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Dogs With a Drug Problem: MDR1 mutation affects more than just Collies – and involves more drugs than ivermectin.

Genetic Mutation Causes Sensitivity to Multiple Drugs.

Article by Mary Straus, published in the Whole Dog Journal, December 2012

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Introduction

Most dog owners are aware that Collies and other herding breeds may be sensitive to ivermectin, used for heartworm prevention and to treat certain parasites. But did you know that these dogs can also be sensitive to a number of other drugs, and that other breeds can also be affected?

It’s been known since 1983 that ivermectin can cause neurologic toxicity in some, but not all, Collies. In affected dogs, toxicity is caused by doses of ivermectin that are 1/200th of the dose needed to cause toxicity in normal dogs. Symptoms of neurologic toxicity can include uncoordination or loss of balance (ataxia), depression, disorientation, excess salivation, pupil dilation, nystagmus (abnormal movement of the eyes), blindness, tremors, recumbency (inability to get up), coma, respiratory compromise, and even death.

But the next big accomplishment in gaining an understanding of exactly what was responsible for the toxic effects of ivermectin in some dogs came in 2001, when Katrina Mealey, DVM, PhD, DACVIM, DACVCP, at Washington State University College of Veterinary Medicine, identified a mutation in the MDR1 gene that causes ivermectin sensitivity. The discovery led to WSU’s development of a test that can detect the mutant gene, so that dogs who are susceptible to this toxicity can be identified.

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Test can save lives

Dogs can have either two copies of the defective gene (homozygous, double recessive), or one defective gene and one normal gene (heterozygous). Dogs with two copies will be most severely affected. Dogs with one copy are less sensitive (able to tolerate a higher dose before adverse effects are seen), but they are more sensitive than normal dogs.

Further research revealed that dogs with the MDR1 mutation are sensitive to a number of different drugs, not just ivermectin. Melissa Best, DVM, who went to veterinary school at WSU, explains, “MDR stands for ‘multidrug resistance.’ The protein encoded by this gene is P-glycoprotein (PGP) and is an important protein for keeping potential neurotoxins from entering the brain. The MDR1 mutation means that this protein is improperly coded and cannot do its job.”

The MDR1 mutation allows drugs to build to toxic levels in the brain, and is now referred to as “multidrug sensitivity.” Toxicity may occur from a single high dose or frequent low doses of problem drugs. Topical application of certain drugs can also cause toxicity, and the effects may last longer, but it generally takes higher doses.

WSU is the sole patent holder for the test to detect the mutant gene. The test requires only a simple, non-invasive cheek swab that you can collect yourself and send to WSU’s Veterinary Clinical Pharmacology Laboratory (VCPL). The test costs $70 (as of December 2012), with a discount for more than four dogs. It can be performed on any dog, including mixed breeds, at any age after weaning. The test will identify whether a dog has one or two copies of the defective gene. It takes about two weeks to get results.

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Heartworm Preventives

All heartworm preventive medications can affect dogs with the MDR1 mutation, including ivermectin (Heartgard), milbemycin (Interceptor, Sentinel), selamectin (Revolution), and moxidectin (ProHeart, Advantage Multi). The very low doses used for heartworm prevention, however, should not cause any harm, even to dogs with two copies of the defective gene.

“I don’t know of any homeopathic or naturopathic alternatives to these drugs, particularly for heartworm,” says Dr. Best. “While I am very pro-holistic care, the risk of death from heartworms is greater than the risk of the drugs (especially at the low doses used for prevention). I recommend using commercial heartworm preventatives under the direction of a veterinarian.”

The higher doses of these medications that are used to treat demodectic mange, sarcoptic mange, ear mites, and other parasites, however, should be avoided in all affected dogs. Generic ivermectin preparations such as Ivomec 1% solution should not be given to affected dogs, as the potential for toxicity from the wrong dosage is too great (the instructions on many websites result in dosages at least 10 times too high; see Ivomec Dosage Instructions for correct information). Long-acting injectable products such as ProHeart 6 may also be problematic for affected dogs.

Toxicity can also occur from eating the manure of other animals, such as horses or sheep, after they are treated for parasites with products containing ivermectin. Pesticides with ivermectin used to treat a home or yard may cause toxicity if an affected dog is exposed to the area afterwards.

Ivermectin has the most potential for toxicity. Dogs with normal MDR1 genes can usually tolerate oral dosages as high as 2,500 mcg/kg of body weight before signs of toxicity are seen, while dogs with two copies of the defective MDR1 gene can only tolerate up to 100 mcg/kg of oral ivermectin. No toxicity was seen when affected dogs were given 28 to 35.5 mcg/kg monthly for one year. (For comparison, the amount of ivermectin in Heartgard is 6 to 12 mcg/kg.)

Toxicity has been seen in affected dogs receiving oral doses that were 30 times the heartworm preventive dose of moxidectin and 10 times the regular dose of milbemycin. Selamectin caused toxicity at 2.5 times the recommended dose when that amount was given orally, but higher doses are tolerated when the product is applied topically, as directed.

Other avermectins can also cause toxicity, including doramectin (Dectomax), eprinomectin (Eprinex), and abamectin.

