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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 was approved for treatment of acne vulgaris in the United States in 2005.

  1. Mechanism of toxicity. The toxic effects are caused by oxidized cytochrome P-450 (CYP) dapsone metabolites, which can cause methemoglobinemia, sulfhemoglobinemia, and Heinz body hemolytic anemia, all of which decrease the oxygen-carrying capacity of the blood.

    1. Dapsone metabolites oxidize the ferrous iron–hemoglobin complex to the ferric state, resulting in methemoglobinemia.

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

    3. Metabolic oxidative stress of the erythrocyte may be visualized with Heinz body precipitates before hemolysis.

    4. Pharmacokinetics. Absorption of dapsone after overdose is delayed; peak plasma levels occur between 4 and 8 hours after ingestion. 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: 14–30 hours with therapeutic doses and potentially more than 77 hours after an overdose (see also Table II–61).

  2. 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 with overdoses of 1.4 g and greater, although recovery from severe toxicity has been reported after ingestion of 7.5 g.

  3. 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 of 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 (See 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 the amount of sulfhemoglobin generated is rarely more than 5%.

    3. Hemolysis may be delayed in onset, usually 2–3 days after acute overdose.

  4. Diagnosis. Overdose should be suspected in cyanotic patients with elevated methemoglobin levels, especially if there is a history of dapsone use or a diagnosis ...

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