Learning Objective

• Plan treatment of internal and external parasites for cats, dogs, horses and ruminants

Anthelmintics

Piperazine

Piperazine is a common “over the counter” (OTC) dewormer for horses, dogs and cats, but is rarely used by veterinarians anymore.

Mechanism of Action

An old, safe anthelmintic, piperazine acts by anticholinergic action at the myoneural junction in worms, leading to flaccid paralysis. Worms then lose motility and ability to maintain their position in the GI tract and are swept along by intestinal peristalsis and passed alive in the feces. Mature worms are more susceptible to the action of piperazine than are lumen-dwelling larvae and immature adults. Migrating larval stages are unaffected by piperazine; therefore treatments are repeated in 2-4 weeks.

Anthelmintic Spectrum

Piperazine’s greatest activity is against ascarids in most species. In horses, it has some activity against cyanthostomes (including benzimidazole-resistant cyanthostomes) and pinworms. Piperazine is used in swine because of excellent efficacy against ascarids and nodular worms. It is seldom used in cattle (only efficacious against nodular worms [Oesophagostomum] and ascarids [Neoascaris], and ascarids do not infect small ruminants. Piperazine is effective for ascarids in chickens. It is sold OTC for dogs and cats as “Once a Month Wormer”, and only removes ascarids (roundworms). It is still used in poultry.

Pharmacokinetics

Piperazine is readily absorbed from the GI tract. Some of the piperazine base is metabolized in tissues and the remainder is excreted unchanged in the urine. Urinary excretion is complete within 24 hours of a dose.

Toxicity

Piperazine is a very safe dewormer. It is almost nontoxic under ordinary circumstances and even neonates can be treated safely. Oral overdoses in dogs and cats can cause emesis, diarrhea, incoordination, and head pressing. Overdose in horses, cattle and swine causes transient diarrhea. In foals with extremely heavy ascarid infections, treatment with piperazine occasionally results in intestinal blockage and rupture due to large masses of worms expelled all at once. Therefore, if a heavy ascarid burden is suspected, it is better to treat with a benzimidazole, which causes a slower death and expulsion of the worms.

Benzimidazoles

The benzimidazoles (BDZs) have been developed since the 1960’s to provide anthelmintics with a wide range of antiparasitic action that are highly efficacious, have a wide safety margin and versatile methods of administration. The first benzimidazole developed was thiabendazole. Following it, related compounds were synthesized to create related drugs and prodrugs with unique properties.

Mechanism of Action

The BZDs inhibit tubulin-microtubule equilibrium in the nematode. Microtubules are thought to be essential for enzyme secretion by parasites. The differences in the sensitivity of mammals and parasites to the effects of BZDs may be due to differences in the structure of microtubules in their respective cells. The extent to which differences in the chemical structures of the BZDs influence their mechanism of action is not known, but simple structural modifications often result in dramatic differences in anthelmintic activity.

Anthelmintic Spectrum

The BZDs are broad spectrum in activity and are often effective against adults, larvae and eggs. The compounds are quite similar chemically, and cross resistance by the parasites frequently occurs.

The benzimidazoles currently used in horses are fenbendazole and oxibendazole. Older benzimidazoles are no longer marketed for horses. In horses, BDZs are effective against ascarids, Oxyuris equi, adult cyathostomes and adult large strongyles. Some have efficacy against Strongyloides westeri, lungworms, tapeworms, and Trichostongylus axei. With high doses, fenbendazole has efficacy against encysted early 3rd stage (EL3), late 3rd stage (LL3) and 4th stage (L4) cyathostome larvae and larvae of large strongyles. But cyathostome resistance to BZDs has become very common, so efficacy should be tested for in practice.

In cattle and sheep, the BZDs are effective against the adult and many larval species of GI nematodes and lungworms. The adult forms of GI parasites are readily expelled by BZDs, and some immature stages are eliminated to a high degree as well. Albendazole and oxfendazole have efficacy against encysted 4th stage larvae of Ostertagia. In general, BZDs have limited activity against ruminant whipworms, filarial worms, tapeworms and flukes (albendazole is good for flukes). In swine, the BZDs are effective against most of the GI nematodes.

In dogs, fenbendazole and febantel are approved for treatment of adult hookworms (Ancylostoma caninum), ascarids (Toxocara canis, Toxascaris leonina), whipworms (Trichuris vulpis), and Taenia tapeworms. They are not effective against Dipylidium tapeworms. These drugs also reduce the colostral transmission of hookworms and ascarids when bitches are treated during pregnancy. Other parasites that may be effectively treated with BZDs include Capillaria plica (bladderworm), Filaroides osleri (tracheal worm), Strongyloides stercoralis and Paragonimus kellicotti. Fenbendazole is effective in treating Crenosoma vulpis and Giardia-infected dogs when used at the label dose.

While not approved in cats, fenbendazole can be safely used extralabel at dosages used in dogs for effective treatment of Ancylostoma tubaeforme, Strongyloides stercoralis, Giardia and Taenia taeniaeformis infections. It may be effective in the treatment of Aleurostongylus abstrusus (cat lungworm), Capillaria aerophilia and feliscatti, and Paragonimus kellicotti.

In birds, the BZDs can be used effectively against respiratory and GI tract parasites. Treatment of zoo birds is usually done at lower daily doses over a long period to ensure safety and a full therapeutic dose. The BZDs are also widely used in zoo and game mammals, reptiles and amphibians. They are also used in treating parasitic infections of subhuman primates and laboratory animals (rabbits, guinea pigs, hamsters, tortoises).

There are widespread reports of parasite resistance to individual BZDs and cross resistance usually occurs. Resistance in sheep and goat nematodes is of economic importance in Australia, New Zealand, South Africa and temperate and tropical North and South America. BZD-resistant small strongyles have been reported widely in horses. The mechanisms of resistance have not been identified. The frequency of anthelmintic treatments has a direct relationship to the development of resistance. If the interval between treatments is shortened to near the prepatent period for the parasite, then selection for resistance is increased, because only the anthelmintic-resistant parasites survive to contribute to the next generation of parasites. BZD resistance is slower to develop if a reservoir of anthelmintic-susceptible larvae are in the environment (known as “refugia”).

Pharmacokinetics

Except for thiabendazole, albendazole, and oxfendazole, these drugs are poorly water soluble and poorly absorbed from the GI tract. Absorption that occurs is rapid, but generally the bioavailability is <1% of the dose administered regardless of the oral formulation (paste, suspension, granules or bolus). Albendazole has a bioavailability of 47%. Benzimidazoles are more effective in ruminants and horses than monogastrics, because the presence of a rumen or caecum retains the BZD; increasing plasma levels and anthelmintic activity. Also, divided doses are more effective than single doses because the antiparasitic action depends on prolonged contact time. The degree of metabolism varies between the different BZDs. Febantel is metabolized to fenbendazole and oxfendazole. In most tissues of treated animals, residues of BZDs are detectable in the liver, so a withdrawal period before slaughter is necessary.

Toxicity

The BZDs are extremely safe in most species. They are usually free of adverse effects at therapeutic dose even in young, sick or debilitated animals. The main toxic effect of BZDs is teratogenicity. This effect varies with the BZD structure and there is variation in species susceptibility. Fenbendazole is not associated with teratogenicity. Albendazole is teratogenic and embryotoxic in dogs and sheep, and associated with poor conception rates in cattle. Albendazole is also associated with aplastic anemia that is potentially fatal in dogs and cats. Fenbendazole is rarely associated with bone marrow suppression, but it has been reported in porcupines, painted storks, pigeons and there is one report in a Doberman pinscher.

