Pharmacology of Phenytoin

Introduction/Overview

Phenytoin, introduced into clinical practice in 1938, represents a cornerstone agent in the management of seizure disorders. As one of the oldest and most extensively studied antiepileptic drugs, its enduring clinical utility is balanced by a complex pharmacological profile characterized by non-linear pharmacokinetics and a narrow therapeutic index. The drug’s primary role involves the suppression of neuronal hyperexcitability, which underlies its efficacy in controlling partial and generalized tonic-clonic seizures. Understanding phenytoin pharmacology is essential for safe and effective prescribing, given its potential for significant drug interactions and toxicity. This chapter provides a systematic examination of phenytoin, from its molecular mechanisms to its clinical application and management.

Learning Objectives

• Explain the molecular mechanism by which phenytoin exerts its anticonvulsant effect, with emphasis on voltage-gated sodium channel modulation.
• Describe the non-linear (Michaelis-Menten) pharmacokinetics of phenytoin, including the implications for dosing, therapeutic drug monitoring, and toxicity.
• Identify the approved clinical indications for phenytoin and common off-label uses in neurological practice.
• Analyze the spectrum of adverse effects associated with phenytoin, distinguishing between common dose-related effects and idiosyncratic reactions.
• Evaluate major drug interactions involving phenytoin, particularly those affecting the cytochrome P450 enzyme system, and apply this knowledge to clinical management.

Classification

Phenytoin is systematically classified within several overlapping categories that define its therapeutic and chemical identity.

Therapeutic and Pharmacological Classification

The primary classification of phenytoin is as an anticonvulsant or antiepileptic drug (AED). More specifically, based on its mechanism, it is categorized as a voltage-gated sodium channel blocker. It belongs to the group of hydantoin derivatives, a chemical class sharing a five-membered ring structure. Unlike many newer agents, phenytoin is not considered a first-line treatment for all seizure types due to its side effect profile and pharmacokinetic challenges, but it remains a drug of significant historical and practical importance, particularly in specific clinical scenarios such as status epilepticus.

Chemical Classification

Chemically, phenytoin is known as 5,5-diphenylimidazolidine-2,4-dione. It is a weak acid with a pK_a of approximately 8.3. Its poor aqueous solubility, especially at physiological pH, is a fundamental property that influences its formulation (requiring solubilization in a highly alkaline vehicle for intravenous use) and its absorption characteristics when administered orally.

Mechanism of Action

The anticonvulsant action of phenytoin is primarily attributed to its ability to limit the sustained, high-frequency repetitive firing of action potentials in neurons. This effect is mediated through a selective interaction with voltage-gated ion channels.

Modulation of Voltage-Gated Sodium Channels

Phenytoin exerts its principal effect by binding to and stabilizing the inactivated state of voltage-gated sodium channels. During an action potential, sodium channels transition from a resting closed state to an open state, allowing sodium influx and depolarization, before entering an inactivated closed state. Phenytoin has a high affinity for this inactivated conformation. By binding to it, the drug slows the rate of recovery (repriming) of sodium channels from the inactivated to the resting state. This use-dependent or frequency-dependent blockade means that the inhibitory effect of phenytoin is markedly enhanced during rapid, repetitive neuronal firing, as occurs during a seizure, while having minimal effect on normal, low-frequency physiological activity. This selective inhibition prevents the spread of seizure activity from an epileptic focus without unduly suppressing normal neuronal function.

Additional Cellular Effects

While sodium channel blockade is the dominant mechanism, phenytoin may influence other pathways at clinically relevant concentrations. A modest effect on voltage-gated calcium channels, particularly high-voltage-activated (L- and N-type) channels, has been observed, which may contribute to the stabilization of neuronal membranes. Phenytoin may also inhibit the release of excitatory neurotransmitters, possibly secondary to its sodium channel effects. Furthermore, it can enhance the activity of the sodium-potassium ATPase pump. It is generally accepted that phenytoin has no direct effect on GABA-ergic inhibition, distinguishing it from other anticonvulsants like benzodiazepines or barbiturates.

