Antiparasitics


Benzimidazoles are poorly soluble and are generally given orally as a suspension. Netobimin can be solubilised and administered via drinking water. Benzimidazoles have also been incorporated into a range of controlled release devices for use in cattle. All are effective against nematodes affecting domestic animals and are ovicidal. Most are also effective against tapeworms and some have activity against adult liver fluke (Fasciola) in ruminants at increased dose rates.


All members of the benzimidazole class have a similar mode of action and act by disrupting energy metabolism in worms by binding to parasite tubulin, a constituent protein present in microtubules and in plasma and mitochondrial membranes. The formation of microtubules is a dynamic process involving the polymerisation of tubulin rings at one end and depolymerisation at the other end. Benzimidazole anthelmintics bind to ß-tubulin causing capping and inhibition of further microtubule formation. The resultant effect is starvation of the parasite due to inhibition of glucose uptake, protein secretion and microtubule production. There is also a reduction in enzyme activity such as acetylcholinesterase secretion, and carbohydrate catabolism by the fumarate reductase system. The mode of action of triclabendazole, on Fasciola hepatica, is at present unknown. It appears to have no tubulin-binding properties, unlike other members of this group, and it must therefore act along alternative pathways.


Benzimidazoles have a low toxicity, and in some cases can be used at over ten times the recommended dose rate. Parasite resistance to anthelmintics has most frequently been associated with repeated use of these drugs against nematodes of sheep, goats and horses and in many countries has limited both their effectiveness and use.


IMIDAZOTHIAZOLES/TETRAHYDROPYRIMIDINES


The imidathiazole group contains two members, tetramisole and levamisole. Tetramisole is a racemic mixture of dextro and levo forms. Levamisole is the levo-isomer and it is with this form that anthelmintic potency resides. The dose rate of levamisole is therefore half that of tetramisole, and it has twice the safety index.


Levamisole is used mainly in cattle and sheep and has good activity against a range of gastrointestinal nematodes and is also highly effective against lungworms. Levamisole can be administered orally, by injection or pour-on, combined in a number of products with a specific flukicide (oxyclozanide or triclabendazole) to form a broad-spectrum drench for worms and fluke. Unlike the benzimidazoles it is not ovicidal. Levamisole is non-teratogenic and is therefore safe to use in pregnant animals. The therapeutic index in relation to other anthelmintics is, however, low. Animals given levamisole may be hyperactive for a few minutes after receiving the recommended therapeutic dose. Toxic signs, due to a stimulant effect on nerve ganglia, may manifest as salivation, bradycardia, muscular tremors and, in extreme cases, death from respiratory failure. Injectable levamisole may cause inflammation at the site of injection.


The drug is rapidly absorbed and excreted, most of the dose being lost from the system within 24 hours of administration. Because of the mode of action of these compounds nematode paralysis occurs quickly and removal of the worms is rapid. In addition to its anthelmintic properties, levamisole has been shown to stimulate the mammalian immune system by increasing cellular activity. The relationship between the immunostimulatory and nematocidal properties of levamisole is unknown.


Pyrantel and morantel are members of the tetrahydropyrimidine group. Morantel is used for the treatment of gastrointestinal worms of cattle and sheep but is not effective against mucosal or arrested stages or against established lungworm infections. Like levamisole, it has no activity against tapeworms and fluke. Pyrantel is used for the treatment and control of nematode and tapeworm infections in horses and nematodes in dogs. It is also active against nematodes in ruminants and pigs. Pyrantel salts (tartrate or pamoate) are active against adult and larval stages of large and small strongyles, ascarids, tapeworms (Anoplocephala) at double the regular dose, and benzimidazole-resistant strains of cyathostomes in the horse.


None of these drugs are particularly toxic and they can be used safely in pregnant and young animals.


The mode of action of these compounds appears to be as selective agonists, mimicking the action of acetylcholine (Ach), causing a rapid, reversible spastic paralysis. Paralysed worms are expelled by normal gut peristalsis.


AVERMECTINS/MILBEMYCINS


These are a series of macrocyclic lactone derivatives, which are fermentation products of the actinomycete Streptomyces avermitilis (avermectins) and Streptomyces cyanogriseus (milbemycins). Avermectins differ from each other chemically in side chain substitutions on the lactone ring, whilst milbemycins differ from the avermectins through the absence of a sugar moiety from the lactone skeleton. The avermectins include abamectin, doramectin, eprinomectin and ivermectin, and are active against a wide range of nematodes and arthropods. Moxidectin is a milbemycin and has a similar wide-ranging activity.


The macrocyclic lactones have been shown to have excellent activity, at very low dose rates, not only against a wide range of nematodes, but also against certain arthropod parasites and hence are sometimes referred to as endectocides. They are active against adult and larval gastrointestinal roundworms and lungworms of ruminants, horses and pigs, although none of these compounds have activity against tapeworms or liver fluke. Avermectins are also active against filarial worms (Parafilaria) in cattle, microfilariae of the canine heartworm (Dirofilaria) in dogs and spiruroid worms, including Habronema and Draschsia, in horses.


The ectoparasites these compounds have activity against include warbles (Hypoderma spp) in cattle, sucking lice (Haematopinus, Linognathus, Selenopotes spp) and mange mites (Psoroptes, Sarcoptes, Chorioptes) in cattle, sheep and pigs. More detailed information on the efficacy of the endectocides against ectoparasites is provided in the section on ectoparasiticides.


Selamectin is used as a preventative against heartworm disease in dogs and is effective against hookworms (Ancylostoma, Uncinaria) and ascarid roundworms (Toxocara, Toxascaris) in dogs and cats. Selamectin has been specifically developed for use in dogs and cats and is also active against fleas and mites in these hosts (see Ectoparasiticides).


Macrocyclic lactones are highly lipophilic and, following administration, are stored in fat tissue from where they are slowly released, metabolised and excreted. Ivermectin is absorbed systemically following oral, subcutaneous or dermal administration, but is absorbed to a greater degree, and has a longer halflife, when given subcutaneously or dermally. A temporary depot appears to occur in the fat and liver, from which there is a slow release. Excretion of the unaltered molecule is mainly via the faeces with less than 2% excreted in the urine. The reduced absorption and bioavailability of ivermectin when given orally in ruminants may be due to its metabolism in the rumen. The affinity of these compounds to fat explains their persistence in the body and the extended periods of protection afforded against lungworms and stomach worms in cattle and sheep. Individual variances in these periods of protection reflect differences in drug distribution, metabolism and excretion. In cattle, injectable and pour-on preparations provide protection for up to 42 days for lungworms and 35 days for stomach worms depending on the product and formulation. The prolonged half-life of these compounds also determines levels of residues in meat and milk, and subsequent compulsory withdrawal periods following treatment. With the exception of eprinomectin, which has a zero milk withdrawal period, treatment with this class of compounds cannot be given to lactating cattle, or during the last 2 months of pregnancy.


Their mode of action has been studied but has still not been completely elucidated. Ivermectin is known to act on γ-aminobutyric acid (GABA) neurotransmission at two or more sites in nematodes, blocking interneuronal stimulation of excitatory motor neurones and thus leading to a flaccid paralysis. It appears to achieve this by stimulating the release of GABA from nerve endings and enhancing the binding of GABA to its receptor on the post-synaptic membrane of an excitatory motor neurone. The enhanced GABA binding results in an increased flow of chloride ions (Cl−) into the cell leading to hyperpolarisation. In mammals, GABA neurotransmission is confined to the central nervous system; the lack of effect of avermectin on the mammalian nervous system at therapeutic concentrations is probably because, being a large molecule, it does not readily cross the blood–brain barrier. More recent evidence suggests that ivermectin may exert its effect through action on glutamate-gated Cl− conductance at the post-synaptic membrane or neuromuscular end-plate.


SALICYLANILIDES/SUBSTITUTED PHENOLS


The salicylanilides/substituted phenols can be regarded as close analogues and include the bromsalans, clioxanide, oxyclozanide, brotianide, niclosamide, rafoxanide and closantel (salicylanilides), nitroxynil, disophenol, bithionol, hexachlorophene, niclofolan (phenol derivatives). With the exception of niclosamide, the salicylanilides and substituted phenols are usually marketed as flukicides for cattle and sheep, being highly effective against adult, and to a lesser extent, immature flukes (Fasciola). Some also possess activity against bloodsucking nematodes such as Haemonchus. Disophenol has been used for treatment of dogs infected with hookworms, and is also effective against mature H. contortus and may be used in sheep for treatment of benzimidazole-resistant H. contortus infections. Niclosamide is highly effective against tapeworms in cattle, sheep, horses, poultry and possibly against immature paramphistomes in ruminants. In a number of countries, it is used mainly for the treatment of tapeworms in dogs and cats.