Available Products

fenbendazole (Panacur®, Safe-Guard®)

oxfendazole (also the active metabolite of albendazole, fenbendazole, febantel) (Synanthic®-only in the US)

albendazole (Valbazen®)

febantel (metabolized to fenbendazole and oxfendazole) (Drontal® plus)

oxibendazole (Anthelcide®)

Macrocyclic Lactones

The avermectins (abamectin, ivermectin, eprinomectin, doramectin, and selamectin) and milbemycins (milbemycin oxime and moxidectin) are macrolide antibiotic derivatives. These drugs have limited antibacterial activity, but marked anthelmintic, insecticidal and acaricidal activity, resulting in their designation as “endectocides”. The introduction of ivermectin as a veterinary parasiticide in France in 1981 revolutionized animal antiparasitic chemotherapy. During the 1980’s and 1990’s, a number of new anthelmintic products were introduced that belong to the avermectin or milbemycin families. They all have similar structures, common mechanisms of action, mutual parasite resistance mechanisms and similar spectra of activity. Those that have some particularly high potency against specific parasites have been developed and marketed for specific purposes. Otherwise these products are all quite similar, and differences in pharmacokinetics are used as marketing advantages. Their remarkable activity and safety have made them important in animal and human health and crop production, but they are not a panacea. None have activity against tapeworms or flukes. There are ecotoxicological concerns with members of the group.

Mechanism of Action

The lipid solubility of the avermectins or milbemycins allows these drugs to penetrate the cuticle of nematodes. So for many GI and filarial nematodes, transcuticular absorption is as great as oral absorption. For blood sucking parasites, such as Haemonchus contortus, and for arthropod ectoparasites the major route of drug uptake is oral. This is supported by greater activity against sucking lice than chewing lice, and against mites that consume blood (Sarcoptes vs Demodex). The observable effects of avermectins and milbemycins varies with the nematode species, but usually involves paralysis of the parasite. They also inhibit release of microfilariae, reduce fecundity (number of eggs in the uterus) of Cooperia, and reduce the reproductive success of ticks.

The principle mechanism of action of the avermectins and milbemycins in parasitic nematodes is to increase membrane permeability to chloride ions. Evidence suggests that the parasiticidal action is from interaction of avermectins with glutamate-gated chloride ion channels. These glutamate-gated chloride channels have not been reported in mammals. This, and the poor ability to cross the blood brain barrier of mammals, are responsible for the safety of these drugs in animals and humans.

Anthelmintic Spectrum

The avermectins and milbemycins are active against a huge number of nematode and arthropod species ¬ too many to list. However, they have several common features and some subtle differentiating features, which you should know. None of them have activity against trematodes and cestodes, as these parasites lack glutamate-gated chloride channels. The avermectins and milbemycins have little effect on adult filarial parasites, but are exquisitely active against the microfilarial stages of these parasites (e.g., heartworm). The activity against many arthropods is excellent, but does depend on contact with or ingestion of host body tissues or fluids. There is excellent activity against all parasitic stages of warble flies and sucking lice, burrowing mites and non-burrowing mites with piercing mouthparts, which ingest host body secretions. Ivermectin and doramectin are highly effective against single-host ticks and suppress the reproduction of many tick species. They are less effective against multihost ticks.

In horses, ivermectin and moxidectin are effective against most GI and lung nematodes. Ivermectin is more than 99% effective against adult cyathostomes, but has limited activity against third and fourth stage larvae and hypobiotic larvae. Moxidectin has better activity against the encysted later third and fourth stage larvae, but is also ineffective against the hypobiotic third stages. Ivermectin has more activity against Gasterophilus (bots) than moxidectin, so the ivermectin dose is lower.

In cattle, eprinomectin, ivermectin, doramectin and moxidectin are extremely effective against the adult, developing and hypobiotic larvae of most GI nematodes and lungworms. The dose-limiting parasites for ivermectin and doramectin are Cooperia and Nematodirus spp. Producers in Canada can also purchase a combination of ivermectin and clorsulon (Ivomec Plus) in the United States for extra label use on their own cattle for treatment of Fasciola hepatica. Doramectin by injection, ivermectin by injection, and topical (pour-on) and injectable milbemycin are approved for psoroptic mange in cattle. Doramectin, ivermectin, eprinomectin and moxidectin are all approved for the treatment of sarcoptic manage.

In sheep and goats, ivermectin is highly effective against all the important pathogenic gastrointestinal nematodes. Use of ivermectin in goats is extralabel, and because of low oral bioavailability, goats are dosed at twice the sheep dose.

In pigs, ivermectin is effective against most important GI, lung and ectoparasites. It has variable activity against Trichuris suis.

In dogs and cats, ivermectin, moxidectin, selamectin and milbemycin oxime are widely used in the prophylaxis of heartworm, D. immitis. These drugs are administered monthly, except for the injectable formulation of moxidectin, which is injected every six months in dogs. Ivermectin, moxidectin, milbemycin and selamectin function by killing larvae of D. immitis introduced by the mosquito into the dog during the month (actually two months) preceding administration of the preventative. Moxidectin functions by killing larvae introduced into the dog during the six months following injection. Thus in areas with a less than year-round heartworm transmission season, the first dose of preventative should be given within one month following the first possibility of infective D. immitis larvae becoming available, and for the monthly products, should be continued until one month after the last possibility of infective larvae being available. In most of Canada, a single injection with the moxidectin product before infective larvae are first available should provide prevention for the entire transmission season.

Assuming good compliance in terms of dose, administration intervals and duration of administration, all these products are very effective for the prevention of heartworm infection in dogs. There is a possibility of a slightly reduced efficacy of some of the monthly products in mixed-breed dogs under field conditions.

All dogs being placed on a preventative for the first time should be tested in advance for heartworm using an antigen test. If this test is negative, then the preventative can be started. If the test is positive, the heartworm status of the dog should be assessed further. In dogs with large numbers of circulating microfilariae there is a very slight risk of a systemic reaction in the hours following the first administration of a macrocyclic lactone preventative; the reaction is thought to be associated with the death of the microfilariae. In Canada, ivermectin, moxidectin and milbemycin oxime are used extralabel to remove circulating microfilariae. Treatment can start as soon as heartworm is diagnosed, or as soon as adulticide therapy is completed, and the drugs are given monthly or biweekly. Milbemycin and moxidectin cause a very rapid drop in numbers of microfilariae in the hours following the initial treatment. Dogs should be watched for systemic reactions, usually characterised by lethargy, salivation, vomiting and tachycardia. Without treatment, microfilariae can persist for up to two years in the absence of adult parasites, and be a source of D. immitis infection for mosquitoes.

The macrocyclic lactones typically have good activity against many canine and feline nematodes including hookworms, roundworms, whipworms and several ectoparasites. At label doses, ivermectin is effective for heartworm prophylaxis in dogs and cats, and treatment of Ancylostoma tubaeforme infections in cats. In a combination product with pyrantel it also controls Ancylostoma caninum, Uncinaria stenocephala, Toxocara canis, and Toxascaris leonina. At extralabel dosages, ivermectin is effective for the treatment of other nematodes, demodectic and sarcoptic mange and ear mites (Otodectes cynotis) in dogs and cats. Milbemycin oxime is labelled for the treatment of Ancylostoma tubaeforme and Toxocara cati in cats and kittens, and for the treatment of Ancylostoma caninum, Toxocara canis, Toxascaris leonina, and Trichuris vulpis in dogs and puppies. It is combined with lufenuron in a product for dogs that will also control fleas (Sentinel®). It is effective at extralabel dosages for the treatment of demodectic and sarcoptic mange. It is also available as a topical product for the treatment of ear mites in dogs and cats. Moxidectin is administered as a 6 month sustained release injection to dogs for heartworm prophylaxis and treatment of hookworms (Ancylostoma caninum, Uncinaria stenocephala). It can also be applied topically in a combination product with imidacloprid for flea control, heartworm prophylaxis and treat hookworms (Ancylostoma tubaeforme) and roundworms (Toxocara cati) in cats. Topical moxidectin with imidacloprid is also used for flea and mange control, heartworm prophylaxis and treatment of Ancylostoma caninum, Toxocara canis, Toxascaris leonina, and Uncinaria stenocephala in dogs. Selamectin is topically applied to dogs to treat infections from fleas, ear mites, sarcoptic mange, ticks (Ripicephalus sanguineus, Dermacentor variabilis), hookworms (Toxocara canis) and heartworm prophylaxis. In cats, selamectin is applied topically to treat fleas and ear mites, hookworms (Ancylostoma tubaeforme) and roundworms (Toxocara cati) and heartworm prophylaxis. Moxidectin can be applied topically for control of sarcoptic and demodectic manage.

