Studies of the pharmacodynamics and modes of action of anthelmintic drugs : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University
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Date
1977
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Massey University
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Abstract
The aim of this work is to extend existing knowledge both with respect to the mode of action of anthelmintics and the biochemical and physiological mechanisms which may be disrupted by drug action. The helminth species examined include nematodes, Ascaris suum, Ascaridia galli and Trichuris ovis and cestodes, Moniezia, T. hydatigena, T. taeniƦformis and Echinoccocus granulosus; the anthelmintics studied were methyridine, diethylcarbamazine, pyrantel, morantel, tetramisole, levamisole, dichlorvos, vincofos, cambendazole and mebendazole. The helminth characteristics selected for most intensive study are (a) the occurrence and properties of helminth cholinesterase and (b) the uptake of glucose. The breadth of the study was limited by the availability of fresh material and not all combinations of helminth and drug were investigated. The histochemical localisation of cholinesterase activity in whole mounts and sections of tapeworms using thiocholine esters revealed a complex network of tegumental receptors feeding a nervous system with efferents to suckers, rostellum and hook muscles. It is suggested that tapeworms have reflex arcsinvolving these structures allowing them to maintain their position in the host intestine in spite of peristaltic action. These arcs are susceptible to anticholinesterase anthelmintics. Other cholinesterase activity is associated with the scolex, cirrus, genital pore and sometimes the tegument. High cholinesterase specific activities against acetylthiocholine were measured in Echinococcus scoleces and tapeworms, but lower levels in nematodes. Differential centrifugation of homogenates was used to study their occurrence in the tissue and facilitate further characterisation. However, the enzyme was widely distributed in these species although somewhat higher in the particulate fractions. Activity was increased little, if any, by attempts to solubilise it with the detergent, Triton X-100. Cholinesterase in some fractions particularly from T. ovis, had a high temperature optimum around 60C, but never showed the phenomenon of autoinhibition by substrate at concentrations up to 10-2M. Cholinesterase in species of worm with high levels of enzyme was more sensitive to eserine inhibition than those with lower levels. In studies of glucose uptake from the medium by Ascaris and two tapeworms, it was confirmed that transport into Ascaris was strongly inhibited by certain benzimidazole anthelmintics. Transport into Ascaris, but not the cestodes, was also discovered to be sensitive to local anaesthetics such as procaine or lignocaine. Uptake into tapeworms was inhibited by the absence of sodium ions, phlorizin, iodoacetate and dinitrophenol. It was less inhibited by benzimidazoles and not at all by organophosphate anthelmintics, but was sensitive to phenolic drugs such as hexachlorophene and nitroxynil. In the dog and sheep, a number of anthelmintic drugs administered intravenously showed predominantly nicotinic effects on blood pressure and respiration supporting the cholinergic action of these drugs. Although sheep red-cell cholinesterase is more sensitive to inhibition than that of all helminths tested, the oral route of administration of anthelmintics remains safe for the host and effective against intestinal parasitic worms.
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Anthelmintics, Helminths, Intestinal worms