Antiparasitic Agents

I. INTRODUCTION.


Antiparasitics are drugs that reduce parasite burdens to a tolerable level by killing parasites or inhibiting their growth. The ideal antiparasitic has a wide therapeutic index (i.e., the toxic dose is at least three times the therapeutic dose), is effective after one dose, is easy to administer, is inexpensive, and does not leave residues (an important consideration for use in food-producing animals).



A. Mechanisms of action
1. Paralysis of parasites by mimicking the action of putative neurotransmitters (Table 16-1)

2. Alteration of metabolic processes
a. Inhibition of microtubule synthesis

b. Inhibition of folic acid synthesis or metabolism

c. Inhibition of thiamine utilization

d. Uncoupling of oxidative phosphorylation

e. Inhibition of chitin formation in arthropods

f. Simulation of insect juvenile hormones

3. Alteration of parasite reproduction
a. Inhibition of replication in protozoans

b. Inhibition of egg production in nematodes

B. Disadvantages of antiparasitics
1. Expense

2. Development of resistant strains

3. Inhibition of host immunity

C. Characteristics of ideal antiparasitics
1. Effective in removing parasites from body

2. Wide therapeutic index: Toxic dose > 3× therapeutic dose

3. Economically justifiable

4. Easy to administer, for example, in feed, injections, and pour-on

5. One-dose treatment

6. No residue problems, especially in food-producing animals

7. Effective against immature form of parasites

D. Current trends include the use of broad-spectrum drugs and combination therapy to increase efficacy.

II. ANTINEMATODAL DRUGS (NEMATOCIDES)


Antinematodal Drugs (Nematocides) may be broad-spectrum or narrowspectrum.



A. Classification of antinematodal drugs
1. Benzimidazoles

2. Nicotinic agonists: levamisole, pyrantel, morantel

3. Macrocyclic lactones: ivermectin, doramectin, eprinomectin, selamectin (avermectins), milbemycin, moxidectin (milbemycins)

4. Miscellaneous nematocides: dichlorvos, piperazine, emodepside, melarsomine

TABLE 16-1. Putative Classical Neurotransmitters of Various Parasites.*


Ach, acetylcholine; DA, dopamine; GABA, γ-aminobutyric acid; Glu, glutamate; NE, norepinephrine; OA, octopamine; 5-HT, serotonin.























Parasite Excitatory Inhibitory
Nematode ACh, Glu Glu, GABA
Cestode 5-HT ACh
Trematode 5-HT ACh, DA, NE
Arthropod ACh, Glu Glu, OA, GABA

*Note that nematodes, cestodes, trematodes, and arthropods also have a large range of excitatory and inhibitory neuropeptides. Some of the same neuropeptides are present in nematodes, trematodes, and arthropods.



B. Benzimidazoles (BZDs) (Figure 16-1)
1. Thiabendazole (Figure 16-1) is the prototypical agent. It is approved for use in ruminants and horses.
a. Preparations. Thiabendazole is the prototype of BZD, which is much less potent than other BZDs, and is no longer used as a nematocide. Other BZDs include albendazole, fenbendazole, oxfendazole, oxibendazole, and febantel (a pro-BZD that is converted to fenbendazole and oxfendazole in animals).

b. Chemistry. All of BZDs, except thiabendazole, have a side chain at position 5, which prevents hydroxylation of position 5 of the BZD. Therefore, these compounds are more potent than thiabendazole as nematocides (Figure 16-2).

c. Mechanism of action. BZDs inhibit microtubule synthesis in nematode cells by interfering with polymerization of (β-tubulins (Figure 16-3). BZDs do not affect microtubule synthesis in animal cells, this is why these drugs are relatively safe in animals. Care should be exercised for some of the BZDs (albendazole) if the animal is in the first one-third of pregnancy.

d. Therapeutic uses
(1) Ruminants. Albendazole (Valbazen®), fenbendazole (Panacur®, etc.), and oxfendazole (Benzelmin®, Synanthic®) are effective against major GI worms (in both the adult and larval stages). In addition, they are effective against lungworms. However, they are ineffective against filariae.

(2) Horses. Fenbendazole, oxfendazole, and oxibendazole (Anthelcide®) are effective against strongyles, but have limited activity against immature strongyles. They are not very effective against migrating larvae of Strongylus vulgaris and S. edentatis, and thus need elevated, multiple doses to treat these parasites. They are effective against Oxyuris, Trichostronylus, and Parascaris. They have limited activity against Strongyloides, Habronema, and Dictyocaulus; and thus may need elevated doses to treat these parasites. They are not effective against Gasterophilus.

