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Professional Version

Ectoparasiticides Used in Small Animals


Michael W. Dryden

, DVM, PhD, DACVM, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University

Reviewed/Revised Nov 2015 | Modified Oct 2022

Flea and tick infestation is a major health problem in dogs and cats, and control presents an economic burden to their owners. Traditionally, a wide array of ectoparasiticides has been available, and switching among brands was frequent, leading to problems in achieving acceptable external parasite control. Veterinarians are uniquely qualified to explain the host/parasite interrelationships and advise owners on selection of the most suitable control program. However, many pet owners still purchase flea and tick products in supermarkets or pet supply shops where professional advice is not available. Recent advances in product technology have greatly expanded the available options for veterinarians and pet owners. However, this wide array of available parasiticides can lead to confusion. Veterinarians should become familiar with these technologic improvements in both insecticidal chemistry and delivery systems and encourage client education by their staff.

Active Chemical Ingredients

Nomenclature can be confusing if the shorter approved name is not used and the full chemical name is written (eg, chlorpyrifos versus 0,0-diethyl 0-[3,5,6 trichloro 2 pyridyl] phosphorothioate). The use of trade names can cause added confusion. Although most commercial products contain only one active ingredient, it is not uncommon for two or more to be combined to provide enhanced efficacy or broader spectrum of activity. All labels should be read carefully for ingredients, age and species restrictions, and directions for use.

Macrocyclic Lactones:

Currently, three macrocyclic lactones are used for control of internal and external parasites in dogs and cats: selamectin and aprinomectin, which are semisynthetic avermectins, and moxidectin, a semisynthetic milbemycin. Although the exact mode of action of macrocyclic lactones is not fully elucidated, it is believed that they bind to glutamate-gated chloride channels in the parasites’ nervous system, increasing their permeability and allowing for the rapid and continued influx of Cl into the nerve cell. This inhibits nerve activity and causes paralysis of the parasite. Selamectin is presented as a single active ingredient; moxidectin is combined with imidacloprid ( see Neonicotinoids: Neonicotinoids: Flea and tick infestation is a major health problem in dogs and cats, and control presents an economic burden to their owners. Traditionally, a wide array of ectoparasiticides has been available... read more , below); and eprinomectin has been combined with fipronil ( see Phenylpyrazoles: Phenylpyrazoles: Flea and tick infestation is a major health problem in dogs and cats, and control presents an economic burden to their owners. Traditionally, a wide array of ectoparasiticides has been available... read more , below), S-methoprene ( see Insect Growth Regulators: Insect Growth Regulators: Flea and tick infestation is a major health problem in dogs and cats, and control presents an economic burden to their owners. Traditionally, a wide array of ectoparasiticides has been available... read more , below), and praziquantel. These macrocyclic lactones are applied topically, rapidly absorbed through the skin, and distributed via the blood. They have activity against a variety of internal and external parasites.

Cholinesterase Inhibitors:

Two groups of compounds, organophosphates and carbamates, share the same mechanism of action—inhibition of acetylcholinesterase. This enzyme normally is responsible for acetylcholine (neurotransmitter) destruction. Applications of organophosphates or carbamates to insects produce spontaneous muscular contractions followed by paralysis. The binding of organophosphates to acetylcholinesterase is more persistent, if not permanent, whereas the interaction with carbamates is reversible. These compounds were once very popular for their prolonged action and potency. However, the use of organophosphates has declined because their low margin of safety and slight variance from approved use or continued use may lead to toxicity. When these compounds are used for flea or tick control, it should be determined before treatment whether any other cholinesterase inhibitor has been used on the animal or in its environment. Organophosphates for small animal therapy include chlorpyrifos, dichlorvos, malathion, diazinon, phosmet, fenthion, chlorfenvinphos, and cythioate. Carbamates include carbaryl and propoxur.

