Safety of Anthelmintics in Animals

Most anthelmintics have wide safety margins (ie, the dosage that can be given to an animal before adverse effects are induced is much higher than the recommended dosage).

The wide safety margin of benzimidazole anthelmintics is due to their greater selective affinity for parasitic beta tubulin than for mammalian beta tubulin. Nonetheless, this selective toxicity is not absolute; some toxic effects based on antimitotic activity (teratogenicity or embryotoxicity) can occur in some target species.

Benzimidazoles' teratogenic effects are believed to be due to disruption of microtubules, and therefore mitotic spindle formation and cell division, within the developing fetus. The most common malformations include encephalocele, meningocele, hydrocephaly, and vertebral fusions or deletions. As a result of these effects, administration of some benzimidazoles (eg, albendazole) is contraindicated in early pregnancy, particularly in sheep.

Compared with that of benzimidazole, the safety index (SI; the ratio of the highest exposure to a drug that does not induce toxicity to the exposure that exerts efficacy) is not as wide for levamisole (SI = 4–6) or for most of the chemicals active against liver flukes (SI = 3–6). In mammals, levamisole toxicity occurs more often than benzimidazole toxicity, although clinical signs of toxicity are unusual unless the normal therapeutic dosage is exceeded. Levamisole toxicity in the host animal is largely an extension of its antiparasitic effect (ie, cholinergic signs such as salivation, muscle tremors, ataxia, urination, defecation, and collapse).

In fatal levamisole poisoning, the immediate cause of death is asphyxia due to respiratory failure. Atropine sulfate can alleviate such clinical signs. Levamisole may cause some inflammation at the site of SC injection, but usually this is transient. Toxicity increases if other anticholinergic drugs (eg, organophosphates) are administered at the same time.

Because of their low absorption from the gut, tetrahydropyrimidines have a high safety margin. Adverse effects (vomiting in dogs and cats) are rare. Toxicity increases when other cholinergic drugs (eg, levamisole, organophosphates) are used simultaneously.

Mammals are generally not adversely affected by macrocyclic lactones. The SI for macrocyclic lactones is typically wide; however, both abamectin and moxidectin are contraindicated in calves and foals < 4 months old, respectively, because of narrow safety margins in these species. Otherwise, single administration at approximately 10 times and multiple administration at 3 times the recommended therapeutic dose levels do not have any secondary effects on healthy host animals.

Mammalian safety appears to depend on P-glycoprotein activity in the blood-brain barrier. P-glycoprotein deficiency in certain animals decreases the ability to pump avermectins, milbemycins, and other drugs across cell membranes. The net effect is an increase in systemic bioavailability because P-glycoprotein–deficient animals are not able to actively pump macrocyclic lactones out of the CNS or efficiently process them. This decreases the ability to redistribute, metabolize, and excrete macrocyclic lactones, as well as antineoplastic drugs, opioids, acepromazine, digoxin, and ondansetron, resulting in toxicity at what would be considered normal doses in most animals.

CNS depression was first recognized in purebred and crossbred Collies following macrocyclic lactone administration and have since been reported in cattle breeds (Murray Grey) and in individual dogs of multiple breeds. Neurological signs (idiosyncratic reactions) including depression, muscle weakness, blindness, coma, and death were observed when high doses were administered.

Susceptibility to CNS toxicity after avermectin administration has been observed in Collie-type dogs. P-glycoprotein is the protein that prevents avermectins from penetrating the blood-brain barrier. A defect in the gene for P-glycoprotein has been identified in these dogs and also in some Australian Shepherds, English Shepherds, and Shetland Sheepdogs.

Genetic testing is now available to identify individual dogs susceptible to ivermectin toxicity. While this individual breed susceptibility may depend on different pharmacokinetic-related factors (dosing, route of administration, drug formulations, etc), extralabel use of macrocyclic lactone formulations intended for other animal species should be avoided in dogs.  

Selamectin use is safe in ivermectin-sensitive Collies. Selamectin was evaluated in dogs and cats at 10 times the recommended doses, and no adverse reactions were observed. Milbemycin oxime is well tolerated in dogs, including Collies. These macrocyclic lactones do not cross the blood-brain barrier.

Amino-acetonitrile derivatives target a nematode-specific receptor absent in mammals and other organisms. Due to this specific mode of action, monepantel has a very favorable safety profile. Monepantel has been administered to lambs in doses up to 30 times higher than the recommended dose without any adverse effects. Furthermore, repeated oral administration of monepantel at 3 times the recommended dose every 5 days over an entire reproductive cycle was not associated with any treatment-related adverse effects on the reproductive performance of rams or ewes or on the viability of their offspring, and it was systemically very well tolerated.

Emodepside appears to be of low acute toxicity in a variety of laboratory animal species when administered by a variety of routes. Although overt clinical signs of toxicity include depressed neurological and respiratory function, they only occur at doses far in excess of the recommended therapeutic dose in cats. Repeated treatment at 3 times the therapeutic dose was tolerated in pregnant and lactating queens, so adverse effects on reproductive function of dams and/or kitten health should not be expected when the product is administered at the recommended dose. Safety in dogs was established only for puppies at least 12 weeks old.

The combination of derquantel and abamectin did not result in any adverse clinical effects in ewes and lambs under field conditions, other than common reports of mild, transient coughing.

Because salicylanilides, substituted phenols, and aromatic amides are general uncouplers of oxidative phosphorylation, their SIs are lower than those of many other anthelmintics. Nonetheless, they are safe if used as directed. Adverse effects most commonly occur in animals under severe stress, in poor nutritional or metabolic condition, or with severe parasitic infections. Mild anorexia and unformed feces may be observed after treatment at recommended dosages. High dosages may cause blindness, hyperthermia, convulsions, and death—classic clinical signs of uncoupled phosphorylation.