Avermectins

Chapter 34


Parasiticide Toxicoses


Avermectins



Avermectins are a group of parasiticidal drugs derived from soil Streptomyces microorganisms. Biochemically they belong to a group of compounds known as macrocyclic lactones and are related to milbemycins. These drugs are widely used for their parasiticidal properties. Representative drugs (and products) include ivermectin (Heartgard; Iverhart), selamectin (Revolution), doramectin (Dectomax), eprinomectin (Eprinex), moxidectin (Proheart; Advantage Multi), milbemycin (Interceptor), and abamectin. In general these drugs have a substantial margin of safety in dogs and cats and are very active against a wide range of parasites, including nematodes and arthropods. Practically they are highly effective at very low doses such as micrograms per kilogram of body weight. These drugs are not active against trematodes or cestodes. As such, they may be combined with other drugs that are active against trematodes and cestodes in some formulations. They are available for oral, topical, and parenteral formulations for use in different domesticated species and humans.



Toxicity of Avermectins and Milbemycins


Because of their wide safety margin, avermectins and milbemycins are used safely in the majority of dogs and cats. However, some specific breeds of dogs are more sensitive to this group of drugs (i.e., collies, Australian shepherds, Shetland sheepdogs, Old English sheepdogs, German shepherds, long-haired whippets, and silken windhounds). Recent findings have determined that these breeds express a mutation in the multidrug resistance (MDR-1) gene. This gene regulates the synthesis of P-glycoprotein, a 170-kDa transmembrane protein responsible for extruding drugs and other xenobiotics from the brain across the blood-brain barrier. A mutation in the MDR-1 gene causes synthesis of a truncated P-glycoprotein molecule that is unable to perform this regulatory role. The result is that breeds of dogs with this mutation cannot efficiently extrude xenobiotics such as avermectins and milbemycins from the brain.. Studies have demonstrated higher concentrations of ivermectin in brain tissues of dogs with the mutated MDR-1 gene than naïve control dogs that have normal-functioning P-glycoprotein.


Collies as a breed have the highest prevalence of the MDR-1 mutation. Research from the United States, Europe, and Japan indicates that 75% of all collies carry this genetic mutation and explains why avermectin toxicosis is more commonly observed in this breed. This statistic includes dogs that are either heterozygous carriers or homozygous for the mutant allele, making the animal sensitive. Note that collies not carrying this mutation (i.e., homozygous for the normal allele) have the same sensitivity to avermectin and milbemycin toxicity as other normal breeds of dogs.


It is worth noting that some mixed breeds of dogs carry a single recessive gene mutation, making them heterozygous carriers. These dogs have sensitivity to avermectins, which is between that of double recessive–sensitive mutants and naïve dogs with normal alleles.



Toxic Dose and Sources of Exposure


The monthly oral dose of ivermectin for prevention of heartworms in dogs and cats is 0.006 to 0.024 mg/kg (6 to 24 µg/kg of body weight), respectively. The median lethal dose (LD50) of ivermectin in beagles is 80 mg/kg body weight. Most dogs with a normal MDR-1 gene tolerate oral dosages as high as 2.5 mg/kg body weight before they start to exhibit clinical signs of poisoning to this drug. However, dogs with a double recessive MDR-1 gene can only tolerate up to 0.1 mg/kg (100 µg/kg of body weight) of ivermectin. Sensitive collies tolerated doses of 28 to 35.5 µg/kg of body weight over a period of 1 year when administered oral chewable formulations of ivermectin. The highest observed nontoxic dose in cats is 1.3 mg/kg of body weight. However, toxicity in cats has been reported after as low as 0.3 mg/kg of body weight subcutaneously. Toxicosis to moxidectin was observed in a collie that received a dose 30 times higher than the recommended dose of 0.003 mg/kg of body weight. Toxicosis to milbemycin has been observed in collies at doses that are 10 times higher than the recommended therapeutic dose of 0.5 mg/kg orally. In one study collie sensitivity to milbemycin oxime at 10 mg/kg of body weight was judged to be clinically equivalent to that of ivermectin at 120 µg/kg of body weight. Selamectin is potentially toxic to sensitive collies at oral doses greater than 15 mg/kg of body weight. For the other avermectins, the minimum toxic doses in sensitive breeds of dogs are not well established.


Typically toxicosis to avermectins and milbemycins is observed in the more sensitive breeds of dogs when dosage errors occur at more than 5 to 10 times higher than recommended doses, depending on a specific drug; when dogs are accidentally given formulations for large animals; or when they eat a large number of drug tablets. Puppies and kittens are also very sensitive to both avermectins and abermectins and care should be taken to avoid iatrogenic intoxication.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Avermectins

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