Chlorinated Hydrocarbons:


The neonicotinoids are a class of insecticides referred to as nitroquanidines, neonicotinyls, chloronicotines, and recently as chloronicotinyls. The neonicotinoids are modeled after natural nicotine. Three compounds in this category are currently available for veterinary use: dinotefuran, imidacloprid, and nitenpyram. All neonicotinoids act as agonists on the postsynaptic acetylcholine receptors in insects. This inhibits cholinergic transmission, resulting in paralysis and death. Imidacloprid is applied as a spot-on topical product and is used primarily to control fleas on both dogs and cats. It also has excellent activity against lice. Although it has potent residual activity, it is readily soluble in water, so swimming and repeated bathing may compromise its duration of activity. Nitenpyram is administered PO in pill form to kill fleas in both dogs and cats. It is absorbed rapidly, with maximal blood concentrations reached within 1.2 hr in dogs and 0.6 hr in cats. Fleas begin to die within 20–30 min of administration, with 100% flea mortality within 3–4 hr. The compound is rapidly eliminated, with >90% excreted in the urine within 24–48 hr, primarily as unchanged nitenpyram. Even though imidacloprid and nitenpyram are classified similarly, their mechanisms of action appear to be different. Although imidacloprid is described as a paralytic, nitenpyram produces hyperexcitability in fleas before death.

The newest addition to the neonicotinoids is dinotefuran, considered a third-generation neonicotinoid. The structure of dinotefuran is unique in that it was derived from that of the acetylcholine molecule rather than nicotine. It has been proposed that dinotefuran does not bind to the same sites as imidacloprid and other neonicotinoids but at a different site in the nerve synapse. Dinotefuran is applied as a topical spot-on with different formulations for dogs and cats. The cat formulation is combined with the insect growth regulator pyriproxyfen and is used primarily to control fleas. The dog formulation contains pyriproxyfen and permethrin and is labeled for control of fleas, ticks, and mosquitoes.


This small group of acaricidal compounds has the proposed mode of action of binding to octopamine receptors, a specific group of receptors found in Acari. In veterinary medicine, the only approved formamidine is amitraz. It is used primarily as an acaricide to control ticks and mites. It is available as a dip for control of canine demodicosis, and it will also control scabies. An amitraz-impregnated collar is also marketed for control of ticks on dogs. Amitraz is not approved for use on cats.


Oxadiazine insecticides can control a broad spectrum of insects and were originally developed for use against a variety of insects infesting vegetables, fruit, and row crops. Indoxacarb is the only member of this group currently being used in veterinary medicine. It is considered a pro-insecticide that is metabolized within the insect to a more active form, which is an N-decarbomethoxylated metabolite that is at least 40 times more potent than parent indoxacarb. This metabolic conversion of indoxacarb, known as bioactivation, is attributed to actions of esterase and amidase enzymes within the insect. The active metabolite exerts its effect by blocking the voltage-gated sodium ion channels in insects. Indoxacarb is administered topically in a spot-on formulation for control of fleas on dogs and cats. Indoxacarb has also been combined with permethrin for control of ticks on dogs.


Isoxazolines are a new class of compounds that have both potent insecticidal and acaricidal activities. Isoxazolines have a novel mode of action and specifically block arthropod ligand-gated chloride channels. Afoxolaner and fluralaner are currently the only two compounds approved for use in veterinary medicine. Both are unique in that they were the first oral flea and tick products. The compounds are readily absorbed after oral administration and provide 4–12 wk of insecticide and acaricide activity.

Insect Growth Regulators:

These compounds inhibit the development of immature stages of insects. They are generally classified as either juvenile hormone mimics (insect growth regulators) or as chitin synthesis inhibitors (insect development inhibitors). Methoprene, fenoxycarb, and pyriproxyfen are similar in structure to insect juvenile hormone and are classified as juvenile hormone mimics. When these compounds are applied to flea larvae or into their environment, they are absorbed by the larvae and act like natural insect juvenile hormone. Juvenile hormone analogues bind to juvenile hormone receptor sites; larvae are prevented from completing metamorphosis and subsequently die. These compounds also have ovicidal and embryocidal activity against flea eggs when applied topically to dogs and cats. Female fleas in the hair coat absorb the juvenile hormone analogue, which affects viability of developing eggs. These compounds are active against a wide range of insects, including mosquito larvae; methoprene is used as a larvicide in the strategic control of mosquito-borne diseases. For flea control, their outdoor use should be limited to specific flea habitats to avoid adverse effects on beneficial insect species.

