response primed by repeated previous malaria infections—the number of parasites will increase with every 2-day cycle of reproduction. A mature infection may involve up to 1012 circulating plasmodia.
At any time after the infection is established, the vast majority of plasmodia will be in some stage of asexual maturation leading to another round of multiplication within the patient’s bloodstream. However, a few parasites will have transformed into sexual stages (gametocytes) that, once ingested by mosquitoes, can perpetuate the transmission cycle. Because each stage of the malarial life cycle exhibits distinct biochemical and other characteristics (i.e., it expresses different proteins or locates in different sites within the body), a drug may kill one stage but have little effect on another. In other words, in each life-cycle stage the parasite manifests unique biological properties that can offer a target for the action of one or more antimalarial drugs.
Currently available antimalarials fall into three broad categories according to their chemical structure and mode of action (Appendix 9-A):
Aryl aminoalcohol compounds: quinine, quinidine, chloroquine, amodiaquine, mefloquine, halofantrine, lumefantrine, piperaquine, tafenoquine
Antifolate compounds (“antifols”): pyrimethamine, proguanil, chlorproguanil, trimethoprim
Artemisinin compounds (artemisinin, dihydroartemisinin, artemether, artesunate)
Atovaquone is an antimalarial in its own class with a unique mode of action; combined with proguanil it is sold under the trade name Malarone®. Several antibacterial drugs (e.g., tetracycline, clindamycin) also have antiplasmodial activity, although in general their action is slow for malaria treatment (as opposed to prophylaxis); they are recommended only in combination with other antimalarial drugs. Drugs active against Plasmodium falciparum also are active against the other three malaria species that affect humans—P. vivax, P. malariae, and P. ovale—with the exception of antifols, which work poorly against P. vivax.