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INTRODUCTION

Methylene blue is an extremely effective antidote for acquired methemoglobinemia. Methylene blue has other actions, including the inhibition of nitric oxide synthase and guanylyl cyclase and the inhibition of the generation of oxygen free radicals. These actions likely explain the beneficial effects of methylene blue in the treatment of refractory hypotension, hepatopulmonary syndrome, priapism, sepsis, and malaria; the modulation of streptozocin-induced insulin deficiency; the prevention and treatment of ifosfamide-induced encephalopathy; and the reduction of the development of postsurgical peritoneal adhesions.15,16,21,24,34,44,53,64

HISTORY

Methylene blue was initially recommended as an intestinal and urinary antiseptic and subsequently recognized as a weak antimalarial.20 In 1933, Williams and Challis successfully used methylene blue for the treatment of aniline-induced methemoglobinemia.69

PHARMACOLOGY

Chemistry

Methylene blue is tetramethylthionine chloride,20 a basic thiazine dye with a molecular weight of 319 Da. It is deep blue in the oxidized state and colorless when reduced to leukomethylene blue.

Mechanisms of Action

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 (Fig. 124–4). Leukomethylene blue effectively reduces methemoglobin to hemoglobin.9,20,65 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 and becomes the most efficient means of methemoglobin reduction.

More recent attention has focused on the ability of methylene blue to reverse refractory hypotension from many causes, including drug overdose, vasoplegia, and sepsis.59,63 Methylene blue inhibits nitric oxide synthase and guanylyl cyclase in vascular smooth muscle. This reduces the amount and effect of nitric oxide. Systemic vascular resistance and cardiac output increase, and the sensitivity of adrenergic receptors to sympathomimetics is enhanced.12,14,27,36,38,68

Pharmacokinetics

The pharmacokinetics of methylene blue were studied in animals and human volunteers after intravenous (IV) and oral administration of 100 mg.9-11,45 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 in healthy volunteers were reached in 1 to 2 hours, but were only approximately 80 to 90 nmol/L, as opposed to 8,000 to 9,000 nmol/L after IV administration.45 Experiments in rats indicated that the substantial differences in whole-blood concentrations achieved by these routes of administration results from extensive first-pass organ distribution into the intestinal wall and liver after oral administration.45 Total urinary excretion at 24 hours accounts for 28.6% of the drug after IV administration compared to 18.5% ...

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