Ivermectin Toxicity

Chapter 93 Ivermectin Toxicity



Nancy E. Scott, MS, DVM, DACVECC



KEY POINTS



• Ivermectin doses as low as 90 to 100 mg/kg have resulted in clinical signs in sensitive dogs; however, the licensed dosage for heartworm prevention is substantially lower.

• Common clinical signs of toxicity include ataxia, vocalization, disorientation, hyperesthesia, blindness, weakness, mydriasis, and bradycardia.

• There is no antidote, so management is primarily supportive care.

• Prognosis for eventual recovery is good. However, severely affected patients may require prolonged medical and nursing care, and the clinical course may be confounded by complications.


IVERMECTIN: THE DRUG



Description


Ivermectin is a broad-spectrum antiparasitic drug that is used commonly in veterinary medicine and generally has a wide margin of safety. It is a fermentation by-product of Streptomyces avermitilis bacteria, and the compound is comprised of 80% or more avermectin B1a and 20% or less of avermectin B1b. Although it bears structural homology to the macrocyclic lactone class of antibiotics, ivermectin has no antibacterial or antifungal activity. Ivermectin is used most commonly as an antiparasitic agent against nematode infestations and external arthropod parasites (e.g., mites).1 It is licensed for use in dogs and cats as a heartworm preventive, prescribed at 6 and 24 μg/kg PO, respectively, to be administered once per month. It is also used in dogs, off-label, to manage ectoparasites and endoparasites at a dosage of 50 to 300 μg/kg PO or SC.2 Other forms of avermectin that have similar mechanisms of action and toxicity and might result in similar clinical signs include moxidectin, eprinomectin, selamectin, milbemycin, and doramectin.



Mechanism of Action


Ivermectin is an agonist of invertebrate-specific, glutamate-activated, inhibitory chloride channels; it causes flaccid paralysis and subsequent death in nematodes and mites. Ivermectin’s toxic effect in mammals is due to the similarity of these invertebrate-specific channels to vertebrate γ-aminobutyric acid (GABAA)-gated chloride channels that inhibit interneurons in the central nervous system (CNS). At higher concentrations, ivermectin potentiates these vertebrate GABAA-gated chloride channels. This can have a toxic effect as CNS concentrations of ivermectin increase and cause hyperpolarization of cell membranes, preventing neuronal depolarization.1,3



Ivermectin Sensitivity


The multidrug-resistance (mdr1) gene codes for a large transmembrane protein called P-glycoprotein (P-gp), which is an integral part of the blood-brain barrier. P-gp is an efflux drug-transport pump that moves a variety of drugs, including ivermectin, from the brain back into the blood. A 4-base pair deletion mutation of the mdr1 gene that encodes P-gp has been found in some ivermectin-sensitive animals, including Collies and other herding dogs. P-gp prevents high levels of ivermectin, and other lipophilic compounds, from accumulating in the CNS by actively pumping the drug out of the cells and back into the blood.4 Forty-eight percent of 25 Collie dogs tested in France were homozygous for the mutant allele that confers ivermectin sensitivity,5 and it has been estimated that as many as 30% to 40% of Collie dogs in the United States are sensitive; this relatively high prevalence should be considered when treating Collie dogs with avermectins.



Pharmacokinetics


Ivermectin is absorbed rapidly when administered either subcutaneously or orally.2 Gastrointestinal (GI) absorption is the more rapid, about 95% is absorbed, and peak plasma concentrations are achieved within 2 to 4 hours after oral administration. Ivermectin is metabolized via oxidation in the liver and excreted in the bile to the feces; less than 5% is excreted in the urine. Its half-life in dogs is approximately 2 days.1



Toxicity


Most dogs tolerate ivermectin dosages up to 2.5 mg/kg PO before they exhibit clinical signs of toxicity.3 No adverse effects were detected in Beagle dogs when administered up to 2 mg/kg PO as a single dose; the lethal dose (LD50) in Beagle dogs has been reported as 80 mg/kg.2,6 However, in dogs that are sensitive to ivermectin, doses as low as 90 to 100 μg/kg have resulted in signs including ataxia and depression. Toxicity has been documented repeatedly in Collie dogs at doses of 100 to 500 μg/kg; ivermectin sensitivity has also been reported in two Australian Shepherds and suspected in an Old English Sheepdog cross.1,6


Published ivermectin tolerances for cats are varied, ranging from 0.2 to 1.3 mg/kg PO or SC,1 to a narrower oral dosage range of 0.5 to 0.75 mg/kg. However, toxicosis has been reported in kittens exposed to as little as 300 to 400 μg/kg SC.3 Younger animals do not have a fully developed blood-brain barrier and as a result may be more susceptible to ivermectin toxicity.

Related posts:

  1. Deteriorating Mental Status
  2. Hyperthermia and Fever
  3. Ventilator-Associated Lung Injury
  4. Allergic Airway Disease in Dogs and Cats and Feline Bronchopulmonary Disease

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Ivermectin Toxicity

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