(3) Swine. Fenbendazole is effective against Ascaris, Oesophagostomum, Hyostrongylus, Trichuris, Metastrongylus, and Stephanurus. Fenbendazole usually kills both adults and larvae (L3, L4).

FIGURE 16-1. Chemical structure of thiabendazole, the prototypical benzimidazole. Metabolism occurs via hydroxylation at position 5. The other benzimidazoles are more potent than thiabendazole because they have a side chain, which prevents hydroxylation at position 5. (Reprint from Figure 13-1, NVLS Pharmacology, by Ahrens, 1996.)


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FIGURE 16-2. Chemical structures of albendazole, fenbendazole, febantel, oxfendazole, and oxibendazole. (Modified from Table 47.1, Veterinary Pharmacology and Therapeutics, 8th ed., by Adams, 2001).


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(4) Dogs and cats. Fenbendazole and febantel (in Drontal® Plus) are effective against ascarids, hookworms, and whipworms in both adult and larva forms.

(5) BZDs have ovicidal activity on nematodes. In addition, production of eggs by nematodes is inhibited within 1 hour of BZD administration.

e. Administration. BZDs are administered orally. In general, one single dose in cattle and horses, and three to five consecutive daily dosages in carnivores and omnivores.

f. Pharmacokinetics
(1) Absorption. GI absorption of BZDs varies, depending on the water solubility of the compound; the ones with better water solubility, for example, albendazole and oxibendazole have better GI absorption than others. Since bile can help dissolve BZDs, absorption of them will be best in animals with a full stomach. Herbivores fed fiber rather than concentrates before receiving and oral dose of BZDs have an increased area under the curve signifying better absorption. This is because the BZDs bind to the dietary fiber preventing them from passing straight through the GI tract and facilitating absorption.

FIGURE 16-3. Benzimidazole (BZD)-induced inhibition of microtubule synthesis in helminthes. BZD binds β-tubulin of helminthes, preventing dimerization with α-tubulin and polymerization of tubulin oligomers into microtubules. (Modified from Figure 57.2, Human Pharmacology, 3rd ed., by Brody, Larner, and Minneman, 1998.)


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(2) Metabolism. The degree of metabolism is related to the C5 substitution of BZD (see Figure 16-1). In general, all BZDs, except thiabendazole, are resistant to metabolism (C5-hydroxylation). Albendazole can be converted to its sulfone or sulfoxide metabolites; these metabolites are also active.

(3) Excretion. The majority of BZDs (except thiabendazole and albendazole) are excreted unchanged in feces.

(4) Plasma t½ and drug residues and withdrawal periods
(a) After oral administration, Tmax for BZDs is 10–20 hours; elimination t½ of albendazole in cattle is 9–14 hours; t½ of fenbendazole in horses is ~10 hours, in cattle is 27–36 hours, and in sheep is 14–35 hours. t½ of oxfendazole in cattle and sheep is 18 hours.

(b) Drug residues persist for 1–3 weeks. They approach the low limit of detection in 2 days; however, residues in the liver are generally detectable in 2 weeks.

(c) The preslaughter withdrawal period in cattle is 27 days for albendazole, 8 days for fenbendazole, and 7 days for oxfendazole. Do not use in lactating dairy cattle (exception, fenbendazole).

(d) The preslaughter withdrawal period in swine following fenbendazole administration is 0 days.

g. Drug resistance. Cross-resistance occurs among all BZDs.

h. Adverse effects. These agents are generally safe, although albendazole may be teratogenic and embryotoxic. BZDs may be toxic to liver and bone marrow in dogs, particularly at high doses.


C. Nicotinic agonists
1. Levamisole is approved for use in ruminants and pigs.
a. Mechanism of action. Levamisole paralyzes worms by selectively activating nematode nicotinic acetylcholine (ACh) receptors, allowing entry of Na+, Ca2+, for excessive body muscle contraction, and thus induces paralysis. (Figure 16-4)

b. Therapeutic uses
(1) Ruminants. Levamisole is effective against most mature GI worms and lungworms, but it has marginal activity against Strongyloides and immature GI worms.