Spinosad, a flea-control medication included in Comfortis and Trifexis (also called Vethical AcuGuard and ComboGuard), increases the risk of neurological toxicity even in normal dogs when combined with high doses of ivermectin (and possibly other drugs) used to treat parasites. While theoretically safe, use caution when combining Heartgard or other ivermectin heartworm preventive drugs with products containing spinosad for affected dogs. Do not combine high doses of ivermectin with spinosad for any dog.

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Other drugs

Some additional drugs are known to cause problems for dogs with the MDR1 mutation, while others are suspected to be problematic. A few drugs affected by PGP appear to be safe to use in normal doses. “There are many known drugs which are pumped out of the brain by p-glycoprotein,” says Dr. Best. “However, not all seem to cause toxicity in mutant dogs. Clearly more research is needed to understand the mechanisms at work.”

Drugs that are known to affect or may affect dogs with the MDR1 mutation include some used to treat cancer, pain, parasites, bacterial infections, diarrhea, vomiting, and anxiety, as well as pre-anesthetic drugs. In addition to ivermectin, the most commonly used problem drugs are acepromazine (Ace), butorphanol (Torbutrol, Torbugesic), and loperamide (Imodium). Most of these drugs require a prescription, but loperamide, an anti-diarrheal medication, is available in over-the-counter preparations.

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Breeding considerations

Ideally, only dogs with no copies of the MDR1 mutation would be used for breeding. This may not be feasible or even optimal in some cases, however, particularly in heavily affected breeds, where the rest of the gene pool would be too limited, which leads to other problems. Any dog with the mutation may pass it along to their offspring, but dogs with just one copy of the mutation can also produce normal puppies, particularly when bred to dogs that do not carry the mutation at all. In this way, the population of affected dogs can be reduced through subsequent generations.

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What to do

Even if you don't plan to breed, all dogs from affected breeds should be tested for the MDR1 mutation for their own protection. Mixed-breed dogs from affected breeds or whose parentage is unknown should also be tested, as it’s impossible to tell for sure just by looking at a dog what its ancestry might be.

Before the genetic test became available, vets often repeated the adage, “White feet, don’t treat!” as a reminder that such dogs might be at risk, since many herding breeds and mixes have white feet. This is not reliable, however, as some dogs with white feet may have normal genes, and dogs with non-white feet may be affected by the mutation. Dr. Mealy recommends testing all mixed-breed dogs with unknown breed status, as one exposure to a drug to which they are sensitive could be fatal.

“The biggest problem I have seen with MDR1 mutants is accidental exposure by owners who were unaware of the problem,” says Dr. Best. “I have seen several dogs die from this problem after being exposed to ivermectin products.

“The worse case that I saw where the dog survived was an Australian Shepherd from Montana who became exposed after licking up a dollop of dewormer that had dropped out of a horse's mouth when the owner was deworming it. The dog was flown on a private jet to WSU, with a private vet tech hired to breathe for the dog, as he was severely affected by the time he had been brought to his veterinarian (within hours of exposure to the drug). That patient was on a ventilator for nearly two weeks and eventually made a full recovery, however the bill was well over $10,000 and not everyone can fly a dog to a referral center on a private jet!!  I have also seen dogs become affected who ate horse manure after the horses had been dewormed with Ivermectin.”

If tests show that your dog is affected by the MDR1 mutation, or if your dog could be affected and has not been tested, make sure that your vet is aware of potential drug sensitivity. You may want to give your vet a copy of the list of drugs from the VCPL website to include in your dog’s file. Be sure to remind your vet of the situation any time that your dog needs to be anesthetized or sedated so that the wrong medications will not be given.

If you use any drug that might cause toxicity, start with low doses and gradually increase the amount that is given over a few days as long as no adverse side effects are seen. Continue to monitor your dog closely for signs of toxicity, particularly when the drug is given daily, as chronic toxicity caused by cumulative effects could develop.

If your dog shows signs of toxicity after applying a topical product, immediately bathe your dog with soap to remove as much of the product from the skin as possible.

If your dog ingests a topical product or if you see signs of toxicity after giving oral medications, contact your vet immediately. If ingestion was recent, your vet may induce vomiting and give activated charcoal. Further supportive care, including IV fluids and ventilation, may be needed if signs are severe. Dogs may recover if supportive care can be offered for long enough, but it can take days or weeks before enough of the drug breaks down on its own. “Sadly,” says Dr. Best, “Because we have no way to get the neurotoxic drugs out once they are in the brain, most dogs are not able to be saved once we recognize a toxicity problem.”

Update: Intravenous lipid emulsion (ILE) has been proposed as a possible treatment for ivermectin toxicosis. This is a relatively new treatment for treating toxicosis of various lipophilic drugs and is only used after traditional therapy has failed. A veterinary specialty practice or vet school would be most likely to have access to this therapy. See A potential new treatment for ivermectin toxicosis, and more for more information.

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You can contact me if you have any comments, but I regret to say that I can no longer respond to questions about individual dogs. See my Contact page for more information. My name is Mary Straus and you can email me at either or

   


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