Phenytoin

Drug absorption and distribution

The absorption process of phenytoin from the gastrointestinal tract proceeds with high variability. The rate of absorption directly depends on the characteristics of the specific dosage form, including the particle size of the active substance and the excipients used. The time to reach maximum concentration ($C_{max}$) in the blood varies over a very wide range and can be from 3 to 12 hours.

Upon entering the systemic circulation, the drug is characterized by a high degree of binding to plasma transport proteins—this figure reaches approximately 90%. Due to the absence of a pronounced depressant effect on consciousness (unlike, for example, phenobarbital), the drug can be used in outpatient practice.

Metabolism and zero-order kinetics

Biotransformation of Phenytoinum occurs in the liver. The main result of this process is the formation of a phenylhydantoin derivative, an inactive metabolite, which is subsequently excreted from the body after a conjugation reaction with glucuronic acid.

A key feature of metabolism is nonlinear pharmacokinetics, or zero-order kinetics. This means that the liver enzyme systems are extremely rapidly saturated with the substrate.

Clinical significance: Even a slight increase in the drug dose under conditions of saturated enzyme systems leads to a sharp spike in its blood concentration. This creates a critically high risk of overdose and the development of toxic reactions. The half-life ($t_{1/2}$) ranges from 12 to 36 hours and, as a direct consequence of enzyme saturation, increases as the concentration of the drug in the blood rises. The main route of metabolite excretion is via the kidneys.

Safety profile and adverse effects

The drug has a wide range of adverse reactions affecting various organ systems.

• Neurotoxicity (CNS effects): patients may experience dizziness, tremor, and psychomotor agitation. Specific neurological symptoms of toxicity include nystagmus, ataxia (loss of coordination), and diplopia (double vision).
• Dermatological and connective tissue changes: hirsutism (excessive male-pattern hair growth) is frequently observed. A unique and very characteristic effect of long-term administration is hyperplastic gingivitis (overgrowth of gingival tissue), which is especially common in young patients.
• Metabolic disorders: the drug can cause folate deficiency, which eventually leads to the development of megaloblastic anemia. Normal vitamin D metabolism is also disrupted, which is fraught with osteomalacia.
• Gastrointestinal tract: dyspeptic symptoms such as nausea and vomiting are possible.
• Effects on the fetus: the drug is strictly not recommended during pregnancy due to proven teratogenic effects (the formation of fetal hydantoin syndrome with malformations).

Drug interactions

Phenytoin is known as a potent inducer of hepatic microsomal enzymes. This mechanism forms the basis of most of its drug interactions.

Due to the induction of hepatic enzyme systems, the drug significantly accelerates the metabolism of co-administered medications. As a result, the clinical concentration and efficacy of such agents (e.g., glucocorticoids, estrogens, theophylline) in the blood drop sharply, which requires mandatory adjustment of their dosages.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The effect of particle size and excipients on the absorption of phenytoin dosage forms
• The mechanism of conjugation of the inactive metabolite with glucuronic acid
• The pathogenesis of megaloblastic anemia development against the background of folate deficiency
• Clinical manifestations of fetal hydantoin syndrome in newborns
• Dose adjustment of estrogens and glucocorticoids when co-administered with enzyme inducers

Other topics in the section "Agents Used in Psychiatry and Neurology"

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