(2) Pigs. It is effective against ascarids, Strongyloides, nodular worms, lungworms, and kidney worms.

c. Pharmacokinetics
(1) Absorption is excellent following oral, parenteral, or topical administration; it can be administered as a pour-on preparation.

(2) In cattle, levamisole is transformed by liver into metabolites (formed by oxidation of imidazoline ring and opening of thiazolidine ring).

(3) The plasma t½ of levamisole is 4–6 hours, and the drug is eliminated from the body in 2 days after being absorbed.

(4) More than 90% of levamisole is excreted as metabolites into urine (90%) and feces (10%) within 48 hours of administration.

(5) The preslaughter clearance periods in cattle are 48–72 hours (PO), 7 days (SC), and 11 days (topical), respectively. The preslaughter clearance period after oral administration in pigs is 72 hours.

d. Adverse effects. Levamisole is one of the most toxic anthelmintics. It has a low safety margin, especially when given by injection. Do not administer to dairy cattle of breeding age, since milk withdrawal periods in these animals have not been determined.
(1) Signs of levamisole poisoning include parasympathetic stimulation, convulsions, CNS depression, and asphyxia, which is primarily the result of respiratory muscle paralysis.

(2) Atropine cannot counteract levamisole-induced depolarizing blockade of skeletal muscle; therefore, it is not an antidote for levamisole overdose.

(3) Coadministration of levamisole and pyrantel, another nicotine-like nematocide, increases toxicity.

2. Pyrantel and morantel
a. Chemistry
(1) Pyrantel, which is inactivated in aqueous solution upon exposure to light, should be stored in tight, light-resistant containers. The drug should be used soon after the preparation of a drench solution or suspension.

(2) Morantel, the methyl ester of pyrantel, is stable in solution.

b. Preparations
(1) Pyrantel tartrate is approved for horses (Strongid-C®) and pigs (Banminth®).

(2) Pyrantel pamoate is approved for horses (Strongid-T®, Strongid-P®) and dogs (Nemex®, and in Drontal®, Heartgard®, etc.), and is used in cats as well.

(3) Morantel tartrate (Rumatel®) is approved for cattle.

c. Mechanism of action. Like levamisole, pyrantel, and morantel paralyze worms by causing depolarizing neuromuscular blockade (Figure 16-4).

d. Therapeutic uses
(1) Horses. Pyrantel is effective against strongyles, ascarids, and pinworms, but not against bots. Pyrantel tartrate is used to prevent nematodes infestation and pyrantel pamoate is used to treat nematodes infestation.

(2) Pigs. Pyrantel is effective against ascarids, nodular worms, and stomach worms.

(3) Dogs and cats. Pyrantel is effective against all GI nematodes, but it has limited efficacy against whipworms.

(4) Ruminants. Morantel is used as a feed additive, which is effective against stomach worms, nodular worms, and other principal intestinal worms.

e. Pharmacokinetics
(1) Absorption
(a) Pyrantel tartrate is water soluble; therefore, GI absorption is excellent following oral administration. Peak plasma concentrations occur 2–3 hours after dosing. Elimination t½ in pigs and horses are ~6 and ~14 hours, respectively.

(b) Pyrantel pamoate is poorly soluble in water, limiting GI absorption. Therefore, pyrantel pamoate is good for the treatment of bowel worms (e.g., pinworms).

(c) Morantel tartrate is absorbed rapidly from the abomasum and small intestine. Peak plasma concentrations occur 4–6 hours after dosing. Plasma t½ of morantel in cattle is not known.

(2) Metabolism and excretion. The absorbed pyrantel and morantel are rapidly metabolized (hydroxylation and conjugation) and excreted, mostly via feces, but also via urine. Preslaughter withdrawal requirements are 1 day for pyrantel tartrate in swine and 14 days for morantel in cattle.

f. Adverse effects. At recommended doses, adverse effects are not common. However, when adverse reactions occur, they are similar to levamisole toxicity.

g. Contraindications. Because morantel and pyrantel have the same mechanism of action as levamisole, these agents should not be used concurrently.

h. Resistance. There is a cross-resistance among pyrantel, morantel, and levamisole.

FIGURE 16-4. Mechanisms of action of antinematodal drugs that interfere with parasite nervous system. LTP = latrophilin; PLC = phospholipasec; PFI = SDPNFLRF-amide; PFZ = SADPNFLRF-amide; GC = guanylyl cyclase.