Pharmacodynamic Consequences

The net pharmacodynamic result is a raising of the seizure threshold and a limitation of the propagation of abnormal electrical discharges. This mechanism is effective against partial (focal) seizures and generalized tonic-clonic seizures, where synchronized, high-frequency neuronal firing is a key feature. It is notably ineffective against absence seizures, which are characterized by low-frequency, rhythmic thalamocortical oscillations, a pattern not susceptible to use-dependent sodium channel blockade.

Pharmacokinetics

The pharmacokinetic profile of phenytoin is complex and clinically significant due to its saturation kinetics, which necessitate careful dosing and monitoring.

Absorption

Oral absorption of phenytoin is variable and formulation-dependent. The drug is highly lipophilic but poorly water-soluble. Absorption occurs primarily in the duodenum and is slow, with peak plasma concentrations (C_max) typically reached 4-12 hours after a single dose. The extended phenytoin sodium capsules (prompt release) demonstrate nearly complete but slow absorption. The bioavailability of oral formulations is approximately 90%. Intramuscular administration is not recommended due to erratic absorption, precipitation at the injection site, and tissue irritation. For rapid effect, the intravenous route is employed, using a specially formulated solution where phenytoin is dissolved in a propylene glycol and ethanol vehicle adjusted to a high pH (≈12) to maintain solubility.

Distribution

Phenytoin is widely distributed throughout the body. It is highly bound (≈90%) to plasma proteins, primarily albumin. Only the unbound (free) fraction is pharmacologically active and available for metabolism. Conditions that decrease serum albumin (e.g., liver disease, nephrotic syndrome, malnutrition, pregnancy) or displace phenytoin from binding sites (e.g., hyperbilirubinemia, uremia, or concurrent use of highly protein-bound drugs like valproate) will increase the free fraction, potentially leading to toxicity even when total plasma levels are within the therapeutic range. The volume of distribution is approximately 0.6-0.7 L/kg. Phenytoin readily crosses the placenta and is present in breast milk.

Metabolism and Elimination

Phenytoin is eliminated almost exclusively by hepatic metabolism, with less than 5% excreted unchanged in the urine. Its metabolism is the source of its most critical pharmacokinetic property: capacity-limited or saturable (Michaelis-Menten) kinetics. The primary metabolic pathway is para-hydroxylation by the cytochrome P450 enzyme system, specifically involving the CYP2C9 and, to a lesser extent, CYP2C19 isoenzymes, to form the inactive metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), which is then glucuronidated and excreted in the urine.

At low plasma concentrations, metabolism follows first-order kinetics, where the elimination rate is proportional to the drug concentration. As concentrations increase, the hepatic enzymes become saturated. At this point, metabolism shifts to zero-order kinetics, where a constant amount of drug is metabolized per unit time, independent of concentration. The plasma concentration at which this transition begins is variable among individuals but typically occurs within or near the therapeutic range (10-20 µg/mL). This relationship is described by the Michaelis-Menten equation:

Elimination Rate = (V_max × C) ÷ (K_m + C)

where V_max is the maximum metabolic rate, K_m is the plasma concentration at which the elimination rate is half of V_max, and C is the plasma drug concentration.

The clinical implication is that within the zero-order range, small increases in dose can lead to disproportionately large increases in steady-state plasma concentration, dramatically raising the risk of toxicity. The apparent half-life (t_1/2) is therefore concentration-dependent, ranging from approximately 12 hours at low concentrations to over 60 hours at saturating concentrations near the upper limit of the therapeutic range.

Dosing Considerations and Therapeutic Drug Monitoring

Initial dosing for adults typically ranges from 5 mg/kg/day, divided into 2-3 doses. Maintenance dosing is highly individualized. Because of the saturable metabolism, dosing adjustments must be made cautiously. The therapeutic range for total phenytoin in plasma is conventionally 10-20 µg/mL (40-80 µmol/L). Monitoring of free (unbound) phenytoin levels (therapeutic range 1-2 µg/mL) is recommended in conditions altering protein binding. Steady-state levels are achieved 5-10 days after a dosage change due to the long and variable half-life. Blood samples for trough levels should be drawn just before the next dose.

