In areas such as Thailand and Vietnam, mosquitoes of the Anopheles dirus and Anopheles minimus species spread the drug resistant parasites. These mosquitoes adapt their biting activity to human behaviour patterns, and maintain intense transmission. Several mechanisms can account for changes in drug sensitivity in the malaria parasites, for example, physiological adaptations due to non genetic changes, selection of previously existing drug resistant cells from a mixed population under drug pressure, spontaneous mutation, mutation of extranuclear genes, or the existence of plasmid-like factors. In an environment where subtherapeutic levels of the antimalarial drugs are present, those parasites which have resistance through their natural variation or through mutations clearly have an important biological advantage. As drug resistance seems to be genetically determined, gametocytes produced by resistant populations will produce more resistant parasites, promoting spread of the resistant forms.
Resistance develops more quickly where a large population of parasites are exposed to drug pressure.
The increasingly rapid spread of resistant malaria may be due to an increasingly efficient mosquito vector. At any rate, the resistant forms undoubtedly have a biological advantage with transmission. In order to appreciate the physiological nature of resistance, it is necessary to look in more detail at the metabolism of the parasites, and the modes of action of the antimalarial drugs. Intraerythrocytic stages of malaria ingest haemoglobin into food vacuoles. A parasite synthesised binding protein, 'haembinder', seems to sequester the membrane-lytic ferriprotoporphyrin IX into the inert haemozoin complex to protect the Plasmodium membranes from damage.