Salicylanilides and substituted phenols appear to be extensively bound to plasma proteins (>99%), which may explain their high efficacy against blood-feeding parasites. Fasciolicidal activity is dependent on the extent to which these drugs persist in the plasma. Rafoxanide and closantel have long plasma half-lives when compared with oxyclozanide. Evidence suggests that the apparent efficacy of these drugs, particularly against immature fluke (Fasciola), may be due more to their persistence in the plasma and the effect they have on maturing adult flukes when they reach the bile ducts, rather than the effect they have on the immature stages themselves. Young flukes probably ingest mainly liver cells, which contain little anthelmintic. As they grow and migrate through the liver they cause extensive haemorrhage and come into contact with anthelmintic. Finally, when the flukes reach the bile ducts they are in contact with even greater concentrations of anthelmintic as the bile ducts are important in the excretion of these compounds, as evidenced by the high proportion of these, and their metabolites, excreted in the faeces rather than the urine.


Salicylanilides and substituted phenols uncouple oxidative phosphorylation and therefore decrease the availability of high-energy phosphate compounds such as adenosine triphosphate (ATP) and reduced nicotinamide-adenine-dinucleotide (NADH–) in the mitochondria. They have also been shown to inhibit succinate dehydrogenase activity and the fumarate reductase system, which is associated with oxidative phosphorylation. Because of the long half-life of the plasma protein-bound molecules, the parasites experience prolonged exposure to the drugs, which reduces the energy available to the parasites.


Plasma binding reduces incorporation of the drugs into host tissues and accounts for the selective parasite toxicity. Looseness of faeces and slight loss of appetite may be seen in some animals after treatment at recommended dose rates. High doses may cause blindness and signs of uncoupled oxidative phosphorylation, i.e. hyperventilation, hyperthermia, convulsions, tachycardia and ultimately death.


Dichlorophen is a chlorinated phenol and is active against tapeworms (Dipylidium, Taenia) in dogs and cats. Its mode of action is thought to be similar to that of the salicyclanides, interfering with oxidative phosphorylation.


PIPERAZINES


Piperazine salts are widely used against ascarids, particularly in dogs and cats, and act as GABA agonists, producing paralysis. Piperazine adipate has been widely used in horses and is effective against adult stages of small strongyles and Parascaris. In pigs, the drug is active against Ascaris and nodular worms Oesophagostomum spp after a single treatment.


Diethylcarbamazine is still marketed in certain parts of the world for the treatment of lungworm infections in cattle. It is primarily active against immature lungworms and because it has to be given over a period of 3 days to achieve its effect, it has been replaced by more modern anthelmintics. The action of diethylcarbamazine on immature lungworm larvae is thought to be a ‘flaccid’ paralysis due to hyperpolarisation of neuronal post-synaptic membranes resulting from an increased flow of Cl− into the cell. It can be used as a preventive for heartworm disease when given to dogs in low daily doses throughout the mosquito season and for 2 months subsequently. The mode of action is incompletely understood, but it is thought to enhance phagocytosis of the microfilariae by the host immune system. It is, however, strictly contraindicated in microfilariae-positive dogs because of a possible but rare shock-type reaction that is sometimes fatal, produced by liberation of substances from dying or dead microfilariae following treatment. It has also been reported to be effective against the lungworm Crenosoma vulpis of dogs and farmed foxes.


ORGANOPHOSPHATES


Several organophosphorus compounds (see ectoparasiticides) are active against nematodes, but are becoming less widely available in many countries. Compounds used in the treatment of nematode infections include coumaphos, trichlorophon, haloxon and dichlorvos. They act by inhibiting cholinesterase resulting in a build-up of acetylcholine, which leads to neuromuscular paralysis of nematodes and their expulsion. This group of drugs is relatively toxic and has been used most frequently in horses, because of the additional insecticidal action against larvae of horse bots.


Coumaphos has been widely used as an ectoparasitic in livestock. It exhibits a cumulative effect on trichostrongyle nematodes if given in feed daily for 1 week; there is a good activity against Haemonchus spp and Cooperia spp in cattle and sheep, but it is less effective against Trichostrongylus, Ostertagia spp and Oesophagostomum spp. Anthelmintic activity can be enhanced if the drench passes via the closed oesophageal groove directly to the abomasum either with sodium bicarbonate in cattle, or copper sulphate in sheep. It is also effective against Capillaria, Ascaridia and Heterakis in chickens. The drug is toxic and may cause mortality in ruminants. Coloured breeds of egg-laying hens are more susceptible to the drug than white breeds and birds should not be treated while they are in lay.


Haloxon is still used in many countries for treatment of nematodes. In cattle, sheep and goats, there is good activity against adult Haemonchus; also Cooperia spp in sheep and Neoascaris in cattle. There is a moderate effect against Ostertagia, Bunostomum, Trichostrongylus and Oesophagostomum but little effect against Nematodirus, Trichuris and Chabertia. It is highly effective against adult stages of Strongylus vulgaris, most small strongyles (also benzimidazole-resistant strains), Parascaris and Oxyuris in the horse. Haloxon is also effective against Capillaria infections of birds (chicken, turkey, quail and pigeons) but is ineffective against Heterakis. In pigs, it is active against adult Ascaris and Oesophagostomum spp but there may be delayed neurotoxicity (posterior paralysis). It is used in some countries in chickens, turkeys, quail and pigeons against Capillaria. The recommended dose range for birds (50–100 mg/kg) is lethal for geese and possibly waterfowl.


Trichlorophon is effective against adult and immature Parascaris, adult pinworms (Oxyuris) and against bots (larvae of Gasterophilus) and, at higher doses, large strongyles (S. vulgaris) and small strongyles in horses. In some countries, trichlorphon is used in combination with various benzimidazoles, pyrantel pamoate or piperazine/phenothiazine for removal of ascarids, pinworms, small strongyles (cyathostomes) and all three species of large strongyles. It shows good efficacy against adults of Ascaris, Trichuris and Hyostrongylus in pigs. At therapeutic doses, there may be mild adverse effects such as transient softening of faeces and mild colic for several hours.


Dichlorvos has a similar spectrum of activity to trichlorophon in horses and pigs; formulation in a slow-release resin increases activity against large and small strongyles and safety in pigs. However, the resin pellets, which appear in the faeces, are toxic to other animals, especially chickens.


ARSENICALS


Thiocetarsamide is an arsenical compound that has been used for many years as an adulticidal drug for treatment of heartworm (Dirofilaria) in dogs. Its efficacy varies depending on the sex and age of worm, and there is a risk to treated animals of pulmonary embolism in the first month following treatment. The drug is highly irritant to subcutaneous tissues and is both hepatotoxic and nephrotoxic with mortality during or following therapy related to the degree of clinical manifestation of heartworm disease. It is now no longer available.


Melarsomine dihydrochloride is a new generation arsenical adulticide that can be used for treatment of canine heartworm disease. It is less nephrotoxic and hepatotoxic than thiocetarsamide and has a higher efficacy using a two-dose strategy. It is generally well tolerated causing only minor tissue reactions and is normally administered intramuscularly into the lumbar muscles.


OTHER DRUGS


Phenothiazine was the first broad-spectrum anthelmintic used for several years but it has now virtually disappeared. It is still available in some countries in combination with trichlorphon and piperazine and can be used for treating benzimidazole-resistant strains of small strongyles. The drug is active against adult stages of small strongyles but has little or no effect on large strongyles, immature stages of small strongyles and Parascaris. At therapeutic doses there may be side effects, such as anorexia, muscular weakness, icterus or anaemia, but seldom mortality.


Epsiprantel is a isoquinoline-pyrazine anthelmintic compound active against tapeworm infections in dogs and cats. It is generally formulated and administered with pyrantel pamoate to give a broader range of activity against both roundworms and tapeworms of dogs and cats.


Praziquantel is an aceylated quinoline-pyrazine and is active against a wide range of adult and larval tapeworms in dogs and cats and at higher dose rates against tapeworms of ruminants. It is the drug of choice against multilocular echinococcosis (Echinococcus multilocularis) and is also active against lung flukes (Paragonimus) and intestinal fluke (Nanophyetus) in dogs. Praziquantel modulates cell membrane permeability causing spastic paralysis of muscle cells in the parasite and, like a number of other cestodicidal drugs, causes damage to the parasite tegument.


Nitroscanate is marketed for treatment of common roundworm and tapeworm infections of dogs. Although active in cats its use in this species is contraindicated due to adverse side effects including posterior paralysis, inappetence and vomiting.


Emodepside is a semi-synthetic compound belonging to a new group of chemicals called the depsipeptides. The compound acts at the neuromuscular junction by stimulating secretin pre-synaptic receptors leading to paralysis and death of the parasites. Emodepside is active against roundworms of dogs and cats.