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D. Macrocyclic lactones (macrolide endectocides). These compounds are antibiotics derived from Streptomyces, with activity against nematodes and arthropods. In addition to having broad-spectrum activity, they are effective at low dosages (μg/kg range).
1. General aspects of macrocylic lactones
a. Chemistry. There are two major groups, the avermectins and milbemycins (Figures 16-5 and 16-6). Ivermectin, doramectin, eprinomectin, and selamectin belong to the avermectin group and have a disaccharide side chain; milbemycin and moxidectin belong to the milbemycin group and do not have the disaccharide side chain and are more lipophilic (Figures 16-5 and 16-6).

b. Mechanism of action. They activate the glutamate-gated chloride channels, thus inhibiting neurotransmission in nematodes (and arthropods) to induce flaccid paralysis.
(1) As part of the result of inhibition of neurotransmission, pharyngeal muscle of nematodes is paralyzed, this interferes with feeding; body movement is also inhibited as is egg laying.

(2) The exact site of action of the macrocyclic lactones depends on the species of the parasite and on the specific macrocyclic lactone; it is likely that there are different subtypes of receptor on the different parasite cells/tissues and selectivity for the receptor subtypes varies with the macrocyclic lactone (Figure 16-4).

c. Adverse effects. Macrocyclic lactones have a high safety margin in ruminants, horses, and swine, and are safe for use in pregnant animals and breeders. Some of the Collie dogs and Murray cattle show high sensitivity to ivermectin.
(1) Local irritation may occur following SC administration.

(2) CNS depression. At high doses, ivermectin may evoke CNS depression as evidenced by listlessness, mydriasis, ataxia, recumbency, and coma. Although macrocyclic lactones activate γ-aminobutyric acid (GABA)-gated Cl channels in animals, the GABA-receptor antagonist picrotoxin does not work well as an antidote.

d. Resistance. Resistances to macrocyclic lactones have occurred in nematodes and arthropods. Cross-resistance among macrocyclic lactones can occur.

2. Ivermectin. It is extracted from Streptomyces avermitilis. The ivermectin injectable (Ivomec®) is dissolved in propylene glycol–glycerol formal mixture.
a. Chemistry. Ivermectin is a mixture of ~80% 22,23-dihydroavermectin B1a and ~20% 22,23-dihydroavermectin B1b.

b. Therapeutic uses and administration
(1) Ruminants. Ivermectin (Ivomec®) is effective against all major GI worms and lungworms. It is administered at 0.2 mg/kg orally or SC, and 0.5 mg/kg topically. The pour-on ivermectin is effective as a nematocide in cattle, but not in goats or sheep because of poor absorption from the skin.

(2) Horses. It is effective against bots, stomach worms, strongyles, pinworms, and ascarids. It is administered at 0.2 mg/kg orally or SC.

(3) Pigs. Ivermectin is effective against major GI worms, lungworms, and kidney worms. It is not effective against Trichinella during the muscular stage. The standard dose is 0.3 mg/kg administered SC.

(4) Dogs
(a) Ivermectin is effective against ascarids, hookworms, and whipworms at 0.2 mg/kg orally. However, this dose may not be safe in some breeds (e.g., Collies) and some individuals, and is therefore not approved for dogs. In the dogs, being highly susceptible to ivermectin, they have a mutation of P-glycoprotein particularly in the endothelial cells of the blood–brain barrier. P-glycoprotein, an ATP-binding cassette transporter (or multidrug transporter) found in the apical membrane of endothelial cells, is responsible for drug exit from the brain. The mutation of P-glycoprotein causes retention of drugs, particularly macrocyclic lactones, in the brain of these dogs.

(b) Both ivermectin and selamectin are potent substrates and inhibitors of the P-glycoprotein in dogs, but moxidectin is a weak one.

(c) Ivermectin (Heartgard®) and other macrocyclic lactones, that is, selamectin (Revolution®), milbemycin (Interceptor®, Sentinel®), and moxidectin (Proheart®) are used as heartworm preventives and are administered to dogs once a month. For this purpose, ivermectin is administered at 6–12 μg/kg. Macrocylic lactones eliminate L4 stage of infective larvae of Dirofilaria immitis.

(d) It is effective as a microfilaricide (50 μg/kg orally). The use of ivermectin as a microfilaricide is extra-label. Ivermectin can be diluted with propylene glycol, if needed.

(5) All species. Ivermectin is effective against all ectoparasites. It is used especially to control mites.

c. Pharmacokinetics
(1) After oral administration, ≤95% of ivermectin is absorbed in monogastric animals and ~30% is absorbed in ruminants.

