Phenytoin Monograph

Introduction

Phenytoin is a phenylhydantoin derivative that constitutes a cornerstone in the management of generalized and focal seizures. The compound has been in clinical use since the 1930s and remains integral to antiepileptic therapy due to its efficacy and unique pharmacodynamic profile. Historically, phenytoin was discovered during the search for anticonvulsant agents that could address refractory seizure activity, and its introduction marked a significant advancement in seizure control. The importance of understanding phenytoin lies in its narrow therapeutic index, nonlinear pharmacokinetics, and extensive interaction potential, which collectively necessitate vigilant monitoring in clinical practice.

Learning objectives contained within this chapter include:

• Describe the chemical structure, mechanism of action, and historical development of phenytoin.
• Explain the pharmacokinetic parameters, including absorption, distribution, metabolism, and excretion, with emphasis on nonlinear elimination.
• Identify common drug–drug interactions and genetic factors influencing phenytoin therapy.
• Apply therapeutic drug monitoring (TDM) principles to optimize dosing and minimize toxicity.
• Interpret clinical case scenarios to illustrate practical decision‑making in antiepileptic management.

Fundamental Principles

Core Concepts and Definitions

Phenytoin is classified as a non‑sulphonyl anticonvulsant. Its therapeutic action is primarily mediated through voltage‑gated sodium channel blockade, which stabilizes neuronal membranes and reduces excitability. The term therapeutic window refers to the concentration range between the minimum effective concentration (C_min) and the concentration associated with significant adverse effects (C_max). For phenytoin, C_min is approximately 5–10 µg/mL, while C_max may exceed 20 µg/mL, indicating a narrow therapeutic index.

The drug exhibits zero‑order kinetics at therapeutic concentrations, meaning that the rate of elimination remains constant regardless of plasma concentration. This contrasts with first‑order kinetics, where elimination rate is proportional to concentration. Zero‑order behavior arises from saturation of the metabolizing enzyme system, primarily cytochrome P450 2C9 (CYP2C9).

Theoretical Foundations

Pharmacokinetic principles governing phenytoin involve the following relationships:

• Absorption: After oral administration, phenytoin displays variable bioavailability (F) due to first‑pass metabolism and intestinal auto‑induction. The absorption rate constant (k_a) is typically 0.5 h⁻¹.
• Distribution: The drug has a large volume of distribution (V_d) of 10–20 L/kg, reflecting extensive tissue binding, particularly to plasma proteins such as albumin. The concentration in plasma (C) can be described by C = (F × Dose) ÷ (V_d × (1 – e^–k_elt)).
• Metabolism: Hepatic metabolism predominates, with CYP2C9 and CYP2C19 contributing to the oxidative pathway. The intrinsic clearance (CL_int) is limited, and the hepatic clearance (CL_hep) is given by CL_hep = (f_u × CL_int) ÷ (1 + (f_u × CL_int) ÷ Q_h), where f_u is the unbound fraction and Q_h is hepatic blood flow.
• Elimination: The overall clearance (CL) is reduced by auto‑induction, and the terminal half‑life (t_1/2) is prolonged, often ranging from 8 to 25 h depending on dose and patient factors.

Mathematical modeling of phenytoin pharmacokinetics frequently employs the Michaelis–Menten equation to account for saturable metabolism:

Rate of metabolism = (V_max × C) ÷ (K_m + C)

Here, V_max represents the maximum metabolic rate, and K_m is the concentration at which metabolism proceeds at half its maximum rate.

Key Terminology

• Auto‑induction: The phenomenon whereby phenytoin increases its own metabolism over time, leading to decreased plasma concentrations.
• Therapeutic drug monitoring (TDM): The systematic measurement and interpretation of drug concentrations in biological fluids to guide dosing.
• Genotype‑phenotype correlation: The relationship between CYP2C9 polymorphisms and phenytoin clearance rates.
• Drug–drug interaction (DDI): Any clinically significant alteration in phenytoin pharmacokinetics due to concomitant medications.
• Protein binding: The proportion of phenytoin that is attached to plasma proteins; only the unbound fraction is pharmacologically active.

Detailed Explanation

Pharmacodynamic Mechanisms

Phenytoin exerts its anticonvulsant effect by preferentially binding to the inactivated state of voltage‑gated sodium channels. This binding prolongs the inactivation period, thereby reducing the frequency and amplitude of action potentials. The drug also modulates calcium channel activity and inhibits the release of excitatory neurotransmitters such as glutamate. At higher concentrations, phenytoin may interact with GABAergic pathways, contributing to its overall inhibitory effect on neuronal firing.

Absorption and Bioavailability

After oral dosing, phenytoin is absorbed in the proximal small intestine. However, absorption is saturable, and the bioavailability is reduced at higher doses. The apparent dissolution rate (k_h) and the dissolution saturation constant (K_sol) influence the overall absorption profile. The equation describing absorption kinetics is:

C(t) = (F × Dose) ÷ (V_d × (1 – e^–k_elt)) × (1 – e^–k_at)

Distribution Characteristics

Phenytoin’s high lipophilicity facilitates distribution into the central nervous system (CNS). The drug partitions into adipose tissue, resulting in a prolonged half‑life. Protein binding is concentration‑dependent; at therapeutic concentrations, approximately 90–95 % of phenytoin is bound to albumin, whereas at higher concentrations (>20 µg/mL), binding may reach 99 %.