PROPERTIES OF ANTHELMINTIC COMPOUNDS


An ideal anthelmintic should possess the following properties:



1. It should be efficient against all parasitic stages of a particular species. It is also generally desirable that the spectrum of activity should include members of different genera, for example in dealing with the equine strongyles and Parascaris equorum. However in some circumstances, separate drugs have to be used at different times of year to control infections with unrelated helminths; the trichostrongyles responsible for ovine parasitic gastroenteritis and the liver fluke Fasciola hepatica are examples.

2. It is important that any anthelmintic should be nontoxic to the host, or at least have a wide safety margin. This is especially important in the treatment of groups of animals such as a flock of sheep, where individual body weights cannot easily be obtained, rather than in the dosing of individual companion animals such as cats or dogs.

3. In general, an anthelmintic should be rapidly cleared and excreted by the host, otherwise long withdrawal periods would be necessary in meat-and milk-producing animals. However, in certain circumstances and in certain classes of animals, drug persistence is used to prophylactic advantage, for example the use of closantel to control Haemonchus in sheep.

4. Anthelmintics should be easily administered, otherwise they will not be readily accepted by owners; different formulations are available for different domestic animal species. Oral and injectable products are widely used in ruminants, and pour-on preparations are available for cattle. Anthelmintic boluses are also available for cattle and sheep. Palatable in-feed and paste formulations are convenient for use in horses, while anthelmintics are usually available as tablets for dogs and cats.

5. The cost of an anthelmintic should be reasonable. This is of special importance in pigs and poultry where profit margins may be narrow.

USE OF ANTHELMINTICS


Anthelmintics are generally used in two ways: therapeutically, to treat existing infections or clinical outbreaks, or prophylactically, in which the timing of treatment is based on knowledge of the epidemiology. Clearly prophylactic use is preferable where administration of a drug at selected intervals or continuously over a period can prevent the occurrence of disease.


THERAPEUTIC USAGE


When used therapeutically, the following factors should be considered:



  • If the drug is not active against all stages it must be effective against the pathogenic stage of the parasite.
  • Use of the anthelmintic should, by successfully removing parasites, result in cessation of clinical signs of infection, such as diarrhoea and respiratory distress; in other words, there should be a marked clinical improvement and rapid recovery after treatment.

PROPHYLACTIC USAGE


Several points should be considered where anthelmintics are used prophylactically:



  • The cost of prophylactic treatment should be justifiable economically, by increased production in food animals, or by preventing the occurrence of clinical or subclinical disease in, for example, horses with strongylosis or dogs with heartworm disease.
  • The cost–benefit of anthelmintic prophylaxis should stand comparison with the control, which can be achieved by other methods such as pasture management or, for example, in the case of dictyocaulosis, by vaccination.
  • It is desirable that the use of anthelmintics should not interfere with the development of an acquired immunity, since there are reports of outbreaks of disease in older stock, which have been overprotected by control measures during their earlier years.
  • Prolonged prophylactic use of one drug should be avoided as this may encourage the development of anthelmintic resistance.

METHODS OF ADMINISTRATION


Traditionally, anthelmintics have been administered orally or parenterally, usually by subcutaneous injection. Oral administration is common by drenching with liquids or suspensions, or by the incorporation of the drug in the feed or water for farm animals and by the administration of tablets to small animals. More recently, paste formulations have been introduced especially for horses and there are now several compounds which have systemic action when applied as pour-on or spot-on formulations to the skin. Methods for injecting compounds directly into the rumen of cattle have also been marketed. A number of rumen-dwelling boluses are available, mainly for cattle, and to a lesser extent for sheep. These are designed to deliver therapeutic doses of anthelmintic at intervals (pulse-release) or low doses over prolonged periods (sustained-release); both prevent the establishment of mature parasite populations and thus limit the contamination of pastures and the occurrence of disease. An apparatus for the delivery of anthelmintics into drinking water at daily or periodic intervals has also been developed.


Some products are marketed for cattle and sheep consisting of a mixture of a roundworm anthelmintic and a fluke drug, but the timing of treatments for roundworms or flukes, whether curative or prophylactic, is often different and the requirement for such combination compounds is therefore limited.


ECTOPARASITICIDES (INSECTICIDES/ACARICIDES)


The control of the ectoparasites found on animals, including fleas, lice, ticks, mange mites, warbles and nuisance flies, is largely based on the use of chemicals. There is a vast world market in these chemicals, with increasingly more spent on flea control products in companion animals.


ECTOPARASITICIDES AND THEIR MODE OF ACTION


Three main chemical groupings have been used as the basis for the common ectoparasiticides: the organochlorines, the organophosphates and the synthetic pyrethroids. Other groups that are also used include the carbamates (primarily in poultry), the formamidines, the triazines, benzyl benzoate and natural plant products such as pyrethrin. The avermectins and milbemycins have also been shown to have a high activity against a range of ectoparasites and these are increasingly used for ectoparasite control, for example mange in sheep, cattle and pigs. There are also compounds which affect the growth and development of insects. Based on their mode of action they can be divided into chitin inhibitors, chitin synthesis inhibitors and juvenile hormone analogues. Insect growth regulators (IGRs) are widely used for flea control in domestic pets and for blowfly control in sheep but have limited use in other host species. For example, lufenuron blocks the formation of larval chitin in fleas, and cyromazine disrupts growth regulation in blowfly larvae on sheep.


ORGANOCHLORINES (OCS)


Organochlorines are now banned in many countries on the grounds of both human and environmental safety. OCs fall into three main groups:



  • Chlorinated ethane derivatives. Includes DDT (dichlorodiphenyltrichloroethane), DDE (dichlorodiphenyldichloroethane) and DDD (dicofol, methoxychlor). Chlorinated ethanes cause inhibition of sodium conductance along sensory and motor nerve fibres by holding sodium channels open, resulting in delayed repolarisation of the axonal membrane. This state renders the nerve vulnerable to repetitive discharge from small stimuli that would normally cause an action potential in a fully repolarised neurone.
  • Cyclodienes. The cyclodienes include chlordane, aldrin, dieldrin, hepatochlor, endrin and tozaphene. They appear to have at least two component modes of action; inhibition of γ-amino butyric acid (GABA) stimulated Cl− flux and interference with calcium ion (Ca2+ ) flux. The resultant inhibitory post-synaptic potential leads to a state of partial depolarisation of the post-synaptic membrane and vulnerability to repeated discharge.
  • Hexachlorocyclohexanes (HCH). Includes benzene hexachloride (BHC) and its γ-isomer, lindane. The mode of action is similar to the cyclodienes with the drug binding to the picrotoxin side of the GABA receptor resulting in an inhibition of GABA-dependent Cl– flux into the neurone.

DDT and BHC were used extensively for flystrike control but were subsequently replaced in many countries by more effective cyclodiene compounds, dieldrin and aldrin. DDT and lindane (BHC) were widely used in dip formulations for the control of sheep scab but the organophosphates and synthetic pyrethroids have largely replaced them. They have the advantage that the effect of the drug persists for a longer time on the coat or fleece of the animal but the disadvantage, at least in food animals, is that they persist in animal tissues. If toxicity occurs the signs are those of central nervous system (CNS) stimulation with hypersensitivity, followed by increasing muscular spasm progressing to convulsions.


ORGANOPHOSPHATES (OPS)


These include a vast number of compounds of which chlorfenvinphos, coumaphos, crotoxyphos, crufomate, cythioate, diazinon, dichlofenthion, dichlorvos, fenthion, iodofenphos, malathion, phosmet, propetamphos, ronnel, tetrachlorvinphos and trichlorphon have been amongst the most commonly used. These can persist in the animals’ coat or fleece for reasonable periods, but residues in animal tissues are short lived. Some have the ability to act systemically, given parenterally, orally or as a pour-on, but the effective blood levels of these are maintained for only 24 hours. The OPs are cholinesterase inhibitors; if acute toxicity occurs, the signs are salivation, dyspnoea, incoordination, muscle tremors and sometimes diarrhoea. There is also concern over chronic toxicity which may be associated with the use of these compounds and which is thought to be the result of inhibition of the enzyme neurotoxic esterase.


SYNTHETIC PYRETHROIDS (SPS)


The common SPs in use include deltamethrin, permethiin, cypermethrin, flumethrin and fenvalerate. The main value of these compounds lies in their repellent effect and since they persist well on the coat or skin, but not in tissue, they are of particular value against parasites which feed on the skin surface, such as lice, some mites and nuisance flies. Pyrethroids act as neurotoxins upon sensory and motor nerves of the neuroendocrine and CNS of insects. All the pyrethroids are lipophilic and this property helps them to act as contact insecticides. Some have the ability to repel and to ‘knockdown’, i.e. affect flight and balance without causing complete paralysis. Because the SPs have a strong affinity for sebum this property has been capitalised upon by incorporating the SPs into ear tags or tail bands. The SPs are fairly safe, but if toxicity does occur it is expressed in the peripheral nervous system as hypersensitivity and muscle tremors. SPs are also extremely toxic to fish and aquatic invertebrates and there are environmental concerns over their use.


