BENZIMIDAZOLE ANTHELMINTICS - GENERAL INTRODUCTION

BENZIMIDAZOLES

            Since their appearance in the early 1960s, the ben­zimidazoles have been subjected to continuous structural modifications to improve their safety and spectrum of activity, culminating in drugs which show efficacy not only against most nematodes but aiso cestodes and trematodes. Because of their poor solubility benzimidazoles are generally dosed orally as suspensions, pastes or boluses, or as powders, granules and pellets for mixing with the diet. A novel formulation of oxfendazole may be given to cattle by injection directly into the rumen using a special dos­ing gun, and the benzimidazole pro-drug netobimin may be administered parenterally as a soluble salt. Second-generation benzimidazoles were the first drugs to be effective against the arrested tissue dwelling L₄ larvae of nematodes such as Ostertagia (which have been responsible for the deaths of many cattle during their over-wintering period). This proved anthelmintic effect has been attributed to their pharmacokinetic profile. Slow elimination of more recent benzimidazoles from the body results in longer contact time with parasites and, conseqently, to greater efficacy. However, persistence of drug and metabolites in the tissues also means that that animals may not be slaughtered for meat until a considerable period has elapsed after treatment, and lactating cows may not be dosed.

            All the benzimidazoles have good activity against nematodes, their larvae and eggs; the more recent analogues have some tapeworm activity (mebendaz­ole is highly effective against larval tapeworms), albendazole is also effective against adult liver fluke. However, the most recent derivative to appear, triclabendazole, is quite different. It is highly effec­tive against all stages of liver fluke, from 1 day old to adult, but has no roundworm activity. The benzi­midazole carbamates have been shown to disrupt energy metabolism in worms, either by inhibiting the enzyme fumarate reductase or by polymerising tubu­lin in the microtubules of cells; It is not known how triclabendazole affects flukes.

            With few exceptions, these drugs are very safe anthelmintics having a high therapeutic index; but care needs to be taken when dosing pregnant animals because the benzimidazoles have been shown to pro­duce embryotoxicity and teratogenicity.

            Perhaps the biggest setback incurred by use of this class of compound has been the onset of drug resis­tance. Thiabendazole resistance was first reported as long ago as 1964, and since then cross-resistance has developed to encompass the other benzimidazoles. The main foci of drug resistance are the sheep-rearing areas of Australasia, where animals are dosed many times during a season to control gastrointestinal nematodes (mainly Haemonchus). Cattle worms, which are not treated so frequently, do not appear to develop drug resistance, but the problem has been recorded in horses which, like sheep, are dosed at fre­quent intervals throughout the year.

            Benzimidazoles such as albendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole and tiabendazole have a similar mode of action. They interrupt parasite energy metabolism by binding to tubulin, thereby disrupting microtubular cell structure and preventing nutrient uptake and other functions. Febantel, netobimin, and thiophanate are probenzimidazoles, which are converted to fenbendazole, albendazole, and lobendazole, respectively, in the body. The symbol 1-BZ is used on the label of products containing benzimidazoles or probenzimidazoles. The anthelmintic activity of the benzimidazoles is related to the duration of therapeutic blood concentrations. Doses may need to be repeated in pigs, dogs, and cats, while single doses are sufficient in ruminants and horses because the rumen or large intestine acts as a drug reservoir. Most benzimidazoles are effective against larval and adult roundworms, and albendazole, febantel, fenbendazole,  oxfendazole, and oxibendazole are also ovicidal. Fenbendazole is used in pregnant and lactating bitches to reduce roundworm infection in puppies. Fenbendazole is authorized for the treatment of Filaroides (Oslerus) in dogs and Aelurostrongylus in cats, but is also used for the control of other lungworms in dogs. Albendazole, febantel, fenbendazole, mebendazole, netobimin, and oxfendazole are also effective against tapeworms, and some are also active against adult liver flukes at a higher dosage. Triclabendazole is effective against both immature and adult flukes but has no activity against nematodes. Some benzimidazoles such as albendazole have been found to be teratogenic in the early stages of pregnancy. These should be used with caution or avoided at mating or during early pregnancy.