The resistance seems to be present in all stages of the parasite metabolism. It is possible that gene amplification is the mechanism by which the metabolic block of a pABA inhibitor is overcome. Both of these compounds inhibit the action of dihydrofolate reductase. As with sulfonides, resistance occurs in all stages of the lifecycle. Interestingly, high levels of resistance to sulfonamides is associated with hypersensitivity to antifols, and vice versa, so combination treatments have had good effects.
Resistant parasites seem unable to produce haemozoin, but they are still able to digest haemoglobin.
A diagrammatic representation of chloroquine action is shown below. These drugs must be protected, and used rationally, to prevent the emergence of inevitably resistant P.falciparum for as long as possible. It is obvious, then, that resistance is an ongoing problem. By 1973, chloroquine was replaced by sulfadoxine-pyrimethamine cocktails, but by 1985, this too was ineffective. In this study of patients who were from an area where chloroquine use had long since died out, only one in five of the falciparum infections were truly resistant to chloroquine- presumably due to the lack of selection pressures.