CARBAMATES


Carbamate insecticides are closely related to the organophosphates (OPs) and are anticholinesterases, but unlike OP compounds they appear to cause a spontaneously reversible block on the enzyme acetylcholinesterase (AchE) without changing it. The two main carbamate compounds in use in veterinary medicine are carbaryl and propoxur, with butocarb and carbanolate also used in the control of poultry ectoparasites. Carbaryl has low mammalian toxicity but may be carcinogenic and is often combined with other active ingredients. Fenoxycarb is used for flea control and appears to have a mode of action closely related to the juvenile hormone analogues, preventing embryonic development in flea eggs, larval development and adult emergence (see Insect growth regulators). It has been formulated with permethrin or chlorpyrifos for use on animals or in liquid concentrate form for environmental flea control.


AVERMECTINS/MILBEMYCINS


These are effective at very low dose levels against certain ectoparasites when given parenterally and by pour-on preparations. They are particularly effective against ectoparasites with tissue stages, such as warbles, bots and mites, and have good activity against bloodsucking parasites such as lice and one-host ticks. As in nematodes, they are thought to affect cell function by direct action in Cl− channels. They have a very wide safety margin. Some avermectins have a marked residual effect and a single treatment given parenterally is still effective against lice or mites hatching from eggs 3–4 weeks later.


Selamectin has high activity against fleas of cats and dogs (Ctenocephalides) and prevents flea infestations on dogs and cats for a period of 30 days. It is safe and effective in controlling mite (Otodectes, Sarcoptes) and tick (Rhipicephalus) infestations.


FORMAMIDINES


The main member of this group is amitraz, which acts at octopamine receptor sites in ectoparasites resulting in neuronal hyperexcitability and death. It is available as a spray or dip for use against mites, lice and ticks in domestic livestock. In cattle, for example, it has been widely used in dips, sprays or pour-on formulations for the control of single-host and multi-host tick species. In dipping baths, it can be stabilised by the addition of calcium hydroxide, and maintained by standard replenishment methods for routine tick control. An alternative method has been the use of total replen ishment formulations whereby the dip bath is replenished with the full concentration of amitraz at weekly intervals prior to use. Amitraz has also been shown to have an expellent action against attached ticks. It has been shown to be effective on controlling lice and mange in pigs and psoroptic mange in sheep.


In small animals, amitraz is available for topical application for the treatment and control of ticks, and for canine demodicosis (Demodex) and sarcoptic mange (Sarcoptes). Amitraz is contraindicated in horses and in pregnant or nursing bitches and cats, although it has been used at a reduced concentration to treat feline demodicosis. Amitraz is also formulated in collars for tick control in dogs.


PHENYLPYRAZOLES


Fipronil is a phenylpyrazole compound which blocks transmission of signals by the inhibitory neurotransmitter, GABA, present in insects. The compound binds within the Cl − channel and consequently inhibits the flux of Cl− ions into the nerve cell resulting in hyperexcitation of the insect nervous system. Fipronil is used worldwide for the treatment and control of flea and tick infestations on dogs and cats and has reported activity against mange mites (Sarcoptes), ear mites (Otodectes), forage mites (Trombicula, Cheyletiella) and dog lice (Trichodectes). It is highly lipophilic and diffuses into the sebaceous glands of hair follicles that then act as a reservoir giving it a long residual activity. Sunlight, immersion in water and bathing do not significantly impact on the performance of products containing this compound. There is evidence that fipronil has an extremely rapid knock-down effect which occurs before the fleas have time to feed and hence it may be especially useful in cases of flea allergic dermatitis.


NITROGUANIDINES AND SPINOSYNS


Imidacloprid is a chloronicotinyl insecticide, a synthesised chlorinated derivative of nicotine. It specifically binds to nicotinic acetylcholine (Ach) receptors in the insect’s CNS, leading to inhibition of cholinergic transmission resulting in paralysis and death. This mode of action is the same as nicotine, which has been used as a natural insecticide for centuries. The favourable selective toxicity of imidacloprid appears to be due to the fact that it only seems to bind to the Ach receptors of insects, having no effect on these receptors in mammals. Its activity appears to be mainly confined to insect parasites and it is available as a spot-on product in many countries for use in dogs and cats for the control of adult fleas providing protection against reinfestation for up to 4–5 weeks.


Spinosad is a fermentation product of the soil actinomycete, Saccaropolyspora spinosa, and has been developed in some countries for use on sheep in the control of blowfly strike and lice.


INSECT GROWTH REGULATORS


Several IGRs are used throughout the world, and represent a relatively new category of insect control agents. They constitute a group of chemical compounds that do not kill the target parasite directly, but interfere with growth and development. IGRs act mainly on immature stages of the parasite and as such are not usually suitable for the rapid control of established adult populations of parasites. Where parasites show a clear seasonal pattern, IGRs can be applied prior to any anticipated challenge as a preventative measure.


Based on their mode of action they can be divided into chitin synthesis inhibitors (benzoylphenyl ureas), chitin inhibitors (triazine/pyrimidine derivatives) and juvenile hormone analogues. IGRs are widely used for flea control in domestic pets and for blowfly control in sheep but have limited use in other host species.


Benzoylphenyl ureas

The benzoylphenyl ureas (diflubenzuron, flufenoxuron, fluaxuron, lufenuron and triflumuron) are chitin inhibitors, of which several have been introduced for the control of ectoparasites of veterinary importance. Chitin is a complex aminopolysaccharide and a major component of the insect’s cuticle. During each moult it has to be newly formed by polymerisation of individual sugar molecules. Chitin molecules, together with proteins are assembled into chains, which in turn are assembled into microfibrils. 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, and 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 as a consequence die during the moulting process. Benzyl phenylureas also appear to show a transovarial effect. Exposed adult female insects produce eggs in which the compound is incorporated into the egg nutrient. Egg development proceeds normally but the newly developed larvae are incapable of hatching. Benzoylphenyl ureas show a broad spectrum of activity against insects but have a relatively low efficacy against ticks and mites. The exception to this is fluazuron, which has greater activity against ticks and some mite species.


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


Diflubenzuron and flufenoxuron are used for the prevention of blowfly 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 preventative, providing 12–14 weeks’ protection. It may also have potential for the control of 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 long-term protection against the one-host tick, Boophilus microplus.


Lufenuron is administered orally and is used for the control of fleas of dogs and cats. The drug accumulates in fat tissue allowing subsequent slow release. Fleas take up the drug through the blood and transfer it to their eggs, which are non-viable within 24 hours of administration. The formation of larval chitin structures is blocked, thereby inhibiting the development of flea larvae and providing environmental control of the flea population. For oral administration, the drug must be administered in the food to allow sufficient time for absorption from the stomach. Injectable treatment is given at 6-monthly intervals whilst oral treatment is given once monthly during summer, commencing 2 months before fleas become active. As lufenuron has no activity against adult fleas, an insecticide treatment may be required if there is an initial heavy infestation or in cases of severe hypersensitivity.


Triflumuron is active against lice and fleas in dogs.


Triazine/pyrimidine derivatives

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


Cyromazine, a triazine derivative, is effective against blowfly larvae on sheep and lambs and also against other Diptera, such as houseflies, mosquitoes, etc. At recommended dose rates, cyromazine shows only limited activity against established strikes and must therefore be used preventatively before anticipated challenge. Blowflies lay eggs usually on damp fleece of treated sheep. Although larvae are able to hatch out, the young larvae immediately come into contact with cyromazine, which prevents the moult to second instars. The use of a ‘pour-on’ preparation of cyromazine has the advantage that efficacy is not dependent upon factors such as weather, fleece length and whether the fleece is wet or dry. In addition, the persistence of the drug is such that control can be maintained for up to 13 weeks after a single pour-on application, or longer if applied by dip or shower.


Dicyclanil, a pyrimidine derivative, is highly active against dipteran larvae and is available as a pour-on formulation for blowfly control in sheep in some countries, providing up to 20 weeks protection.


Juvenile hormone analogues

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, and final development occurs to the adult stage. The juvenile hormone analogues bind to juvenile hormone receptor sites, but because they are structurally different are not destroyed by insect esterases. As a consequence, metamorphosis and further development to the adult stage does not proceed.