Extralabel Dosages in Small Animals

Ivermectin (1% Injection formulation) as a microfilaricide for D. immitis 50 µg/kg PO (D)

Ivermectin (1% Injection formulation) for treatment of Ancylostoma caninum, Toxocara canis, Toxascaris leonina, Trichuris vulpis, Eucoleus boehmi, and Capillaria spp. 200 µg/kg SC or PO (D)

Ivermectin (1% Injection formulation) for treatment of Ancylostoma tubaeforme and Toxocara cati 200 µg/kg SC or PO (C)

Ivermectin (1% Injection formulation) for treatment of Sarcoptes scabiei, Pneumonyssoides caninum, Cheyletiella yasguri and Otodectes cynotis 200-300 µg/kg SC or PO (D,C)

Ivermectin (1% Injection formulation) for treatment of Demodex canis 400-600 µg/kg PO q 24 hr until skin scrapes are negative (D)

Ivermectin (1% Injection formulation) for treatment of Oslerus osleri 400 µg/kg SC once (D)

Ivermectin (1% Injection formulation) for treatment of Aelurostrongylus abstrusus 400 µg/kg SC once (C)

Milbemycine oxime tablets as a microfilaricide for D. immitis 0.5 mg/kg PO (D)

Milbemycine oxime tablets for treatment of Sarcoptes scabiei 2 mg/kg PO q 7 days for 3 doses or 0.75 mg/kg q 24 hr for 30 days (D)

Milbemycine oxime tablets for treatment of Demodex canis 1-2 mg/kg q 24 hr until skin scrapes are negative (D)

Milbemycine oxime tablets for treatment of Cheyletiella spp. and Pneumonyssoides caninum 2 mg/kg q 7 days (D)

Selamectin solution for treatment of Cheyletiella spp., Linognathus setosus (lice) 6 mg/kg topically q monthly (D,C)

Selamectin solution for treatment of Pneumonyssoides caninum 6 to 24 mg/kg topically q 2 wk for 3 treatments (D)

Ivermectin may be used in birds with a reasonable safety margin. In fish, the margin of safety may be narrow, since morality occurs in salmon at double the oral therapeutic dose. There are large species differences in tolerance of reptiles; snakes appear to be tolerant while chelonians are more sensitive.

Macrocyclic Lactone Resistance

The emergence of parasites resistant to the avermectins and milbemycins has been reported in many parts of the world. Resistance is primarily seen in sheep and goat nematodes, but resistance has been seen by Cooperia spp. in cattle. Ivermectin resistance in horses by ascarids has now been reported, and the widespread use of the drug is likely to select for more resistance. Increased levels of P-gp transporters in parasites results in more efficient efflux of the drug and appears to be a mechanism of resistance to macrocyclic lactones. As moxidectin has less affinity for P-gp, parasite resistance is generally less with than that see with ivermectin. Among the factors contributing to resistance, frequent dosing is the most important, while depending on the genetic basis of resistance, under dosing may also contribute.

In horses, dewormer efficacy and resistance is detected by the fecal egg count reduction test (FECRT), which measures the eggs per gram of feces (EPG) before and 10-14 days after deworming.

FECRT% = [(pretreatment EPG-post-treatment EPG)/pretreatment EPG] x 100

For ivermectin or moxidectin, FERCT values < 95% indicate resistance.

Macrocyclic lactone resistance has not been reported in small animal nematodes, but there are reports of resistance in Sarcoptes mites and D. immitis.

Pharmacokinetics

The pharmacokinetics of the avermectins and milbemycins are affected by the animal species it is used in, the specific formulation used, and the route of administration. The degree of lipid solubility (resulting in fat accumulation) determines the persistence of each of the different products. Following administration, residues tend to be lowest in the brain and highest in liver, bile and fat. Fecal excretion is the major route of elimination, accounting for 98% or more of excreted ivermectin, with the remainder appearing in the urine, except that up to 5% of the dose may be excreted in the milk of lactating animals. Because of high human safety and low milk concentrations, eprinomectin and moxidectin are approved for use in dairy cows with no milk withdrawal time. If products labeled for beef cattle are used in dairy cows or if any are used in lactating goats, violative milk residues may be detectable for 60-90 days.

While moxidectin is the most lipid soluble of the macrocyclic lactones, it has the least affinity for the P-gp transporter. This is significant for clinical efficacy (ie, it has a long duration of antiparasitic activity) and for adverse effects (ie, more will cross the blood-brain barrier and will not be pumped out as readily as the other drugs with higher affinity for P-gp).

Adverse Drug Reactions

Manufacturers clearly warn against the extralabel use of avermectins and milbemycins in other species or at other dosages. However, many studies have demonstrated their clinical efficacy and safety when used in an extralabel manner, including laboratory and exotic mammals, birds, fish and reptiles. Extralabel use is the responsibility and liability of the veterinarian, so should be carried out cautiously.

Avermectins and milbemycins cause the release of the endogenous inhibitory neurotransmitter gamma amino butyric acid (GABA). GABA is confined to the central nervous system of mammals, and normally, the avermectins and milbemycins do not cross the blood-brain barrier well, so do not have access to the GABA transmitter sites. When significant amounts do reach the CNS, neurotoxicity is seen as ataxia, vomiting (from the ataxia), mydriasis, impaired vision or blindness, tremors, and depression and may be followed by recumbency and death. The multi-drug-resistance gene (mdr1, ABCB-1) encodes a large transmembrane protein, P-glycoprotein (P-gp), which is an integral part of the blood-brain barrier. P-gp functions as a drug-transport pump at the blood-brain barrier, transporting a variety of drugs from the brain back into the blood. The chemical structure of the macrocyclic lactones influences their affinity for P-gp, with moxidectin having the least affinity. A deletion mutation of the mdr1 gene is associated with macrocyclic lactone sensitivity. The 4 base pair deletion results in a frame shift, generating several stop codons that prematurely terminate P-gp synthesis. Dogs that are homozygous for the deletion mutation display the ivermectin-sensitive phenotype, while those that are homozygous normal do not display increased sensitivity to ivermectin. Heterozygous dogs usually tolerate single doses, but may show toxicity with multiple doses and drug accumulation. Known ivermectin-sensitive dogs (eg, Collies, Shetland Sheepdogs Australian Shepherds, Old English Sheepdogs, and white German Shepherd Dogs) tolerate single ivermectin doses up to 100 µg/kg, therefore the heartworm preventative dose of 6 µg/kg/month is safe even in these breeds.

In cases of macrocyclic lactone toxicity, do not treat affected animals with benzodiazepines (eg, diazepam) or barbiturates, as they potentiate the toxicity of the macrocyclic lactones and prolong the duration of neurotoxicity. Benzodiazepines increase the frequency of chloride channel opening in the presence of GABA, further hyperpolarizing membranes. Barbiturates increase the duration of GABA-mediated chloride channel opening. If necessary to control CNS manifestations of toxicity, propofol infusion is recommended. For ivermectin, selamectin, and milbemycin, treatment is mainly supportive. Most animals will recover over time, depending on the degree of toxicity, with appropriate nutritional and fluid support. Moxidectin is the most toxic; due to its high degree of lipid solubility and its lower affinity for P-gp, concentrations that accumulate in the CNS are not as readily pumped back across the blood-brain barrier. Successful treatment of ivermectin and moxidectin overdoses have been reported using intravenous lipid emulsion. Lipophilic substances, such as ivermectin and moxidectin, are drawn into the “lipid sink” of the fat emulsion and a concentration gradient develops between tissue and blood which causes the intoxicant to move away from the brain (or other areas of high concentration) to the “lipid sink” and greatly speeds clinical recovery. The currently recommended protocol from human medicine is an emulsion of 20% soybean oil in water (commonly used as the fat component of parenteral nutrition), administered as an IV bolus of 1.5 mL/kg followed by 0.25 mL/kg/min infusion. The upper limit recommended for initial dosing is 10 ml/kg over 30 minutes. This antidote does not work in homozygous mdr-1 deletion dogs as they also lack the P-gp transporters in the bile canaliculi required for biliary excretion of these drugs.

