Adverse Drug Reactions in Herding Breeds of Dogs and Cats
Do you own a collie or an Australian shepherd? Have you been cautioned that they may be particularly sensitive to certain drugs, or have you heard not to give them certain medications? Parasiticidal drugs, especially the avermectin group of dewormers: ivermectin (Heartguard®), selamectin (Revolution®), milbemycin (Interceptor®), and moxidectin (ProHeart®) may result in toxicity of the central nervous system when given above therapeutic levels. Do you ever wonder why these potentially lethal reactions occur when most other breeds have a wide safety margin when using these drugs? Most idiosyncratic drug reactions in veterinary patients are seen in herding breeds of dogs or in cats, which have a narrower therapeutic dose range for these drugs. These same breeds of dogs can be sensitive to various treatments such as chemotherapy as well.
It has recently been determined that some herding breeds of dogs have a single mutation in a gene coding for a particular protein (P-glycoprotein) that will drastically affect the absorption, distribution, metabolism, and excretion of a variety of medications used in veterinary medicine. In herding breeds of dogs there is a defined mutation called MDR1-1∆ (multidrug resistance gene), also called ABCB1, which affects P-glycoprotein function.
P-glycoprotein is a rather larger protein that functions as a pump to transport drugs across cell membranes. This pump requires energy in the form of ATP allowing it to function against steep concentration gradients. When a drug is transported by P-glycoprotein it is actively transported from intracellular (within the cell) to extracellular space (outside the cell). It is speculated that this protein serves an important function in protecting living beings, from one-celled organisms to the most complex animal systems, by minimizing that particular being’s exposure to potentially toxic substances. The protein functions by pumping toxins out of protected sites and promoting their excretion and elimination.
The primary absorptive site for orally administered drugs is the villus tip of enterocytes (intestinal cells) located with the gastrointestinal (GI) tract. P-glycoprotein is present on the luminal border of these intestinal epithelial cells where it transports drugs from the cytoplasm back into the intestinal lumen where they can be eliminated. In this way, P-glycoportein plays an additional role in drug elimination by limiting intestinal absorption and promoting fecal excretion of potentially toxic substances.
There are many barriers throughout the body protecting what is termed “privileged tissue”. These barriers include the blood-brain, blood-placenta barrier, and the blood-testes barrier. The term “privileged” means that very few substances are allowed across this barrier. P-glycoprotein has an important function in this barrier by minimizing the distribution of a substance to these tissues. In dogs totally lacking this protein they are considered to be homozygous for the defect (in their genetic make-up they have 2 genes for the MDRI-l∆ mutation) and ivermectin a common dewormer and heartworm preventative, in even low doses will induce neurologic toxicosis. This is true for many other drugs as well, even including many chemotherapy agents like doxorubicin and vincristine, and cardiac drugs such as digoxin and corticosteroids.
P-glycoprotein itself does not have any metabolic functions but it does work in conjunction with the CYP3A enzyme. The CYP3A enzyme is one of the most abundant cytochrome enzymes and is responsible for the metabolism of approximately 60% of all known drugs.
Complicated relationships may occur between P-glycoprotein, CYP3A, substrates, and even other substances called inhibitors. A drug inhibitor is a drug that interferes with the P-glycoprotein/CYP3A substrate system. Drugs such as Erythromycin, Ketoconazole, Cyclosporine and Tracrolimus are all drug inhibitors. Using any one of these inhibitor drugs concurrently with another drug eliminated by P-glycoprotein substrates such as Vincristine or Digoxin may result in drug toxicosis regardless of whether the MDR1-1∆ mutation is present or not..
Breeds in which the MDR1-1∆ mutation has documented occurrences include: Longhaired whippet, Silken windhound, Collie, Australian shepherd, English shepherd, the McNab collie, Old English sheepdog, Shetland sheepdog, and the German shepherd. White-coated dogs such as the white German shepherd have a greater frequency of the MDR1-1∆ mutation than do other colors.
A study published in the American Journal of Veterinary Research during 2002 found that 75% of the collies from the Northwestern United States had at least one mutant gene (heterozygous) for the MDR1-1∆ mutation, while 35% of those had two mutant genes and are termed homozygous for the defective gene. In Australian sheepdogs, 16.6 % of the population carries the defective gene, while Shetland sheepdogs are affected at an 8.4% level and Old English sheepdogs at a lesser 3.6% level. Other herding dogs such as the bearded collie and Australian cattle dog have not been shown to harbor the defective gene, presumably as a result of their varied ancestry.
It is important to test for the MDR1-1∆ mutation for it allows veterinarians to determine whether it is safe to administer drugs that are eliminated by the P-glycoprotein. A simple cheek swab sample may be submitted for DNA analysis to determine the existence of the MDR1-1∆ mutation in any particular pet. These samples should be forwarded to:
Veterinary Clinical Pharmacology Laboratory (VCPL)
College of Veterinary Medicine
Washington State University
In pets reacting to acute exposure to avermectins or other drugs and treatments eliminated by P-glycoprotein, the clinical signs will become severe within a few hours of exposure. Most of the clinical signs relate to depression of the Central Nervous System (CNS) and include ataxia, weakness, and recumbency (the pet is unable to get up), and in severe cases a coma may develop. The pet may also appear to be blind and muscle tremors may sometimes occur. Additional clinical signs include mydriasis (dilated pupils), hypothermia (low body temperature), shallow breathing, vomiting or salivation. Clinical signs may persist for days or weeks, dependent upon the type of drug resulting in the toxicity.
Temporary relief is sometimes achieved with physostigmine, neostigmine or treatment with picrotoxin. Additional treatment is supportive and may require: fluid therapy, respiratory support, maintenance of body temperature, and/or the use of a feeding tube. Length of treatment depends upon the half-life of the drug causing the toxicity. The half-life of a drug refers to the length of time it takes to eliminate 1⁄2 of the drug in one individual’s system. With ivermectin the toxicity typically lasts 2 days, while it may take up to 11 days to eliminate selamectin or up to 19 days for moxidectin.
Diagnosis is typically made through exposure to the medication, knowledge of the breed of dog, and classical clinical signs.
Bonagura, John, and David Twedt, Ed. Kirk’s Current Veterinary Therapy XIV. Saunders/Elsevier. 2009. Pp. 125-127.
Mealey, Katrina, DVM, PHD. “Adverse Drug Reactions in Herding-Breed Dogs: The Role of P-Glycoprotein”. Compendium on Continuing Education for the Practicing Veterinarian. Pp. 23-33.
“More on Pharmacogenetics in Animals.” Antech Diagnostics News. May 2009. Pp. 1-2.