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With so many canine and feline flea and tick products on the market, you practically need a course to help you decide which one to use. According to Ronald Baynes, DVM, PhD, an associate professor of pharmacology at North Carolina State University College of Veterinary Medicine, knowing the mechanism of action is key to sorting things out.

Organophosphates and carbamates (kills and repels fleas and ticks)

Among the first class of products used on pets was the organophosphate and carbamate insecticides used in foggers, dips, and sprays. These anticholinesterase insecticides work by inhibiting acetylcholine esterase, the enzyme responsible for breaking down the neurotransmitter acetylcholine at cholinergic nerve endings. Inhibition prevents breakdown of acetylcholine, consequently the insect nervous system is overstimulated leading to tremors, seizures and death. These products kill both fleas and ticks on contact and repel fleas and ticks, but are generally considered unsafe for use in cats.

Pyrethrins and pyrethroids (kills and repels fleas and ticks)

A second class of products that has been available for many years is the pyrethrins and synthetic pyrethroids such as permethrin and fenvalerate. They work by binding to the voltage-dependent sodium channels in nerves, preventing the channel from normally closing, and finally leading to either repetitive discharge or membrane depolarization that reduces the ability to produce impulses. These effects on the neuron are manifested as tremors and eventually death of the insect. Originally, pyrethrins were available only as sprays and dips. Because of their lower toxicity to animals and humans compared with organophosphates some are approved for use in dogs and cats. When used as sprays though, some cats have developed signs of toxicity after grooming the spray off their coats or as a result of overuse by owners. Pyrethroid toxicosis in cats is often associated with exposure to pyrethroids that are only approved for use in dogs. Like the anticholinesterases, pyrethrins kill and repel both fleas and ticks.

Formamidines (kills and repels ticks)

Another class of topical agents is the formamidines, which is represented by amitraz, the only formamidine used in veterinary medicine. It was originally used in dips for treatment of mites but is now also licensed for use as an agent for killing and repelling ticks and also impregnated into some tick collars for dogs. Amitraz binds to octopaminergic agonists in ticks. But because it binds alpha-2 adrenergic receptors in pets, high doses can result in toxicosis similar to xylazine toxicosis, and clinical signs can include central nervous system (CNS) depression, bradycardia (low heart rate), polyuria (excessive urination), and sedation.

Avermectins (Fleas and heartworm at high enough doses)

A fourth class of products that has been in use on small animals for over two decades is the avermectins which belong to a larger class of drugs known as macrolide endectocides which work externally and internally in the pet. Like fipronil, which is in another drug class, they target specifically the GABA-gated and glutamate-gated chloride channels, and by activating these sites cause an inhibitory effect. When this effect is excessive, neurotransmission is difficult and this results in death of the insect. Avermectins are generally less toxic at their labeled dose than the pyrethroids to mammals because they have a larger molecular weight (>800kD) and consequently don’t cross the CNS well in pets where GABA-mediated neurotransmission is limited to the CNS.

Avermectins were originally licensed for treatment of heartworm but now are used also for treatment of fleas and ticks or in combination with flea treatments. There are two types of avermectins used in flea and tick medications. The first is ivermectins such as selemectin (Revolution, Pfizer Animal Health). The dose for prevention of heartworm was 6µg/kg. For treatment of fleas the dose is higher. Thus Revolution treats both flea infestation and heartworm.

The other macrolide endectocide found in flea treatment products is milbemycin. At the current dose used, it is not effective as a flea prevention; rather it is used in combination with a flea control compound (lufenuron) as part of a product that treats both fleas and heartworm. Another milbemycin, moxidectin, is combined with imidacloprid (Advantage Multi, Bayer Animal Health) in a product that controls fleas, heartworm, and other nematodes.

Insect Growth Regulators (Fleas only)

Around the early 90’s drugs with mechanisms of action unrelated to the nervous system started coming onto the market. Insect Growth Regulators (IGRs) were the first class. They affect development of the insect from juvenile to larvae. As a result it takes a while for them to affect the flea population. Consequently they are used in conjunction with an adulticide such as a pyrethroid or pyrethin.

IGRs are further divided into two subclasses. Juvenile hormone analogs (JHA) such as methoprene, and pyriproxyofen. They falsely signal insects to remain immature. Methoprene is used as a spray on. Pyriproxofen is used as a spot-on in combination with an adulticide in cats (Vectra for cats, Summit VetPharm). The second subclass of IGRs is the insect development inhibitor such as lufenuron (Program Sentinel, Novartis Animal Health). Sentinel is luferon plus milbemycin (for preventing heartworm) which inhibits chitin formation leading to deformed fleas. Lufenuron is an oral product. When fleas bite animals treated with lufenuron they ingest the chemical and their offspring develop improperly.

Phenylpyrazole (kills fleas and brown dog tick)

Another newer class of insecticides called the phenylpyrazoles is represented by fipronil (Frontline, Merial). Like the avermectins, fipronil works at GABA-gated and glutamate-gated channels leading to disinhibition of signals; however, it is a non-competitive inhibitor. This means it does not bind to the same site of the GABA receptor as GABA, rather it binds to a separate site and thus affects GABA’s ability to bind. This receptor site is specific to ectoparasites and not in mammals. Unlike the avermectins, note that fipronil blocks rather than activates the GABA-gated chloride channels from performing normal inhibitory function and this leads to insect death. Fipronil kills both fleas and all stages of brown dog tick. Like the IGR and avermectins, it is not a repellant. The ticks do not fall off immediately. Fipronil can be combined with methoprene (Frontline Plus, Merial) to kill developing fleas. Both are available as spot-ons.