(2) In swine, after oral and SC administrations of ivermectin, the peak plasma level of the drug is reached in 12 and 48 hours, respectively.

(3) Following IV injection, the plasma t½ of ivermectin is 1.6–1.8 days in dogs, and 2.7–2.8 days in ruminants.

(4) Following SC injection, the plasma t½ of ivermectin in cattle is 8 days. The long plasma t½ after SC administration is probably due to the solvent system (propylene glycol–glycerol formal), which slows down the absorption from injection site.

(5) Following administration, highest concentrations of ivermectin are found in liver and bile, and lowest concentration is found in the brain.

(6) Ivermectin is metabolized in liver and fat to polar and nonpolar fatty acid esters, respectively.

(7) Fecal excretion accounts for 98% of elimination of ivermectin.

(8) Ivermectin remains in tissues with long persistency; one dose is usually effective for 2–4 weeks. Preslaughter clearance periods: swine: 5 days (PO), 18 days (SC); sheep: 11 days (PO); cattle: 35 days (SC), 49 days (topical). Ivermectin should not be administered to dairy cows that are >20 months old.

3. Doramectin (Dectomax®)
a. Chemistry. Doramectin is an analog of ivermectin (having a cyclohexyl group at C-25). The solvent for doramectin is 90% sesame oil—10% ethyl oleate, which slows down absorption from the injection site.

b. Therapeutic uses. Doramectin is used only in cattle at 0.2 mg/kg SC.

c. Pharmacokinetics. Pharmacokinetics of doramectin in cattle are very similar to that of ivermectin. Preslaughter withdrawal periods are 35 days (SC) and 45 days (topical). It should not be administered to dairy cows that are > 20 months old.

4. Eprinomectin. (Eprinex®)
a. Chemistry. Eprinomectin is an analog of ivermectin (having an epi-acetylamino group at the 4”-position).

b. Therapeutic uses. Eprinomectin is used topically in cattle (0.5 mg/kg) to control most GI nematodes, lungworms, and ectoparasites the same way as ivermectin.

c. Pharmacokinetics
(1) Eprinomectin is absorbed after topical administration and reaches peak plasma level within 2–5 days of application and declines to undetectable level in 4 weeks. The majority of the topical dose is absorbed in 7–10 days. More than 85% of eprinomectin is excreted into feces as parent compound.

(2) No preslaughter or milk withdrawal period is required after eprinomectin treatment, since drug residue levels are below legally acceptable limits in meat and milk after topical administration.

5. Selamectin (Revolution®)
a. Chemistry. The chemical structure of selamectin is closer to doramectin than ivermectin. There is one lactone ring short in selamectin structure when compared with those of doramectin and ivermectin.

b. Therapeutic uses. It is applied topically in dogs and cats (≥6 weeks old), 6 mg/kg, once a month
(1) In cats, selamectin prevents heartworms and kills ascarids, hookworms, fleas, and ear mites.

(2) In dogs, selamectin prevents heartworms and kills fleas (adults, larvae, and eggs), sarcoptic mites, ear mites, and ticks. Failures have been reported for selamectin as an ectoparasiticide.

c. Pharmacokinetics
(1) After topical application, there is 4% bioavailability in dogs and 74% bioavailability in cats. The high bioavailability in cats is attributed to their grooming activity and slow metabolism; as a result, selamectin serves as a nematocide in cats, but not in dogs.

(2) After topical application, plasma selamectin concentrations reach maximal in 72 hours in dogs and 15 hours in cats. Plasma t½ of selamectin in dogs and cats are 14 hours and 69 hours, respectively.

(3) After a single topical administration, clinically effective concentrations of selamectin as a heartworm preventive persist for > 30 days.

(4) After topical application, substantial amount of topical selamectin is stored in sebaceous glands to provide persistent activity against ectoparasites.

(5) Selamectin is metabolized in the liver into desmethyl selamectin, and its oxidation product. Selamectin is excreted mostly in the feces as unchanged compound along with a small amount of metabolites. d. Adverse effects. Selamectin is safer than ivermectin in dogs; selamectin is safe in pregnant animals and ivermectin-sensitive Collies. Selamectin-treated cats may show hypersalivation, which is due to the ingestion of isopropyl alcohol, a solvent in the preparation.

