Hemolysis is the most common untoward reaction and develops in almost every individual treated with 200-300 mg of dapsone per day. Doses of 100 mg or less in normal healthy persons and 50 mg or less in healthy individuals with glucose-6-phosphate dehydrogenase deficiency do not cause hemolysis. Methemoglobinemia also is common. A genetic deficiency in the NADH-dependent methemoglobin reductase can result in severe methemoglobinemia after dapsone administration. While diminished red-cell survival usually occurs during the use of sulfones—presumably a dose-related effect of their oxidizing activity—hemolytic anemia is unusual unless the patient also has a disorder of either the erythrocytes or the bone marrow. The hemolysis may be so severe that manifestations of hypoxia become striking.
Anorexia, nausea, and vomiting may follow oral administration of sulfones. Isolated instances of headache, nervousness, insomnia, blurred vision, paresthesias, reversible peripheral neuropathy, drug fever, hematuria, pruritus, psychosis, and a variety of rashes have been reported. An infectious mononucleosis-like syndrome occurs occasionally. The sulfones may induce an exacerbation of lepromatous leprosy by a process analogous to the Jarisch-Herxheimer reaction. This "sulfone syndrome" may develop 5-6 weeks after initiation of treatment. Its manifestations include fever, malaise, exfoliative dermatitis, jaundice with hepatic necrosis, lymphadenopathy, methemoglobinemia, and anemia.
Used properly, the sulfones may be given safely for many years in doses adequate for the successful therapy of leprosy. Treatment should be initiated with a small dose and then increased gradually. Patients must be under consistent laboratory and clinical supervision. The reactions induced by the sulfones, especially those related to the "sulfone syndrome," may require the cessation of treatment as well as the institution of specific measures to reduce the threat to life.
ABSORPTION, DISTRIBUTION, AND EXCRETION
Dapsone is absorbed rapidly and nearly completely from the GI tract. Di-substituted sulfones (e.g., sulfoxone) are absorbed incompletely when administered orally and largely excreted in the feces. Peak concentrations of dapsone in plasma are reached within 2-8 hours after administration; the mean t/2 is ~20-30 hours. About 70% of the drug is bound to plasma protein.
The sulfones are distributed throughout total body water and are present in all tissues. They are retained in skin and muscle and especially in liver and kidney. The sulfones persist in the circulation for a long time because of reabsorption from the bile; periodic interruption of treatment is advisable for this reason. Dapsone is acetylated in the liver by the same enzyme that acetylates isoniazid. Daily administration of50-100 mg results in serum levels exceeding the usual minimal inhibitory concentrations, even in rapid acetylators, in whom the serum t/2 of dapsone is shorter than usual.
Approximately 70-80% of a dose of dapsone is excreted in the urine as an acid-labile mono-N-glucuronide and mono-N-sulfamate.
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