Methaemoglobinaemia
Methaemoglobin results when the haem iron in haemoglobin is converted
from the ferrous state (Fe++), the reduced form, to
the (Fe+++) ferric ion, the oxidized form (20). This
process is coupled to redox cycles in the red cell. In the main cycle,
driven by the NAD-cytochrome b5 reductase (the main methaemoglobin
reductase), haemoglobin and methaemoglobin are cycled (Figure 1). In the
second, a cell redox cycle system is driven by the oxidation of
haemoglobin, with methaemoglobin as the product. Although the main
enzyme responsible for intraerythrocytic methaemoglobin reduction is the
NADH-cytochrome b5-reductase, there are alternative pathways. These
include an NADPH-dependent methaemoglobin reductase (which has
substantially reduced activity in G6PD deficiency), and direct reduction
by intracellular ascorbate and glutathione (Figure 1). Methaemoglobin
reduction is a first order process. Under normal steady state conditions
approximately 3% of the body’s haemoglobin is oxidized each day to
methaemoglobin but, because of back-conversion, the average proportion
of methaemoglobin is less than 2% of the corresponding haemoglobin
concentration. Numerous factors influence this balance (including foods,
drugs, exercise, smoking, hypoxia).
Methaemoglobin is a dark blue-brown colour compared with the bright red
of oxygenated haemoglobin, so the skin colouration in
methaemoglobinaemia resembles that in cyanosis caused by increased
concentrations of deoxygenated haemoglobin. Methaemoglobin has a
distinct spectrum from haemoglobin. Methaemoglobinaemia can be measured
by spectrophotometry of fresh blood samples in the laboratory or,
utilizing the same principle, by continuous transcutaneous oximetry
devices. During exposure to the oxidizing agent methaemoglobinaemia
increases, although there is substantial interindividual variation in
iatrogenic methaemoglobinaemia with a skew distribution of steady state
values. Interquartile ranges typically extend from approximately 60 to
140% of the median values and, for a given drug exposure, individual
values can range tenfold in large series. With daily primaquine dosing
methaemoglobinaemia has an estimated elimination half-life of
approximately 1.5 days (Figure 2) i.e. 90% of the new steady state is
reached in approximately 6 days.
Several different oxidant chemicals and drugs can cause
methaemoglobinaemia. Although methaemoglobin production (i.e. haem
oxidation) by 8-aminoquinolines is generally considered not to lie in
the causal pathway to haemolysis or antimalarial activity (26), it does
provide an approximate correlate of these activities within the
8-aminoquinoline class. Under the rigorous test of the experimental
challenge studies conducted in the USA in the late 1940s and early 1950s
drugs, or drug concentrations, which produced less than 6% steady state
methaemoglobinaemia were associated with sub-optimal radical cure rates
(23-25) (Figure 3). As for iatrogenic haemolysis, there is a slight
delay before intraerythrocytic methaemoglobin levels begin to rise
following 8-aminoquinoline administration. This presumably reflects
depletion of the oxidant defences (notably reduced glutathione) (27). In
a large recent study of vivax malaria conducted on the Thailand-Myanmar
border the relationships between primaquine and carboxyprimaquine plasma
concentrations, relapses, CYP2D6 polymorphisms and methaemoglobinaemia
were investigated. After adjusting for age and partner drug, the day 7
concentrations of primaquine and carboxyprimaquine were not associated
with the risk of recurrence, but a 1% absolute increase in day 7
methemoglobin was associated with a hazard ratio for recurrence of 0.9
(95% CI: 0.85-0.99, p=0.02) (28).
Tafenoquine is a slowly eliminated 8-aminoquinoline which has been
introduced recently. It is notable that the currently recommended dose
of tafenoquine (adult dose 300mg), which provides radical cure rates
which are inferior to the lower dose of primaquine (total dose 3.5mg/kg)
in South-East Asia (29), is associated with methaemoglobin
concentrations which are less than half those associated with the lower
dose primaquine regimen (30,31) (Figure 4).