Systemic ectoparasite control and how it works

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Treatment and prevention of flea infestations have been part of the job of companion animal veterinarians for decades. The most significant breakthrough in this area was the discovery of effective topical medications like fipronil (Frontline) in the 1990s, which put baths and powders on the back of storage shelves. Since then, many other topicals that work when absorbed by the animal’s skin and sebaceous glands have been developed. But some pet owners are still hesitant about using them because of the potential danger to people and other animals. Thus, oral products were the next major innovation in the management of fleas.

Before the isoxazoline class of flea/tick preventatives was launched, spinosad (Comfortis, Trifexis) and nitenpyram (Capstar) were the only oral alternatives to topical flea control. They begin killing fleas about 30 minutes after being administered. Although spinosad is a macrocyclic lactone and nitenpyram a neonicotinoid insecticide, both act on the nicotinic acetylcholine receptors of the flea. When a flea consumes the blood of an animal treated with spinosad or nitenpyram, it ingests the drug, which blocks acetylcholine-mediated neurotransmission, leading to flea paralysis and death. All fleas on cats and dogs treated with nitenpyram die within 6 hours; all fleas on cats treated with spinosad die within 24 hours; and all those on dogs similarly treated die within 4 hours.^1,2 Because these drugs are more selective for the nicotinic receptors of insects, the risk of adverse events in canine and feline patients is low.

Although the introduction of oral flea control was a huge win for pets, their parents, and veterinary professionals, the treatment of ticks remained topical. The advent of prescription-only isoxazolines in the 2010s revolutionized flea and tick management in dogs and cats. All isoxazolines—be they administered orally, as are fluralaner (Bravecto), lotilaner (Credelio), sarolaner (Simparica), and afoxolaner (NexGard) or transdermally, as fluralaner (Bravecto) and sarolaner (Revolution Plus)—are absorbed into the bloodstream of the patient. And, like spinosad and nitenpyram, they work exclusively on the neurotransmitter receptors of insects and arachnids. Rather than targeting nicotinic receptors, isoxazolines target chloride receptors that are gated by glutamate and gamma-aminobutyric acid (GABA) and inhibits them at the neuromuscular junction. The selectivity of isoxazolines is significantly higher for insect/arachnid neurons than mammalian neurons. This results in uncontrolled neuronal activity in the flea and tick, leading to paralysis and death. These drugs bind tightly to plasma proteins, allowing for dosing intervals of 30 days or more, depending on the product.^3-5

Many pet owners prefer oral flea/tick preventatives because there is virtually no chance that a person or another pet will get the drug on their skin via contact with the treated animal—a concern I often hear from parents of young children. From the perspective of prevention, many in the field hope for increased owner compliance when flavored chewable medication is prescribed for their pet. Oral drugs also provide an added benefit in that there is no question they will be accidentally washed off if the pet is bathed too soon after administration. However, some owners are more cautious about medications that circulate through an animal’s body, preferring those that are limited to the skin. Although rare, the adverse effects of isoxazolines can be significant. All contain boxed warnings about the risk of such adverse events as seizures, tremors, and ataxia. The warning also recommends exercising caution when prescribing to patients with a history of seizures and notes that isoxazolines can cause seizures even in patients with no known history of seizures.⁴ In my experience, discontinuing an isoxazoline that precipitated a seizure is curative. More common side effects are vomiting, diarrhea, lethargy, and inappetence.^3,5

In addition to killing fleas and ticks, isoxazolines are an effective off-label treatment for cutaneous myiasis (skin infestation by the larvae of certain fly species) and for many other ectoparasites, including Demodex, Sarcoptes, and Otodectes mites, suckling lice, Psoroptes cuniculi (rabbit ear mite), and Triatoma (the vectors of Chagas disease).⁴ Especially with regard to Demodex and Sarcoptes, isoxazolines are far more effective, safer, and easier for pet owners to manage than ivermectin.

Although highly effective at killing fleas, ticks, and other ectoparasites, the main drawback of isoxazolines—other than a rare risk of seizure— is that they don’t repel ectoparasites. Given their rapid speed of kill (8 hours for fleas and 12 hours for ticks with fluralaner in dogs, for example³), most patients will not be exposed to the parasites for a significant period of time. However, patients with flea allergy dermatitis (FAD) and those exposed to a heavy tick burden may benefit from concurrent treatment with a topical preventative that both repels and kills, thus provides 2 layers of defense against fleas and ticks.

Isoxazolines kill ticks and fleas often before they have the chance to cause disease. However, every patient (and pet owner) is an individual, and not all patients are candidates for an isoxazoline. Seizures must be discussed with owners before these drugs are prescribed to adult animals. If clinical signs of FAD are present or if routine tickborne disease antibody testing is positive when using only an isooxazoline drug, clinicians must discuss compliance and the option of adding or changing preventative medications with pet owners.

Jeffrey Haymaker, VMD is an associate veterinarian at Mount Laurel Animal Hospital and 24-hour Emergency Service in New Jersey. His veterinary interests include internal medicine and surgery. He works in the primary care department as well as in the emergency service. Haymaker is a member of the American Veterinary Medical Association and is the treasurer of the Southern New Jersey Veterinary Medical Association. He is also an adjunct instructor of veterinary technology at Manor College in Jenkintown, Pennsylvania.

References

1. CAPSTAR - Nitenpyram Tablet. US Product Label. Elanco US Inc; 2020.
2. COMFORTIS - Spinosad Tablet, Chewable. US Product Label for Dogs and Cats. Elanco US Inc; 2018.
3. BRAVECTO - fluralaner tablet, chewable for dogs. US product label. Merck Animal Health; 2019.
4. Plumb, D. Clinical Decision Support for Veterinary Teams. Plumb’s Veterinary Drugs. Accessed August 3, 2022. https://plumbs.com
5. SIMPARICA CHEWABLES - Sarolaner Tablet, Chewable. US Product Label. Zoetis Inc; 2017.