Antimalarial Drugs

For a drug to be effective, it must be present in appropriate concentrations at its site of action. There are various factors influencing the effective concentration of a drug. Firstly, it is a factor of the dose administered and secondly, it also depends on the extent and rate of its absorption, distribution, binding, biotransformation and excretion (Benet et al, 1985).

Antimalarial drugs can be divided into three basic groups according to their mechanism of action. The first is the quinine-type of derivatives. Drugs in this group include the older agents like quinine, primaquine and chloroquine, in addition to relatively newer agents like mefloquine. The pharmacological action of these drugs is directed against the food vacuole of the malaria parasite (Krogstad et al, 1985).

Antimalarial drugs such as chloroquine and mefloquine that are given to cure malaria infections do not eliminate mature Plasmodium falciparum gametocytes from the bloodstream. A person who has been successfully treated with schizontocidal antimalarial drugs may thus be healthy but infective for on average two months until the gametocytes die off naturally, or until another drug such as primaquine is given that does eliminate the gametocytes.

Resistance to the quinine-type of drugs is mostly a result of the ability of the parasite to prevent the intracellular accumulation of these drugs to toxic levels. At least two MDR (multidrug-resistant) efflux pumps, implicated in resistance to quinine-compounds have been identified and characterised (pfmdr1 and pfmdr2; Krogstad et al, 1987; Cowman, 1991). These transporters play an important but not exclusive role in the acquisition of chloroquine resistance by the parasite. The locus of chloroquine resistance has since been mapped to a 40kb region on chromosome 7 (Wellems et al, 1990; Wellems et al, 1991; Wellems, 1992). Recently Wellems and Plowe showed that chloroquine resistance is associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively (Djimde et al, 2001).

The second group of drugs is directed against the folate-metabolism of the parasite. Pyrimethamine, its derivatives, chloroguanides as well as sulphonamides and sulphones are examples of drugs in this group. The mechanism of action of this group of drugs is clearly defined. Agents in this group interfere either with the incorporation of p-aminobenzoate into folate (inhibitors of the folate biosynthesis) or bind to and inhibit dihydrofolate reductase-thimidylate synthetase (DHFR-TS; Peterson et al, 1990; Basco et al, 1995b).

The last group comprises the newer compounds like artheter and artemisinin. The mechanism of their action is as yet largely unknown. It has however been postulated that the action of artemisinin is due to its interaction with hemozoin. Hemozoin is the polymerised form of haem released from red cell haemoglobin, found in the parasite food vacuole when the protein part of the haemoglobin is digested to serve as amino acid source for the malaria parasite (Hong, 1994).