Therapeutic Uses/Clinical Applications

Approved Indications

• Treatment of Tonic-Clonic (Grand Mal) and Partial (Focal) Seizures: Phenytoin is effective for the prophylaxis and long-term management of these seizure types. Its use as a first-line monotherapy has declined in favor of newer agents with more favorable pharmacokinetic and side effect profiles, but it remains a viable option.
• Treatment and Prophylaxis of Seizures During or Following Neurosurgery: It is commonly used perioperatively in patients undergoing craniotomy or with recent head trauma to prevent postoperative seizures.
• Treatment of Status Epilepticus: Intravenous phenytoin (or its prodrug, fosphenytoin) is a standard second-line agent for the management of generalized convulsive status epilepticus, typically administered after failure of first-line benzodiazepines. Fosphenytoin is often preferred due to its better solubility, compatibility with other IV fluids, and reduced risk of soft tissue injury.

Off-Label Uses

• Neuropathic Pain: Phenytoin has demonstrated efficacy in certain neuropathic pain syndromes, such as trigeminal neuralgia, through its membrane-stabilizing properties, though it is generally not a first-choice agent.
• Cardiac Arrhythmias: Historically used for digitalis-induced arrhythmias due to its effects on cardiac sodium channels, this use has been largely superseded by more specific antiarrhythmic drugs.
• Prophylaxis of Seizures in Severe Traumatic Brain Injury: While sometimes used, guidelines often favor other agents like levetiracetam due to phenytoin’s adverse effect profile.

Adverse Effects

Adverse effects are common with phenytoin and can be categorized as dose-related (pharmacological), chronic, or idiosyncratic.

Dose-Related and Neurological Effects

These effects correlate with plasma concentrations, particularly free drug levels, and are often reversible with dose reduction.

• Cerebellar-Vestibular Effects: Nystagmus (often the earliest sign), diplopia, ataxia, slurred speech, and dizziness. These typically appear as levels approach or exceed 20 µg/mL.
• Central Nervous System Depression: Lethargy, sedation, and cognitive impairment at higher concentrations.
• Gastrointestinal Effects: Nausea and vomiting, especially with oral loading doses.

Chronic Adverse Effects

• Connective Tissue Abnormalities: Long-term use is associated with gingival hyperplasia, occurring in up to 50% of patients. It is thought to be mediated by inhibition of collagenase activity and fibroblast proliferation. Meticulous oral hygiene can mitigate but not prevent it.
• Peripheral Neuropathy: A predominantly sensory neuropathy may develop with chronic use.
• Osteomalacia and Vitamin D Deficiency: Phenytoin induces hepatic enzymes that accelerate the catabolism of vitamin D, potentially leading to hypocalcemia and bone demineralization.
• Cosmetic Effects: Coarsening of facial features, hirsutism, and acne.
• Hematological Effects: Megaloblastic anemia due to interference with folate metabolism; supplementation with folic acid may be required.

Idiosyncratic and Hypersensitivity Reactions

These are not dose-dependent and can be severe.

• Skin Rashes: Maculopapular rashes occur in 5-10% of patients. More severe reactions include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are medical emergencies. The risk of severe rash is higher in patients with the HLA-B*15:02 allele, particularly in Asian populations.
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Also known as anticonvulsant hypersensitivity syndrome, this multiorgan reaction features fever, rash, lymphadenopathy, eosinophilia, and involvement of organs such as the liver, kidneys, or heart.
• Hepatotoxicity: Ranging from mild transaminase elevations to fulminant hepatic necrosis, often as part of a hypersensitivity syndrome.
• Hematologic Toxicity: Rare instances of agranulocytosis, thrombocytopenia, or aplastic anemia.

