A42: Antidotes in Depth

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 may explain the beneficial effects of methylene blue in the treatment of refractory hypotension, hepatopulmonary syndrome, treatment of priapism, modulation of streptozocin-induced insulin deficiency, prevention and treatment of ifosfamide-induced encephalopathy, in the treatment of sepsis, and the reduction of the development of postsurgical peritoneal adhesions.^{15,16,21,25,34,44,52,59}

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 treatment of aniline-induced methemoglobinemia.⁶⁴

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. 127–4). Leukomethylene blue then becomes available to reduce methemoglobin to hemoglobin.^9,20,60 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.

Recently, attention has focused on the ability of methylene blue to reverse refractory hypotension due to many causes including drug overdose, vasoplegia, and sepsis. 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.^{12,14,36,27,38,63}

Pharmacokinetics

The pharmacokinetics of methylene blue were studied in animals and human volunteers following intravenous (IV) and oral administration of 100 mg.^{9, 10, and 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 were reached in 1 to 2 hours, but were only 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, compared with 18.5% ...