Lufenuron, a benzoylphenyl urea, inhibits the formation of chitin (a polymer of N-acetyl glucosamine), which is a major component of insect exoskeletons. During each larval molt, chitin is reformed by polymerization. Lufenuron interferes with polymerization and deposition of chitin, killing developing larvae either within the egg or after hatching. Lufenuron is administered PO to dogs or cats or by injection to cats. Female fleas feeding on treated animals are prevented from producing viable eggs or larvae. Other insect development inhibitors, such as diflubenzuron (another chiton inhibitor) and cyromazine (a moulting disruptor), also have considerable activity against developing fleas. Insect growth regulators and insect development inhibitors affect many insect species that undergo complete metamorphosis, but they have little or no activity against ticks or other Acari, which undergo incomplete metamorphosis.


This group of compounds has broad-spectrum activity that is both insecticidal and acaricidal. The members of this group currently available for use in veterinary medicine worldwide include fipronil and pyriprole. These compounds bind to γ-aminobutyric acid and glutamate-gated receptor sites of insect nervous systems, inhibiting the flux of Cl into nerve cells, which results in hyperexcitability. These compounds have broad-spectrum activity against fleas, ticks, mites, and lice. Numerous fipronil-containing formulations are available worldwide, including an alcohol-based fipronil-only spray, several spot-on formulations that contain only fipronil, a spot-on combination with the insect growth regulator methoprene, and numerous combination formulations that contain fipronil and various pyrethroids. Fipronil is very lipophilic; it accumulates in the sebaceous glands, has very low solubility in water, and has prolonged residual activity on both dogs and cats.

Pyrethrins and Pyrethroids:

These compounds rapidly disrupt sodium and potassium ion transport in nerve membranes, resulting in spontaneous depolarizations, augmented neurotransmitter secretion, and neuromuscular blockade, causing paralysis. Although the activity is rapid, without sufficient exposure paralyzed insects can also recover rapidly. The synergists piperonyl butoxide and N-octyl bicycloheptene dicarboxymide interfere with the insect detoxification mechanism and can potentiate the activity of pyrethroids. Natural pyrethrum is extracted from chrysanthemum flowers and is notable for its rapid but brief action and relative lack of toxicity in dogs and cats.

Synthetic pyrethroids are pyrethrum-like compounds that generally have greater potency and residual effects but are less well tolerated in cats. Some pyrethroids, such as permethrin, can be highly toxic to cats. Pyrethroids are generally classified by developmental generation. First-generation pyrethroids are generally unstable in heat and sunlight (eg, allethrin); second-generation are more photostable, isomeric mixtures (eg, cypermethrin, permethrin); third-generation are photostable and more neurologically active isomers obtained by isomeric enrichment (eg, lambda-cyhalothrin, β-cyfluthrin); and fourth-generation are nonester pyrethroids (eg, MTI 800, flufenprox, etofenprox).


Spinosyns are a novel family of insecticides derived from the fermentation of the actinomycete, Saccharopolyspora spinosa. The two most abundant products derived from the fermentation process are spinosyns A and D, which are the major active components of spinosad. Spinosad is used to control a wide variety of insects, including flies and fleas. Spinosyns have a novel mode of action, primarily targeting binding sites on nicotinic acetylcholine receptors distinct from other insecticides such as neonicotinoids. Spinosyns also affect γ-aminobutyric acid receptor function, which may contribute further to their insecticidal activity. These actions cause excitation of the insect nervous system, leading to involuntary muscle contractions, prostration with tremors, and finally paralysis. Spinosad has activity against fleas and is formulated as a chewable tablet for dogs and cats. A topical spot-on spinosyn formulation called spinetoram has been developed for cats.


