Antiparasitics, drugs which kill or inhibit the growth of parasitic organisms, may be subdivided into the following therapeutic categories:
These categories form the major headings of the drugs to be discussed in this section. Drugs which belong to more than one category will be listed in the one reflecting their dominant use.
Ideal parasite control is based on good husbandry practices. Vaccination based control is the second best approach because it does not leave residues in edible products and is potentially effective for the life of the animal. However, because neither of these is universally applicable, chemotherapy remains a primary means of controlling parasitic infections/infestations.
Historically antiparasitic drugs have been nearly as toxic as the parasites they were intended to remove. They caused "set-back" that may erase any economic gain resulting from removal of parasites. They were difficult to administer. Worst of all, most were not very effective.
Many relatively non-toxic drugs are now available because widespread screening for active compounds with low host toxicity and intentional design based on biochemical knowledge have been successful. These have led to products that exploit differences between host and parasite with respect to unique enzymes, essential enzymes, or pharmacological properties.
The following list of characteristics of an ideal antiparasitic can provide a framework within which to evaluate the relative strengths of each of the agents when selecting a drug for clinical use.
Antiparasitics can be given by many routes. The ideal route depends on the number and kind of animals that must be treated and the stability and pharmacokinetics of the drug be administered.
Major classes of common antinematodals include the following with a prominent examples in parentheses: avermectins (ivermectin), benzimidazoles (mebendazole, fenbendazole), pyrimidine (pyrantel, morantel), organophosphates (dichlorvos, trichlorfon, coumaphos), and imidazothiazoles (levamisole, tetramisole-L, butamisole).
The first member of the anthelmintic macrolides to be commercially available was ivermectin. Dose forms are now available for many species. Some sample trade names are: Eqvalan, Heartgard 30, and Ivomec. Moxidectin is a macrolide that is available in other countries and may soon be sold in the U.S. (Lynn'95).
Ivermectin has one of the broadest clinical antiparasitic spectrums known. It includes gastrointestinal parasites such as ascarids, adult large strongyles, adult/4th stage larvae of small strongyles, pinworms, large stomach worms, hair worms, and immature stages of stomach bots. It is also effective against parasites that end up in the skin or lungs. For example, the immature form of onchocerca, which causes summer dermatitis in horses, is removed as are lung worms. Several parasites that live in or on the skin are also affected, e.g., cattle grubs, lice, and mites. Some stages of some blood borne filarids, e.g., immature Dirofilaria immitis, are removed.
Ivermectin causes tonic paralysis of peripheral musculature in nematodes and ectoparasites (ticks, mites, insects). It potentiates release and action of GABA. In vertebrates such neurons and receptors are in the CNS where ivermectin achieves low concentrations. Ivermectins are ineffective in cestodes and trematodes, perhaps because they lack GABA-mediated control of peripheral musculature.
Although well absorbed from the gastrointestinal tract, they cross the blood brain barrier poorly. They are eliminated primarily in the feces in animals. There is little data from human studies.
Ivermectins are relatively safe for species that have an approved dose form; horse, dog, cattle, and swine. They have no known teratogenic effect in these species. There is evidence of substantial teratogenicity in mice, rats, and rabbits, the species most commonly used for preclinical testing. (Brown '96)
At high doses the ivermectins can cause CNS signs, including lethargy, ataxia, mydriasis, tremors, and death.
Adverse effects, in horses, of an injectable form that is no longer available may represent signs that could be seen with overdose (Louisiana study). These signs include eyelid edema, fever, increased rate and depth of respiration, disorientation, signs of colic, extreme depression, and death within minutes. Death occurred in 1 horse of 3,316 treated.
DOGS, ESPECIALLY COLLIES(Boraski, 1984) were claimed to have special sensitivity to ivermectin. Some collie strains developed severe adverse reactions when given ivermectin at a dose of 100 mcg/kg; 16 x the label dose now recommended. At a dose of 6 mcg/kg (the approved dose), the drug is well tolerated in collies and other breeds of dogs (Lynn'95, p266). A single PO dose of 2 mg/kg and PO doses of 0.5 mg/kg q1d for 14 weeks were well tolerated by dogs. Doses greater than 20 mg/kg given to laboratory dogs causes mydriasis, depression, tremors, ataxia, coma, and death. No teratogenic effects where observed after giving pregnant bitches repeated PO doses of 0.5 mg/kg. (Note: Some of these doses in this paragraph were previously in error because they were listed as mg/kg instead of mcg/kg. The author apologizes for this error.)
