Ectoparasiticides Used in Large Animals

• Products are available as topical formulations, ear tags, and premises treatments.

• Efficacy depends on the specific compound and formulation; most are effective against flies, fly larvae, lice, ticks, and mites.

• Animal and human toxicity concerns have limited the use and availability of these compounds. Atropine is the most commonly used antidote.

• Use and availability have also decreased due to environmental concerns.

The organophosphates, which comprise a large group of chemicals, are available for topical application (dichlorvos, tetrachlorvinphos, coumaphos, trichlorfon, phosmet, and pirimiphos), in ear tags (chlorpyrifos, coumaphos, diazinon, and pirimiphos), and for premises applications. Coumaphos is still approved for use as a miticide against varroa mites in honey bees but is no longer recommended due to resistance and accumulation in beeswax.

Due to safety concerns (animal, human, and environmental), only a few organophosphates are still used for on-animal treatment, and those for nonanimal applications are being restricted (eg, malathion).

The organophosphates are generally active against fly larvae, flies, lice, ticks, and mites on domestic production animals, although activity varies between compounds and formulations. A brief list of some compounds and their use is provided in the table Organophosphates for Ectoparasites; not all parasites are listed, and details on animal production status and withdrawal times are not included. All labels must be carefully read before use to ensure compliance with current regulations.

Organophosphates are neutral esters of phosphoric acid or its thio analogue that inhibit the action of acetylcholinesterase (AChE) at cholinergic synapses and at muscle end plates. The compound mimics the structure of acetylcholine (ACh); when it binds to AChE, it causes transphosphorylation of the enzyme. The transphorylated AChE is unable to break down accumulating ACh at the postsynaptic membrane, leading to neuromuscular paralysis. The extent of transphorylation of the enzyme helps to determine the activity of the organophosphate. Eventually, the AChE is metabolized by oxidative and hydrolytic enzyme systems.

Organophosphates can be extremely toxic in animals and humans, inhibiting AChE and other cholinesterases (see Insecticide and Acaricide Toxicity). Chronic toxicity results from inhibition of the enzyme neuropathy target esterase (NTE) or neurotoxic esterase and is associated with particular compounds.

NTE hydrolyzes the fatty acids from the membrane lipid, phosphatidylcholine. Inhibition of NTE appears to cause structural changes in neuronal membranes and a decrease in conduction velocity, which may be manifest as caudal paralysis in some animals. Breeds of cattle sensitive to organophosphates (eg, Charolais, Simmental, and Brahman) should not be treated with them.

Cases of organophosphate toxicity are treated primarily with atropine. Pralidoxime chloride (2-PAM) also can be used. Organophosphates should not be used simultaneously or within a few days before or after treatment or exposure to other cholinesterase-inhibiting drugs, pesticides, or chemicals. They should not be applied to young, sick, convalescent, or stressed animals.

Carbamate insecticides are closely related to organophosphates and are anticholinesterases. Unlike organophosphates, they appear to cause a spontaneously reversible block on AChE without changing it. The main carbamate compound used in veterinary medicine is propoxur, used primarily for premises treatments.

Cases of carbamate poisoning are treated with atropine. Carbaryl has been withdrawn from the veterinary market, and 2-PAM is contraindicated for treatment of carbamate poisoning because it has been shown to worsen outcomes.

• Products are available in topical formulations, as dips, in ear tags, and as premises treatments.

• Both products have activity against biting and nuisance flies, lice, and ticks on domestic production animals.

• Resistance has been documented with many pyrethroids; nonetheless, their use has increased with decreasing use of organophosphates.

Natural pyrethrins are derived from pyrethrum, a mixture of alkaloids from Chrysanthemum spp. Pyrethrum extract, prepared from the pyrethrum flower head, contains several molecules collectively known as pyrethrins (pyrethrin I and II, cinerin I and II, and jasmolin I and II).

Pyrethrins are lipophilic molecules that generally undergo rapid absorption, distribution, and excretion. They provide excellent knockdown (rapid kill) but have poor residual activity because of instability. Pyrethrin I is the most active ingredient for kill, and pyrethrin II for rapid insect knockdown. These are most commonly used in short-acting sprays and premises applications.

