It acts as an antagonist at
GABA-receptors (those gated by the neurotransmitter gamma-aminobutyric acid) and other
ligand-gated chloride channels.
Isoxazolines, among the chloride channel modulators, bind to a distinct and unique target site within the insect GABA-gated chloride channels, thereby blocking pre-and post-
synaptic transfer of chloride ions across
cell membranes. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of the
central nervous system and death of
insects and
acarines.[3]
Safety
Toxicity for mammals
According to clinical studies performed prior to marketing:
The oral toxicity profile of afoxolaner consists of a
diuretic effect (rats only), effects secondary to a reduction in food consumption (rats and rabbits only) and occasional
vomiting and/or
diarrhoea (dogs, 120 and 200 mg/kg bodyweight (bw)) following high oral doses. No treatment-related effects on vomiting or diarrhoea were noted following oral doses of up to 31.5 mg/kg bw in the
pivotal target animal safety study, nor in the EU field trial.[4]
Extralabel use of afoxolaner in a pet pig has been described without any adverse effects.[7] Experimental use in commercial pigs also did not result in any adverse effects.[8]
Selectivity for
insect over
mammalian GABA-receptors has been demonstrated for other
isoxazolines.[9] The selectivity might be explained by the number of pharmacological differences that exist between GABA-gated chloride channels of
insects and
vertebrates.[10]
Afoxolaner is the
active ingredient of the veterinary medicinal products Nexgard, Frontpro, and Nexgard Spectra (in combination with
milbemycin oxime).[13][14][15] They are indicated for the treatment and prevention of
flea infestations, and the treatment and control of
tick infestations in
dogs and
puppies (8 weeks of age and older, weighing 4 pounds (~1.8 kilograms) of body weight or greater) for one month.[16] These products are administered orally and poisons
fleas once they start feeding.
^Casida JE (April 2015). "Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety". Chemical Research in Toxicology. 28 (4): 560–566.
doi:
10.1021/tx500520w.
PMID25688713.