There is now a special tablet formulation, HEARTGARD 30 (Merck) for use in preventing heartworms so there is no longer any reason to use dose forms prepared for other species. Nonetheless, because it underscores a major principle of therapy, the following anecdote is worth reading.
<<< AN IVERMECTIN STORY >>> The following is an excerpt from a letter written by a practitioner. (Schulze 1984) "...Recently at the suggestion of a sales representative, I gave an injection of Eqvalan to a heavily parasitized canine pup of a large mixed breed (not Collie). Approximately 0.15 cc was given deep intramuscularly (gastrocnemius). The animal appeared in otherwise good health at presentation. Within one hour, an agitated client returned with a critically ill animal. It exhibited just about every imaginable sign, from prostration, ptyalism, opisthotonos, nystagmus, thrashing and paddling, extensor rigidity, to coma and death within another 15 minutes. It was like watching every page of a veterinary toxicology text flashing before my eyes. Forget the LD-50s!
"This embarrassed veterinarian has given his first and last ivermectin injection to a canine. Needless to say, I am hesitant to continue my 0.2% ivermectin oral regimen of successful heartworm control in the same species." [end of quote]
<<< MORALS >>> Certain morals can be drawn from this anecdote. First, be extremely cautious when using new drugs in species other than those for which they were specifically approved. Second, route of administration and dose formulation do make a difference and are often species specific.
Many studies have shown that although ivermectin is not approved for use in cats, single PO doses of 0.024 mg/kg are effective against Ancylostoma braziliense and Ancylostoma tubaeforme. A dose of 0.3 mg/kg is required for Toxocara cati. Doses of 0.024 mg/kg were shown to be effective in preventing Dirofilaria immitis adults from appearing in infected cats when given 30 to 45 days after artificial infection. Thus, this drug and dose should be satisfactory as a heartworm preventive when given q1mo (Lynn'95).
Advantages of ivermectin include its broad spectrum of action, its effectiveness against many immature forms, and its lack of cross-resistance with other major anthelmintic groups, e.g., the benzimidazoles and cholinesterase inhibitors.
Many dose forms are now available including an injectable for swine and cattle; an oral paste for horses; and an oral tablet for dogs. The tablet for dogs is intended for heartworm prevention and is given only once per month. Collies have a reputation for being especially sensitive to the effects of ivermectin, but the oral dose form can be used in them at recommended doses.
Disadvantages appear to be few, but the drug is very expensive. Moreover, it is still sufficiently new that its true warts may not have been appreciated.
Moxidectin is a new macrolide that is being used in South America. Its commercial introduction into the U.S. is pending (Lynn'95). It is effective against a wide variety of parasites.
IM to horses: Gasterophilus intestinalis, Parascaris equorum, Strongylus vulgaris, Strongylus edentatus, Oxyuris equi, Habronema muscae.
PO to cattle: 99% effect on adult and 4th stage Ostertagia ostertagi, Cooperia spp., Nematodirus helvetianus. Adult Trichostrongylus ... LONG LIST).
PO to sheep
PO to Dogs: D. immitis and hookworms (Ancylostoma caninum and Uncinaria stenocephala), Toxacara canis, and Toxascaris leonina.
Eight benzimidazoles are available for clinical use including: thiabendazole, mebendazole, fenbendazole, cambendazole, oxibendazole, flubendazole, oxfendazole, and albendazole. In addition, there are pro-benzimidazoles. These are prodrugs that yield benzimidazoles after biotransformation. Febantel is an example. It yields febendazole and oxfendazole following injection (Armour 1983). (See structures below)
Less soluble derivatives, e.g., albendazole, fenbendzole, and oxfendazole, appear to be more effective because of the increased exposure afforded by the prolonged dissolution in the gut. For the others especially, repeated administration with small dose intervals seems to increase their effectivess because of the increased exposure (Armour 1983). Armour states that because the rumen acts as a slow release site for these drugs to the lower gi tract, they are more effective in ruminants than other species. Representatives, such as mebendazole, have poor bioavailability so systemic actions are minimal. In fact, these may be part of the reason for their low toxicity. Others, such as thiabendazole, are rapidly absorbed and are eliminated in the urine.