Pyrethroids (often classified as first through fifth generation) are synthesized chemicals modeled on the natural pyrethrin molecule. They are more stable and thus have longer residual activity and a higher potency than natural pyrethrins. They are often combined with synergists (eg, piperonyl butoxide and N-octyl bicycloheptene dicarboximide [MGK 264]; see miscellaneous compounds), macrocyclic lactones, organophosphates, and insect growth regulators.

A brief list of some pyrethroids and their use is provided in the table Pyrethroids for Ectoparasites; not all parasites are listed and details on animal production status and withdrawal times are not included. All labels must be carefully read before use to ensure compliance with current regulations and to determine the fly, tick, and lice species that the products are effective against. Cats are particularly vulnerable to toxicity from permethrin; products labeled for other species should not be used on cats. Availability of pyrethroid products is country-dependent.

The mode of action of pyrethrins and pyrethroids appears to be interference with sodium channels of the parasite nerve axons, resulting in delayed repolarization and eventual paralysis. Synthetic pyrethroids can be divided into two groups (types I and II, depending on the presence or absence of an alpha-cyano moiety):

• Type I compounds have a mode of action similar to that of DDT, involving interference with the axonal Na⁺ gate leading to delayed repolarization and repetitive discharge of the nerve.

• Type II compounds also act on the Na⁺ gate but do so without causing repetitive discharge.

The lethal activity of pyrethroids seems to involve action on both peripheral and central neurons, while peripheral neuronal effects alone probably produce the knockdown effect.

Pyrethroids are generally safe in mammals and birds but are highly toxic to fish and aquatic invertebrates. Concerns have been expressed over their environmental effects, particularly in relation to the aquatic environment, leading to their withdrawal as sheep dips in some countries. Pyrethroid insecticides available for use on large animals are considered safe but have general precautionary statements on their labels, particularly in relation to disposal and their potential ecotoxicological effects.

• Products are available in topical formulations, in ear tags, and in subcutaneous and intramuscular injections

• Ectoparasite activity depends on the active molecule, the product formulation, and the method of application.

• With the exception of abamectin (EPA registered), these are registered with the FDA.

• The FDA-registered compounds are often referred to as endectocides due to activity against a wide range of nematodes as well as arthropods.

Avermectins and the structurally related milbemycins, collectively referred to as macrocyclic lactones, are fermentation products of Streptomyces avermitilis and S cyaneogriseus, respectively. Avermectins differ from each other chemically in side chain substitutions on the lactone ring, whereas milbemycins differ from the avermectins through the absence of a sugar moiety from the lactone skeleton.

Macrocyclic lactones can be administered PO, parenterally, or topically (as pour-ons and spot-ons). The method of application depends on the host and, to some extent, on the target parasites. In cattle, for example, available endectocide products can be administered PO, by injection, or topically using pour-on formulations.

• Pour-ons are generally more effective against lice (Linognathus, Haematopinus, and to some extent Bovicola) and head fly (Haematobia/Lyperosia) infestations than equivalent compounds administered parenterally.

• In sheep, PO administration of some endectocides has little effect against psoroptic mite infestations (Psoroptes ovis); however, parenteral administration increases activity, providing both protection and control depending on the product used.

A brief list of some macrocyclic lactones used for ectoparasites of cattle is provided in the table Macrocyclic Lactones for Ectoparasites of Cattle. Not all ectoparasites are listed and details on animal production status and withdrawal times are not included. All labels must be carefully read before use to ensure compliance with current regulations and to determine the fly, tick, mite and lice species that the products are effective against.

In addition to the uses in the table, ivermectin, administered SC for swine, has efficacy against lice (Haematopinus suis) and mange mites (Sarcoptes scabiei suis) as well as warbles (Oedemagena tarandi) in reindeer and grubs (Hypoderma bovis) in American bison. Ivermectin administered PO or SC, also is used to treat Oestrus ovis (nasal bot fly) in sheep. Doramectin as an intramuscular injection for swine has efficacy against sucking lice (H suis) and mange mites (S scabiei suis).

