse effects and drug interactions, phenytoin is no longer considered first-line chronic therapy, though it remains important for status epilepticus.

Pharmacokinetics

Absorption

Highly formulation-dependent (particle size, excipients matter)
Absorption from GI tract nearly complete in most patients; time to peak ranges from 3-12 hours

Protein Binding

~90% bound to serum albumin
Small changes in the bound fraction dramatically alter free (active) drug
Displacement occurs with: hyperbilirubinemia, warfarin, valproate, sulfonamides, phenylbutazone
Low albumin states (liver disease, nephrotic syndrome, neonates, elderly) → elevated free drug → toxicity even at "therapeutic" total levels

Volume of distribution

Low Vd = 0.6-0.7 L/kg in adults (due to high protein binding)

Metabolism

95% metabolized in hepatic ER by CYP2C9/2C10 (primarily) and CYP2C19
Principal metabolite: parahydroxyphenyl derivative (inactive)
Only a small proportion excreted unchanged in urine

Nonlinear (Zero-Order / Michaelis-Menten) Kinetics - KEY CONCEPT

Phenytoin dose vs serum concentration: saturation kinetics

At low levels: first-order kinetics (constant fraction eliminated per unit time). As levels rise within the therapeutic range, hepatic metabolism becomes saturated, shifting to zero-order kinetics (constant amount eliminated per unit time). This means:

Small dose increases → disproportionately large rise in serum level
Half-life increases markedly at higher concentrations (t½ = 12-36 h average; much longer at high levels)
Steady state after a dose change takes 5-7 days at low-mid levels, and 4-6 weeks at higher levels
Therapeutic drug monitoring (TDM) is essential

Therapeutic range (total): 10-20 mcg/mL
Free phenytoin therapeutic range: 1-2 mcg/mL

Correction for hypoalbuminemia (Winter-Tozer equation): Corrected level = measured total ÷ [(0.2 × albumin) + 0.1]

Enzyme Induction

Phenytoin is a major CYP inducer (CYP1A2, CYP2C, CYP3A4). Clinically important inductions include:

Oral contraceptives (CYP3A4) → contraceptive failure → unplanned pregnancy (especially dangerous given phenytoin's teratogenicity)
Warfarin (CYP2C9) → reduces anticoagulant effect initially, but phenytoin also displaces warfarin from proteins - complex interaction
Valproate, tiagabine, ethosuximide, lamotrigine, topiramate, oxcarbazepine

Drug Interactions

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

Isoniazid (especially in slow acetylators)
Fluoxetine, fluvoxamine
Metronidazole
Miconazole
Omeprazole
Valproate (also displaces from protein binding)
Fluorouracil
Sulfonamides

Drugs that DECREASE phenytoin levels:

Alcohol (chronic use), barbiturates, carbamazepine (CYP inducers → increased metabolism)
Antacids (reduce absorption)

Phenytoin REDUCES levels of:

Oral contraceptives
Warfarin
Most other ASMs (valproate, lamotrigine, topiramate, tiagabine)
Corticosteroids, cyclosporine, some antibiotics

Adverse Effects

Dose-Related (CNS) - most common

Level (mcg/mL)	Signs
10-20 (therapeutic)	Mild sedation in some
20-30	Nystagmus (horizontal)
30-40	Ataxia, dysarthria, diplopia
>40	Mental confusion, lethargy, encephalopathy
Very high	Paradoxical seizure worsening, decerebrate rigidity

Chronic Use Effects

Gingival hyperplasia - occurs in ~20% of patients; due to altered collagen metabolism; especially problematic in children
Hirsutism - particularly distressing in women
Coarsening of facial features
Peripheral neuropathy - diminished deep tendon reflexes
Cerebellar atrophy - with high chronic doses
Megaloblastic anemia - due to folate interference
Osteomalacia / decreased bone density - via induction of vitamin D metabolism (CYP3A4)
Behavioral changes

Cardiovascular (IV administration)

Cardiac arrhythmias with hypotension when infused too rapidly - minimize by infusing phenytoin at ≤50 mg/min (or fosphenytoin at ≤150 mg phenytoin equivalents/min)
Greater risk in elderly and those with cardiac disease, but can occur in young healthy patients
Purple glove syndrome - purplish-black discoloration + edema + pain distal to injection site; fosphenytoin has lower incidence

