Phenytoin

Introduction Overview

Generic Name

Phenytoin

Brand Name

Dilantin, Phenytek

Dosage Form

Oral (capsules, chewable tablets, oral suspension), Intravenous (IV) solution, Intramuscular (IM) injection (generally avoided), Extended-release capsules

Drug Class

Hydantoin anticonvulsants

Pharmacokinetics

Phenytoin exhibits complex pharmacokinetics characterized primarily by its absorption, distribution, metabolism, and elimination properties that influence its therapeutic efficacy and safety profile.

Absorption:
Phenytoin is well absorbed from the gastrointestinal tract, primarily the small intestine, with oral bioavailability approaching 90%. Different formulations exhibit varied absorption characteristics; immediate-release forms are absorbed relatively quickly, whereas extended-release capsules demonstrate delayed and prolonged absorption, allowing for once-daily dosing in some cases. Chewable tablets require multiple daily dosing due to shorter duration of action. The oral suspension provides a useful option for patients with swallowing difficulty and allows more precise dose titration. Food can affect the rate but not the extent of phenytoin absorption. Clinicians must account for erratic absorption when switching between formulations or dosages to maintain stable serum concentrations.

Distribution:
Phenytoin is extensively bound to plasma albumin (approximately 90%), with only the free (unbound) fraction being pharmacologically active. This high plasma protein binding means that conditions altering albumin levels—such as liver disease, malnutrition, or uremia—can increase the free phenytoin concentration, elevating the risk of toxicity even if total drug levels appear therapeutic. Phenytoin distributes into body tissues with an apparent volume of distribution ranging between 0.6 to 0.8 L/kg. It crosses the blood-brain barrier effectively, exerting its anticonvulsant effects centrally. It also crosses the placenta and is found in breast milk, which necessitates caution during pregnancy and lactation.

Metabolism:
Phenytoin is metabolized primarily in the liver through aromatic hydroxylation, catalyzed mainly by cytochrome P450 enzymes CYP2C9 and CYP2C19. It exhibits dose-dependent (nonlinear) metabolism, due to the saturation of hepatic enzymes; as phenytoin serum concentrations approach therapeutic levels, small increases in dose can disproportionately elevate plasma concentrations, increasing toxicity risk. Genetic polymorphisms in metabolizing enzymes can affect plasma levels and patient sensitivity. Induction of hepatic enzymes by phenytoin can also alter the metabolism of concurrent drugs, leading to complex drug interactions. The metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) is inactive and excreted renally.

Elimination:
Phenytoin and its metabolites are eliminated primarily by renal excretion, with a half-life ranging broadly from 7 to 42 hours depending on dose and individual variability. The nonlinear kinetics coupled with hepatic metabolism saturation complicates dosing and necessitates monitoring of plasma levels to maintain therapeutic concentrations (typically 10-20 mcg/mL total phenytoin). Renal impairment does not significantly affect clearance of parent drug, but accumulation of inactive metabolites may occur. Due to saturable elimination, steady-state concentrations may take several days to achieve, and dose adjustments require careful clinical and laboratory evaluation.

Dosage Forms

Available Dosage Forms:
Phenytoin is available in multiple formulations tailored for diverse clinical needs. The oral form includes extended-release capsules (commonly 100 mg), chewable tablets, and oral suspension. The oral suspension is typically provided at 125 mg per 5 mL and requires shaking before dosing. Injectable forms include intravenous (IV) solutions for slow administration (limited to 50 mg/min infusion rate) and intramuscular (IM) injections, although IM administration is generally discouraged due to erratic absorption and tissue irritation risks.

Dosages for Adults and Adolescents:
For seizure control, adults commonly receive a loading dose of 1 g orally divided over several doses spaced at two-hour intervals for rapid attainment of therapeutic levels, followed by maintenance doses of 100 mg three to four times daily or once-daily 300 mg extended-release capsules if well tolerated and seizure-free. Intravenous therapy loading doses range from 10 to 15 mg/kg administered slowly with a maintenance dose of 100 mg every 6 to 8 hours IV. Pediatric dosing varies according to age and indication, with loading doses of 15 to 20 mg/kg IV for status epilepticus and maintenance doses adjusted by weight ranging from 5 to 10 mg/kg/day divided into multiple doses. For arrhythmias, adults may receive loading doses of 1.25 mg/kg IV every 5 minutes (cumulative up to 15 mg/kg) or oral doses of 250 mg four times daily for a day, with maintenance doses of 300 to 400 mg daily divided. Pediatric arrhythmia dosing is similar but adjusted for age and weight.

