Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from Postgraduate Medical Journal (August 1973) 49, 573-583. Antimalarial drugs and their actions W. PETERS M.D., B.S., D.T.M. & H. Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA Summary malignant tertian malaria parasite, Plasmodium New antimalarial drugs are required, partly because falciparum. The mortality from falciparum malaria of the emergence of drug resistant strains of malaria alone was 16%. This figure is appalling, especially parasites and partly because better compounds are so since (a) malaria is preventable and (b) treatable. needed to cure relapsing tertian malaria. In reviewing Most fatalities occur because the diagnosis is missed, the diverse modes of action of currently used anti- and the diagnosis is missed in most instances simply malarials, against a background of the patho- because the physician fails to ask the patient or his genesis of malaria, attention is drawn to deficiencies relatives the one question, 'Where have you been, in our knowledge. Even less do we understand how the and when?' This lesson is brought home by com- malaria parasite becomes resistant to certain drugs, paring falciparum mortality rates between civilian in particular chloroquine. New approaches to the and military cases in the United States. Between problem include the application of combinations of 1966 and 1969, 10% of civilians with falciparum malaria died there (Neva et al., 1970). Among existing antimalarials, and the search for new drugs on by copyright. an unprecedentedly vast scale. Out of over a quarter military personnel the fatality rate was only 0-3 % million compounds that have recently been screened, a (Canfield, 1972). handful are now in clinical trial and are showing great A massive drive to eradicate malaria was spon- promise for the treatment of multiple resistant sored by the World Health Organization on the falciparum malaria. The paper concludes by sum- basis of guidelines laid down in 1957 (W.H.O., marizing current recommendations for the prophylaxis 1957). It was based primarily on the deployment of and therapy of malaria due to drug resistant parasites. DDT and other chlorinated hydrocarbon insecticides to break the cycle of malaria transmission by killing vector anophelines as they rested in houses. Anti- AT the turn of the century malaria was still endemic malarial drugs were given as a supplementary in swampy areas of England such as the Thames measure, partly for the relief of acute malaria and http://pmj.bmj.com/ estuary. With increasing urbanization, land utiliza- partly to speed the elimination of the parasite pool tion and swamp clearance, breeding of the anophe- in the human population. Both prongs of this two- line mosquito vectors came under control and forked attack have been badly blunted by the autocthonous malaria rapidly faded away. Today, development of drug resistance. By the end of 1968 however, we are witnessing a resurgence of malaria, some fifteen vector anopheline species had become not acquired within these shores, but imported by resistant to DDT, thirty-six to dieldrin and thirteen travellers returning from the many parts of the of the fifteen to both. Already one species (Anopheles tropical world where the transmission of this disease albimanus in Central America) is resistant to the on October 2, 2021 by guest. Protected continues on a vast scale. In spite of some 20 years new generationof insecticides, the organophosphates. of international campaigns to control or eradicate On the parasite side the situation is no better. It has this threat, malaria still occurs in territory occupied taken very little time fromthelarge-scaleintroduction by some 1000 million people, nearly one third of the of a new drug to the appearance of parasites with the world's population. ability to survive it (Table 1). This has been a The scale of international travel to and from the particularly severe problem in the case of P. falci- world's more wealthy countries is increasing on an parum. unprecedented scale so that malaria, like other New antimalarial drugs are needed, not only 'exotic' diseases, preventable as it may be, neverthe- because of the resistance problem, but also because less is on the increase. In the U.K. an average of existing drugs do not include any that are able to 120 cases of malaria a year have been reported produce a radical cure of relapsing tertian malaria between 1960 and 1970, with a mortality of 4-7% due to Plasmodium vivax unless given in subtoxic (Bruce-Chwatt, 1971). Most fatalities were due to the doses for at least a week. Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from 574 W. Peters TABLE 1. Appearance of drug resistance secondary exoerythrocytic liver schizonts that are Year resistance first responsible for relapses in benign tertian malaria Year recognized in man, due to P. vivax and ovale. (The existence of this Drug introduced and where phase in Plasmodium malariae is still in dispute.) The pathogenic effects of malaria are all related to 'Antifols' the asexual Proguanil 1948 1949 (experimental) erythrocytic stages of the parasites (i.e. 1950 Java (in field use) the direct damage they do to their host cells), the Pyrimethamine 1952 1952 Gambia more distant effects due to the products of their Cycloguanil metabolism, and the immunological response of the embonate 1963 1964 S. Rhodesia host. The direct damage consists of acute haemo- Sulphadoxine 1964 1968 Cambodia Mepacrine 1935 1946 New Guinea lysis, both of infected and uninfected red cells, with Chloroquine 1945 1961 Colombia (but probably its attendant anaemia. The indirect damage is caused seen and not by various factors, such as the release of toxic mat- recognized in erials of unknown nature (see review by Maegraith Panama, 1956) & Fletcher, 1972), which trigger a chain of events that include changes in capillary permeability, the Pathogenesis of malaria and the place of antimalarial production of pharmacologically active peptides, drugs in prevention and treatment anoxic anoxia, and possibly some degree of dissemi- The malaria parasite undergoes two phases of nated intravascular coagulation. These events may asexual reproduction in man, the first in paren- occur to a lesser or greater degree in malaria caused chymal cells of the liver and the second in red blood by any of the species of Plasmodium that infect man cells. From parasites of the latter phase are derived but are usually more severe in falciparum infection. gametocytes which undergo further development This type of disease, justifiably known as 'malignant culminating in sexual reproduction only after they tertian malaria', is aggravated in addition by the are ingested by a suitable mosquito. The mosquito tendency of the infected erythrocytes to adhere by copyright. to phase terminates in the production of infective capillaries of the deep circulation, and particularly to forms, the sporozoites that enter the circulation of a those of the brain. In this situation interference new mammalian host together with secretions of the with cerebral microcirculation can lead to the con- mosquito's salivary glands. The cycle is represented dition known as cerebral malaria. in Fig. 1. Disturbances of renal vascular function may give rise to decreasing glomerular filtration and anuria with all its consequences. Sudden haemolytic crises * cc: PrOPb I cs aC i associated with falciparum malaria can produce the -in condition known as 'blackwater fever'. The patho- genesis of this syndrome is still incompletelyhttp://pmj.bmj.com/ understood. It is known that it used to be associated with the administration of quinine and that incidence of this complication has diminished greatly in 1 :$+ (mu C*}'.C').: recent years, but it is also possible that host genetic cy*6.SA _ factors such as G-6-PD deficiency may play a role. Treatment of malaria consists of the administra- tion of specific drugs to destroy the intraerythrocytic (Noc-b parasites and of non-specific supportive measures on October 2, 2021 by guest. Protected aimed at correcting the general disturbances of host function. Certainhighlyeffectiveblood schizontocides in fact possess general pharmacological properties FIG.I. Diagram oflife-cycle ofmalaria parasites showing that are of value also in a general manner. The anti- sites of action of antimalarials. inflammatory action of chloroquine, for example, undoubtedly plays a role in the remarkably rapid Antimalarial drugs may affect one or more phases response of a child with cerebral malaria to systemic of this cycle. The compounds are given names that administration of this compound. describe the type of action for which they are A few drugs are of value, not only for their action normally employed, e.g. chloroquine is known as a on the asexual blood stages, but also as a means of 'blood schizontocide', whereas primaquine is usually blocking the transmission of the parasites through described either as an 'anti-relapse drug', a 'tissue the anopheline vectors. Such drugs are pyri- schizontocide' or a 'gametocytocide'; the first two of methamine which has a potent sporontocidal action, these both describe the action of primaquine on the and primaquine which appears to act upon the Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from Antimalarial drugs 575 gametocytes, rendering them non-infective. Prima- properties of a modest nature was methylene blue, quine, while having some action too upon the and further work on this type of chemical structure asexual blood stages, is too toxic to be employed led in the 1920's to the evolution of a number of generally for treatment, but is at present the drug 8-aminoquinolines. In the early 1930's pamaquine of choice for the elimination of the secondary tissue was developed by Schulemann and his collaborators stages of relapsing malarias (i.e.