Methoprene is a terpenoid compound with very low mammalian toxicity that mimics a juvenile insect hormone and is regularly used for flea control. It is sensitive to light and will not persist outdoors. It has been used extensively and successfully in indoor environments and on pets in the form of collars, shampoos, sprays and dips and also as a feed through larvicide for hornfly (Haematobia) control on cattle. The other member of this group used for the control of fleas in dogs and cats is pyriproxyfen.


MISCELLANEOUS COMPOUNDS


Piperonyl butoxide (PBO) is a methylnedioxphenyl compound that has been widely used as a synergistic additive in the control of arthropod pests. It is commonly used as a synergist with natural pyrethrins, the combination having a much greater insecticidal activity than the natural product alone. The degree of potentiation of insecticidal activity is related to the ratio of components in the mixture, such that as the proportion of PBO increases, so the amount of natural 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 PBO. The enhancement of activity of synthetic pyrethroids is normally less dramatic but PBO may be included in several formulations. PBO inhibits the microsomal enzyme system of some arthropods and has been shown to be effective against some mites. In addition to having low mammalian toxicity and a long record of safety, PBO rapidly degrades in the environment.


Various products from natural sources, as well as synthetic compounds, have been used as insect repellents. Such compounds include cinerins, pyrethrins and jasmolins (see pyrethroids), citronella, indalone, garlic oil, MGK-264, butoxypolypropylene-glycol, DEET (N1N-diethyl-M toluamide) and DMP (dimethylphthalate). The use of repellents is advantageous as legislative and regulatory authorities become more restrictive towards the use of conventional pesticides.


METHODS OF PESTICIDE APPLICATION AND USES


FARM ANIMALS


Traditionally, ectoparasiticides have been applied topically as dusts, sprays, foggers, washes, dips and occasionally used in baits to trap insects. However, with the advent of pour-on and spot-on formulations with a systemic effect, the parenteral administration of drugs such as the avermectins and closantel and the use of impregnated ear tags, collars and tail-tags, the methodology of control applications to animals has changed.


Traditional methods

To be successful, the use of insecticides in dusts, sprays or washes usually requires two or more treatments, since even the most diligent applicant is unlikely to be successful in applying these formulations at the right concentration to all parts of the animal’s body. The interval between treatments should be linked to the persistence of the chemical in the skin, hair or wool and to the life cycle of the parasite, further treatment being given prior to completion of another cycle.


Dip baths or spray races containing the necessary concentration of insecticide are used to control mites, lice and ticks and certain dipterans such as blowflies on sheep on a worldwide basis and on cattle in tropical areas. This technique is more successful in sheep where the persistence of insecticide is greater in the wool fleece than in the hair coat found in cattle. It is important to remember that the concentration of insecticide in a dip bath is preferentially ‘stripped’ or removed as sheep or cattle are dipped, and so must be replenished at a higher than initial concentration, sufficient to maintain an adequate concentration of the active ingredient. Most dips are based on the organophosphate group and synthetic pyrethroids. Despite human and environmental safety concerns, some countries have reintroduced organochlorines because of developing resistance to organophosphates.


Insect control in dairies or stables may be aided by the use of various resins strips incorporating the insecticide; dichlorvos and trichlorfon are often used for this purpose. Sometimes baits containing synthetic pheromones, sugars or hydrolysed yeasts, plus insecticide are spread around animal premises to attract and kill dipterans.


Pour-on, spot-on or spray-on

Those available at present contain organophosphates with a systemic action such as fenthion or phosmet, the avermectins/milbemycins or the synthetic pyrethroids. They are recommended for the control of warbles and lice in cattle and lice and keds in sheep. A valuable development is that of pour-on phosmet for the control of sarcoptic mange in pigs and cattle. A single treatment in pigs gives very good results and, if used in sows prior to farrowing, prevents transmission to the litter; two treatments at an interval of 14 days are necessary in cattle. The synthetic pyrethroids are also available as sprays, pour-ons or spot-ons for the treatment of lice and the control of biting and nuisance flies in cattle, sheep and goats.


Ear tags, collars, leg and tail bands

These are based primarily on the synthetic pyrethroids and occasionally the organophosphates. They are recommended for the protection of cattle against nuisance flies. The tags are usually made of polyvinylchloride impregnated with the insecticide. When attached to an animal’s ear the insecticide is released from the surface, dissolves in the sebum secreted by the skin and is then spread over the whole body by the normal grooming actions or ear flapping and tail swishing as well as by bodily contact between cattle. As the insecticide is rapidly bonded to the sebum on the animal’s coat the treatment is rain-fast; also the tag or tail band continues to release a supply of chemical under all climatic conditions. Since the drugs are located in the sebum, they are not absorbed into the tissue so there is no need for a withdrawal period prior to slaughter, nor is it necessary to discard milk. The common SPs marketed for this purpose are cypermethrin and permethrin. Under conditions of heavy fly challenge a tag should be inserted in each ear, possibly augmented by a tail band.


Parenteral treatment

The avermectins/milbemycins and closantel may be given parenterally to control some ectoparasites. For example, the endectocides have good activity against warbles, lice, many mites and also the one-host tick Boophilus. Closantel is available in some tropical countries for use against one-host ticks and sucking lice.


COMPANION OR PET ANIMALS


Ectoparasiticides are mainly used as dusting powders, aerosols, washes/shampoos, spot-on preparations and impregnated collars, whilst some are available for oral use. They are mainly used for the control of fleas, lice and mange in dogs and cats and for lice, mange and nuisance flies in horses.


Dusting powders

The powders should be shaken well into the animal’s fur or hair and, in the case of house pets, into the bedding. The powders commonly used contain pyrethroid-based insecticides with or without the synergist, piperonyl butoxide. These are particularly useful for fleas and lice and repeat treatments are generally recommended every 2–3 weeks.


Aerosols

Although easy to use, some of the noisier sprays can upset pets. Overzealous spraying in confined spaces, such as in a cat basket, may produce toxic effects. Sprays available are generally based on pyrethroids and carbamates or a mixture of organophosphates such as dichlorvos plus fenitrothion, or a mixture of the synergist piperonyl butoxide with OPs or pyrethroids. Depending on the spray, the aerosol container should be held at 15–30 cm from the animal and sprayed for up to 5 seconds for cats and a little longer for dogs. A repeat treatment is often recommended in 7–14 days; but only one spray application with fipronil can give up to 3 months’ protection against reinfestation with fleas in dogs and cats. The aerosol sprays are very effective for fleas and lice, but several treatments may be necessary for mange mites. The synthetic pyrethroids are also available as a wash or spot-on for horses for the control of flies including midges, which are responsible for ‘sweet-itch’.


Aerosols containing the insect growth regulator, methoprene, are available for the control of larval populations of fleas in the environment.


Baths

These are available as shampoos, emulsifiable concentrates, wettable agents or creams for the control of fleas, lice and mange mites. Most preparations are for dogs and care is needed if they are used for cats. Common ingredients are carbaryl, propoxur and the OP phosmet; amitraz is particularly useful for demodectic mange in dogs. The instructions for bathing should be carefully followed and, where necessary, care taken that the insecticide is properly rinsed from the coat. Organophosphate shampoos should not be used when dogs have insecticidal collars.


Insecticidal collars

These are used primarily for flea control and are based on the organophosphates, carbamates and synthetic pyrethroids. The period of protection is claimed to be 3–4 months, but the success of this method of application is variable. Occasional problems arise from contact dermatitis and care should be exercised that the animals do not receive other organophosphate treatments. Apart from collars, impregnated medallions are also available in some countries. Care should be taken with the use of collars in pedigree long-haired cats and greyhound dogs due to individual susceptibility to OP poisoning.


Collars have also been introduced containing deltamethrin for the control of biting flies, including sandflies, as a means of prevention of infection with transmissible diseases such as leishmaniosis.


Oral preparations

One organophosphate, cythioate, is marketed as an oral preparation. It is specifically for the treatment of demodectic mange and flea infestations in dogs and flea infestation in cats; the daily administration of tablets is recommended as a supplement to topical application.


Other preparations

Spot-on preparations containing fenthion, deltamethrin, fipronil, imidocloprid, emodepside and selamectin are now available for the control of fleas, and in some cases ticks, on dogs and cats. In horses, lice and areas of mange mite infestation can be treated topically, but the problem of nuisance or pasture flies remains. It has been suggested that ear tags impregnated with cypermethrin be attached to the saddle or mane as a possible means of incorporating the synthetic pyrethroid into the sebum.


POULTRY ECTOPARASITES


The carbamates and the organophosphate, malathion, are the most widely used. Individual birds are dusted and the insecticide applied in the poultry house, nesting boxes and litter. Cypermethrin is available for the environmental treatment of poultry red mites (Dermanyssus).