The benzimidazoles have such a broad spectrum of action that it is useless to list it. Some tapeworms and bots are resistant. There is also variation among the members as to which is more effective, e.g., against tapeworms or flukes than the others. Mebendazole has good activity against many tapeworms. Albendazole has activity against flukes like Fasciola hepatica.
The mechanism of action of benzimidazoles is not clearly delineated and may differ from one member of the group to another. Interference with microtubular function and inhibition of helminth-specific mitochondrial fumarate reductase system have both been described. Thiabendazole may have both actions. Mebendazole may only bind to tubulin.
Inhibition of the fumarate reductase would interfere with energy production in the parasite. Binding to tubulin may impair many processes. Cytoplasmic microtubules disappear in tegumentary and intestinal cells. Secretory processes, e.g., from Golgi apparatus and acetylcholine release, are impaired. Glucose uptake by cells is decreased. Microtubular function may be common to all of these processes. These processes are not significantly altered in host cells although the mechanism of selectivity may be differential binding to subunits of tubulin, this is not proven for all benzimidazoles.
Teratogenic effects have been shown for albendazole, cambendazole, oxfendazole, and parbendazole. If these drugs are to be used in early pregnancy, it must be for good reason and at the lowest recommended doses.
Acute toxicity is extremely difficult to produce with these drugs and LD50s are almost impossible to define for drugs such as thiabendazole and fenbendazole. They are regarded as safe up to 20 to 30 times the recommended dose. The earliest sign of toxicity noted in horses with mebendazole is a slight diarrhea.
Cambendazole produces idiosyncratic reactions that have caused it to be removed from the market in some countries. (USA)
Advantages of benzimidazoles include their palatability, safety, and broad spectrum.
Disadvantages include the increasing resistance of parasites to this group of drugs. Furthermore, there is significant cross-resistance among the members.
Febantel [Rintal ]is a pro-benzimidazole which yields both fenbendazole and oxfendazole. Its spectrum includes Strongyles, oxyurids, and ascarids of horses. There are no known contraindications, but several species of cyathostomes are reported to be resistant. The dose must be increased to 50 mg/kg from the normally used 6 mg/kg eliminate Strongyloides westeri from foals. The drug has a wide margin of safety in both young and old horses, stallions, and pregnant mares. It can be given with trichlorfon to control bots. It is available as a paste and as a suspension.
Pyrantel and Morantel are the members of this group. The basis of difference between them and the various dose forms in which they are available is solubility in the gut. Oxantel belongs to the same group and is used in humans for trichuriasis.
Pyrantel is available as the pamoate and tartrate derivative. Combantrin is pyrantel pamoate. Banminth, Nemex, Strongid-T, and Strongid-P are examples of pyrantel tartrate. Pyrantel tartrate is rapidly absorbed from the gut. Pyrantel pamoate is poorly absorbed. The pyrantel salts are stable in solid form, but not in solution. Because they are photodegradable they must be used quickly once opened.
Morantel is available as the tartrate. Rumantel, Nemantel, and Strongid are examples of morantel tartrate.
Parasites exhibit spastic paralysis and apparently cannot maintain their position. Paralysis is caused by nicotinic action at neuromuscular junction of parasites, i.e., these drugs are depolarizing neuromuscular blocking agents. The depolarization leads to increased contraction of parasite muscles. Note that piperazine causes hypERpolarization which would lead to decreased spike frequency and contraction. Thus, piperazine and pyrantel would be expected to be antagonistic. Pyrantel can also cause complete neuromuscular blockade in animals if dose is high enough. At recommended doses, this is not a hazard.
Morantel is used in cattle for Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Nematodirus, and Oesophagostomum.
Pyrantel is used in dogs, horses, and swine, for ascarids, hookworms, and strongyles.
