Phenytoin Toxicity

Mechanism of action

Phenytoin blocks voltage-sensitive sodium channels in neurons. This action leads to a delay in neuronal electrical recovery from inactivation. ^[1] Phenytoin's inhibitory effect is dependent on the voltage and frequency of neural cell firing by selectively blocking the neurons that are firing at high frequency. Phenytoin prevents the electrical spread of a focus of irritable tissue from entering normal tissue.

Phenytoin administration has been associated with toxic effects. Phenytoin toxicity depends on the route of administration, duration, exposure, and dosage. The route of administration is the most important determinant of toxicity. Phenytoin may be administered orally or intravenously. In addition, fosphenytoin (water-soluble phenytoin prodrug) may be administered intramuscularly.

Pharmacokinetics

Phenytoin is a weak acid and has erratic GI absorption. Following ingestion, phenytoin precipitates in the stomach's acid environment; this characteristic is particularly important in the setting of an intentional overdose. Peak blood levels occur 3-12 hours following single dose ingestion, but absorption can be extended up to 2 weeks, especially in massive overdose. Oral exposures are associated predominantly with CNS symptoms.

The parenteral form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol and adjusted to a pH of 12; sodium hydroxide is added to maintain solubility. Extravasation of the solution may cause skin irritation or phlebitis. Phenytoin administered intravenously at a rate higher than 50 mg/min may cause hypotension and arrhythmias. These complications are believed to be secondary to the diluent, propylene glycol. However, cardiac toxicity was reported even after rapid administration of fosphenytoin that does not contain propylene glycol, suggesting intrinsic phenytoin cardiac toxicity. Orally administered phenytoin is rarely, if ever, associated with cardiac toxicity.

Phenytoin has a small volume of distribution of 0.6 L/kg and is extensively bound to plasma proteins (90%). Blood levels of phenytoin reflect only total serum concentration of the drug. Only the free unbound phenytoin has biological activity. Because CNS tissue levels are higher than in serum, levels may underestimate CNS concentrations of phenytoin. ^[2]

Population groups that are predisposed to elevated free phenytoin levels include neonates, elderly persons, and individuals with uremia, hypoalbuminemia (due to pregnancy, nephrotic syndrome, malignancy, malnutrition), or hyperbilirubinemia. These patients may exhibit signs of toxicity when drug levels are within the therapeutic range (see Lab Studies). Certain medications can interfere with phenytoin levels.

Hepatic microsomal enzymes primarily metabolize phenytoin. Much of the drug is excreted in the bile as an inactive metabolite, which is then reabsorbed from the intestinal tract and ultimately excreted in the urine. Less than 5% of phenytoin is excreted unchanged in the urine. Individuals with impaired metabolic or excretory pathways may exhibit early signs of toxicity. Genetic polymorphism in the cytochrome enzymes that metabolize phenytoin may be responsible for variable rates of metabolism and thus susceptibility to toxicity, even in individuals taking appropriate doses. ^{[3, 4]}

Phenytoin metabolism is dose dependent. Elimination follows first-order kinetics (fixed percentage of drug metabolized during a per unit time) at the low drug concentrations and zero-order kinetics (fixed amount of drug metabolized per unit time) at higher drug concentrations. This change in kinetics reflects the saturation of metabolic pathways. Thus, very small increments in dosage may result in adverse effects.

In the 2021 Annual Report of the American Association of Poison Control Centers' National Poison Data System, 872 single exposures to phenytoin were reported. Of these, 527 were unintentional toxicities, 284 were intentional, and 342 were reported as an adverse reaction. In addition, four single exposures to fosphenytoin were reported, two as major adverse reactions and two as unintentional. ^[5]

Phenytoin is a category D drug. Various congenital anomalies have been reported from usage during pregnancy (see fetal hydantoin syndrome). No scientific data have demonstrated that effect or outcome of acute toxicity is based on sex.

Neonates and elderly patients are at greater risk for toxicity because of impaired metabolism and decreased protein binding. Decreased protein binding contributes to higher levels of biologically active medication at therapeutic measured total phenytoin blood levels (see Lab Studies).

Of the 872 reported exposures to phenytoin in 2021, a total of 24 were in children younger than 6 years, 20 in patients 6-19 years of age, and 804 in those 20 years and older. ^[5]

Death or severe morbidity rarely occurs with an intentional overdose as long as the patient receives good supportive care. Of the 872 reported toxic exposures to phenytoin in 2021, 735 were treated in a health care facility. Of this subset of patients, 77 had no significant outcome, 282 had minor effects, 274 had moderate morbidity, and 37 had major morbidity; two deaths were reported. ^[5]

The most common complications involve undiagnosed injuries sustained as a result of the phenytoin-induced ataxia.

Movement disorders have been associated with phenytoin use including dyskinesia, myoclonus -asterixis, dystonia, parkinsonism, tics, and restless leg syndrome. ^[6]