Malaria: Treatment, overview

Broadly speaking, anti-malaria drugs can be divided into four major classes

• Blood schizonticides

• Antifolates

• Antimitochondrials

• Redox process-based agents

Blood schizonticides

When the malaria parasite leaves the liver and penetrates an erythrocyte, it can at last begin a haemoglobin diet. However, it cannot use the iron-containing haem group. What is more, released ferriprotoporfyrin IX (syn. = haemin) is toxic for the parasite. It contains trivalent iron (ferric = Fe³⁺). Normally the parasite polymerises haemin to non-toxic malaria pigment. Chloroquine, quinine, mefloquine and halofantrine interfere with the detoxification of haemin in the digestive vacuole of the parasite. The drugs prevent this detoxification so that haemin can generate free radicals and membrane damage follows. It is therefore logical that the drugs are not active against the parasitic stages which precede the blood forms (sporozoites, liver forms) and which do not consume haemoglobin.

Antifolates

Folic acid is an important metabolic factor. Humans obtain this vitamin from the food they eat. The malaria parasite, on the other hand, must produce it for itself. Para-aminobenzoic acid (PABA) is used at an early stage of the biosynthesis of folic acid by the enzyme dihydropteroate synthetase. This step is inhibited by structural analogues of PABA, such as sulphonamides and sulphones, e.g. sulphanilamide, sulphadoxine and dapsone. The next synthesis step is catalysed by dihydrofolate reductase. This step is prevented by pyrimethamine, trimethoprim and cycloguanil (prodrug = proguanil), to such an extent that tetrahydrofolate – the end product – is not formed. The combination of these two sequential inhibitors forms the basis of Fansidar® (similar to cotrimoxazole). Resistance to both antifolates is easily developed, however (a specific point mutation in each gene is sufficient).

Antimitochondrial products

Although artemisinin derivatives and 8-aminoquinolines cause mitochondrial swelling, this organelle is not their chief target. Some antibiotics such as tetracycline and clindamycin prevent protein synthesis by mitochondrial ribosomes (these are similar to the ribosomes found in bacteria). They are slow-acting. Atovaquone is a naphthoquinone which specifically destroys the electron transport chains of Apicomplexa. The molecule is rather similar to ubiquinone (coenzyme Q) which plays a role in the energy transfer between cytochrome B and C1. The enzymes of Plasmodium falciparum are 1000 times more sensitive to atovaquone than the corresponding enzymes in humans. Resistance can easily develop if it is used in monotherapy.

Redox reactions

Primaquine and etaquine exercise their action via redox-active quinone metabolites. They are selectively toxic for the pre-erythrocytic stages and are the only medicaments which kill hypnozoites. Etaquine has in addition a pronounced blood schizonticidal action.

Category: Medicine Notes