6. Milbemycin (Interceptor® and in Sentinel®) is extracted from Streptomyces hygroscopicus aureolacrimosus.
a. Chemistry. Commercial milbemycin consists of ~80% A4 milbemycin and ~20% A3 milbemycin (Figure 16-6).

b. Therapeutic uses. Milbemycin is approved for use in dogs only and is effective against the infective larvae of D. immitis, hookworms, whipworms, and ascarids. Milbemycin at the recommended dose of 0.5 mg/kg, orally, once a month, can be used in all dog breeds, including Collies, and is safe in pregnant dogs and breeders (because it is a weak substrate of P-glycoprotein). This dose of milbemycin is effective as a microfilaricide as well.

c. Pharmacokinetics. Following oral administration, ~90% of the dose passes through the GI tract unchanged. The remaining ~10% is absorbed. It reaches peak plasma concentration within 2–5 hours after oral administration. It is subsequently excreted into the bile; close to 90% of the dose is eliminated in the feces. The plasma t½ of milbemycin is 1–3 days.

d. Adverse effects. Milbemycin has a high safety margin in dogs. However, milbemycin-killed microfilaria can cause hypersensitivity manifested by lethargy, pyrexia, salivation, emesis, coughing, tachypnea, and/or shock. These adverse effects are also seen when ivermectin is used as a microfilaricide.

7. Moxidectin. It is manufactured from Streptomyces cyanogriseus moncyanogenus culture.
a. Chemistry. Unlike other macrocyclic lactones, moxidectin is a single compound, but not a mixture of two closely related compounds.

b. Therapeutic uses. Moxidectin is used to treat equine and bovine nematodes and ectoparasites, and as a canine heartworm preventive for once a month use. The equine preparation (Quest®) is a 2% oral gel (0.4 mg/kg), the bovine preparation (Cydectin®) is a topical solution (0.5 mg/kg), and the canine preparation (Proheart®) is in tablets (3 μg/kg, PO). There is a new moxidectin product that is in combination with a fleacide imidacloprid (Advantage Multi®) topical solutionthat is a canine and feline heartworm preventive for once a month use. The dosage is 2.5 mg/kg in dogs and 1 mg/kg in cats. This product is also effective against ascarids, hookworms, and whipworms as well as ear mites.

c. Pharmacokinetics
(1) Moxidectin is more lipophilic than ivermectin; as a result, tissue levels persist longer than ivermectin.

(2) Moxidectin is excreted mainly in feces as parent compound. Only 15% of moxidectin is present in feces as hydroxylated metabolites.

(3) Plasma t½ are ~80 hours in horses and 20 days in dogs when given orally. When applied topically in dogs and cats, Tmax are 9.3 and 1.4 days, and t½ are 35 and 15 days, respectively. Information is not available for cattle after topical administration.

(4) When administered topically in cattle, no preslaughter or milk withdrawal period is required, since drug residue levels are below legally acceptable limits in meat and milk after topical administration.

d. Adverse effects. Adverse effects of moxidectin are similar to those of ivermectin. The topical product for dogs and cats should not be administered orally; the adverse effects can be very severe when administered orally.

FIGURE 16-5. Structure of 22,23-dihydroavermectin B1a, the major component of ivermectin. Ivermectin also contains ≤20% 22,23-dihydroavermectin B1b, which is identical except that the substituent in the 25 position is isopropyl instead of butyl. (Reprint from Fig. 47.3, Veterinary Pharmacology and Therapeutics, 8th ed., by Adams, 2001.)


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FIGURE 16-6. Structure of milbemycin oxime. (Reprint from Fig. 47.7, Veterinary Pharmacology and Therapeutics, 8th ed., by Adams, 2001.)


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E. Miscellaneous antinematodal drugs
1. Dichlorvos (Atgard®), an organophosphate, is marketed for use in pigs only.
a. Mechanism of action. Dichlorvos inhibits ACh breakdown by irreversibly inhibiting ACh esterase (AChE). (See Figure 2-6 for illustration.)

b. Therapeutic uses. Dichlorvos is effective against major GI worms, for example, whipworms, nodular worms, Strongyloides, hookworms, and ascarids in pigs. It has little or no activity against migrating larvae of ascarids and hookworms.