Specific Patient Populations:
Dose adjustments and therapeutic monitoring are critical in populations with altered pharmacokinetics, including patients with hepatic impairment, renal disease, pregnancy, the elderly, and pediatric patients. In pregnancy, seizure control outweighs potential teratogenic risks, mandating careful dosing and monitoring. Breastfeeding requires caution due to phenytoin excretion in breast milk. Patients requiring neurosurgery prophylaxis may be administered doses of 100 to 200 mg IV or IM every 4 hours during surgery and postoperatively, though IV or fosphenytoin is preferred over IM due to tissue irritation risks. Individuals of Asian ancestry may require HLA-B*1502 testing due to increased risk of severe cutaneous adverse reactions.

Mechanism Of Action

Phenytoin exerts its anticonvulsant effects primarily through stabilization of neuronal membranes and reduction of repetitive neuronal firing by modulating voltage-gated sodium channels. At the molecular level, phenytoin binds preferentially to the inactive state of sodium channels in neurons, prolonging their inactivation. This action reduces high-frequency repetitive firing of action potentials, which is a hallmark of epileptic seizures, by inhibiting the recovery of sodium channels to the active state, thereby stabilizing excitable membranes and diminishing abnormal electrical activity.

Beyond sodium channel modulation, phenytoin indirectly influences synaptic neurotransmission by limiting calcium influx during repetitive firing, which decreases the release of excitatory neurotransmitters such as glutamate. This decreases neuronal excitability and seizure propagation. Some evidence also suggests that phenytoin modulates GABAergic inhibitory neurotransmission, contributing to its anticonvulsant efficacy, though this is considered a secondary effect.

Pharmacodynamically, phenytoin's mechanism distinguishes it from other anticonvulsants like benzodiazepines, which enhance GABA receptor activity, or levetiracetam, which binds to synaptic vesicle protein SV2A. Its selective voltage-dependent sodium channel blockade allows it to target overactive neurons while sparing normal neuronal function, which contributes to its clinical utility in focal and generalized tonic-clonic seizures.

Clinical studies have consistently demonstrated that phenytoin reduces seizure frequency and severity through these mechanisms. However, its narrow therapeutic window and complex pharmacokinetics necessitate careful dose titration and monitoring during therapy. Recent research is exploring phenytoin analogs and derivatives aiming to retain its efficacy with improved safety and pharmacokinetic profiles.

Pharmacological Actions

Blocks voltage-gated sodium channels in neuronal membranes, reducing repetitive firing.
Stabilizes neuronal membranes to prevent hyperexcitability and seizure propagation.
Reduces synaptic release of excitatory neurotransmitters such as glutamate by modulating calcium influx.
Exhibits anticonvulsant activity primarily against generalized tonic-clonic and focal seizures.
Induces hepatic microsomal enzymes, affecting metabolism of co-administered drugs.
Displays nonlinear (saturable) pharmacokinetics affecting dose-response and toxicity risk.
Crosses the blood-brain barrier to exert central nervous system effects.
Modulates, to a lesser extent, GABAergic neurotransmission contributing to inhibitory tone.
Demonstrates antiarrhythmic properties by stabilizing cardiac membranes and reducing aberrant electrical activity.
Used prophylactically to prevent post-neurosurgical seizures due to membrane-stabilizing effects.
Impairs folate metabolism, leading to potential deficiency and associated clinical consequences.
Possesses a long half-life, allowing for sustained anticonvulsant effect with appropriate dosing.
Can cause induction of cytochrome P450 enzymes thereby influencing pharmacokinetics of other medications.

