Absorption and Distribution
The gastrointestinal absorption of phenytoin is highly variable. The rate of absorption depends directly on the characteristics of the specific formulation, including the particle size of the active substance and the excipients used. The time to reach maximum concentration ($C_{max}$) in the blood varies widely, ranging from 3 to 12 hours.
Once in the systemic circulation, the drug exhibits a high degree of plasma protein binding—reaching approximately 90%. Because it lacks significant central nervous system depression at standard doses (unlike phenobarbital, for example), the drug can be used in outpatient settings.
Metabolism and Zero-Order Kinetics
Biotransformation of Phenytoinum occurs in the liver. The primary pathway yields a phenylhydantoin derivative—an inactive metabolite—which is subsequently excreted following conjugation with glucuronic acid.
A key metabolic feature is nonlinear pharmacokinetics, or zero-order kinetics. This means hepatic enzyme systems become rapidly saturated.
Clinical Significance: Even a minor increase in dose when enzymes are saturated leads to a sharp, disproportionate spike in blood concentration. This creates a critically high risk of overdose and toxicity. The elimination half-life ($t_{1/2}$) varies from 12 to 36 hours and, as a direct consequence of enzyme saturation, increases as drug concentrations rise. Metabolites are excreted primarily via the kidneys.
Safety Profile and Side Effects
The drug has a broad spectrum of adverse reactions affecting multiple organ systems:
- Neurotoxicity (CNS effects): Patients may experience dizziness, tremor, and agitation. Specific neurological signs of toxicity include nystagmus, ataxia (impaired coordination), and diplopia (double vision).
- Dermatological and Connective Tissue Changes: Hirsutism (excessive male-pattern hair growth) is frequently observed. A unique and highly characteristic side effect of long-term therapy is gingival hyperplasia (overgrowth of gum tissue), which is especially prevalent in younger patients.
- Metabolic Disturbances: The drug can cause folate deficiency, eventually leading to megaloblastic anemia. Normal vitamin D metabolism is also disrupted, predisposing the patient to osteomalacia.
- Gastrointestinal Tract: Dyspeptic symptoms such as nausea and vomiting may occur.
- Fetal Effects: The drug is strictly contraindicated in pregnancy due to its proven teratogenic effect (causing fetal hydantoin syndrome with characteristic congenital malformations).
Drug Interactions
Phenytoin is a potent inducer of hepatic microsomal enzymes. This mechanism underlies the majority of its drug interactions.
By inducing hepatic enzyme systems, the drug significantly accelerates the metabolism of co-administered medications. As a result, the clinical concentrations and efficacy of such agents (e.g., glucocorticoids, estrogens, theophylline) drop sharply, requiring mandatory dosage adjustments.