| Chemical Groups, Members, and General Indications | ||
|---|---|---|
| Group | Drugs | General Indications1 |
| Macrolide Endectocides |
|
|
| Benzimidazoles |
|
|
| Probenzimidazoles |
|
|
| Imidazothiazoles |
|
|
| Pyrimidines |
|
|
| Substituted Piperazines |
|
|
| Organophosphate |
|
|
| Trivalent Arsenicals |
|
|
|
1Note: Indications may not apply to all members of the group equally.
There may be dose forms for some indications and species, but not others. Note also that
details of larvae vs adults are not noted in every case. Refs: Barragry'95 Webster, LT, Jr., GG8th'90 USPDI'94 Courtney & Roberson'95 | ||
| Chemical Groups and General Mechanisms of Antinematodal Drugs | ||
|---|---|---|
| Group/Drug | Mechanism | Effect on Parasite |
| Macrolide Endectocides |
|
Flaccid paralysis |
| Benzimidazoles |
|
|
| Probenzimidazoles |
|
|
| Imidazothiazoles |
|
|
| Pyrimidines, e.g., pyrantel |
|
|
| Substituted Piperazines |
|
|
| Organophosphates |
|
|
| Trivalent Arsenicals |
|
|
| 1Courtney & Roberson'95 Barragry'95 Webster, LT, Jr., GG8th'90 USPDI'95 | ||
Ivermectins are relatively safe for species that have an approved dose form; horse, dog, cattle, and swine. They have no known teratogenic effect.
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 avilable 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 mg/kg; 16 x the label dose now recommended. At a dose of 6 mg/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.
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.
<<< MORALS >>>
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).
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.
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.
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.
RELATIVELY NON-TOXIC.
GASTROINTESTINAL IRRITATION and VOMITION in few animals
Multiple generation studies -- no evidence of problems.
SEVERE REACTIONS in dogs that have circulating microfilariae