The route of administration and product formulation influence the rates of absorption, metabolism, excretion, and subsequent bioavailability and pharmacokinetics of individual compounds. Avermectins and milbemycins are highly lipophilic, a property that varies with only minor modifications in molecular structure or configuration. After administration, these compounds are stored in fat, from which they are slowly released, metabolized, and excreted.

Ivermectin is absorbed systemically after PO, SC, or dermal administration; it is absorbed to a greater extent and has a longer half-life when administered SC or dermally. Excretion of the unaltered molecule is mainly via the feces, with < 2% excreted in urine of ruminants. In cattle, the decreased absorption and bioavailability of ivermectin administered PO may be due to its metabolism in the rumen.

The affinity of these compounds for fat explains their persistence in the body and the extended periods of protection afforded against some species of internal and external parasites. The prolonged half-life of these compounds also determines residue levels in meat and milk and the subsequent compulsory withdrawal periods after treatment in food-producing animals.

Macrocyclic lactones bind to glutamate receptors of glutamate-gated chloride channels, triggering Cl^– ion influx and hyperpolarization of parasite neurons, leading to flaccid paralysis. These molecules have low affinity for mammalian ligand-gated chloride channels and do not readily cross the blood-brain barrier.

Amitraz is the only formamidine used as an ectoparasiticide. It appears to act by inhibition of the enzyme monoamine oxidase and as an agonist at octopamine receptors. Monoamine oxidase metabolizes amine neurotransmitters in ticks and mites, and octopamine is thought to modify tonic contractions in parasite muscles. Amitraz has a relatively wide safety margin in mammals; the most frequently associated adverse effect is sedation, which may be associated with an agonist activity of amitraz on alpha-2 receptors in mammalian species.

Amitraz is available as a spray or dip for use against mites, lice, and ticks in domestic production animals. It controls lice and mange in pigs and psoroptic mange in sheep. In cattle, it has been used in dips, sprays, or pour-ons for control of single-host and multihost tick species.

In dipping baths, amitraz can be stabilized by the addition of calcium hydroxide and maintained by standard replenishment methods for routine tick control. An alternative method involves the use of total replenishment formulations in which the dip bath is replenished with full concentration of amitraz at weekly intervals before use. Amitraz is contraindicated in horses.

Imidacloprid is a chloronicotinyl insecticide, a synthesized chlorinated derivative of nicotine. Spinosad is a fermentation product of the soil actinomycete Saccharopolyspora spinosa. Both compounds bind to nicotinic acetylcholine receptors (but at different sites) in the insect’s CNS, leading to inhibition of cholinergic transmission, paralysis, and death.

Spinosad has been developed in some countries for use on sheep to control blow fly strike and lice. It also has been developed as a premises spray and granular formulation for control of insects. Spinosad is no longer available in feed-through or ear tag formulations in the US, though it is approved for systemic use in dogs and cats in the US.

Insect growth regulators (IGRs) constitute a group of chemical compounds that do not directly kill the adult parasite but interfere with growth and development of different stages. Because they act mainly on immature parasite stages, IGRs are not usually suitable for rapid control of established adult parasite populations.

Where parasites show a clear seasonal pattern, IGRs can be applied before any anticipated challenge as a preventive measure. They are widely used for blow fly control in sheep. Some are incorporated into feed to prevent development of fly stages in manure.

Based on their mode of action, IGRs can be divided into the following categories:

• chitin synthesis inhibitors (benzoylphenyl ureas)

• chitin inhibitors (triazine/pyrimidine derivatives)

• juvenile hormone analogues (S-methoprene, pyriproxyfen)

Several benzoylphenyl ureas have been introduced to control ectoparasites. Chitin is a complex aminopolysaccharide and a major component of the insect’s cuticle. During each molt, it has to be newly formed by polymerization of individual sugar molecules. The exact mode of action of the benzoylphenyl ureas is not fully understood. They inhibit chitin synthesis but have no effect on the enzyme chitin synthetase. It has been suggested that they interfere with the assembly of the chitin chains into microfibrils. When immature insect stages are exposed to these compounds, they are not able to complete ecdysis and die during molting.