Concomitant administration of ivermectin at higher than label doses (eg, for the treatment of demodex) with spinosad (Comfortis®, a nicotinic acetylcholine receptor agonist given monthly for flea control) has resulted in dogs showing signs of ivermectin toxicity. An investigation into this reaction showed a significant increase in ivermectin plasma concentrations when it was coadministered with spinosad, thought to be due to spinosad inhibition of the P-gp transporters for ivermectin, resulting in accumulation of ivermectin.

These drugs may be safely administered to breeding and pregnant animals and help prevent colostral transfer of some nematodes. Due to the high concentration in the gel product and its lipid solubility, moxidectin should not be given to young foals or severely debilitated animals with low fat stores.

Originally, ivermectin was available as in injectable formulation in horses, but was withdrawn due to an association with fatal clostridial myositis.

Adverse reactions may be seen in several species in association with the death of pathogenic and incidental parasitic species (cattle-warbles, dogs-heartworm microfilaria, humans-microfilaria).

The use of ivermectin has an environmental impact, as ivermectin degrades slowly in the environment. Poor degradation of fecal material from sustained bolus-treated animals is associated with the death of dung beetles. In some areas, the impact of endectocides on dung insects may be reduced by not treating at times when susceptible stages of a particular species are present. Fecal residues from moxidectin-treated animals are less toxic to dung beetle larvae than from animals treated with ivermectin.

Available Products

ivermectin (Eqvalan®, Ivomec®, generics)

milbemycin oxime (Interceptor®, Sentinel®)

moxidectin (Cydectin®, Quest®, Guardian®, ProHeart®, Advantage Multi®)

doramectin (Dectomax®)

eprinomectin (Eprinex®)

selamectin (Revolution®)

Pyrimidines

The pyrimidines (pyrantel, morantel, oxantel) are cholinergic agonists. They have broad spectrum activity against GI nematodes and are widely used in horses, swine and small animals. Pyrantel is available as tartrate and pamoate salts. Oxantel is available as the pamoate salt.

Mechanism of Action

The pyrimidines are cholinergic, depolarizing neuromuscular blocking agents.

Anthelmintic Spectrum

In horses, the tartrate and pamoate salts are equally effective against most GI nematodes. Pyrantel can be given at twice the label dose for treatment of tapeworms. In the US, there is a daily feed formulation of pyrantel tartrate that is very effective in reducing parasitism, but when horses are removed from the daily regimen, they are more susceptible to parasite challenge than intermittently treated horses. Resistance to pyrantel by cyantostomes has recently been documented.

Currently, there are no Canadian pyrimidine products available for ruminants.

In pigs, pyrantel tartrate is used for its activity against Ascaris and Oesophagostomum infections.

In dogs and cats, pyrantel pamoate is very effective against hookworms (Ancylostoma caninum, Uncinaria stenocephala, Ancylostoma tubaeforme) and roundworms (Toxacara canis, Toxascaris leonina, Toxocara cati), but has poor activity against whipworms and no activity against tapeworms or heartworms. Oxantel pamoate is formulated with pyrantel pamoate to extend the activity against whipworms (Trichuris vulpis) in dogs.

Pharmacokinetics

Following oral administration, pyrantel is well absorbed in the horse, dog, pig and rat. There is less absorption in ruminants. The drug is quickly metabolized in the body, and little unchanged drug is excreted in the urine and most of the metabolites are eliminated in bile. Administration with food prolongs passage through the GI tract, thus prolonging contact time with the parasite and improving efficacy. The nematodes absorb the drug throughout their whole body, so prolonged exposure to the drug is more important for efficacy than dosage.

Adverse Drug Reactions

In general, pyrantel and oxantel are extremely safe anthelmintics. In dogs, the toxic dose is 138 times the therapeutic dose. They are not recommended in severely debilitated animals because their cholingeric mechanism of action is more pronounced in these animals. (On the other hand, there isn’t really anything safer to use in debilitated animals.) Administration with other cholinergic drugs like levamisole, and muscle relaxants and tranquilizers is contraindicated. Withdrawal times for slaughter must be followed.

Available Products

pyrantel pamoate (Strongid® P, T; Pyr A Pam Plus®, Dolpac®)

pyrantel tartrate (Strongid® C in the US, Pro-banminth® Premix)

oxantel pamoate (Pyr A Pam Plus®, Dolpac®)

Closantel

Closantel (Flukiver®) is a salicylanilide that is highly bound to plasma proteins and targets parasites that ingest blood such as Haemonchus sp. Salicylanilides uncouple oxidative phosphorylation, decreasing the availability of adenosine triphosphate and nicotinamide adenine dinucleotide in the mitochondria; decrease energy available to parasites. Closantel may also disrupt mechanisms that maintain pH homeostasis in the parasite. Since immature and hypobiotic larval stages of Haemonchus sp. do not ingest blood, closantel is only active against larval stages.

Closantel is approved for the treatment of Haemonchus contortus infection in sheep and lambs, especially where resistance to macrocyclic lactones and fenbendazole have been demonstrated. It is an oral drench that should not be repeated at less than 49 day intervals. It is best used as part of an integrated parasite management program on the farm, otherwise resistance can also develop to it. It should not be used in dairy sheep as there is no known milk withdrawal time.

Emodepside

Emodepside (Profender®, with praziquantal) is from new class of anthelmintics, the cyclooctadepsipeptides, owned by Bayer Animal Health. Emodepside is active against intestinal parasites of small animals, poultry, ruminants and horses, but so far only the topical product has been developed as a product for cats (with praziquantal to treat tapeworms). The topical cat formulation is not effective on dogs, but an oral product for dogs is available in Europe.

Mechanism of Action

Emodepside binds to a presynaptic latrophilin receptor in nematodes, which leads to the release of a currently unidentified transmitter. The transmitter (or modulator) exerts its effects at the postsynaptic membrane and induces a flaccid paralysis of the pharynx and the somatic musculature nematode parasites via the Ca2+-activated K+ channel.

Anthelmintic Spectrum

Emodepside is efficacious against a variety of gastrointestinal nematodes. In cats, it is efficacious against mature and immature nematodes (Toxocara cati, Toxascaris leonina, Ancylostoma tubaeforme).

Pharmacokinetics

Two to three days after topical administration to cats, maximum serum concentrations were approximately 32.5 μg/L, but two peaks were observed. It is likely that emodepside partially distributes from the central compartment into another compartment (probably fat) and from there slowly redistributes to the systemic circulation. Emodepside is slowly eliminated from the serum with a half-life of about 9 days.

Adverse Drug Reactions

The topical emodepside/praziquantal formulation is very safe in cats, but small areas of alopecia at the treatment site have been reported. If ingested, it may cause vomiting and salivation. It is safe in pregnant and lactating queens.

Nitroscanate

Nitroscanate (Lopatol®) is a broad spectrum oral anthelmintic for dogs (not labelled but can be used in cats). It is a diphenylether that interferes with energy production in the parasite. Nitroscanate is indicated for treatment and control of roundworms and tapeworms in dogs (Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Ancylostoma braziliense, Uncinaria stenocephala, Strongyloides stercoralis, Dipylidium caninum, Taenia hydatigena, Taenia pisiformis, Taenia ovis and Spirometra erinacei). It is not indicated for the treatment of Trichuris vulpis. It is poorly absorbed from gastrointestinal tract. Peak blood concentrations are reached 12 to 24 hours after oral administration; the presence of food in the stomach is associated with higher blood concentrations and an empty stomach at the time of treatment is associated with lower blood concentration. Feeding at the time of administration slows the passage of the content through the GI tract and extends the exposure time of the parasites to the drug. The majority of an oral dose is excreted in the feces and the remainder in the urine unchanged or as metabolites. Nitroscanate irritates the GI mucosa, resulting in relatively high incidence of vomiting (10%±20% of treated dogs) within 3±5 h after treatment, but with no reduction in efficacy. Fasting for 12 to 24 h prior to treatment followed by a small quantity of food after administration reduces vomiting. Nitroscanate is safe to use in pregnant bitches and in puppies as young as 2 weeks of age. Wash hands after use as the product is mildly irritating to the skin. Tablets should not be broken or divided.

