Page 577 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

544 SECTION |VI Insecticids

VetBooks.ir mediated through the neurotransmitters GABA and gluta- Table 43.2. Some chelonians appear to be highly sensitive
to MLs, with the leopard tortoise (Geochelone pardalis)
mate, with higher concentrations required for GABA-
developing signs at dosages as low as 25 μg/kg (Teare
mediated effects than for glutamate-mediated actions
(Lanusse et al., 2009). Glutamate-gated channels are and Bush, 1983). White lions appear to be more sensitive
unique to invertebrates (Trailovic and Nedelijovic, 2011). than tawny lions (Lobetti and Caldwell, 2012). Young
Binding of MLs to glutamate-gated chloride channels animals in general may be more sensitive than adults
causes increased conductance of chloride through the cell because their immature BBB are more permeable to iver-
membrane, resulting in hyperpolarization and flaccid mectin (Sanford et al., 1988).
paralysis of invertebrate musculature, particularly in
nematodes and arthropods (Lanusse et al., 2009). Clinical Effects
Paralysis of pharyngeal pump musculature decreases the
ingestion of nutrients while paralysis of somatic muscula- The clinical signs of ML toxicosis have been reported in
tures impedes the ability of the parasite to remain at its several studies (Pullium et al., 1985; Paul et al., 1987;
site of predilection in the host, resulting in death of the Tranquilli et al., 1987) as well as case reports of toxicosis
parasites. Additionally, effects on the GABA and in various species. In most species, signs generally are
glutamate-mediated activity of the musculature of the those of CNS depression, although in some species,
female reproductive system result in decreases in oviposi- GABA-mediated cholinergic effects have also been
tion (Fellowes et al., 2000). reported. Ocular effects have been reported with ML
Glutamate-mediated chloride channels sensitive to overdoses and include mydriasis, miosis (less common),
MLs are found uniquely in nematodes and arthropods. absent menace response and blindness. Although multifo-
Cestodes and trematodes lack ML binding sites, and are cal retinal edema and separation were described in two
therefore unaffected by MLs. In mammals, ML-sensitive dogs (Kenny et al., 2008), other cases in cats, dogs, and
GABA-mediated chloride channels are restricted to the horses did not show abnormalities on fundic examinations
CNS, from which the MLs are largely excluded through (Meekins et al., 2015; Pollio et al., 2016). In all reported
the action of a p-glycoprotein efflux pump (see MLs and cases, vision returned upon recovery from toxicosis.
p-glycoprotein defective animals in previous section). After ingesting ivermectin at about 200 μg/kg of an
When the p-glycoprotein transporter is overwhelmed ivermectin anthelmintic paste, a dog with the ABCB1
(e.g., in overdose situations), defective (e.g., ABCB1 mutation exhibited dehydration, bradycardia, respiratory
defect), or compromised (e.g., pharmacologically inhib- depression, cyanosis, mydriasis, and a diminished gag
ited), entry of MLs into the mammalian CNS may lead to reflex (Heit et al., 1989). Signs of ML toxicosis in dogs
signs of toxicosis. may also include hypersalivation, vomiting, lethargy,
ataxia, tremors, hyperthermia or hypothermia, disorienta-
tion, lack of menace response, blindness, head-pressing,
TOXICITY seizures, coma, and death (Merola and Eubig, 2012).
Signs reported with ML toxicosis in cats include mild
Toxicity Data
diarrhea, posterior ataxia, miosis or mydriasis, vocaliza-
At the doses used as parasiticides in veterinary medicine, tion, ataxia, tremors, sternal recumbency, coma, and
MLs have low levels of toxicity to most animal species death. (Song, 1991; Merola and Eubig, 2012). ML toxico-
with at least a 10-fold margin of safety for ruminants, sis in calves can cause depression, ataxia, diarrhea, dys-
horses, swine, and dogs with normal P-GP (Campbell pnea, tachycardia, recumbency, increased respiratory
et al., 1983; Bennett, 1986; Lanusse et al., 2009). For rates, muscular fasciculations, mydriasis, extensor rigidity
example, the dosage of ivermectin used to prevent heart- of the limbs, and miosis or mydriasis (Gupta, 2007). In
worms and intestinal nematodes in dogs is 6 μg/kg body sheep, ML toxicosis is characterized by depression and
weight, which is over 30 times less than the dosage of incoordination. In horses, ataxia, depression, mydriasis,
200 600 μg/kg that is often used in dogs to manage ecto- depressed respiratory rate and drooping lower lip visual
parasites such as Demodex mites. Dogs with ABCB1 impairment have been reported (Leaning, 1983).
defects would not be expected to show clinical signs until Ten lions that were administered 0.2 0.5 mg/kg of
levels of 80 100 μg/kg of ivermectin were administered, doramectin subcutaneously and then subsequently fed the
while most dogs with normal P-GP can generally tolerate carcass of a horse that had recently received doramectin
dosages of 200 μg/kg/day, although some dogs may show via injection developed ataxia, hallucinations, and mydri-
mild signs at that dosage (Merola et al., 2009; Merola and asis 3 5 days following doramectin administration; two
Eubig, 2012). In beagle dogs, the oral LD 50 of ivermectin affected lions died (Lobetti and Caldwell, 2012). Post
is 80,000 μg/kg body weight (Pullium et al., 1985). Toxic mortem lesions consisted of cyanosis, pulmonary edema,
and therapeutic dosages for some MLs are listed in pleural effusion and pericardial effusion, and brain and