ANTIPROTOZOALS


Unlike other antiparasitic agents, for which a few chemical structural classes exhibit a wide spectrum of biological activity, antiprotozoal activity exists in a wide spectrum of chemical classes, each of which possess only a narrow spectrum of activity. The classification of antiprotozoal compounds is complex and for the purposes of this chapter they are divided into eight main groups, each of which may be further subdivided on the basis of structural similarities.


ANTIPROTOZOALS AND THEIR MODE OF ACTION


ANTIMONIALS AND ARSENICALS


Antimonials contain the group V metal, antimony, and have been used extensively for the treatment of leishmaniosis. The antimonials selectively inhibit enzymes that are required for glycolytic and fatty acid oxidation in tissue amastigotes found within macrophages.


Tartar emetic (antimony potassium tartrate) was the first antimonial used for this purpose in cases of human leishmaniosis. It was also used in the treatment of Trypanosoma congolense congolense and T. v. vivax infections in cattle and T. b. evansi infections in camels. Extravascular injection causes severe necrosis and the compound has a narrow chemotherapeutic index resulting in about 6% mortality during routine treatment.


Pentavalent antimony compounds meglumine antimoniate (Glucantime or N-methylglucamine antimoniate), sodium antimony gluconate and sodium stibogluconate (Pentostam) have been the first-line drugs for the treatment of leishmaniosis in humans and are the principal antimonials used for the treatment of canine leishmaniosis. The precise chemical structure of these drugs is difficult to identify. Drug tolerance to antimonials in human and canine leishmaniosis is known and there may be considerable rates of treatment failure and relapses. These drugs may show marked toxic effects such as arthralgia, nephrotoxicity and cardiotoxicity, leading rarely to sudden death. Antimonials are administered either by intralesional infiltration in simple single cutaneous lesions or by intramuscular injection in all cases with systemic involvement. Antimony is excreted quickly from the body so that daily treatment is necessary throughout each course of treatment. Meglumine antimoniate and allopurinol given simultaneously have been shown to maintain dogs in clinical remission.


Arsenicals are substituted benzene arsonic acid salts or esters and have been used in the treatment of trypanosomiosis (tryparsamide, melarsamine) and coccidiosis (arsenilic acid, roxarsone). Melarsamine is effective against trypanosomes of the T. brucei group (T. b. evansi). Roxarsone was used primarily as a growth promoter but had some activity against Eimeria tenella and E. brunetti in chickens when used alone or in combination with nitromide or dinitolmide. Arsenicals have a low safety index and have been superseded by comparatively less toxic compounds.


SUBSTITUTED AROMATICS


Amidines and diamidines

Pentamidine has the widest spectrum within the group with activity against Leishmania, Trypanosoma, Babesia and Pneumocystis, and is used mainly in human medicine. Stilbamidine has been used for the treatment of leishmaniosis. Amicarbilide is active against Babesia and diminazene aceturate is active against both Babesia and Trypanosoma. Very little is known about the mode of action of this class of compounds. Antiparasitic activity may be related to interference with aerobic glycolysis as well as interference with synthesis of parasite DNA.


Diminazene is highly active against babesiosis in cattle, sheep, pigs, horses and dogs although the small Babesia spp are generally more refractory to treatment than large ones. There appears to be a wide range of individual animal tolerance to the drug; it is well tolerated in horses at the recommended dose, although higher doses may cause severe side effects. Various treatment regimens are used for eliminating babesiosis in cattle, horses and dogs. In most cases the recommended dose is given in divided doses, e.g. 5 mg/kg, twice at 24-hour intervals, to eradicate Babesia spp infections in horses, or 1.75 mg/kg twice at 24-hour intervals to reduce or avoid neurotoxic side effects in horses (lethargy, incoordination and seizures) and dogs (ataxia, opisthotonus, nystagmus, extensor rigidity, coma and even death). Local reactions can occur in cattle and in horses there may be skin sloughing and abscessation following injection. In camels there may be mortality at the recommended dose rate.


Diminazine is also effective against Trypanosoma congolense congolense and T. v. vivax, but less active against T. b. brucei and T. b. evansi infections and shows no activity against T. c. simiae. Widespread use may lead to development of diminazene-resistant T. v. vivax and T. c. congolense strains. As a rule, diminazene-resistant strains are susceptible to isometamidium. Trypanosomes resistant to other drugs (except quinapyramine) are commonly susceptible to diminazene.


Phenamidine is used for treating canine and equine babesiosis and has also been used in Babesia bigemina infections in cattle. Frequent relapses may occur in B. gibsoni infections in dogs. The mechanism of drug action is uncertain but may be similar to that of pentamidine and diminazene.


Arylamides and urea derivatives

Nitolmide and dinitolmide are arylamides (nitrobenzamides) used as coccidiostats in poultry appearing to affect first-generation meronts; they are active against Eimeria tenella and E. necatrix infections but have limited activity against E. acervulina. Both drugs have been used in combination with roxarsone as in-feed coccidiostats for use in chickens.


Nicarbazin (phenyl urea) is also used as a coccidiostat in the control of coccidiosis in chickens and turkeys in shuttle programmes (starter feed only) usually in the winter and for that reason resistance of coccidia to nicarbazine is not yet widespread. It is also used in combination with narasin as it shows synergistic effect with the ionophores. It affects second-generation meronts, impairing oocyst formation and allowing treated birds to develop immunity against coccidia. There may be problems with side effects, as it can cause increased sensitivity to heat stress during summer, which results in growth depression and mortality in broilers. The drug should not be fed to laying hens because of toxic side effects (reduced hatchability, interruption of egg laying).


Imidocarb diproprionate is a phenyl urea and is the drug of choice for the treatment of babesiosis in cattle, horses and dogs. It appears to act directly on the parasite leading to an alteration in morphology, and is effective in both treatment and prevention without interfering with the development of immunity.


Ethopabate is an arylamide and has a similar mode of action to the sulphonamides acting as a para-aminobenzoic acid (PABA) agonist, blocking the utilisation of PABA into amino acids and DNA synthesis. It has been administered in combination with amprolium to achieve a broader spectrum of activity for the prophylaxis and treatment of coccidiosis in chickens and turkeys. With chicken coccidia, it has a good innate activity against Eimeria acervulina, is less active against E. maxima and E. brunetti and has no activity against E. tenella.


Quinuronium sulphate was for many years the drug of choice in treating bovine babesiosis (B. bigemina, B. bovis, B. divergens); and it is active against large Babesia spp of pigs, horses and dogs. The drug has a low therapeutic index and may stimulate the parasympathetic nervous system resulting in excessive salivation, frequent urination, or dyspnoea caused by anticholinesterase activity. The mode of action is unknown.


These compounds have similar modes of action and act by uncoupling oxidative phosphorylation through inhibition of glycerol phosphate oxidase and glycerol phosphate dehydrogenase, which prevents re-oxidation of NADH and decreased adenosine triphosphate (ATP) synthesis.


Sulphonic acids

Suramin and trypan blue were amongst the first antiprotozoals. Suramin was one of the first antitrypanosomal drugs developed and shows high efficacy against trypanosomes of subgenus Trypanozoon (T. b. brucei, T. b. evansi, T. equiperdum) and is the drug of choice for T. b. evansi infections (surra) in camels and horses. The drug inhibits enzymes in the glucose metabolism pathway preventing re-oxidation of NADH and decreased ATP synthesis. It may be toxic in horses, causing oedema of sexual organs, lips and eyelids or painful hoofs. Intramuscular administration can cause severe necrosis at the injection site and sub-optimal dosing (less than 1 g/100 kg body weight) may lead to suramin-resistant strains.


Trypan blue is an azo-napthalene dye used for the treatment of babesiosis and was the first specific drug with activity against B. bigemina in cattle, but its use leads to blue staining of meat and milk, and it has been largely replaced by the diamidines.


Napthoquinones

Menoctone, parvaquone and buparvaquone are napthoquinones with marked anti-theilerial activity. They appear to block electron transport at the ubiquinone level. The mechanism of selective toxicity might be due to a difference between parasite and mammalian ubiquinone.


Menoctone was the first drug with high antitheilerial activity, causing marked degeneration in appearance of macroschizonts and suppression of parasitaemia in established Theileria parva parva infections in cattle. Its use has now been discontinued.


Parvaquone is highly active against theileriosis (Theileria p. parva and T. annulata) infections in cattle when treatment is performed in the early stage of infection, allowing development of protective immunity without apparent clinical signs. Buparvaquone is an analogue of parvaquone with a substituted alkyl group, which slows down metabolic degradation of the parent compound, increasing efficacy against these species.