Diethylcarbamazine

Diethylcarbamazine (Decacide®, DEC) is a piperazine derivative that once was commonly used as a daily heartworm preventative as a syrup, powder or tablet. DEC is also effective at preventing hookworm and roundworm infections, but not in eradicating already established adult worms. DEC should only be administered to heartworm negative dogs, as it is microfilaricidal. A rapid kill of a large number of microfilaria can cause a fatal anaphylactic reaction. Because of poor client compliance with daily administration, DEC is available, but not commonly prescribed anymore for heartworm prevention. DEC has also been used successfully in the treatment of Filaroides osleri tracheobronchitis.

Melarsomine

Melarsomine (Immiticide®) is the new therapy for adult heartworm infections in dogs. It is safer and more efficacious than caparsolate, and much more convenient to administer. For adulticide therapy, melarsomine is injected deeply into the epaxial muscles. Two intramuscular injections are given 24 hrs apart. Proper injection technique is mandatory. Severely infected dogs can be treated with a single dose initially, then treated in 1-2 months with the standard regimen. While melarsomine is safer and more efficacious than caparsolate (it has < ½ the elemental arsenic), it still has a narrow safety margin. A single dose of 3 times the recommended dose can result in pulmonary inflammation and edema and death. An accurate body weight on the patient is mandatory.

Praziquantel

Praziquantel (Droncit®, Drontal® with pyrantel, Dolpac®, Profender®) is active against a wide range of adult and larval cestodes of humans and animals. It is rapidly absorbed after oral administration or IM or SC injection and distributes to all organs, including crossing the blood-brain barrier. This distribution is an asset in the treatment of larval or adult tapeworms that can be found in muscle, brain, peritoneal cavity, bile ducts and the intestine. It is hepatically metabolized and eliminated in bile where it then exerts its anticestodal action. Smaller dogs and cats require relatively higher doses because of their higher metabolic rate. Praziquantal is rapidly absorbed by cestodes and causes an instantaneous tetanic concentration in the parasite’s musculature. It also causes vacuolization of the tegument, so that the parasites are lysed within 4 hours of treatment. Praziquantal has a wide margin of safety and it is safe to use in pregnant and breeding animals. In dogs, praziquantal is approved for the removal of Dipylidium caninum, Taenia pisiformis, Taenia hydatigena, Echinococcus granulosus, Echinococcus multilocularis and Mesocestoides corti. Praziquantal is approved for the removal of Dipylidium caninum and Taenia taeniaeformis in cats. It is added to ivermectin (Zimectrin® Gold) and moxidectin (Quest Plus®) for horses to eliminate Anoplocephala perfoliata and Anoplocephala magna.

Espirantel

Espirantel (Cestex®) is a relative of praziquantal that is marketed as an oral tapeworm anthelmintic. Unlike praziquantal, only trace amounts of espirantel are absorbed after an oral dose. Therefore it is not effective against extra-intestinal cestodes. It appears to be as safe as praziquantal.

Antitrematodal Drugs

As liver flukes are not a significant problem in Canada, there is only one drug with a label claim, and that is albendazole, the benzimidazole compound. In the US, chorsulon (Curatrem®) is available as an oral product on its own and in combination with ivermectin (Ivomec®-F) in a SC injectable formulation. Clorsulon is very effective against Fasciola hepatica and Fasciola magna, but not against other trematodes or nematodes of clinical importance.

Antiprotozoal Drugs

Coccidiosis is generally an enteric disease caused by Eimeria or Isospora species, which are typically host specific. Coccidiosis causes economic losses in cattle, sheep, goats, dogs, cats, rabbits, poultry and swine. Members of the genus Cryptosporidium are recognized as serious intestinal and respiratory pathogens of humans and domestic animals. Toxoplasma gondii and Sarcocystis species are related parasites that cause abortion, death and production losses in ruminants and can cause clinical disease in other species. Sarcocystis neurona and Neospora hughesi cause equine protozoal myeloencephalitis (EPM). Neospora caninum has emerged as a pathogen causing encephalitis and paralysis in dogs and abortions in ruminants. Babesia and Hepatozoon are piroplasm infections of dogs, rarely seen in Canada except in imported racing Greyhounds from the US.

Anticoccidial drugs can act on extracellular stages (sporozoites, merozoites) to prevent penetration of the cells or on the intracellular stages to stop or inhibit development. A few anticoccidials affect the sporolation of the oocysts after they are excreted, and a few affect excystation. Anticoccidials can act at specific times during the life cycle or exert their effects at several phases. They are classified as coccidiostatic if they arrest the development of the parasite but do not kill the coccidial stages and as coccidiocidal if they kill most of the coccidial stages. Factors such as length of time on medication, dosage, and species of coccidia can cause a compound to appear as coccidiostatic in some instances but coccidiocidal in other circumstances.

Sulphonamides

Sulphonamides were the first effective anticoccidials used, and they are still widely used in the treatment of coccidiosis in ruminants and small animals. They are used at coccidiocidal doses in the treatment of clinical disease. Sulphonamides are structurally similar to para-aminobenzoic acid (PABA), which bacteria require to synthesize folate (folic acid). As a structural analog to PABA, the sulphonamides competitively inhibit folate synthesis, which is necessary for the bacterial production of thymidine, purines, and certain amino acids needed by the developing coccidial stages. Sulphonamides are most active against the asexual stages and have lesser activity against the sexual stages of coccidia. Mammalian cells use preformed folate and normally are not affected by therapeutic doses of sulphonamides. Sulphonamides are often administered in combination with dihydrofolate reductase inhibitors for the synergism of blocking two steps in folate synthesis.

Sulphonamides used in veterinary medicine for the treatment or prevention of coccidiosis include sulfachloropyrazine, sulfadiazine, sulfadimethoxine, sulfadoxine, sulphamethazine, sulfamethoxazole, and sulfaquinoxaline. The pharmacokinetics of the individual sulpha drugs varies, but in general, they are weak acids, have a moderate volume of distribution and a fairly long elimination half-life. Degree of protein binding can be considerable, but varies between drug and species. Most are well absorbed orally, even in adult ruminants.

Potentiated Sulphonamides

The diaminopyrimidines are dihydrofolate reductase inhibitors that are frequently combined with sulphonamides for antibacterial activity, but also have antiprotozoal activity. The most common members of this group used in veterinary medicine are trimethoprim, ormentoprim and pyrimethamine.

Trimethoprim is available in combinations with sulphonamides (Bactrim®, Septra®, Di-Trim®, Tribrissen®). Trimethoprim is readily absorbed orally in monogastrics and neonatal ruminants, but is degraded in the rumen otherwise. Trimethoprim has a high volume of distribution and a short elimination half-life as compared to sulphonamides. Trimethoprim crosses the blood-brain barrier and CSF levels are about 40% of plasma levels. Pyrimethamine is available as an individual drug (Daraprim®) and has a greater affinity for protozoal dihydrofolate reductase. It achieves therapeutic concentrations in the CNS. In the US, sulfadiazine/pyrimethamine (ReBalance®) is available in a suspension as a treatment for EPM.

Mammalian toxicity of these drugs is associated with interference with folate synthesis in the bone marrow leading to blood dyscrasias. A hemorrhagic syndrome has been reported in poultry and dogs treated with sulfonamides. It is most often reported with the use of sulfaquinoxaline in chickens for coccidiosis and in dogs given the products labelled for poultry. Sulfaquinoxaline is a vitamin K antagonist that causes an effect similar to that of warfarin (the anticoagulant found in rat poison). Sulfaquinoxaline may have additional adverse effects on coagulation; this may explain why supplementation of feed with vitamin K does not always prevent the syndrome in chickens. Rapid discontinuation of medication and initiation of therapy with vitamin K may reverse the effects.

Decoquinate

Decoquinate (Deccox®) is a quinolone anticoccidial approved for chickens and cattle as feed and water additives. It is coccidiostatic, by interrupting sporozoite development by interfering with cytochrome-mediated electron transport in the parasite mitochondria. The inhibited sporozoites can resume development if the decoquinate stops being administered to the animal.

