Isoxazolines are a new class of synthesized chemicals with broad-spectrum ectoparasiticidal activity against fleas and ticks in dogs and cats, and against mites in poultry. In parasites, isoxazolines produce their insecticidal and tickicidal effects by targeting noncompetitive gamma-aminobutyric acid (GABA) receptors. Isoxazolines bind to the chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Eventually, affected parasites are paralyzed and die. Binding of isoxazolines to these receptors is much more selective in fleas, ticks, and mites than in mammals, including humans.
In September 2018, the US FDA alerted pet owners and veterinarians that isoxazolines, including afoxolaner, fluralaner, sarolaner, and lotilaner, can have neurologic effects in some dogs, such as muscle tremors, ataxia, and seizures.
Afoxolaner is an active ingredient, alone and in combination with milbemycin oxime, as an insecticide and an acaricide in dogs. Afoxolaner is also used for the treatment of sarcoptic and demodectic mange. It has a chemical structure of C26H17ClF9N3O3, with a molecular weight of 625.88.
The acute oral LD50 and dermal LD50 of afoxolaner in rats are >1,000 mg/kg and >2,000 mg/kg, respectively.
Afoxalaner is given to dogs and puppies (>8 weeks of age) orally has a chewable with a recommended dose of 2.7–7 mg/kg. The parasiticidal effect lasts for a month. It is rapidly absorbed with maximum blood levels within 2–12 hours, and a bioavailability of 74%. The half-life of afoxolaner is greater in Collies than in Beagles. Ninety-nine percent of absorbed afoxolaner may bind to blood proteins. Elimination half-life is 14 hours, and excretion of afoxolaner and its metabolites occurs primarily via the biliary route.
In general, afoxolaner is safe in dogs. At higher doses (100, 300, and 1,000 mg/kg, PO), afoxolaner produced a diuretic effect in rats, reduction in food consumption in rats and rabbits, and vomiting and diarrhea in dogs.
There is no specific antidote for afoxolaner poisoning in pets. Treatment rests with preventing further exposure and supportive measures. Gastric lavage and administration of activated charcoal are advised if the exposure is via accidental ingestion.
Fluralaner is another systemic insecticide and acaricide belonging to the isoxazoline class that is orally administered to cats and dogs. It has a chemical structure of C22H17Cl2F6N3O3, with a molecular weight of 556.29.
In 2014, the US FDA approved the use of fluralaner in a chewable tablet for dogs that is administered at 12-week intervals. Fluralaner is used singly or in combination with moxidectin against fleas and ticks in dogs and cats. In a field study, a single fluralaner dose administered orally to dogs provided at least 12 weeks of flea- and tick control. A new fluralaner and moxidectin topical application for cats is effective against fleas, ticks, heartworm, and intestinal parasites for 2 months.
Fluralaner produces toxicity by inhibiting GABA-gated chloride channels (GABAA receptors) and l-glutamate-gated chloride channels, with selectivity for insect neurons over mammalian neurons.
Oral administration of fluralaner at the highest recommended treatment dose (56 mg/kg) at 8-week intervals is well tolerated. It has a safety margin of >5 times the labeled dose in healthy dogs ≥8 weeks of age and weighing ≥2 kg. Even at the highest dose, it is deemed safe to be handled by humans.
Sarolaner is a member of the isoxazolines, and it exerts broad-spectrum killing effects against fleas, ticks, and mites. It has a chemical formula of C23H18Cl2F4N2O5S, with a molecular weight of 581.364.
Sarolaner is available as a chewable tablet for administration to dogs >6 months of age, according to their body weight (2 mg/kg). Sarolaner exerts insecticidal and acaricidal effects by inhibiting the function of the GABA and glutamate receptors at the neuromuscular junctions in insects.
Sarolaner is rapidly absorbed following oral administration with a bioavailability of >85%. The half-life of sarolaner is 11–12 days. The metabolism of sarolaner is minimal in the dog, as it can bind >99.9% to plasma proteins. It is eliminated via biliary excretion.
When repeated on a monthly basis, sarolaner is safe at 30 mg/kg in rodents and 20 mg/kg in dogs ≥ 8 weeks.
Lotilaner is another member of the isoxazolines class. It has a chemical formula of C20H14Cl3F6N3O3S, with a molecular weight of 596.8.
The systemic veterinary product containing lotilaner provides immediate and persistent pesticidal activity against fleas and ticks for 1 month in dogs and cats. It is also used for the control of flea allergy dermatitis.
Lotilaner produces toxicity by a potent noncompetitive antagonistic binding to the GABA-gated chloride channels in fleas, ticks and lice, yet it has no effect on dog GABAA receptors. Lotilaner is an effective broad-spectrum insecticide and acaricide in dogs and cats for a period of 35 days and it has a good safety record for pets and their owners.