Metabolic Pathways

Hepatic metabolism is the primary elimination route. The oxidative pathway involves the cytochrome P450 system, with CYP2C9 being the major isoenzyme responsible for converting phenytoin to inactive metabolites. The rate of metabolism can be described by the Michaelis–Menten equation, where V_max is approximately 20 mg/h and K_m is 10 µg/mL. The saturation of CYP2C9 at therapeutic concentrations leads to zero‑order kinetics.

Elimination and Clearance

The total clearance (CL) of phenytoin is influenced by hepatic blood flow (Q_h), intrinsic clearance (CL_int), and the fraction unbound (f_u). The following relationship is commonly used:

CL = (f_u × CL_int) ÷ (1 + (f_u × CL_int) ÷ Q_h)

Auto‑induction reduces CL by increasing CL_int over time, resulting in a decreased half‑life. Conversely, inhibition of CYP2C9 by concomitant drugs can reduce CL and prolong t_1/2.

Factors Affecting Pharmacokinetics

• Age: Pediatric patients may exhibit higher clearance rates due to increased metabolic capacity, whereas elderly patients may have reduced clearance.
• Genetics: Polymorphisms in CYP2C9 (*2, *3 alleles) can lead to reduced enzymatic activity, requiring lower doses.
• Protein Binding Alterations: Hypoalbuminemia, competing drugs (e.g., valproic acid), or acidic gastrointestinal conditions may increase the free fraction, thereby increasing toxicity risk.
• Auto‑Induction: Sustained therapy leads to increased metabolic enzyme expression, decreasing plasma concentrations over time.
• Drug Interactions: Concomitant use of enzyme inducers (e.g., carbamazepine) or inhibitors (e.g., fluconazole) can significantly modify phenytoin levels.

Clinical Significance

Relevance to Drug Therapy

Phenytoin remains a first‑line agent for various seizure types, including tonic–clonic, myoclonic, and partial seizures. Its efficacy, however, is tempered by its narrow therapeutic index and complex pharmacokinetics. Clinicians must balance effective seizure control with the risk of adverse effects such as nystagmus, ataxia, and gingival hyperplasia. Additionally, phenytoin’s interaction profile can complicate polypharmacy regimens commonly encountered in patients with comorbid conditions.

Practical Applications

Therapeutic drug monitoring (TDM) is indispensable for phenytoin management. The standard approach involves measuring trough concentrations at steady state, typically 12–16 h after dosing. Adjustments are guided by the following approximate relationships:

• Increase dose by 10 mg/kg/week for a 2 µg/mL rise in concentration.
• Decrease dose by 10 mg/kg/week for a 2 µg/mL drop.
• Consider a 5–10 mg/kg dose increment when initiating therapy, followed by gradual titration.

Because of the nonlinear kinetics, small dose changes may produce disproportionate concentration changes, necessitating cautious titration.

Clinical Examples

Case 1: A 35‑year‑old male with newly diagnosed generalized tonic–clonic seizures begins phenytoin therapy at 300 mg daily. After 4 weeks, the serum concentration is 18 µg/mL, exceeding the therapeutic range. The clinician reduces the dose to 250 mg and monitors levels. The concentration falls to 12 µg/mL within 2 weeks, achieving seizure control without toxicity.

Case 2: A 60‑year‑old female with epilepsy and chronic kidney disease is on phenytoin 200 mg daily. She develops nystagmus and ataxia. Serum concentration is 22 µg/mL. The dose is reduced to 150 mg, and the patient’s symptoms resolve. This illustrates the importance of monitoring in patients with altered protein binding or reduced clearance due to comorbidities.

Clinical Applications/Examples

Case Scenario 1: Pediatric Seizure Management

A 7‑year‑old boy presents with newly diagnosed focal seizures. Initial dose of phenytoin is 15 mg/kg/day divided into two doses. After 2 weeks, the serum concentration is 9 µg/mL, and seizures persist. The dose is increased by 5 mg/kg/day. Subsequent monitoring shows a concentration of 14 µg/mL, achieving seizure control. This scenario demonstrates the need for individualized dosing and the role of TDM in pediatric patients.

Case Scenario 2: Drug Interaction with Valproic Acid

A 45‑year‑old woman with bipolar disorder and epilepsy is on valproic acid 500 mg/day and phenytoin 200 mg/day. She reports new-onset slurred speech. Serum phenytoin concentration is 18 µg/mL. The clinician reduces phenytoin to 150 mg and observes improvement. Valproic acid displaces phenytoin from protein binding sites, increasing the free fraction and toxicity risk. This case underscores the necessity of monitoring when combining antiepileptics.

Problem‑Solving Approach to Dose Adjustments

1. Confirm steady‑state trough concentration.
2. Assess therapeutic and toxic thresholds.
3. Calculate dose adjustment using the proportional relationship between dose and concentration.
4. Re‑measure after 1–2 weeks to confirm target range.
5. Consider genetic testing for CYP2C9 polymorphisms if unexpected responses occur.

Summary/Key Points

• Phenytoin is a phenylhydantoin antiepileptic with a narrow therapeutic window and nonlinear pharmacokinetics.
• Zero‑order elimination arises from saturation of CYP2C9, leading to concentration‑dependent clearance.
• Therapeutic drug monitoring is essential; trough concentrations should remain within 5–10 µg/mL.
• Auto‑induction reduces plasma concentrations over time, necessitating dose adjustments.
• Drug interactions, particularly with enzyme inducers or inhibitors, can drastically alter phenytoin levels.
• Genetic polymorphisms in CYP2C9 can influence metabolism, requiring individualized dosing strategies.
• Clinical pearls: small dose changes may produce large concentration shifts; always re‑measure after adjustments; monitor for signs of toxicity such as ataxia and nystagmus.

References

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