Black Box Warnings

The United States Food and Drug Administration mandates a boxed warning for intravenous phenytoin regarding the risk of cardiovascular collapse and severe hypotension, especially with rapid administration. The propylene glycol vehicle is a myocardial depressant and vasodilator. Therefore, IV phenytoin must be administered no faster than 50 mg/min in adults (or 1-3 mg/kg/min in pediatric patients) with continuous monitoring of blood pressure and electrocardiogram. Extravasation can cause severe tissue injury, including necrosis (“purple glove syndrome”).

Drug Interactions

Phenytoin is involved in numerous and clinically significant drug interactions, primarily mediated through induction of hepatic cytochrome P450 enzymes and its own saturable metabolism.

Interactions Affecting Phenytoin Concentrations

Drugs that Increase Phenytoin Levels: Agents that inhibit CYP2C9 or CYP2C19 can decrease phenytoin metabolism, leading to toxicity.

• Enzyme Inhibitors: Amiodarone, chloramphenicol, fluconazole, isoniazid, omeprazole, sertraline, sulfonamides, and valproic acid. Valproate also displaces phenytoin from plasma proteins, increasing the free fraction.
• Other: Acute alcohol intake may inhibit metabolism, while chronic use induces it.

Drugs that Decrease Phenytoin Levels: Agents that induce CYP enzymes can increase phenytoin metabolism, potentially leading to subtherapeutic levels and seizure breakthrough.

• Enzyme Inducers: Carbamazepine, rifampin, chronic alcohol use, and St. John’s wort.

Interactions where Phenytoin Affects Other Drugs

As a potent inducer of CYP3A4 and other enzymes (e.g., CYP2C9, CYP2C19) and possibly drug transporters, phenytoin can significantly reduce the plasma concentrations and efficacy of many co-administered drugs.

• Anticoagulants: Reduces warfarin effect; requires careful INR monitoring.
• Antimicrobials: Decreases levels of doxycycline, chloramphenicol, certain antivirals (e.g., indinavir), and antifungal azoles.
• Cardiovascular Drugs: Reduces levels of quinidine, disopyramide, mexiletine, verapamil, and many statins.
• Psychotropic Drugs: Decreases levels of tricyclic antidepressants, many antipsychotics, benzodiazepines, and buspirone.
• Immunosuppressants: Markedly reduces cyclosporine, tacrolimus, and sirolimus levels, risking organ rejection.
• Other Antiepileptics: Reduces levels of carbamazepine, lamotrigine, topiramate, oxcarbazepine, tiagabine, and zonisamide.
• Steroids: Reduces efficacy of corticosteroids and oral contraceptives, increasing risk of contraceptive failure.

Contraindications

Absolute contraindications include a history of hypersensitivity to phenytoin or other hydantoins. Relative contraindications warrant extreme caution and include sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular block, Adams-Stokes syndrome (due to cardiovascular risks of IV administration), and hepatic impairment. Phenytoin is generally contraindicated in patients with absence seizures, as it may exacerbate them.

Special Considerations

Pregnancy and Lactation

Pregnancy (Pregnancy Category D): Phenytoin is a known teratogen. Exposure during the first trimester is associated with a 2- to 3-fold increased risk of major congenital malformations, collectively termed the fetal hydantoin syndrome. Features may include craniofacial abnormalities (cleft lip/palate, broad nasal bridge), distal digital hypoplasia, growth deficiency, and cardiac defects. There is also an increased risk of neurodevelopmental delay. Enzyme induction can lead to vitamin K deficiency in the newborn, increasing the risk of hemorrhagic disease. Management requires careful preconception counseling; if phenytoin must be continued, monotherapy at the lowest effective dose is recommended, with supplemental folic acid (≥1 mg/day) and vitamin K during the last month of pregnancy.

Lactation: Phenytoin is excreted in breast milk in low concentrations (approximately 10-20% of maternal plasma levels). The relative infant dose is considered low, and breastfeeding is generally not contraindicated, though the infant should be monitored for sedation, poor feeding, or rash.