Amprolium

Amprolium (Amprol®, Corid®) is a thiamine analog that acts on the first generation schizont to prevent merozoite and has some activity against sexual stages and the sporolating oocyst. Coccidia are 50 times more sensitive to the effects of thiamine deficiency than poultry and mammals. But if overdosed, amprolium easily causes thiamine deficiency in ruminants, manifested as polioenchephalomalacia. Thiamine injections are antidotal as long as CNS damage is not too severe. The solution formulation is labeled for the treatment of clinical caecal coccidiosis in growing chickens and laying birds and calves. The feed mix is labeled for chickens and turkeys (but not laying birds in production) and calves for the prevention of coccidiosis. There is a warning not to use in calves to be used for breeding, but I know of no reason why amprolium would affect reproduction. In my clinical experience, amprolium is an effective preventative of coccidiosis, but it is not very effective as treatment of a clinical outbreak.

Ionophores

The ionophore antibiotics were found to have anticoccidial activity in the 1960s, and are widely used in poultry and ruminants. Ionophores that have anticoccidial activity act against extracellular sporozoites and merozoites, intracellular sporozoites, and gametogenous stages. The ionophores form lipophilic complexes with alkali metal cations and transport these cations across biological membranes. They stimulate the Na+/K+-ATPase, but increase Na+ influx at a rate exceeding the capacity of the pump to remove the excess of Na+. Increasing intracellular Na+ increases Cl- levels to maintain electroneutrality within the sporozoite. This draws water into the sporozoite, and as coccidia have no osmoregulatory organelles, the intracellular swelling damages the coccidia. The ionophores are good preventatives, but are not useful for treating clinical cases of coccidiosis. Although ionophore antibiotics are used for growth promotion in cattle and pigs, they do not promote growth in chickens and may reduce rate of growth if administered to chickens not exposed to coccidiosis. The prophylactic use of all antimicrobials as growth promotants in food animals has fallen under greater scrutiny due to fears of the spread of antibiotic resistance. Because of the complexity and high degree of specificity of ionophore resistance, it appears that ionophores do not contribute to the development of antimicrobial resistance to important human drugs and they should not be eliminated from use in animal feeds. However, some ionophores are now completely ineffective against avian coccidia.

The ionophores are extremely toxic to horses and other monogastrics. Ruminants only absorb about 50% of a dose of monensin, but monogastrics absorb almost all of an administered dose. Care should always be taken to prevent susceptible animals from getting into ionophore-containing feeds. The ionophores are rapidly metabolized by the liver, excreted in bile and eliminated in the feces.

The relative toxicities of the ionophores from lowest to highest are salinomycin < lasalocid < or = narasin < or = monensin (but lasalocid < monensin) < maduramicin. Ionophore toxicity causes cellular electrolyte imbalances, elevating extracellular potassium and intracellular calcium, resulting in severe cellular damage and death. The dose necessary to cause toxicity is variable among species, with horses being the most sensitive and turkeys being more sensitive than chickens. Skeletal and cardiac muscle cells are generally the most severely affected; however, the specific tissues affected and resulting clinical signs vary from species to species. Skeletal muscle is primarily affected in dogs, ostriches, sheep and turkeys. Cardiac muscles are affected in cattle, and both myocardium and skeletal muscles are damaged in horses. Age-related differences in ionophore sensitivity occur in poultry, with adult birds more sensitive to the toxic effects of ionophores than young birds. Ionophore toxicity occurs from dose errors in mixing with feed, accidental ingestion of treated feed by sensitive species, ingestion by cattle and sheep of poultry litter from maduramicin-treated flocks, concurrent administration with a medication that potentiates toxicosis, or accidental feed mill contamination of presumably untreated feed. Heat stress and water deprivation exacerbate toxicity in chickens when lasalocid is administered at one to two times the recommended dose. Ionophore antibiotics may adversely affect the hatchability of eggs. Lasalocid, maduramicin, monensin, and salinomycin are not labeled for use in replacement or laying chickens. Maduramicin, lasalocid and monensin are not labeled for use in replacement or breeding turkeys. When used according to label directions there are no meat withdrawal times for most of these products. With extralabel use (e.g. laying birds) prescribing veterinarians should consult the Canadian gFARAD for extralabel withdrawal information. The cardiotoxicity may be acute and cause death rapidly, or chronic damage may result in cardiomyopathy and cardiac failure over several months. There is no antidote; only supportive therapy.

Monensin (Rumensin®) is available for cattle as a feed additive and as an intrarumenal bolus (much safer to use on farms with horses and dogs). It has been approved for use in dairy cattle, but for the treatment of ketosis. Its antimicrobial effect in the rumen influences the production of volatile fatty acids, which promotes growth and feed efficiency, helps prevents bloat and aids in the prevention of ketosis in dairy cattle. Monensin prevents clinical signs of tryptophan-induced acute bovine pulmonary edema in cattle and appears to reduce the development of lactic acidosis in cows suffering from grain overload. Monensin may reduce abortion and control neonatal losses from toxoplasmosis in sheep. There is no slaughter withdrawal time.

Lasalocid (Bovatec®) is available as a feed additive for cattle. It is labelled for sheep in the US but not in Canada. It will also prevent bloat, promote growth and improve feed efficiency, and reduce lactic acidosis following grain overload.

Salinomycin (Posistac®) is available as a feed additive for cattle and pigs with no slaughter withdrawal time.

Diclazuril

Diclazuril (Clinicox® 0.5% Premix) is a benzeneacetonitrile derivative anticoccidial used in broiler chickens and turkeys. Diclazuril is often effective against ionophore-resistant coccidia and strains resistant to various other drugs such as amprolium, clopidol, robenidine, and zoalene. When used as directed, there is no meat withdrawal time necessary. Diclazuril is approved in the US as a treatment for EPM (Protazil®).

Ponazuril

Ponazuril (Marquis®), an active metabolite of the swine coccidiostat toltrazuril, approved for use in horses with EPM due to Sarcocystis neurona. A recent case series shows that it may also be effective therapy for EPM due to Neospora hughesi. Ponazuril is available in a convenient paste formulation. The elimination half-life of ponazuril in the horse is 4.5 days. Ponazuril is dosed at 5 mg/kg once a day for 28 days and appears to be well tolerated in horses.

Toltrazuril

Toltrazuril (Baycox®) is approved in Canada for treatment of preclinical coccidiosis due to Isospora suis in neonatal piglets, for the prevention of clinical signs of coccidiosis and reduction of coccidian shedding in lambs with a history of coccidiosis caused by Eimeria crandallis and Eimeria ovinoidalis, and for the prevention of clinical signs of coccidiosis and reduction of coccidian shedding in calves. It’s a single dose oral therapy. It is slowly absorbed and highly distributed. It excreted mainly in feces with an elimination half-life of 51 hr in swine. It has a long withdrawal time in swine (70 days). Do not use in piglets intended to be used as barbecue pigs or veal calves since they may be marketed before the withdrawal period is up. The withdrawal time is 48 days in lambs and 63 days in calves. Toltrazuril is highly efficacious in the control of coccidiosis in puppies and kittens. In Europe, there is a liquid formulation approved for use in dogs in combination with emodepside. In Canada, the large animal product can be used extralabel at 50 mg/kg PO q 24 hr for 3 treatments.

Halofuginone

Halofuginone (Halocur®) is approved as an aid in reducing clinical signs of cryptosporidiosis caused by Cryptosporidium parvum in new born calves, when administered orally (after colostrum or milk/milk replacer feeding) for the first 7 days of life to clinically normal calves. Halofuginone is quinazolinone anti-protozoal that has cryptostatic action on Cryptosporidium parvum. It is mainly active on the free stages of the parasite (sporozoite, merozoite). It is a very lipid soluble drug with a Vd of 10 L/kg. The elimination half-life is 31 hr after oral administration. Do not use in calves that are ill, scouring or off-feed. Halofuginone has a narrow safety margin, with toxicity seen at 2X the therapeutic dose and consists of increasing diarrhea, inappetance, dehydration and collapse.

In clinical use, beneficial effects of halofuginone treatment have been inconsistent.

