Mode of Action of Antimalarial Drugs

Chloroquine, quinine, quinacrine and related drugs are effective antimalarial agents only against parasites that degrade haemoglobin. This fact prompted an examination of the role of ferriprotoporphyrin IX (FP), a product of haemoglobin degradation, in the mode of action of chloroquine. FP was identified as a high affinity drug receptor of malaria parasites by showing that it has the appropriate affinity for chloroquine, with a dissociation constant on the order of 10(-8) M, and specificity for amodiaquine, quinacrine, quinine and mefloquine. Moreover, FP and its complex with chloroquine impair the ability of cell membranes to maintain cation gradients, and they lyse normal erythrocytes, Plasmodium berghei and P. falciparum. The amount of FP required for lysis is less than 0.1% of the haem in erythrocytic haemoglobin. Recently, evidence has been obtained that FP in the parasite forms transient, non-toxic complexes with cytoplasmic haem binders and that FP in this form can interact with chloroquine. Thus, chloroquine and related drugs may act as antimalarial agents by shunting FP away from natural haem binders and into toxic drug-FP complexes. In addition FP released from haemoglobin, either spontaneously or by oxidant drugs, may contribute to haemolysis and protection against malaria in patients with Heinz body haemolytic anaemias.