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Methylene blue is an extremely effective antidote for acquired methemoglobinemia. Methylene blue also has other actions, including inhibition of nitric oxide synthase and guanylyl cyclase, and inhibition of the generation of oxygen free radicals. These effects are offered as explanations of the beneficial effects of methylene blue in the hepatopulmonary syndrome, treatment of priapism, modulation of streptozocin-induced insulin deficiency, prevention and treatment of ifosfamide-induced encephalopathy, use in sepsis, treatment of refractory hypotension, and reduction of development of postsurgical peritoneal adhesions.14,15,19,22,28,34,42,50

Methylene blue was initially recommended as an intestinal and urinary antiseptic and subsequently recognized as a weak antimalarial.18 In 1933, Williams and Challis successfully used methylene blue for treatment of aniline-induced methemoglobinemia.54

Methylene blue is tetramethylthionine chloride,18 a basic thiazin dye. Methylene blue is an oxidizing agent, which, in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and NADPH methemoglobin reductase, is reduced to leukomethylene blue (see Fig. 127–4). Leukomethylene blue then becomes available to reduce methemoglobin to hemoglobin.10,18,51 Reduction of methemoglobin via this NADPH pathway is limited under normal circumstances. However, in the presence of methylene blue, the role of the NADPH pathway is dramatically increased (four to five times in dogs) and becomes the most efficient means of methemoglobin reduction. This property makes methylene blue the treatment of choice for methemoglobinemia.

The pharmacokinetics of methylene blue were studied in animals and human volunteers following intravenous (IV) and oral administration of 100 mg.10–12,35 Methylene blue exhibits complex pharmacokinetics consistent with extensive distribution into deep compartments, followed by a slower terminal elimination with a half-life of 5.25 hours. Peak concentrations after oral administration were reached in 1 to 2 hours, but were approximately 80 to 90 nmol/L, as opposed to 8000 to 9000 nmol/L following IV administration. The substantial differences in whole-blood concentrations achieved by these routes of administration can be attributed to extensive first-pass organ distribution into the intestinal wall and liver, following oral administration.35 Total urinary excretion at 24 hours accounts for 28.6% of the drug following IV administration versus 18.5% after oral administration. In both cases, one-third was in the leukomethylene blue form.

Reports of the paradoxical induction of methemoglobinemia by methylene blue suggest an equilibrium between the direct oxidization of hemoglobin to methemoglobin by methylene blue and its ability (through the NADPH and NADPH-methemoglobin-reductase pathway, and leukomethylene blue production) to reduce methemoglobin to hemoglobin.5,6 Methylene blue does not produce methemoglobin at doses of 1 to 2 mg/kg. The equilibrium seems to favor the reducing properties of methylene blue, unless excessively large doses of methylene blue are administered4,17,53 or the NADPH methemoglobin reductase system is abnormal. This equilibrium constant may vary substantially, as 20 mg/kg IV in dogs and 65 mg/kg intraperitoneally in rats failed to produce methemoglobinemia.45 In the earliest studies, 50 to 100 mL of a ...

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