Therapeutic Or Clinical Uses

Management and prevention of generalized tonic-clonic (grand mal) seizures.
Treatment of complex partial (focal) seizures with or without secondary generalization.
Prophylaxis of seizures following neurosurgery or head trauma.
Acute treatment of status epilepticus as an intravenous agent after benzodiazepine administration.
Management of cardiac arrhythmias, particularly digitalis-induced ventricular arrhythmias.
Control of certain types of epilepsy where other anticonvulsants are ineffective or contraindicated.
Off-label use in some neuropathic pain conditions due to neuronal membrane stabilization.
Prevention of seizures in patients with traumatic brain injury at risk of developing epilepsy.
Treatment of seizures in pediatric patients with age-appropriate dose adjustments.
Adjunctive therapy in refractory seizures where monotherapy is insufficient.
Seizure control in pregnant women balancing teratogenic risk and maternal health.
Use in patients unable to take oral medications via intravenous administration during acute settings.
Management of chronic epilepsy requiring long-term maintenance therapy.
Treatment of seizure disorders associated with genetic or metabolic conditions affecting neuronal excitability.

Side Or Adverse Effects

Common neurologic effects including dizziness, drowsiness, confusion, and impaired coordination.
Gingival hyperplasia causing gum swelling and bleeding; dental hygiene is important.
Nystagmus and abnormal involuntary eye movements as dose-related phenomena.
Diplopia and visual disturbances impacting daily activities.
Ataxia and impaired balance increasing fall risk, especially in elderly.
Rash and hypersensitivity reactions ranging from mild eruptions to severe Stevens-Johnson syndrome.
Hepatotoxicity presenting with elevated liver enzymes, jaundice, and possible liver failure.
Bone marrow suppression including leukopenia, thrombocytopenia, and anemia.
Peripheral neuropathy with chronic use.
Gastrointestinal disturbances such as nausea, vomiting, and constipation.
Cognitive impairment including confusion and mood changes such as depression or anxiety.
Teratogenic effects including fetal hydantoin syndrome when used in pregnancy.
Potential for cardiac arrhythmias or hypotension with rapid IV administration.
Possible drug-induced lupus erythematosus and connective tissue disorders.
Risk of suicidal ideation and behavior requiring close psychiatric monitoring.

Precautions

Perform thorough allergy history as patients allergic to hydantoin derivatives should avoid phenytoin.
Monitor liver function tests prior to and during therapy due to risk of hepatotoxicity.
Assess baseline and periodic serum phenytoin levels to maintain therapeutic range and avoid toxicity.
Use caution in patients with porphyria as phenytoin may exacerbate symptoms.
Adjust dosing in hepatic impairment because of altered metabolism and clearance.
Advise strict adherence to dosing regimen to prevent breakthrough seizures and withdrawal seizures.
Do not discontinue therapy abruptly; gradual tapering is necessary to avoid status epilepticus.
Evaluate bone health and vitamin D status as phenytoin may induce osteomalacia.
Screen patients of Asian descent for HLA-B*1502 allele to reduce risk of severe cutaneous adverse reactions.
Counsel women of childbearing potential on contraception efficacy reduction and pregnancy risks.
Avoid concurrent use with delavirdine due to contraindicated interactions.
Educate patients to avoid alcohol which can alter phenytoin blood levels and efficacy.
Monitor for mood changes or suicidality and provide psychiatric support if needed.
Inform dental care providers of phenytoin use to manage gingival hyperplasia proactively.
Advise on the potential for impaired motor skills; caution with driving or operating machinery.

Warnings

Contraindicated in patients with known hypersensitivity to phenytoin or related hydantoins.
Avoid concurrent use with delavirdine due to serious drug interactions.
Pregnancy category D; potential for fetal harm but seizure control benefits may outweigh risks.
Risk of severe dermatologic reactions including Stevens-Johnson Syndrome and toxic epidermal necrolysis.
May cause serious blood dyscrasias including agranulocytosis and aplastic anemia.
Slow intravenous administration is essential to prevent cardiac arrhythmias and hypotension.
Phenytoin toxicity can be life-threatening; monitor serum levels closely especially during dose changes.
May exacerbate seizures if discontinued suddenly or serum levels fall precipitously.
Potential for suicidal thoughts or behaviors; close monitoring of psychiatric status is required.
May decrease the efficacy of hormonal contraceptives and increase risk of unintended pregnancy.
Increased risk of bleeding during delivery in babies exposed in utero; prepare accordingly.
Risk of bone disease with chronic use necessitates monitoring and supplementation as appropriate.
Impaired cognitive function and sedation may affect quality of life and safety.
Not recommended for intramuscular use due to erratic absorption and local tissue necrosis.
Use caution with drugs metabolized by CYP450 as phenytoin induces hepatic enzymes affecting their levels.

