The effects of anthelmintic drugs on intermediary metabolism of parasites can be examined using techniques developed for the investigation of metabolic regulation. Most attention has been paid to the pathways of respiratory metabolism in parasites, since maintenance of high energy levels is essential to an organism's survival. Respiratory metabolism is thus a prime target for anthelmintic attack. Parasites differ from their hosts in a number of pathways of respiratory metabolism and they produce incompletely-oxidised organic acids as end products. A variety of anthelmintic drugs have been shown to inhibit some enzymes of these pathways, including phosphoenolpyruvate carboxykinase, malate dehydrogenase, and the fumarate reductase, 'succinoxidase' and succinate decarboxylase systems. Energy synthesis in mitochondria from parasites is also inhibited by many anthelmintics: this target is a particularly important one since its properties differ significantly from those of the host. This process requires considerable study and it may not necessarily be valid to equate 'uncoupling' in mammalian tissues with that in parasite tissues. Changes in ATP levels affect flux through the respiratory pathways; a complete assessment of effects of anthelminstics on the respiratory pathways of parasites would include measurement of the uptake and utilization of carbon sources (e.g., glucose and glycogen), of metabolic intermediates, including adenine nucleotides, and of excreted end products. Sites of change can then be identified and studied in greater detail. Comparison of the effect of mebendazole in vivo and in vitro on unrelated species, Moniezia expansa and Fasciola hepatica adults, sheds some light on the mechanism of its anthelmintic effects. This drug elicits similar changes in proportions and totals of adenine nucleotides in the two species, but it differs in the rapidly of its effect, its effect on glucose uptake and glycogen depletion, and in changes in respiratory end product. Consequently mebendazole may not act in the same way against these two species. It also affects a number of other systems in other parasites: the suggestion of a single 'mode of action' may be inappropriate for this compound. Respiratory metabolism is not the only system affected by anthelmintics: other parasite systems are also attacked, but the final effect of lethal anthelmintic is observed as changes in the respiratory metabolic pathways. Some anthelmintics, for example, levamisole, affect the respiratory pathway directly, but also affect other systems (the nervous system in the case of levamisole) and may be effective in vitro but not in vivo. In these cases it is necessary to distinguish between effects that may be subordinate to a primary effect, and to take host and permeability factors into account. © 1979.