Miscellaneous diphenyls

Robenidine is a guanidine derivative and affects the late first-generation and second-stage meronts of Eimeria. It is both coccidiostatic and coccidiocidal and is used for the treatment of coccidiosis in chickens, turkeys and rabbits. It has a broad spectrum of activity but in rabbits it is active against intestinal Eimeria spp only. It is thought to interfere with energy metabolism by inhibition of respiratory chain phosphorylation and ATPase activity.


Dapsone and acedapsone are sulphones active against Plasmodium and are generally used in combination products only for treating human malaria. Their mode of action is similar to the sulphonamides, acting as antifolate drugs, blocking the incorporation of PABA to form dihydrofolic acid.


PYRIDINE DERIVATIVES


Decoquinate and methylbenzoquate are 4-hydroxy-quinolones that act on the sporozoites and first-generation meronts of Eimeria, interfering with electron transport at the cytochrome B level and mitochondrial metabolism. Hydroxyquinolines are almost entirely coccidiostatic with activity against sporozoites and trophozoites of all Eimeria spp. As single compounds they have only limited success as a result of serious and immediate drug resistance in the field, such that methylbenzoquate-resistant Eimeria cannot be controlled by the drug at any level.


Decoquinate has been used for the control of coccidiosis in poultry and is used for the prevention and control of coccidiosis in cattle and sheep.


Methylbenzoquate is usually administered in combination with clopidol or meticlorpindol, mainly in shuttle or rotation programmes to achieve a broader spectrum of activity for the prophylaxis and treatment of coccidiosis in chickens and turkeys.


Iodoquinol is a 4-hydroxyquinolone that is active against Entamoeba.


Quinine, chloroquine, droxycholoquine, primaquine and mefloquine are quinolines used primarily as antimalarial treatments in human medicine, inhibiting electron transport processes by inhibiting pyrimidine synthesis.


Primaquine diphosphate is active against tissue stages of Plasmodium, but is much less active against erythrocytic stages. It has been shown to be active against Babesia felis in cats at 0.5 mg/kg by intramuscular injection, although doses above 1 mg/kg caused mortality. It has also been used in the treatment or prevention of avian malaria (100 mg/kg per os).


Clopidol and meticlorpindol are pyridinols and are active against first-generation meronts, arresting sporozoite and trophozoite development; they are effective against all Eimeria spp in chickens, although resistance problems limit their use to shuttle programmes. Both compounds need to be given before or shortly after exposure and are used as a coccidiostats. Clopidol is used in the prevention of coccidiosis in chickens, partridge, guinea fowl, pheasants and rabbits with a high safety index.


Emetine and dehydroemetine are isoquinolines with activity against Entamoeba. The acridine derivative, quinacrine, is active against Plasmodium and Giardia. Acriflavine hydrochloride is active against Babesia bigemina and other large Babesia spp.


PYRIMIDINE DERIVATIVES


Amprolium is structurally similar to thiamine (vitamin B1) and is a competitive thiamine antagonist. Because of the relatively high thiamine requirement of rapidly dividing coccidian cells compared with most host cells, the drug has a high safety margin. Amprolium acts on first-generation meronts, thereby preventing differentiation of merozoites, but has poor activity against some Eimeria spp. It is often used in combination with ethopabate but its use has declined in many countries for safety and tolerance reasons in food-producing animals. Amprolium, and amprolium + ethopabate, have been used as feed additives for use in chickens, guinea fowl and turkeys for the prevention of coccidiosis, showing activity against Eimeria tenella and E. necatrix, and to a lesser extent against E. maxima of chickens, and also the pathogenic Eimeria spp of turkeys.


Amprolium + ethopabate have been combined with sulphaquinoxaline and pyrimethamine to extend their activity spectrum and to improve efficacy against amprolium-resistant Eimeria spp, but such combinations have been discontinued in some countries because of residue problems.


Amprolium, and amprolium + ethopabate have also been used for the treatment and control of coccidiosis in pheasants (but are not active against all Eimeria spp); lambs and calves; sows to control disease in suckling pigs pre- and post-farrowing; and rabbits to control intestinal Eimeria spp, but they are ineffective against hepatic coccidiosis in rabbits.


Pyrimethamine and trimethoprim are both folate antagonists with activity against Pneumocystis and are useful for treating various types of coccidiosis (eimeriosis, toxoplasmosis, sarcocystosis, neosporosis), malaria and bacterial infections. These compounds target the enzyme dihydrofolate reductase, inhibit pyrimidine biosynthesis and DNA metabolism and are usually used in combination with long-acting sulphonamides. As antifolates they synergise the anticoccidial action of sulphonamides by blocking the same biosynthetic pathway.


Halofuginone is a quinazoline affecting first- and second-generation meronts of Eimeria and is used in the control of coccidiosis in chickens and turkeys. The drug has also been shown to possess marked antitheilerial activity in cattle, and is available in some countries for the prevention and treatment of cryptosporidiosis in calves. It has also been shown to be effective against acute sarcosporidiosis in goats and sheep (Sarcocystis capracanis and S. ovicanis, respectively at 0.67 mg/kg on two successive days). The therapeutic index of halofuginone is low and overdose may produce severe diarrhoea and cachexia.


Allopurinol is a pyrazolpyrimidine and is a xanthine oxidase inhibitor, used alone or in combination with meglumine antimonate for the treatment of leishmaniosis in dogs.


Aprinocid is no longer available due to the rapid emergence of resistant strains, but it was used a feed additive for the prevention of coccidiosis in broiler chickens with a broad spectrum of activity except against Eimeria tenella. The compound inhibits sporulation of oocysts and may be coccidiostatic after a short medication period or coccidiocidal after long periods of medication. Arprinocid acts against coccidia by inhibiting hypoxanthine transport.


PHENATHRIDIUMS


This group of compounds, which includes isometamidium, homidium and quinapyrimine, has been used exclusively in the treatment of trypanosomiosis. The mode of action appears to be interference with nucleic acid synthesis by intercalative DNA binding. Other drugs of this series, pyrithridium, phenidium chloride and dimidium bromide, were replaced because of a high incidence of delayed toxicity, including marked liver damage and severe local reaction at the injection site.


Isometamidium is a synthetic hybrid of the diazotised p-aminobenzamidine moiety of diminazene molecule linked with homidium chloride. The drug is highly active against Trypanosoma vivax vivax infections in ruminants and horses as well as against T. c. congolense infections in ruminants, horses and dogs. It is less active against T. b. brucei and T. b. evansi infections in horses, ruminants, camels and dogs. The recommended dose is usually well tolerated by cattle. However, intramuscular injection can cause severe local reactions at the injection site. Intravenous injection in horses and camels may avoid local reaction but may cause systemic toxicity (salivation, tachycardia, profuse diarrhoea, hindleg weakness and collapse due to histamine release).


Homidium salts (bromide or chloride) are effective against T. v. vivax infections in cattle but less so against T. c. congolense and T. b. brucei. Their limited protective activity in cattle depends on severity of challenge and may last 3–5 weeks. Homidium can also be used for treating T. v. vivax and T. c. congolense infections in horses and dogs. Widespread use in cattle resulted in appearance of resistant T. c. congolense strains in east and west Africa. Homidium-resistant trypanosomes can be controlled by diminazene or isometamidium at increased dose rates. The drug is generally well tolerated at the recommended dose and also at higher dose levels, but may be irritant at sites of injection. Deep intramuscular injection effectively reduces local irritations. Severe reactions may occur in horses after intramuscular injection, whereas intravenous injection seems to be well tolerated.


Quinapyrimine is highly active against T. c. congolense, T. v. vivax, T. b. brucei and T. b. evansi and reaches therapeutic levels quickly. The target of action of quinapyramine is protein synthesis, displacing magnesium (Mg2+) ions and polyamines from cytoplasmic ribosomes, leading to an extensive loss of ribosomes and condensation of kinetoplast DNA. The drug can cause local and systemic reactions (salivation, shaking, trembling, diarrhoea, collapse) in cattle, horse, dogs and pigs within minutes of treatment. Unexpected acute toxicity and the rapid development of drug-resistant strains of T. c. congolense have limited its usefulness in treating trypanosomiosis in cattle. However, the drug seems to be safe and efficient for treating surra (T. b. evansi) in camels and horses as well as T. b. evansi infections in pigs. Quinapyramine-resistant strains are usually controlled by isometamidium. Quinapyramine is active against suramin-resistant strains of T. b. evansi and T. b. brucei.


TRIAZONES


Toltrazuril is a symmetrical triazone compound and is active against all intracellular stages of coccidia found in chicken, geese, ducks and cattle, sheep, goats and pigs. Toltrazuril is used therapeutically for the treatment of outbreaks of coccidiosis. It can be administered via drinking water and, because of its long residual activity, it can be used intermittently, allowing development of protective immunity.