No adverse effects were described by Theodorides, 1985. However, at increasing doses, one would expect signs of neuromuscular blockade or other evidence of nicotinic action. For example, in humans, oral doses may cause transient, mild gastrointestinal signs.
of morantel include dairy cows, for which it is not approved [Need to check '95] . Pyrantel should not be mixed with rations containing bentonite. (Bentonite is a soft, porous clay from volcanic ash.)
Withdrawal times are: morantel in cattle, 14 days; pyrantel in pigs, 24 hours.
Should not use pyrantel, morantel and levamisole together. Pyrantel is mutually antagonistic with piperazine on membrane potential, but can be used with organophosphates and certain other antiparasitic and antimicrobial drugs. Pyrantel can be used in the presence of Dirofilaria immitis. It can also be used in pregnancy, nursing, weanlings, and males used for breeding.
Morantel is effective against adult gastrointestinal parasites of cattle.
Pyrantel is non-toxic and has a short withdrawal time in swine. It is the only APPROVED anthelmintic that, when fed continuously, kills just-hatched larvae of A. suum in gut to prevent appearance of milk spots on liver of pigs.
Morantel is not too good against larval forms in cattle. Pyrantel should not be used in severely debilitated animals. May cause vomiting in smal animals.
Major examples of organophosphates include dichlorvos, trichlorfon, and coumaphos.
ATGARD V swine
Value of resins
Irreversible inactivation of acetylcholinesterase, leading to excessive cholinergic activity at relevant sites. It would be expected to reduce plasma cholinesterase activity to minimal levels, thus making the host more susceptible to other cholinomimetic agents and cholinesterase inhibitors.
Organophosphates are effective against bots, ascarids, and tapeworms. They are also used topically against insects and arachnids.
The adverse effects are discussed with special reference to dichlorvos. Those of other organophosphates will be very similar.
The margin of safety is very narrow. The drugs are safe to approximately 2-times the recommended dose.
Signs of toxicity are typical of acetylcholinesterase inhibitors and include evidence of excessive acetylcholine at muscarinic and nicotinic receptors. Early signs include salivation, lacrimation, urination, dyspnea, and defecation which have the mnemonic of SLUDD. Treatment is with atropine and pralidoxime.
Formulations of the organophosphate compounds are very specific for the target species, especially in flea collars and in the resins intended for oral administration. For more information on why a resin formulation intended for one species might be toxic or ineffective when given to another species consult Roberson (JBM5th 830-831).
A summary of the Roberson material follows. Dichlorvos is formulated in resins to make a slow release dose form. Variations in geometry, size and method of formulation (including coating or not coating), of pellet plus the quantity of dichlorvos allow for a range of diffusion rates suitable for different host animals. Task, for the dog, has smaller pellets and faster release rate to accomodate the shorter gastrointestinal tract. For swine, Atgard V has larger pellets and a moderate release rate for the longer tract. Pellets may contain 20% dichlorvos. A moderate release rate may cause 50-55% loss during passage through the tract of swine in 24 hours. Usually, enough dichlorvos is eliminated in the feces to be effective as an insecticide for fly larvae.
Two principle difficulties associated with dichlorvos are overcome by resins. First, they decrease the toxicity of the volatile, toxic drug. Second, they protect the drug within the vehicular reservoir from moisture to slow hydrolytic degradation.
There are important Contraindications to the use of dichlorvos. The drug should not be used within a few days of use or exposure to cholinesterase inhibitors.
An important source of exposure is routine use of these agents around the owner's premises.
Dichlorvos should not be used concurrently with other anthelmintics, tranquilizers, muscle relaxants, or modified live-virus vaccines. The drugs, which may also have actions on the CNS, skeletal muscle, and/or muscarinic receptors may increase the toxicity of dichlorvos. Presumably, the live-virus vaccines act as stressors that may exacerbate the toxicity.
Dichlorvos should not be used in animals with diarrhea or severe constipation or intestinal blockage.
Puppies and kittens weighing less than 1 lb and less than 10 days old are not good risks.
Dogs with heartworms should not be treated.
Advantages of dichlorvos are that it is inexpensive and is effective against bots. Other organophosphates share these properties.
The primary disadvantage is the low therapeutic index.
