How does methylene blue work in the treatment of methemoglobinemia?

Methylene blue is a drug with many clinical applications, including treatment of infectious diseases such as malaria, a cyanide antidote, a dye for diagnostics, and even has the potential as a therapy for Alzheimer Disease and septic shock. It is indicated for the treatment of drug-induced  methemoglobinemia - an increase in the methemoglobin content of red blood cells (RBCs), caused by oxidation of hemoglobin heme iron atoms by reactive oxygen species such as hydrogen peroxide. Various exogenous agents, including therapeutic drugs, can result in oxidative stress in red blood cells and lead to methemoglobinemia.

Three new pathways have been launched on PharmGKB in order to explain some of the mechanisms and the genes involved in the regulation of oxidative stress in red blood cells (RBCs), including the pharmacodynamics of methylene blue:

1. Pentose Phosphate Pathway (Erythrocyte)
2. Oxidative Stress Regulatory Pathway (Erythrocyte)

3. Methylene Blue Pathway, Pharmacodynamics

Methylene blue itself is an oxidizing agent but is reduced to leukomethylene blue by BLVRB. Leukomethylene blue then reduces methemoglobin to hemoglobin, cycling back to methylene blue. This process requires NADPH from the pentose phosphate pathway and thus is dependent on G6PD. NADPH is also required by many other mechanisms that regulate oxidative stress in RBCs and prevent the formation of methemoglobin.

Pharmacogenetics of methylene blue
Methylene blue is contraindicated in the EU in individuals with a deficiency in BLVRB or G6PD, due to their role in the action of the drug. Cases of adverse events including hemolytic anemia in G6PD deficient individuals treated with methylene blue have been reported - these and the safety of methylene blue are discussed in the methylene blue pathway, PD.