Contraindication

Known hypersensitivity or allergy to phenytoin or related hydantoins such as ethotoin, fosphenytoin, or mephenytoin.
Concurrent administration with delavirdine (Rescriptor) due to contraindicated drug interaction.
History of liver impairment linked to phenytoin use requiring avoidance.
Patients with previous severe dermatologic reactions attributed to phenytoin.
Use in patients with acute intermittent porphyria due to potential exacerbation.
Avoid use in individuals with certain cardiac conduction abnormalities unless under strict monitoring.
Known hypersensitivity to any ingredient in phenytoin formulations.
Inability to swallow capsules or tablets where no suitable alternate dosage form is available.
Severe hypotension or cardiovascular instability where intravenous administration may pose risks.
Patients with known vitamin D deficiency and bone disorders require careful evaluation before use.

Drug Interactions

Phenytoin is a potent inducer of cytochrome P450 enzymes (CYP2C9, CYP2C19, CYP3A4), reducing plasma concentrations of many drugs including oral contraceptives, warfarin, corticosteroids, and antiretrovirals.
Drugs that inhibit or induce CYP enzymes can respectively increase or decrease phenytoin serum levels, e.g., cimetidine, omeprazole, rifampin, carbamazepine.
Concurrent use with other CNS depressants (e.g., benzodiazepines, alcohol) can enhance sedation and respiratory depression.
Antacids can reduce phenytoin absorption if taken simultaneously; separate administration by at least 2 hours.
Folic acid supplements may reduce phenytoin efficacy, and phenytoin may cause folate deficiency.
Phenytoin may increase metabolism of folic acid, leading to anemia and other hematologic effects.
Concomitant use with other anticonvulsants may require dose adjustments due to pharmacokinetic interactions.
Phenytoin can decrease the effectiveness of certain chemotherapeutic agents by inducing metabolism.
Use with drugs that prolong the QT interval or affect cardiac conduction requires caution due to additive effects.
Warfarin dosing needs close monitoring when administered with phenytoin due to altered anticoagulation.
St. John's wort and other herbal supplements can reduce phenytoin levels by enzyme induction.
Valproic acid can increase free phenytoin levels by displacing it from plasma proteins, raising toxicity risk.
Sulfonamides and isoniazid may inhibit phenytoin metabolism, increasing its plasma concentration.
Concurrent use with delavirdine is contraindicated due to significant interactions lowering efficacy.
Phenytoin may reduce efficacy of hormonal contraceptives by inducing their clearance.

Preparations Of The Drug

Phenytoin Sodium Extended Release Capsules - commonly 100 mg, used for maintenance dosing.
Phenytoin Sodium Chewable Tablets - dosing requires 2-3 times daily administration, not suitable for once-daily use.
Phenytoin Oral Suspension - typically 125 mg/5 mL dosage, for patients with swallowing difficulties or pediatric use.
Intravenous Phenytoin Sodium Injection - used in acute settings such as status epilepticus, administered slowly with max infusion rate of 50 mg/min to avoid cardiovascular side effects.
Intramuscular Phenytoin Injection - generally avoided due to erratic absorption and severe local tissue reactions; fosphenytoin preferred if parenteral administration is needed.
Phenytoin Infatabs - chewable option designed for pediatric patients and those requiring flexible dosing.
Phenytek Capsules - another branded extended-release capsule formulation of phenytoin sodium.
Dilantin Capsules/Tablets - widely used immediate-release and extended-release phenytoin formulations.
Phenytoin Sodium Injection for IV use in emergency seizure control, requiring dilute preparation and filtered administration.
Commercially available formulations are subject to FDA approval and quality standards to ensure bioequivalence and stability.