Pediatric Considerations

Children metabolize phenytoin more rapidly than adults, often requiring higher mg/kg doses to achieve therapeutic levels. The saturable pharmacokinetics still apply and must be carefully managed. Intravenous administration must be weight-based and slow (not exceeding 1-3 mg/kg/min). Chronic use in children carries the same risks of gingival hyperplasia, hirsutism, and effects on bone metabolism. Cognitive and behavioral effects should be monitored.

Geriatric Considerations

Elderly patients often have reduced serum albumin, increasing the free fraction of phenytoin. Hepatic metabolism and renal excretion may be diminished. Consequently, lower initial and maintenance doses are typically required. The therapeutic range for total phenytoin may be misleading; monitoring free levels is often more appropriate. Increased sensitivity to CNS side effects like ataxia and sedation is common, increasing fall risk.

Renal and Hepatic Impairment

Renal Impairment: Uremia can decrease protein binding, increasing the free fraction of phenytoin. Total plasma levels may appear normal or low while free levels are toxic. Monitoring free phenytoin concentrations is essential. Dose adjustment is not typically required for reduced renal excretion of the parent drug, but accumulation of the inactive glucuronide metabolite may occur.

Hepatic Impairment: Liver disease impairs the metabolism of phenytoin, potentially leading to accumulation. Hypoalbuminemia, common in liver disease, also increases the free fraction. Both factors significantly increase the risk of toxicity. Dose reduction is necessary, and therapy should be initiated at the low end of the dosing range with close monitoring of free drug levels and clinical signs of toxicity.

Summary/Key Points

• Phenytoin is a first-generation hydantoin anticonvulsant whose primary mechanism is use-dependent blockade of voltage-gated sodium channels, stabilizing neuronal membranes against high-frequency firing.
• Its pharmacokinetics are characterized by saturable (Michaelis-Menten) hepatic metabolism, leading to non-linear kinetics. Small dose increases within the zero-order range can cause disproportionate rises in plasma concentration and toxicity.
• Therapeutic drug monitoring of total (10-20 µg/mL) and, when indicated, free (1-2 µg/mL) phenytoin levels is critical for safe management.
• Major clinical uses include treatment of focal and generalized tonic-clonic seizures, prophylaxis in neurosurgery, and as a second-line agent for status epilepticus (IV formulation).
• Adverse effects are common and include dose-related cerebellar signs (nystagmus, ataxia), chronic effects (gingival hyperplasia, osteomalacia, peripheral neuropathy), and potentially life-threatening idiosyncratic reactions (SJS/TEN, DRESS).
• Phenytoin is a potent inducer of hepatic CYP450 enzymes, decreasing the efficacy of a wide array of drugs (e.g., warfarin, oral contraceptives, many AEDs). Its own metabolism is susceptible to inhibition and induction by other agents.
• Special populations require careful management: it is a teratogen (Pregnancy Category D), elderly patients are more sensitive to CNS effects, and hepatic/renal impairment alters protein binding and metabolism, necessitating free level monitoring.

Clinical Pearls

• When adjusting an oral maintenance dose, changes should generally not exceed 50 mg at a time, and sufficient time (7-10 days) should be allowed to assess the new steady-state level before further adjustment.
• In conditions of hypoalbuminemia (e.g., cirrhosis, nephrotic syndrome) or when a displacing drug like valproate is added, the measured total phenytoin level may be misleadingly low; clinical assessment for toxicity and measurement of free phenytoin are essential.
• Intravenous phenytoin must always be administered slowly (≤50 mg/min in adults) in a large vein with continuous cardiovascular monitoring to avoid hypotension and cardiac arrhythmias related to its propylene glycol vehicle.
• For patients requiring long-term therapy, baseline and periodic monitoring should include a complete blood count, liver function tests, and vitamin D/calcium levels, along with routine dental evaluations for gingival hyperplasia.
• Given the complexity of its pharmacology and the availability of newer agents with fewer interactions and more linear kinetics, the use of phenytoin often requires a clear justification and a commitment to meticulous therapeutic drug monitoring.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.