Clindamycin

Clindamycin, the lincosamide antimicrobial, is currently the suggested drug for the treatment of disseminated toxoplasmosis in cats and dogs. It is well absorbed after oral administration, and has a long elimination half-life. It has a high volume of distribution and is widely distributed in tissues. Clindamycin is active against tachyzoites of Toxoplasma gondii and is initially coccidiostatic but becomes coccidiocidal after a few days of therapy. Clindamycin binds to ribosomes and interferes with protein synthesis.

Imidocarb

Imidocarb (Imizol®) has recently been approved in the US for the treatment of babesiosis in dogs. Babesiosis is a tick-transmitted piroplasm that is mainly seen in racing Greyhounds originating in the southern US that may be brought into Canada by Greyhound rescue organizations. Imidocarb is also used to treat canine hepatozoonosis in the southern US. Imidocarb is a cholinesterase inhibitor that is administered intramuscularly or subcutaneously.

Ectoparasiticides

Parasitic arthropods of veterinary importance include fleas, lice, flies, mites and ticks. Mechanisms of ectoparasite pathology include:

blood loss resulting in anemia

physical damage and irritation to skin

allergic reactions to venoms and toxins

decreased resistance to other diseases

reductions in weight gains, milk and egg production

reduction in reproductive efficiency

transmission of other disease producing agents

Chemicals used to control external parasites are known as ectoparasiticides. Many ectoparasiticides are pesticides not drugs. Instead of a DIN (drug identification number), these products have a PCP (pest control product) number. It is illegal to use a PCP product in an extralabel manner, even by veterinary prescription. So you cannot use a bovine product on a llama or a dog product on a horse.

Botanicals

The botanicals are derived from flowers, leaves, stems or roots of plants. Plant oils have been used for centuries for their attractant, repellent or toxic effects on arthropods. Several plant derivatives are incorporated into commercial products.

Pyrethrins and Synthetic Pyrethroids

The pyrethrins are a collection of six natural insecticidal esters derived from Chrysanthemum plants, which appeals to the pet owner who wants a “natural” product. They have excellent knockdown activity and very low mammalian toxicity. But they are easily decomposed by UV light, so have poor residual activity. Their activity can be prolonged by microencapsulation or by addition of stabilizers. Pyrethrins are almost always combined with piperonyl butoxide, a synergist that helps prevent pyrethrin breakdown by flea microsomal enzymes. Synthetic pyrethroids are analogs of pyrethrin that have been altered to more stable molecules with longer residual activity.

Mechanism of Action

The pyrethrins and pyrethroids alter gating kinetics of sodium channels in nerves. This causes either repetitive discharges or membrane depolarization and subsequent death of the insect. They also suppress GABA and glutamate receptor channel complexes and voltage-activated Ca2+ channels. The pyrethroids are further classified on the basis of symptoms and effects on target insects. Type I pyrethroids (permethrin, resmethrin) cause rapid onset of hyperactivity and repetitive action potentials. Type II pyrethroids (fenvalerate, cypermethrin) are lethal at low doses with few behavioural changes.

Toxicity

Pyrethrins and pyrethroids are extremely safe ectoparasiticides. Toxic doses are usually 1000X the therapeutic dose. Mammalian toxicity resembles insect toxicity with nerve and muscle disorders. Clinical signs in mildly affected dogs and cats include hypersalivation, vomiting, diarrhea, mild tremors, hyperexcitability or depression. In severely affected animals, signs include hyperthermia, hypothermia, disorientation and seizures. The synthetic pyrethroid, permethrin, is toxic to cats at doses safe for dogs. Permethrin toxicosis can be treated with intravenous lipid emulsion. Muscle tremors can be treated with methocarbamol.

Available Products

Pyrethrin products – many flea and tick products

Synthetic Pyrethroids: Permethrin (Preventic LA®, etc.) superior stability gives them residual activity up to 28 days (Do not use on cats!)

Cyfluthrin (Cylence®)

Cypermethrin (Eliminator® fly tags)

Lambda-cyhalothrin (Saber®)

Organophosphates

The organophosphates (OPs) bind to and inhibit acetylcholinesterase (AChE). OPs are often characterized as irreversible inhibitors of AChE, but eventually the phosphorylated AChE is hydrolysed, releasing the recovered enzyme. Clinical signs of toxicity result from accumulation of acetylcholine at cholinergic receptors in the CNS. Infrequently, a non-antiAChE effect, referred to as OP ester-induced delay neuropathy occurs. The onset of the neuropathy is delayed for 7-21 days post OP exposure. Clinical signs are more severe in young animals, and include weakness, ataxia, and proprioceptive deficits that mainly affect the hindlimbs. Several OPs are teratogenic.

Carbamates

The carbamates also inhibit AChE, but differently than the OPs. Carbamates compete for enzyme active sites utilizing a process known as carbamylation, a reaction which blocks the action of the enzyme without changing it structurally. If the bond between the enzyme and the carbamate is hydrolysed (as with the antidote, 2-PAM), the fully active enzyme is released. Carbaryl is quite safe and is commonly used in shampoos, sprays and dusts for livestock, dogs and cats. Propoxur is used in flea and tick collars.

Amitraz

Amitraz (Mitaban®) is an acaricide that inhibits monoamine oxidase (MAO). MAO is responsible for the metabolism of neurotransmitter amines (eg, norepinephrine) in the nervous system. Amitraz is used in dips and collars (Preventic® collars) for mites and ticks on dogs, and in a dip for lice on swine. Toxicity occurs easily, especially if used on damaged skin. Avoid the use of amitraz in animals receiving other MAO inhibitor drugs (eg, selegeline). Do not let dogs eat the end of the collars. Yohimbine is the antidote for amitraz toxicity.

Insect Growth Regulators and Insect Development Inhibitors

Insect growth regulators (IGRs) and insect development inhibitors (IDIs) have no adulticidal properties. Because they affect preadult stages of insects and mites, effective environmental control is not achieved for several weeks after initiating use and they are not helpful to the flea-allergic animal. IGRs mimic effects of endogenous insect growth hormone (IGH). IGH maintains the insect in its larval stage and prevents maturation to the pupa and adult. Only when IGH levels decline in the insect, does development proceed. IGRs falsely signal the larvae to remain in its immature stage. Failure to molt and further develop ultimately results in the death of the larva. IGRs currently used in veterinary medicine are methoprene and pyriproxifen.

Methoprene is an IGR with an extremely low toxicity to mammals. Methoprene containing sprays and collars are used on dogs and cats, and it is often formulated with adulticidal compounds for premise flea control. Methoprene is light sensitive and has no outdoor residual effect.

Pyriproxifen (Nylar®) is a carbamate that mimics IGH. It is one of the newest and most potent IGRs. It is stable in UV light. At low concentrations, it has ovicidal and larvicidal activity, and may have some delayed adulticide effects. It is available in sprays and premise sprays in combination with pyrethrins and permethrin and it is incorporated into a flea collar that claims 13 month protection from fleas for dogs and cats.

Insect development inhibitors (IDIs) interfere with the development of the insect’s exoskeleton by inhibiting chitin synthesis or deposition pathways. Lufenuron (Program®) is a once a month oral flea control product for dogs and cats. There is also a 6 month injection available for cats (which I do not recommend due to association with feline fibrosarcommas). Lufenuron is strongly lipophilic and accumulates in adipose tissues of treated animals. The release of lufenuron from fat allows for maintenance of effective blood levels of drug for weeks after administration. When a flea ingests lufenuron-containing blood, it passes the drug into its eggs. The resulting offspring fail to develop into adult fleas. It is only effective against fleas, and works best in a “closed” environment for the non-allergic pet. It is available in combination with milbemycin as Sentinel®.

Macrocyclic Lactones

Ivermectin

In addition to its anthelmintic activity, ivermectin is labelled for treating ectoparasites in livestock. It has also been used extra-label (the cow injectable formulation) for the treatment of mites in dogs and cats. A dose of 200 mcg/kg is used to treat sarcoptic mange and doses of 400-600 mcg/kg SID have been used for dogs with chronic demodectic mange. I always administer ivermectin to small animals PO. Subcutaneous administration has a risk of anaphylaxis from the vehicle. Ivermectin can also be used to treat ear mites. Some practitioners will dose dogs and cats at 200 mg/kg SC or PO for this. I prefer to instill a few drops of ivermectin directly into the ear canal. The pour-on formulation has been used topically at 500 mcg/ml to treat sarcoptic manage in shelter dogs.

