Selamectin is a semi-synthetic compound of the avermectin class. Selamectin paralyses and/or kills a wide range of invertebrate parasites through interference with their chloride channel conductance causing disruption of normal neurotransmission. This inhibits the electrical activity of nerve cells in nematodes and muscle cells in arthropods leading to their paralysis and/or death.

Selamectin has adulticidal, ovicidal and larvicidal activity against fleas. Therefore, it effectively breaks the flea life cycle by killing adults (on the animal), preventing the hatching of eggs (on the animal and in its environment) and by killing larvae (environment only). Debris from selamectin-treated pets kills flea eggs and larvae not previously exposed to selamectin and thus may aid in the control of existing environmental flea infestations in areas to which the animal has access. Selamectin is active against adult fleas (Ctenocephalides spp.) as well as mites (Otodectes cynotis, Notoedres cati), lice (Felicola subrostratus) and gastrointestinal nematodes (Toxocara cati, Ancylostoma tubaeforme). Activity has also been demonstrated against heartworm (D. immitis) larvae.

For fleas, the onset of efficacy is within 24 hours for 5 weeks after product application.

Sarolaner is an acaricide and insecticide belonging to the isoxazoline family. The primary target of action of sarolaner in insects and acarines is functional blockade of ligand-gated chloride channels (GABA-receptors and glutamate-receptors). Sarolaner blocks GABA- and glutamate-gated chloride channels in the central nervous system of insects and acarines. Disruption of these receptors by sarolaner prevents the uptake of chloride ions by GABA and glutamate gated ion channels, thus resulting in increased nerve stimulation and death of the target parasite. Sarolaner exhibits higher functional potency to block insect/acarine receptors compared to mammalian receptors. Sarolaner does not interact with known insecticidal binding sites of nicotinic or other GABAergic insecticides such as neonicotinoids, fiproles, milbemycins, avermectins, and cyclodienes. Sarolaner is active against adult fleas (Ctenocephalides spp.) as well as several tick species such as Dermacentor reticulatus, Ixodes hexagonus, Ixodes ricinus, and Rhipicephalus sanguineus.

For ticks (I. ricinus), the onset of efficacy is within 24 hours of attachment for one month after product application.

Following topical administration of the Stronghold Plus both selamectin and sarolaner are well absorbed with bioavailability mean values of 40.5% and 57.9%, respectively and distribute systemically. In cats, selamectin and sarolaner are low clearance compounds with long half-life values, 12.5 days and 41.5 days respectively, following topical administration.

In cats the primary route of selamectin elimination is in faeces and the majority is parent compound. Identification of selamectin metabolites in faeces indicated that metabolic clearance also contributes to the elimination. The primary route of elimination for sarolaner is biliary elimination of parent sarolaner, with contributions by metabolic clearance.