*CYP, cytochrome P450; UGT, UDP-glucuronosyltransferase.

*CYP, cytochrome P450; UGT, UDP-glucuronosyltransferase.

TOXICITY The toxic effects of phenytoin depend on the route of administration, the duration of exposure, and the dosage.

When fosphenytoin is administered intravenously at an excessive rate in the emergency treatment of status epilepticus, the most notable toxic signs are cardiac arrhythmias, with or without hypotension, and/or CNS depression. Cardiac toxicity occurs more frequently in older patients and in those with known cardiac disease but also can develop in young, healthy patients. These complications can be minimized by administering fosphenytoin at a rate of <150 mg of phenytoin sodium equivalent per minute. Acute oral overdosage results primarily in signs referable to the cerebellum and vestibular system; high doses have been associated with marked cerebellar atrophy. Toxic effects associated with chronic treatment also are primarily dose-related cerebellar-vestibular effects but also include other CNS effects, behavioral changes, increased seizures frequency, gastrointestinal (GI) symptoms, gingival hyperplasia, osteomalacia, and megaloblastic anemia. Hirsutism is an annoying untoward effect in young females. Usually, these phenomena can be diminished by proper adjustment of dosage. Serious adverse effects, including those on the skin, bone marrow, and liver, probably are manifestations of rare drug allergy and necessitate drug withdrawal. Moderate elevation of hepatic transaminases sometimes is observed; since these changes are transient and may result in part from induced synthesis of the enzymes, they do not necessitate drug withdrawal.

Gingival hyperplasia, apparently due to altered collagen metabolism, occurs in ~20% of patients during chronic therapy and is probably the most common toxicity in children and young adolescents. It may be more frequent in individuals who also develop coarsened facial features. Toothless portions of the gums are not affected. The condition does not necessarily require withdrawal of medication and can be minimized by good oral hygiene.

A variety of endocrine effects have been reported. Inhibition of vasopressin release has been observed in patients with inappropriate secretion of this hormone. Hyperglycemia and glycosuria appear to be due to inhibition of insulin secretion. Osteomalacia has been attributed to altered metabolism of vitamin D and the attendant inhibition of intestinal Ca2+absorption. Phenytoin also increases the metabolism of vitamin K and reduces the concentration of vitamin K—dependent proteins that are important for normal Ca2+ metabolism in bone, perhaps explaining why the osteomalacia does not always respond to vitamin D.

Hypersensitivity reactions include morbilliform rash in 2—5% of patients and occasionally more serious skin reactions, including Stevens-Johnson syndrome. Systemic lupus erythematosus and potentially fatal hepatic necrosis have been reported rarely. Hematological reactions include neutropenia and leucopenia, or more rarely, red-cell aplasia, agranulocytosis, and thrombocy-topenia. Lymphadenopathy is associated with reduced immunoglobulin A (IgA) production. Hypoprothrombinemia and hemorrhage have occurred in the newborns of mothers who received phenytoin during pregnancy; vitamin K is effective treatment or prophylaxis.

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