Milbemycin

Milbemycin (Interceptor®, Senntinel® with lufenuron) can be used to treat demodectic mange in dogs at a dose of 0.5-1.0 mg/kg SID (usual course 90 days). Because only the heartworm preventative product is available, this is very expensive for this use. Milbemycin has also been successfully used to treat sarcoptic mange using a dose of 0.75 mg/kg SID for 30 days.

Selamectin

Selamectin (Revolution®) is a doramectin analog developed for use in dogs and cats as a topical formulation. It is the only macrocyclic lactone with efficacy against fleas, and it has efficacy against heartworm, hookworms, roundworms (cats), ear mites and sarcoptic mites and ticks. It has a rapid “knockdown” during the flea feeding phase. Flea control lasts 28 days. When administered topically, selamectin rapidly spreads over the skin surface, but is also absorbed systemically and concentrates in sebaceous glands, which provides a depot for slow release onto the skin surface. There are reports of inefficacy in cases of sarcoptic mange.

Moxidectin

Moxidectin (Advantage Multi®) is applied once a month topically in a formulation containing imidacloprid and will control internal parasites and ectoparasites including fleas (from the imidacloprid), mites, sarcoptic and demodectic mange. It is better at keeping demdectic manage under control than as a treatment for a severe case. As this product is a drug and not a pesticide (the other imidacloprid products are pesticides), it can be used in an extralabel manner. The cattle formulation of moxidectin is sometimes used as an alternative to cattle ivermectin in the extralabel treatment of demodectic manage.

Imidacloprid

Imidacloprid (Advantage® for cats [pesticide], Advantage® II for dogs with pyriproxyfen [pesticide], Advantage Multi® [drug], Advantix® [pesticide]) is applied topically to dogs or cats at 10 mg/kg and it spreads rapidly over the skin surface to kill adult fleas through depolarization of post-synaptic nicotinic receptors. 100% flea kill is achieved in 24 hours and it has residual efficacy against reinfestation for up to 28 days in cats and 42 days in dogs. It also has a contact larvicidal effect in the animal’s environment. It is applied once a month, and it is not affected by bathing or swimming. It is a very safe product for dogs and cats and is not teratogenic or mutagenic. Alone, imidacloprid no activity against ticks, so it is combined with moxidectin or permethrin in the other Bayer products. In the US, there is a similar product containing dinotefuran, along with permethrin and pyriproxifen (Vectra 3D) for monthly flea and tick control.

Fipronil

Fipronil (Frontline®) is GABA inhibitor, that is available in the US but not in Canada as a topical spray or pour on (Top Spot) to be dosed at 10 mg/kg once a month. Fipronil spreads over the skin and high concentrations persist on the hair coat, giving it a residual effect against fleas and ticks. The residual effect is not affected by sunlight, swimming and bathing with shampoo only reduces the effect 37 days after application. It is safe for use on puppies and kittens and not teratogenic or mutagenic. Anecdotally, it appears to have some efficacy against ear mites.

Nitenpyram

Nitenpyram (Capstar®) belongs to the chemical class of neonicotinoids. Nitenpyram only kills adult fleas. Nitenpyram begins working within 30 minutes. In studies, it achieved greater than 90% effectiveness against adult fleas on dogs within 4 hours and cats within 6 hours. Nitenpyram can be given as often as needed, even once daily. Laboratory and clinical studies showed that nitenpyram is safe for use in dogs, cats, puppies and kittens 4 weeks of age and older and 2 pounds of body weight or greater. Capstar tablets are safe for pregnant or nursing dogs and cats and may be used together with other products, including heartworm preventives, corticosteroids, antibiotics, vaccines, de-worming medications, shampoos and other flea products.

Spinosad

Spinosad (Comfortis®, Trifexis® with milbemycin) is an insecticide and acaricide derived from a family of natural compounds produced from fermentation of the actinomycete, Saccharopolyspora spinosad.

Mechanism of Action

Spinosad is a nicotinic acetylcholine receptor agonist chemically related to macrolides. The mode of action of spinosad is excitation of the insect nervous system, leading to involuntary muscle contractions, prostration with tremors, and paralysis. Spinosad also has effects on GABA receptor function that may contribute further to its insect activity. Spinosad has rapid adulticidal efficacy (kills 53.7% of adult fleas within 30 min and 100% at 4 hr). Flea killing action lasts for 4 weeks after a dose.

Spectrum of Activity

Spinosad is approved for control of fleas (Ctenocephalides spp.) on dogs. Extralabel doses of 50 and 100 mg/kg have high efficacy against existing tick (R. sanguineus) infestations within 24 hr of dosing, and appear to have some post-treatment residual tick control in dogs for up to 1 month.

Pharmacokinetics

Spinosad is rapidly absorbed after oral administration of the chewable tablets. It is slowly eliminated, with a mean plasma elimination half-life of 271 hours in dogs. It appears to have a high volume of distribution as measurable concentrations are found in the milk of lactating bitches.

Adverse Drug Reactions

Spinosad is not approved for use in cats. In clinical trials, the most common adverse reaction attributed to spinosad was vomiting. Additional adverse reactions observed were itching, decreased activity, diarrhea, inflammation of the skin, redness of the skin, decreased appetite and redness of the ear.

Concomitant administration of ivermectin at higher than label doses (eg, for the treatment of demodex) with spinosad has resulted in dogs showing signs of ivermectin toxicity. An investigation into this reaction showed a significant increase in ivermectin plasma concentrations when it was coadministered with spinosad, thought to be due to spinosad inhibition of the P-gp transporters for ivermectin, resulting in accumulation of ivermectin.

Isoxazolines

The isoxazoline class of parasiticides are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels and L-glutamate-gated chloride channels. They are very active against fleas, ticks and mites. Their rapid action against ticks may help in prevent the transmission of tick borne diseases. Because of their mechanism of action, use with caution in dogs with a history of seizures or concurrently with fluoroquinolones.

Fluralaner

Fluralaner (Bravecto®) is a very potent acaricide and insecticide. Bravecto® is available in Canada as chewable tablets containing 112.5 mg, 250 mg, 500 mg, 1000 mg or 1400 mg of fluralaner for dogs and puppies 6 months of age and older and weighing ≥2 kg. Each tablet is formulated to provide a minimum dose of 25 mg/kg body weight. Fluralaner is administered orally as a single dose every 8-12 weeks. Fluralaner kills fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and for the treatment and control of tick infestations with Dermacentor variabilis (American dog tick) for 12 weeks. Fluralaner is also indicated as an aid in the treatment and control of tick infestations with Ixodes scapularis (black-legged tick) and Rhipicephalus sanguineus (brown dog tick) for 12 weeks. Fluralaner is also highly effective in the treatment of demodectic or sarcoptic mange. A single oral dose may control these skin parasites completely without the toxicity concerns of ivermectin or moxidectin.

Oral absorption increases with food. Peak fluralaner concentrations are reached between 2 hours and 3 days following oral administration and the elimination half-life ranges between 9.3 to 16.2 days. It appears to be well tolerated in dogs, with the most frequent adverse reaction reported being vomiting.

Fluralaner topical solution for cats is indicated for the treatment and prevention of fleas for 12 weeks and for the treatment and control of Dermacentor variabilis and Ixodes scapularis ticks for 8 weeks.

Afoxolaner

Afoxolaner (NexGard®) is also highly efficacious against fleas and ticks on dogs. It is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis), and the treatment and control of Black-legged tick (Ixodes scapularis), American Dog tick (Dermacentor variabilis), Lone Star tick (Amblyomma americanum), and Brown dog tick (Rhipicephalus sanguineus). To be effective, it must be administered every 30 days. Anecdotally, it appears to have efficacy for the treatment of demodectic mange but there are no published studies supporting this yet.

Sarolaner

Sarolaner (Simparica®) is another once a month oral chewable for dogs for the treatment and persistent control of fleas and ticks for at least one month. It also can be used for the treatment of Otodectes ear mites and Sarcoptes and Demodex mange mites.