Toxicity of antimalarial drugs.

The toxicity of antimalarial drugs sets an unusual and interesting problem for the clinician. Unlike most clinical situations, antimalarial drugs are provided to healthy people who are requesting treatment to provide extra security against ill health whilst travelling in malarial areas. Any significant degree of toxicity from these drugs undermines the whole logic behind the advice given to travellers. A risk-benefit assessment is necessary to decide between different regimens'. The toxicity of the drug must be balanced against the risk from malaria, as well as the efficacy of the drug. It has been estimated that travellers going on short (three week) trips to subSaharan Africa, who take some reasonable antimosquito precautions but take no chemoprophylaxis, have only a 1% chance ofcontracting clinical malaria. Clinical malaria has a mortality of no more than 1% if a policy of seeking medical advice or taking empiric antimalarial treatment for fevers is followed. Overall, the mortality of travellers who do not take chemoprophylaxis is therefore about 1 in 10000 trips'. Clearly, the risk to travellers going to endemic areas for longer periods or shorter times will be correspondingly higher or lower; and travellers visiting areas of low endemicity will be at much lower risk. Decisions on chemoprophylaxis are normally based on the requirements of the typical traveller. From this, it is clear that any drug which has a frequency of fatal side-effects of 1 in 10 000, should not be used for routine prophylaxis. Furthermore, as non-toxic, though less effective, drugs are available, it is unlikely that drugs with a known frequency offtal side-effects of less than 1 in 40 000 should be considered for routine use. This theoretical view has been followed in practice whenever toxicity has been measured. In 1985 Fansidar was withdrawn as a recommended drug for routine prophylaxis on the basis ofan estimated fatal adverse reaction rate of about 1 in 20 0002. A year later amodiaquine was withdrawn because of an incidence of fatal neutropenia of about 1 in 20003. Unfortunately, there are few good techniques available to measure rates of severe adverse effects which are lower than 1 in 10 000. Prospective trials are not large enough to reliably detect side effects or adverse effects ofsuch frequencies and the much less reliable techniques of post-marketing surveillance must be used. This depends on using isolated case reports, reports to government agencies and to the pharmaceutical industry. These reports have to be assessed in the context of estimates of overall drug usage. Clearly, such estimates are very imprecise and drugs often have to be used for several years before even this imperfect information can be obtained. In contrast, frequent but mild side effects are much easier to determine. Care is needed in interpreting the nature of mild side-effects because placebo controlled trials have shown that patients often suffer from non-specific side effects such as nausea, dizziness and headaches. In this review, I will attempt to summarise the main knowledge available on the incidence of major adverse effects and an outline of what is known about the minor side effects of the antimalarial drugs.