There are a number of neonicotinoids: These products stimulate the nicotinic receptors of systems like organophosphates do but by an indirect mechanism. They have a much lower affinity for the nicotinic receptors of humans than insects so are safer than organophosphates. The receptors are widely distributed in insects and are uniquely matched for them and consequently have few side effects in dogs and cats. The neonicotinoids do not repel fleas so it takes time for the fleas to fall off. They may be combined with pyrethroids to repel fleas and ticks.

There are three neonicotinoid products on the market—imidacloprid (Advantage, Bayer Animal health), nitenpryam (Capstar, Novartis Animal Health) and dinotefuran (Vectra 3D, Summit VetPharm).

Imidocloprid is a spot-on and is combined with permethrins (Advantix, Bayer Animal Health) to treat ticks and repel fleas. The permethrins repel both ticks and fleas. Unlike the old spray on permethrin products, Advantix is less likely to cause toxicity in pets because it’s administered as a spot-on. Baynes, whose area of research is on dermal absorption of insecticides explains, “The insecticides like the many veterinary insecticides approved by US EPA are retained on the skin surface upper epidermis of the pet and work laterally across the body. Many studies have shown that dermal absorption is limited and very little if any of these insecticides get into the general systemic circulation blood. The exceptions of course include the US FDA approved topical avermectins which are systemically available to treat endo- and ecto-parasites” Furthermore, because the spot-ons are administered between the scapula, cats are not likely to lick them off. Owners should however be aware that although K9 Advantix is similar to Advantage in that they both contain the neonicotinoid safe for cats and dogs, the K9 Advantix also has permethrin and because of concerns of potential permethrin toxicity in cats, it should be given as labeled only to dogs.

Nitenpryam (Capstar) is an oral neonicotinide which is readily absorbed into the bloodstream reaching maximal concentration in 1 hour in dogs and 0.6 hours in cats. The half-life is 27 hours. It can be given every other day to act as an adulticide. It provides a quick kill because it doesn’t have to travel along the dermis to the rest the rest of the body. Fleas feed on the blood and die. Fleas begin falling off the dog or cat within 30 minutes. This type of fast-acting flea product can then be followed with a longer acting spot-on.

A third neonicotinoid is the spot-on dinotefuran (Vectra®).


Another new compound, spinosad (Comfortis™, Lilly Animal Health) targets nicotinic acetylcholine receptors of a type that is different from those targeted by other insecticides such as the neonicotinoids. These receptor sites are very specific to insects and thus spinosad has little toxicity to mammals. Like nitenpryam, Comfortis is given orally and thus it starts acting very rapidly (as soon as 30 minutes). It has a 100% knockdown in 4 hours is indicated for the prevention and treatment of flea infestations on dogs for one month.


Finally, one of the newest classes, metaflumizone (Promeris for Cats; Promeris Duo, Fort Dodge Animal Health), a semicarbazone, like pyrethrins works at the voltage-gated sodium channels; however, according to Doug Rugg, Pharmaceutical Research and Development for Fort Dodge, “Metaflumizone blocks the voltage-dependent sodium channels rather than enhancing them. Consequently it leads to flaccid paralysis and death of the flea rather than repetitive nerve firing and death the way pyrethroids do.” Promeris is a spot-on and like the other spot-ons leads to good knockdown of fleas within about 24 hours. Promeris Duo also contains amitraz, discussed above, for ticks.

While the number of products can be confusing, Baynes says, “By knowing the mechanism of action, veterinarians can better decide on which product to use when the one they are using fails to work well.”

Posted May 15, 2009 (Modified from an article first published in Veterinary Forum June 2008)

References and Further Reading:

  1. Bloomquist, JR. (2003). Chloride channels as tools for developing selective insecticides. Arch. Insect Biochem. Physiol. 54: 145–156.
  2. Buckingham S, Lapied B, Corronc H, Sattelle F. (1997). Imidacloprid actions on insect neuronal acetylcholine receptors. J Exp Biol. 1997;200(Pt 21):268592
  3. Grossman, MR. (1993). Amitraz toxicosis associated with ingestion of an acaricide collar in a dog. J Am Vet Med Assoc. 203(1):5557.
  4. Hovda LR, Hooser SB. (2002). Toxicology of newer pesticides for use in dogs and cats. Vet Clin North Am Small Anim Pract. 32(2):455467
  5. Hugnet C, Buronrosse F, Pineau, X., Cadore, JL., Lorgue G, Berny PJ. (1996). Toxicity and kinetics of amitraz in dogs. Am J Vet Res. 57(10):15061510.
  6. Meyer EK. (1999). Toxicosis in cats erroneously treated with 45 to 65% permethrin products. J Am Vet Med Assoc 215(2): 198-203
  7. Richardson JA. (2000). Permethrin Spot-On Toxicoses in Cats. J. Vet. Emerg. Critical Care, 10(2): 103106.
  8. Schroeder ME., and Flattum, RF. (1984). The mode of action and neurotoxic properties of the nitromethylene heterocycle insecticides. Pest. Biochem. Physiol. 22: 148160.
  9. Sheets, L.P. (2001). Imidacloprid: A neonicotinoid insecticide. In: Handbook of Pesticide Toxicology, Volume 2. (Krieger, RI Ed), Academic Press, New York, NY. Pp11231130.
  10. Tomizawa, M., and Casida, JE. (2003). Selective toxicity of neonicotinoids attributable to specificity of insects andmammalian nicotinic receptors. Annu. Rev. Entomolo. 48: 339364.
  11. Zhao, X., Yeh, JZ., Salgado, VL., Narahashi, T. (2005). Sulfone metabolite of fipronil blocks gamma-aminobutyric acid- and glutamate-activated chloride channels in mammalian and insect neurons. J. Pharmacol. Exp. Ther. 314(1):363–373.


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