Antimalarials

The causative agents of malaria are plasmodia, unicellular organisms (Order Hemosporidia, Class Protozoa). The infective form, the sporozoite, is inoculated into skin capillaries when infected female Anopheles mosquitoes (A) suck blood from humans. The sporozoites invade liver parenchymal cells, where they develop into primary tissue schizonts. These give rise to numerous merozoites that enter the blood. The preerythrocytic stage is asymptomatic. In blood, the parasite enters erythrocytes (erythrocytic stage), where it again multiplies by schizogony, resulting in the formation of more merozoites. Rupture of the infected erythrocytes releases the merozoites and pyrogens. A fever attack ensues and more erythrocytes are infected. The generation period for the next crop of merozoites determines the interval between fever attacks. With Plasmodium vivax and P. ovale, there can be a parallel multiplication in the liver (paraerythrocytic stage). Moreover, some sporozoites may become dormant in the liver as “hypnozoites” before entering schizogony.

Different antimalarials selectively kill the parasite’s different developmental forms. The mechanism of action is known for some agents: Chloroquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme released from digested hemoglobin, free heme being toxic for the schizonts. Pyrimethamine in-

via its active metabolite cycloguanil. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p.274). Dihydrofolate reductase is also blocked by cycloguanil, the active form of proguanil. Atoquavone suppresses synthesis of pyrimidine bases, probably by interfering with mitochondrial electron transport. Artemesinin derivatives (artemether, artesunate) originate from the East Asian plant Qinghaosu (Artemisia sp.) Its antischizontal effect appears to involve a re-

action between heme iron and the epoxide group of these compounds.

Antimalarial drug choice takes tolerability and plasmodial resistance into account.

Tolerability. The oldest antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated.

Plasmodium falciparum, responsibleforthe most dangerous form of malaria, is particularly prone to develop drug resistance. The prevalence of resistant strains rises with increasingfrequencyofdruguse.Resistancehas been reported for chloroquine and also the combination pyrimethamine/sulfadoxine.

Drug choice for antimalarial chemoprophylaxis. In areas with a risk of malaria, continuous intake of antimalarials affords the best protection against the disease, though not against infection. Primaquine would be effective against primary tissue schizonts of all plasmodial species; however, it is not used for long-term prophylaxis because of unsatisfactory tolerability and the risk of plasmodial resistance. Instead, prophylactic regimens employ agents against blood schizonts. Depending on the presence of resistant strains, use can be made of chloroquine, and/or proguanil, mefloquine, the tetracycline doxycycline, as well as the combination of atoquavone and proguanil.

These drugs do not prevent the (symp- tom-free) hepatic infection but only the dis- ease-causing infection of erythrocytes (“suppression therapy”). On a person’s return from an endemic malaria region, a two-week course of primaquine is adequate for eradication of the late hepatic stages (P. vivax and

P. ovale).

Protection from mosquito bites (with nets, skin-covering clothes, etc.) is a very important prophylactic measure.

Therapy. Antimalarial therapy employs the same agents, in addition to the combinations of artemether plus lumefantrine or pyrimethamine plus sulfadoxine.