N,N-diethyl-3-methylbenzamide (DEET, previously called N,N-diethyl-meta-toluamide) remains the most effective among currently available insect repellents for people. It is a broad-spectrum repellent effective against mosquitoes, biting flies, chiggers, fleas, and ticks. However, the effectiveness of DEET formulations for dogs and cats has not been proved, and safety is a concern because concentrated formulations containing DEET have caused weakness, paralysis, liver disease, and seizures in pets. DEET should not be administered to dogs or cats.

The synthetic pyrethroid permethrin is a rapidly acting neurotoxicant that can produce what is termed a “hot-foot” effect and is often described as a repellency. Various permethrin formulations are labeled as repellents for ticks, mosquitoes, and fleas.


Synergists are generally not considered toxic or insecticidal but are used with insecticides to enhance their activity. They are used primarily to potentiate the activity of pyrethrum or pyrethroids. Synergists inhibit cytochrome P450–dependent monooxygenases or glutathione S-transferases, enzymes produced by microsomes in insect tissues. They bind the oxidative enzymes that would normally break down the insecticide and prevent them from degrading the toxicant. Piperonyl butoxide and N-octyl bicycloheptene dicarboxamide are common synergists.

Target Parasite Efficacy

Because of specific formulation and drug delivery technology, certain insecticides are used in a wide variety of ectoparasite control products. Efficacy of specific compounds can vary against target species, and resistance to insecticides may develop in specific locations, especially with incorrect, prolonged, or repeated use. It cannot be assumed that ticks and fleas are controlled by the same active compounds; product labels should be carefully read. Products that contain compounds specifically active against the target parasite should be chosen, whether the concern is fleas, ticks, mites, or a combination of these parasites.

Duration of activity (ie, “knockdown” or sustained effects) can be the primary concern in product choices. Products should be evaluated based on both their immediate and residual speed of kill. A rapid residual speed of kill is critically important when attempting to manage flea allergy dermatitis and to reduce the chances of a tick transmitting a pathogen.

Modern parasiticides available for flea and tick control in companion animals provide superior parasite control, but an understanding of the life cycle of the parasites, along with the mode of action of the particular molecules, is also important. Often, perceived product failures are a result of massive reinfestation from the environment, incorrect product use, or unrealistic expectations.


Although LD50 data concerning the safety or toxicity of an insecticidal product is often helpful, LD50 values are not always the best indicator of the safety of specific insecticide formulations applied to pets or premises. Consideration must be given to the concentration of product (mg/mL), application rate (mg or g/m2 for environmental products, and mcg or mg/kg for topicals), route of exposure (dermal or oral), total dose, and the species exposed. The actual risk of exposure during treatment, after treatment, or after accidental ingestion can be assessed only after evaluation of these criteria.

Because animal toxicity can be modified by formulation technology, active ingredients are not the sole guide to safety assessment of a product. Most commercially available products have undergone adequate safety evaluation for regulatory approval; the label noting such approval remains the best source of information. Cats are sensitive to many insecticides, and use of these insecticides on or near cats must be done with caution. Human and environmental safety also should be considered, especially when treating premises (eg, some compounds may break down into more toxic components; older products on the shelf might have been withdrawn because of safety concerns). Generalizations should not be made, because formulations generally safe for grass application may induce skin reactions, or even fatal reactions, in sensitive individuals and certain breeds of dogs and cats.

Delivery Systems

Consumer convenience is an important factor in product choice, especially for flea and tick control. An array of delivery systems has historically been available: powders, aerosols, sprays, shampoos, rinses, dips, spot-ons, mousses, injectables, oral tablets or liquids, and impregnated collars. However, the safety, efficacy, and ease of use of the newer spot-on and oral application systems have rendered many of the older application technologies essentially obsolete.

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