Benzoylphenyl ureas also appear to have a transovarial effect. Exposed adult female insects produce eggs in which the compound is incorporated into the egg nutrient. Egg development proceeds normally; however, the newly developed larvae are incapable of hatching. Benzoylphenyl ureas show a broad spectrum of activity against insects but have relatively low efficacy against ticks and mites. The exception is fluazuron, which has greater activity against ticks and some mite species.

Benzoylphenyl ureas are highly lipophilic molecules. When administered to the host, they build up in body fat, from which they are slowly released into the bloodstream and excreted largely unchanged.

Diflubenzuron and flufenoxuron are used to prevent blow fly strike in sheep. Diflubenzuron is available in some countries as an emulsifiable concentrate for use as a dip or shower. It is more efficient against first-stage larvae than second and third instars and is therefore recommended as a preventive, providing protection for 12–14 weeks. It may also have potential to control a number of major insect pests, such as tsetse flies.

Fluazuron is available in some countries for use in cattle as a tick development inhibitor. When applied as a pour-on, it provides longterm protection against the 1-host tick Rhipicephalus (formerly Boophilus) microplus.

Triazine and pyrimidine derivatives are closely related compounds that are also chitin inhibitors. They differ from the benzoylphenyl ureas both in chemical structure and mode of action (ie, they appear to alter the deposition of chitin into the cuticle rather than its synthesis).

Cyromazine, a triazine derivative, is effective against blow fly larvae on sheep and lambs and also against other Diptera, such as houseflies and mosquitoes. At recommended dosage rates, cyromazine shows only limited activity against established strikes and must therefore be used preventively. Blow flies usually lay eggs on damp fleece of treated sheep. Although larvae are able to hatch, the young larvae immediately come into contact with cyromazine, which prevents the molt to second instars.

The efficacy of a pour-on preparation of cyromazine does not depend on factors such as weather, fleece length, and whether the fleece is wet or dry. Control can be maintained for up to 13 weeks after a single pour-on application, or longer if cyromazine is applied by dip or shower.

Dicyclanil, a pyrimidine derivative, is highly active against dipteran larvae. A pour-on formulation, available in some countries for blow fly control in sheep, provides up to 20 weeks of protection.

The juvenile hormone analogues mimic the activity of naturally occurring juvenile hormones and prevent metamorphosis to the adult stage. Once the larva is fully developed, enzymes within the insect’s circulatory system destroy endogenous juvenile hormones, prompting development to the adult stage. The juvenile hormone analogues bind to juvenile hormone receptor sites; however, because they are structurally different, they are not destroyed by insect esterases. Metamorphosis and further development to the adult stage does not proceed. S-Methoprene is a terpenoid compound with very low mammalian toxicity that mimics a juvenile insect hormone and is used as a feed-through larvicide for horn fly (Haematobia) control on cattle.

Piperonyl butoxide and MGK 264 (N-octyl bicycloheptene dicarboximide) are used as synergistic additives in the control of arthropod pests. They are commonly formulated together with insecticides such as pyrethrins. The extent of potentiation of insecticidal activity is related to the ratio of components in the mixture; as the proportion of piperonyl butoxide or MGK 264 increases, the amount of pyrethrins required to evoke the same level of kill decreases.

The insecticidal activity of other pyrethroids, particularly of knockdown agents, can also be enhanced by the addition of piperonyl butoxide or MGK 264. Piperonyl butoxide inhibits the microsomal enzyme system of some arthropods and is effective against some mites. In addition to having low mammalian toxicity and a long record of safety, it rapidly degrades in the environment.

Various products from natural sources, as well as synthetic compounds, have been used as insect repellents, including the following compounds:

• cinerins

• pyrethrins and jasmolins

• citronella oil

• di-N-propyl isocinchomeronate

• butoxypolypropylene glycol

• picaridin

• N,N-diethyl-3-methylbenzamide (DEET)

• dimethyl phthalate (DMP)

The use of repellents is advantageous as legislative and regulatory authorities become more restrictive toward the use of conventional pesticides. They are used mainly to protect horses against blood-sucking arthropods, particularly midges (Culicoides).

Insecticides may be used to provide environmental control of some insects by application to premises. The insect pheromone (Z)-9-tricosene is incorporated into some products to attract insects to the site of application.

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