Diclazuril and clazuril are asymmetrical triazones with a broad spectrum of activities against various coccidia in birds and animals at low concentrations (0.5–2 ppm in feed). Diclazuril has a strong anticoccidiocidal activity and has been developed as a feed additive for the prevention of coccidiosis in chickens and turkeys. It is active against developing first- and second-generation meronts and gamonts of Eimeria tenella and other pathogenic Eimeria spp of chickens; but developmental stages most affected by diclazuril varies with the Eimeria species. It is highly effective against all stages of E. tenella but only against gamont stages of E. maxima. Due to the development of resistance, it is used frequently in shuttle programmes. Diclazuril is also used for the treatment of rabbit coccidiosis, showing high activity against hepatic and intestinal coccidiosis, and in the treatment and prevention of coccidiosis in sheep.


Clazuril has only limited action against some chicken coccidia, but is highly active against coccidiosis in pigeons.


BENZIMIDAZOLES


The benzimidazoles have been described in more detail in the Anthelmintics section at the beginning of this chapter.


Benzimidazoles such as mebendazole, fenbendazole or albendazole are active against Giardia infections in man, farm animals and dogs; repeat treatments may be necessary, however, to eliminate parasites because of reinfection.


ANTIBACTERIALS


Sulphonamides

Sulphonamides, such as sulphadimidine, sulphamethoxypyrizidine, sulphaguanidine, sulphaquinoxaline and sulphachloropyrazine, are structural antagonists of para-aminobenzoic acid (PABA), which is incorporated into folic acid. They inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid at the dihydropteroate synthase step. Tetrahydrofolate is an important cofactor in many active single carbon transfer reactions, required for the synthesis of certain amino acids, purines and especially the synthesis of de-oxythymidylate, required for DNA synthesis. Large doses used for therapeutic applications often cause toxicity (haemorrhagic syndrome, kidney damage and growth depression).


Sulphonamides were among the first anticoccidials and are active against first- and second-stage meronts, being coccidiostatic at low doses and coccidiocidal at higher doses. Many of the compounds used in chickens had a broad spectrum of activity against intestinal Eimeria spp but only a moderate effect on E. tenella in chickens, but their use has been stopped in many countries. Sulphonamides have also been used in the treatment of coccidiosis in cattle, sheep, pigs, dogs, cats and rabbits. When given in combination with pyrimethamine and other diaminopyrimidines, long-acting sulphonamides (e.g. sulphadoxine or sulphamethoxine) are highly active antibacterials, antimalarials and anticoccidials.


Nitroimidazoles

The nitroimidazoles include dimetridazole, ornidazole, ronidazole, tinadazole, carnidazole and metronidazole, which appear to interfere with RNA synthesis, and nifursol, which acts by causing damage to lipids and DNA within the cells.


These compounds exhibit potent activity against trichomonads, Histomonas, Spironucleus and Giardia, and were the drugs of choice for these infections in turkeys and gamebirds. Ronidazole, dimetridazole and nifursol were used in the treatment of Histomonas infections in turkeys and gamebirds (pheasants, partridge); however, because of concerns over mutagenicity their use has been suspended in many countries. Carnidazole is used for the treatment of trichomoniosis in pigeons. Metronidazole, ornidazole and tinazole are used in humans for the treatment of giardiosis and amoebiosis.


Nitrofurans

The nitrofurans, which include furazolidone, nitrofurazone and nitrofurantoin, are relatively broad-spectrum bactericidal drugs and have coccidiostatic activity; concerns over toxicity and carcinogenicity have restricted their widespread use and they are prohibited from use in many countries. Furazolidone has been used for the prevention and treatment of coccidiosis in chickens, turkeys and pigs and for the treatment of bacterial digestive tract infections and giardiosis. Nitrofurazone is active against second-generation meronts of Eimeria tenella and E. necatrix infections in poultry, and has been used for control of coccidiosis in lambs and goat kids.


Ionophores

The polyether ionophores are fermentation products of Streptomyces or Actinomadura. These are currently the most widely used anticoccidial compounds used mainly for the control of poultry coccidosis. Monensin, narasin, salinomycin, maduramicin and semduramicin are ‘monovalent’ ionophores preferentially binding to monovalent ions, sodium and potassium (Na+, K+), although divalent cations are also bound. Lasalocid has the ability to complex divalent cations (Ca2+, Mg2+) and is termed a ‘divalent’ ionophore. The effect is to destroy cross-membrane ion gradients. They may also block host carbohydrate transport and hence deprive carbohydrate supply from intracellular parasites.


Ionophores act upon the intestinal free forms of coccidian stages (sporozoites, merozoites and gametocytes) when the drug comes into contact with them in the intestinal lumen.


These compounds are extremely toxic to horses. Ionophores such as monensin, narasin and salinomycin may cause severe growth retardation when administered with tiamulin, and most of the ionophores may interact with sulphonamides, chloramphenicol and erythromycin.


Monensin has been used extensively in the broiler industry but drug tolerance, as with other ionophores, limits its use to shuttle programmes. It is effective against coccidia in cattle, sheep and rabbits when used prophylactically in feed.


Narasin is given in combination with nicarbazine to improve coccidiosis control, and the drug combination may be used in the starter phase of shuttle programmes followed by a different ionophore in the grower–finisher phase.


Salinomycin has broad-spectrum activity and better activity against Eimeria tenella and E. acervulina than other related ionophores, including drug-tolerant Eimeria spp in the field. In turkeys, it may cause severe toxicity with growth depression, excitement, paralysis of head and legs and death if feed containing recommended or lower doses is fed for long periods.


Lasalocid may alter water excretion in treated birds via dietary electrolytes to the extent that wet litter may be a problem at higher drug concentrations. At concentrations of 75 ppm activity against E. tenella is good but insufficient against E. acervulina. In the field, lasalocid may improve control of coccidiosis where E. tenella strains show tolerance to other ionophores.


Macrolide and lincosamide antibiotics

This group of compounds is better known and more widely applied for the treatment of bacterial and fungal infections. The mode of action appears to be an inhibition of protein synthesis. Spiramycin inhibits protein synthesis by inhibiting the translocation of peptidyl-t-RNA. It has been used for the treatment of Toxoplasma infections. Clindamycin is a lincosamide with a similar mode of action, and has been used to treat Plasmodium, Babesia and Toxoplasma infections.


Amphotericin B is a polyene macrolide antibiotic used mainly as an antifungal agent but is also used as a second-line drug for the treatment of Leishmania. The drug is extremely nephrotoxic but lipid and unilamellar liposome formulations of amphotericin B have been developed with lower toxicity.


Aminoglycoside antibiotics

Aminogycoside antibiotics are bactericidal agents and are widely applied for the treatment of Gram-negative bacterial infections. Aminoglycosides are not absorbed from the gastrointestinal tract and treatment via this route is reserved for the treatment of gastrointestinal infections. Parmomycin has activity against Entamoeba, Giardia, Balantidium and Leishmania.


Tetracycline antibiotics

The tetracyclines are broad-spectrum antibacterials active against a range of Gram-positive and Gram-negative bacteria, but also against the Rickettsiales (Rickettsia, Ehrlichia, Anaplasma), and Mycoplasma and Chlamydia. The mode of action is thought to be through inhibition of protein synthesis.


Oxytetracycline, tetracycline and chlortetracycline have similar properties and may be given orally or by intramuscular injection. Doxycycline is more lipophilic than the other tetracyclines and is better absorbed orally and penetrates better into the lung and cerebrospinal fluid. Members of this group exhibit the broadest antiprotozoal activity and have been used for the treatment of Plasmodium, Balantidium, Theileria and Entamoeba. Oxytetracycline has been shown to control active Babesia divergens infections in cattle by continuous administration of 20 mg/kg every 4 days.


USE OF ANTIPROTOZOALS


The use of antiprotozoals as therapeutic or prophylactic agents is similar to that described for anthelmintics.


METHODS OF ADMINISTRATION


Anticoccidials used for controlling enteric coccidia principally belonging to the genus, Eimeria, are administered in feed. In the poultry industry, it is usual to employ anticoccidials in broiler birds continuously in feed until just before slaughter. In layer replacement stock, pullets are medicated continuously until commencement of egg-laying. Continuous use of anticoccidials may lead to ineffective treatment due to drug resistance; as a consequence, various rotational programmes have been developed by the poultry industry to reduce or avoid this problem.


Antiprotozoals are generally used in two ways: therapeutically, to treat existing infections or clinical outbreaks, or prophylactically, in which the timing of treatment is based on knowledge of the epidemiology. Clearly prophylactic use is preferable where administration of a drug at selected intervals or continuously over a period can prevent the occurrence of disease.


Table 14.2 Trypanocidal drugs.


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Jun 11, 2017 | Posted by in GENERAL | Comments Off on Antiparasitics

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