Idiosyncratic / Hypersensitivity (drug allergy)

Skin reactions: rash, Stevens-Johnson syndrome (rare)
Bone marrow suppression (rare)
Hepatotoxicity (rare)
These require drug withdrawal

Teratogenicity - Fetal Hydantoin Syndrome

Craniofacial abnormalities, limb defects, growth retardation, cognitive impairment
Use during pregnancy requires careful risk-benefit assessment; folate supplementation is recommended

Special Situations

Hypoalbuminemia / Renal failure:
Report free phenytoin levels rather than total. In uremia, not only is albumin reduced, but the protein binding affinity is also decreased - total levels are misleading. Use the Winter-Tozer correction formula.

Status Epilepticus:
Use IV fosphenytoin (preferred over phenytoin IV due to safety profile). Dosing as "phenytoin equivalents" (PE): loading dose 15-20 mg PE/kg IV.

Drug-drug interactions in ICU:
Phenytoin is notorious for complex interactions with antibiotics, antifungals, and sedatives used in critically ill patients.

Summary Table

Property	Value
Class	Hydantoin
Mechanism	Voltage-gated Na⁺ channel blockade
Seizure types	Focal, focal-to-bilateral tonic-clonic, generalized tonic-clonic; IV for status epilepticus
Protein binding	~90% (albumin)
Vd	0.6-0.7 L/kg
Metabolism	CYP2C9 >> CYP2C19 (hepatic); zero-order (saturation) kinetics
Half-life	12-36 h (average 24 h; longer at high levels)
Therapeutic range	Total: 10-20 mcg/mL; Free: 1-2 mcg/mL
Key adverse effects	Nystagmus → ataxia → encephalopathy; gingival hyperplasia; hirsutism; teratogenicity
Key interactions	CYP2C9/2C19 inhibitors ↑ levels; phenytoin induces CYP3A4 ↓ OCP/warfarin

Sources:

Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 651-652
Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 411-413
Tietz Textbook of Laboratory Medicine, 7th Ed.

Recent evidence note (2025): A network meta-analysis in Neurology (PMID 39808752) comparing antiseizure medications for post-stroke seizures, and NCS guidelines on seizure prophylaxis in intracerebral hemorrhage (PMID 39707127), both suggest that phenytoin/fosphenytoin is being replaced by levetiracetam and newer agents in acute neurocritical care settings due to its interaction profile and adverse effects - consistent with its declining role as a first-line agent.

Summarise it

Phenytoin - Summary

Class: Hydantoin antiseizure drug (oldest non-sedating AED, since 1938)

Mechanism: Blocks voltage-gated Na⁺ channels - slows recovery from inactivation, limiting repetitive high-frequency neuronal firing.

Uses

Focal seizures, tonic-clonic seizures, status epilepticus (IV)
Avoid in: absence seizures, JME, Dravet syndrome (can worsen them)
No longer first-line for chronic epilepsy

Key Pharmacokinetics

Protein binding: ~90% to albumin - free drug rises dangerously in hypoalbuminemia
Metabolism: CYP2C9 > CYP2C19; saturable (zero-order/Michaelis-Menten kinetics)
Narrow therapeutic index: 10-20 mcg/mL (total); small dose increases → disproportionate level rise
Half-life: 12-36 h (longer at high concentrations)
Enzyme inducer: Reduces OCP, warfarin, and many other drug levels

Adverse Effects

Dose-related (CNS)	Chronic use	Idiosyncratic
Nystagmus → ataxia → encephalopathy	Gingival hyperplasia	SJS/rash
Paradoxical seizures at toxic levels	Hirsutism, coarse facies	Hepatotoxicity
IV: arrhythmia, hypotension	Osteomalacia, megaloblastic anemia	Bone marrow suppression

Teratogenic - fetal hydantoin syndrome (craniofacial defects, cognitive impairment)
Purple glove syndrome with IV extravasation - use fosphenytoin IV instead

Key Interactions

Levels increased by: isoniazid, fluconazole, valproate, fluoxetine, metronidazole
Phenytoin lowers: oral contraceptives, warfarin, lamotrigine, most other AEDs

One-liner

Phenytoin = Na⁺ channel blocker with saturation kinetics, narrow therapeutic window, extensive interactions, and significant chronic toxicity - largely replaced by newer agents but still relevant for status epilepticus.

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