Levamisole is the levo-rotatory form of tetramisol. The dextro isomer contributes to the toxicity, but not the therapeutic effect so it has been removed in marketed preparations. Levamisol restores cell-mediated immune function in peripheral T-lymphocytes and stimulates phagocytosis in monocytes.
Levamisole causes nicotinic stimulation of ganglia and CNS in susceptible worms. Parasites are presumably much more sensitive to these effects than the host. Parasites are paralyzed and expelled alive. At higher concentrations, levamisole interferes with nematodal carbohydrate metabolism where it blocks fumarate reductase and succinate oxidase.
Levamisole has a broad spectrum of activity against many intestinal round worms, lungworms, and D. immitis microfilariae.
Levamisole is safe, i.e., will not cause serious problems at up to 5-times the recommended dose. Adverse effects of levamisole include signs of CNS and parasympathetic ganglionic stimulation. At 2 to 3- times the recommended dose, cattle lick their lips, salivate, and shake their head. At higher doses, one may see excitement, tremors, and death.
Advantages of levamisole are that it has a pour-on and an injectable dose form and affects larval stages dwelling in the tissues. It is also well-known for its ability to enhance immune function in animals with certain deficits. It does not appear to enhance a fully functional immune system.
Disadvantages of levamisole include the adverse effects noted above.
Butamisole is related to levamisole. It is supplied in a propylene glycol, benzyl alcohol base for injection subcutaneously. Preparations containing butamisole include Styquin.
The spectum of activity include whipworms and hookworms.
The drug is free of serious adverse effects up to 3-times the recommended dose. Because dosing is important, it is recommended that 1.0 ml syringes be used when treating animals weighing less than 10 pounds.
Adverse effects include pain during injection, sterile abscess or seroma formation after injection, and transient listlessness.
In contrast to its relative levamisole, there are important contraindications to the use of butamisole indicating its greater toxicity. Butamisole is contraindicated in
Bunamidine apparently enhances the toxicity of butamisole since there have been reports of deaths when the drugs were used simultaneously.
Advantages of butamisole are its effectiveness and, although not without toxicity, it is safer than some of the alternatives.
No fasting is required for use of butamisole.
It appears to have no negative effects on reproduction. It is safe during pregnancy and has no effect on male fertitility.
Butamisole can also be used safely with phenothiazine tranquilizers (e.g., chlorpromazine) and organophosphate products.
Butamisole cannot be used in debilitated animals or animals with renal or hepatic disease. Its spectrum of activity is limited, involving primarily adult hookworms.
Many "wormers" are available at your corner drug or pet store without prespcription. Veterinarians should be generally familiar with these less effective products because many of the clients will know them well. Generally, these are old drugs that have significant disadvantages when compared to newer drugs released recently.
This drug, which is present in many comercial preparations is given orally to dogs and cats after 18-24 hr fast for Ascarids and some effect on hookworms. One should follow
with a cathartic 1 hr after treatment. The animal can be fed within 4-8 hours after treatment. Occasionaly, the animal may vomit, but otherwise it is relatively safe. The drug is HIGHLY FLAMMABLE.
Toluene is present in may commercial preparations. It is flammable, i.e., it burns. It comes in gelatin capsules.
Toluene is safe for mammals on an acute basis, but long term, repeated exposure to any aromatic hydrocarbon is inadvisable. "Overdosage produces transitory incoordination, muscle tremors, vomiting, and central nervous system depression." Theodorides 1985.
Treatment of toxicity caused by toluene includes warm water gavage (flush stomach via the mouth with a tube), mineral oil, and oxygen therapy. One should avoid the use of digestible oils, alcohol, and epinephrine as emergency treatment. Toluene will partition into oil based solvents. Because mineral oil is neither digested nor absorbed, this is tantamount to elimination. Digestible oils, however, will release the tolene as they are digested, allowing it to be absorbed as well.
Toluene is inconvenient to use because one should fast animals 12 hours before and 4 hours after treatment.
Toluene is used to remove ascarids and hookworms of dogs and cats. It has some activity against whipworms e.g., Trichuris vulpis.
New Refs not used in preparing these notes, yet.
Random Notes that need to be included in appropriate place in antiparasitic notes.