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INTRODUCTION

Dapsone is an antibiotic used for treatment of and prophylaxis against various infections, including leprosy, malaria, and Pneumocystis carinii pneumonia. The anti-inflammatory and immune-suppressant effects of dapsone make it valuable for the treatment of some rheumatologic and rare dermatologic disorders. A 5% topical formulation is used for treatment of acne vulgaris.

MECHANISM OF TOXICITY

The toxic effects are caused by oxidized cytochrome P450 (CYP) dapsone metabolites, which can lead to methemoglobinemia, sulfhemoglobinemia, and Heinz body hemolytic anemia, decreasing the oxygen-carrying capacity of the blood.

  1. Methemoglobinemia occurs when dapsone metabolites oxidize the ferrous iron–hemoglobin complex to the ferric state.

  2. Sulfhemoglobinemia occurs when dapsone metabolites irreversibly sulfate the pyrrole hemoglobin ring.

  3. Delayed hemolysis secondary to erythrocyte oxidative stress may be preceded by the appearance of Heinz body precipitates on the blood smear.

  4. Pharmacokinetics. Absorption of dapsone after overdose is delayed; peak plasma levels occur between 4 and 8 hours after ingestion. Bioavailability ranges from 84% to 100%. The volume of distribution is 1.5 L/kg, and protein binding is 70–90%. Dapsone is metabolized by two primary routes: acetylation and CYP oxidation. Both dapsone and its acetylated metabolite undergo enterohepatic recirculation and oxidation. Currently, the isoenzymes thought to be primarily responsible for oxidation are CYP2C19 >> CYP2B6 > CYP2D6 > CYP3A4. The average elimination half-life is dose dependent and variable: 10–50 hours with therapeutic doses and potentially more than 77 hours after an overdose (see also Table II–66). Dapsone concentrations persist in the liver and kidneys for up to 3 weeks after discontinuation of treatment.

TOXIC DOSE

Although the adult therapeutic dose ranges from 50 to 300 mg/d, dosing and patient tolerance are limited by toxic effects. Chronic daily dosing of 100 mg can cause methemoglobin levels of 5–12%. Hemolysis has not been reported in adults with doses of less than 300 mg/d. Persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency, congenital hemoglobin abnormalities, or underlying hypoxemia may experience greater toxicity at lower doses. Death has occurred after overdoses of 1.4 g and greater, although recovery from severe toxicity has been reported after ingestion of 7.5 g.

CLINICAL PRESENTATION

Manifestations of acute dapsone intoxication include vomiting, cyanosis, tachypnea, tachycardia, altered or depressed mental status, and seizures. Methemoglobinemia and sulfhemoglobinemia usually are observed within a few hours of the overdose, but intravascular hemolysis may be delayed. The illness lasts several days. Clinical manifestations are more severe in patients with underlying medical conditions that may contribute to hypoxemia.

  1. Methemoglobinemia causes cyanosis and dyspnea. Drawn blood may appear "chocolate" brown when the methemoglobin level is greater than 15–20%. Because of the long half-life of dapsone and its metabolites, methemoglobinemia may persist for several days, requiring repeated antidotal treatment.

  2. Sulfhemoglobinemia also decreases oxyhemoglobin saturation and is unresponsive to methylene blue. Sulfhemoglobinemia can produce a cyanotic appearance at a lower percentage of total hemoglobin compared with methemoglobin, but ...

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