Methaemoglobinaemia and G6PD deficiency
The discrepancy between 8-aminoquinoline haemolytic toxicity and
methaemoglobinemia has been noted widely (26). In the research which led
to registration of primaquine, Edgcomb et al (24) noted no correlation
between haemolysis and methaemoglobinaemia following pamaquine or
primaquine. The erythrocytes in G6PD deficiency have a reduced ability
to reduce methaemoglobin in the presence of “electron-donors”, such as
the bioactive metabolites of primaquine or methylene blue (this is the
basis of the methylene blue methaemoglobin reduction test developed to
diagnose G6PD deficiency). This is because of the reduced
intraerythrocytic activity of the NADPH dependent methemoglobin
reductase. Brewer et al showed that whereas G6PD deficient individuals
had increased levels of methaemoglobinaemia following oral sodium
nitrite (an oxidizing agent which does not cause haemolysis), they haddecreased levels of methaemoglobinemia following primaquine (26)
(Figure 7). This apparent paradox was explained by the iatrogenic
haemolysis of the older erythrocytes which contained the highest
concentrations of methaemoglobin. Other mechanisms are also possible,
such as the sequestration of the primaquine oxidant metabolites in the
oxidized haemoglobin Heinz bodies. The mechanism of 8-aminoquinoline
haemolytic toxicity has not been explained satisfactorily but clearly
involves more than broad oxidant stress.