c. Pharmacokinetics. Dichlorvos is a lipophilic liquid that is incorporated into polyvinyl chloride resin pellets. As these pellets traverse the GI tract, dichlorvos diffuses into the intestinal fluid, allowing the drug to come into contact with nematodes. The pellets release ~50% of the drug in 48 hours. When passed into the feces, the pellets still contain ~50% of the original dose of dichlorvos, enough to kill fecal fly larvae. Information regarding elimination and t½ of dichlorvos is not available.

d. Adverse effects. Accumulation of ACh by dichlorvos can stimulate cholinergic receptors to induce the SLUDD (salivation, lacrimation, urination, diarrhea, dyspnea) syndrome. Acute death may result from respiratory paralysis and cardiovascular arrest.

e. Contraindications. Dichlorvos is not to be given to weak animals, those exposed to other anti-cholinesterase (anti-ChE) agents, or those with GI disorders.

2. Piperazine
a. Chemistry. Piperazine is available in adipate, citrate, hydrochloride, tartrate, and phosphate forms. Piperazine is inactivated by moisture, CO2, and light; therefore, containers should be tightly closed and protected from light.

b. Mechanism of action. Piperazine is a GABA-receptor agonist that hyperpolarizes nematode muscle, causing flaccid paralysis of worms (Figure 16-4).

c. Therapeutic uses. Piperazine has a limited spectrum of action but is effective against ascarids and nodular worms in all species; however, its use is limited in ruminants, because ascarids are not a significant problem in this species.

d. Pharmacokinetics
(1) Absorption. Piperazine salts are well absorbed from the GI tract.

(2) Metabolism and excretion. Some piperazine is metabolized in the liver and the remainder (30–0%) is excreted in the urine. Urinary excretion of piperazine starts as early as 30 minutes after dosing, and is complete within 24 hours. The plasma t½ is ~2 hours.

e. Adverse effects. Piperazine is a safe drug, but large doses may produce vomiting, diarrhea, and ataxia. The ataxia is due to a GABA-mimetic effect of piperazine on CNS neurons and is particularly seen in young animals given high doses.

3. Emodepside
a. Chemistry. Emodepside is a semisynthetic cyclic depsipeptide.

b. Mechanism of action. Is a selective agonist of the presynaptic latrophilin receptor, a Gq-coupled receptor, of nematodes, which increases the release of inhibitory neuropeptides PF1 and PF2, and opens img -activated K + channels, thereby causing flaccid paralysis of the locomotive and pharyngeal muscles in nematodes (Figure 16-4).

c. Therapeutic uses. It is used topically (as a spot-on product) with an anticestodal drug praziquantel (Profender®) for the treatment of nematodes in cats. Emodepside is effective against ascarids and hookworms (mature and immature adults as well as L4 larvae). Cost of production has prevented the marketing of emodepside for large animals.

d. Pharmacokinetics. The drug is absorbed through the skin and enters the circulation. It appears that from the blood the drug gets deposited into adipose tissue and from these sites leaches back into the blood. The drug is eliminated via the bile and leaves in the feces mainly as unmodified emodepside. Tmax is 40 hours and t½ is 8.3 days.

e. Adverse effects. Alopecia may be seen at the application site. Salivation and vomiting may occur, which is due to licking the application site. Tremors may show up when cats are overdosed with emodepside. Do not use in kittens under 8 weeks of age. It is safe to be used in pregnant and lactating cats.

III. DRUGS FOR HEARTWORM PREVENTION AND THERAPY



A. Introduction. Treatment and prevention of heartworm involve three aspects as follows:
1. Removal of adult heartworms requires an adulticide.

2. Interruption of the life cycle requires a microfilaricide. Treatment to eliminate microfilaria should be initiated 3–4 weeks after the adulticide treatment. Some clinicians choose not to treat microfilaria.
a. Microfilaricidal treatment reduces the incidence of glomerulonephritis, which may be induced when microfilaria are present in a large number.

b. Microfilaricidal treatment eliminates the source of heartworm infestation (minor reason for eliminating microfilaria).

3. Prevention of infection requires a larvicide.

B. Adulticides eliminate both immature (L5) and adult heartworms. The heartworm adulticide melarsomine is used solely in canine species. Cats should not receive this adulticide treatment because of potential severe reactions occur when heartworms are killed in this species.
1. Melarsomine (Immiticide®)
a. Chemistry. Melarsomine is a trivalent arsenic compound.

b. Administration. Melarsomine is administered into lumbar muscle.
(1) The regular dose regimen is 2.5 mg/kg once a day for 2 days.
(a) Since melarsomine is highly irritable, the first injection should be into the right lumbar muscle, and the second into the left lumbar muscle.

(b) The two-dose regimen eliminates all adult heartworms in 60–80% of treated dogs. The regimen can be repeated in 4 months, which would increase the efficacy to 98%.

(2) For dogs with severe infestation, a single dose (2.5 mg/kg) is followed by the full two-dose treatment 1 month later. The initial single dose would kill 88% of male and 17% of female worms, hence providing some relief of clinical signs, while reducing the risk of complication from pulmonary embolism. This regimen would remove all heartworms in 85% of treated dogs.

c. Mechanism of action. Melarsomine denatures proteins/enzymes by binding to the sulfhydryl groups of cysteine residues.

d. Pharmacokinetics
(1) Absorption. Following IM injection, melarsomine is completely absorbed in 15 minutes and the blood concentration peaks at 8 minutes. The elimination t½ is ~3 hours.

(2) Distribution. Melarsomine is found in both plasma and red blood cells. The drug is widely distributed in the body, but is concentrated in the liver and kidneys.

(3) Metabolism and excretion. Melarsomine is metabolized in the liver and excreted into bile. Both melarsomine and its metabolites can be found in feces and urine after administration.

e. Adverse effects
(1) Mild localized edema may occur following IM injection.

(2) Overdose may result in distress, restlessness, pawing, salivation, vomiting, tachycardia, tachypnea, dyspnea, abdominal pain, hindlimb weakness, and recumbency. Severe cases terminate in circulatory collapse, orthopnea, coma, and death.

(3) Liver toxicity. These animals may show anorexia, persistent vomiting, depression, melena, and jaundice. Serum alanine aminotransferase (ALT), alkaline phosphatase (AP), and bilirubin concentrations may increase.

(4) Nephrotoxicity. These animals may show albuminuria, renal case and azotemia with blood urea nitrogen concentration of > 100 mg/dL.

(5) Toxicity can be alleviated by IM administration of 3 mg/kg dimercaprol (BAL) within 3 hours of the onset of symptoms. However, dimercaprol may reduce the efficacy of melarsomine.

(6) Thromboembolic pneumonia may be seen, which is due to dead worms accumulation within 3 weeks of treatment. Signs of pneumonia include coughing, dyspnea, hemoptysis, fever, and lethargy. The affected dogs need absolute rest for 2 weeks, and can be treated with anti-inflammatory drugs, particularly glucocorticoids and antibiotics. Glucocorticoids can be used to prevent the adulticide-induced thromboembolic pneumonia.

C. Microfilaricides. Some practitioners choose not to use microfilaricide, particularly if dogs do not harbor large number of microfilaria.
1. Preparations. Macrocyclic lactones, for example, ivermectin and milbemycin, are used as microfilaricides and this use is extra-label; however, these are the only drugs that may be safely and effectively used for this purpose.

2. Administration
a. Ivermectin. Therapy entails one dose (50 μg/kg) administered orally or SC. This drug should not be used in Collies as a microfilaricide.

b. Milbemycin. One dose (0.5 mg/kg) is administered orally; the treatment may be repeated in 2 weeks. This drug can be safely used in Collies.

3. Adverse effects. Transient weakness, pale membranes, intestinal hyperperistalsis, and tachypnea may be seen following administration of a microfilaricide, suggesting a mild cardiovascular shock resulting from reactions to dead microfilaria. The higher the microfilaria count, the greater the chance of encountering noticeable adverse effects. These adverse effects can be treated or prevented with glucocorticoids.

D. Larvicides for heartworm prevention. Macrocyclic lactones (e.g., ivermectin, moxidectin, milbemycin, and selamectin)
1. Administration. Macrocyclic lactones kill L4 larvae. Ivermectin, moxidectin, and milbemycin are administered orally at dosages of 6–12 μg/kg, 3 μg/kg, and 500 μg/kg, respectively, once a month. The first dose is given within 1 month of the first exposure to mosquitoes. The last dose is given within 1 month following the last exposure to mosquitoes. Because it takes 2.5 months for L4 larvae to develop into L5 larvae, the elimination of larvae in the L4 stage once a month is sufficient to prevent heartworm infestation.

2. See II D 2, 57 for other information on mechanism of action, pharmacokinetics, and adverse effects of macrocyclic lactones.

IV. ANTICETODAL DRUGS


May 28, 2017 | Posted by in GENERAL | Comments Off on Antiparasitic Agents
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