Page 1271 - Cote clinical veterinary advisor dogs and cats 4th

MDR1 Mutation 639

English shepherd, border collie, German • Macrocyclic lactones: mydriasis, hypersaliva- CNS depressants such as diazepam should
shepherd, McNab dog), sighthound breeds tion, ataxia, blindness, paresis, stupor, muscle be avoided. Recently the use of IV lipid
VetBooks.ir RISK FACTORS • Loperamide: paresis, ataxia, stupor toxicity has been discussed, but there are no Diseases and Disorders
tremors; may progress to coma
emulsion for reversal of macrocyclic lactone
(long-haired whippet, silken windhound)
• Chemotherapeutic agents: anorexia; vomit-
clinical studies in dogs at this time.
Breed is a risk factor, based on the percentage
lipid emulsion administration) has not been
of animals known to harbor the MDR1 ing, diarrhea; signs of opportunistic infec- • The lipid rescue protocol (involving IV
tions or hemorrhage possible if neutropenia
mutation: or thrombocytopenia, respectively effective for treating ivermectin toxicosis in
• Australian shepherd: 50% • Antiemetics: signs of mild to moderate CNS MDR1 mutant/mutant dogs.
• Border collie: 5% dysfunction (usually depression) • For loperamide, an opioid antagonist such
• Collie: 75% • Preanesthetic agents: prolonged and more as naloxone can reverse CNS depression.
• English shepherd: 15% profound CNS depression • Chemotherapeutic agents, antiemetic agents,
• German shepherd: 5% • Emodepside: CNS depression preanesthetic agents: supportive care (p. 152)
• Long-haired whippet: 65% • Apomorphine: CNS depression
• McNab: 30% Drug Interactions
• Old English sheepdog: 35% Etiology and Pathophysiology • Spinosad, ketoconazole, and cyclosporine can
• Shetland sheepdog: 15% • The MDR1 gene mutation is inherited in a inhibit P-glycoprotein, causing an acquired
• Silken windhound: 35% simple mendelian fashion. P-glycoprotein deficiency in dogs that do
• Mixed-breed dogs (presumed to be herding- • Heterozygotes and homozygotes experience not carry the MDR1 mutation.
breed crosses): 10% enhanced drug sensitivity. • Concurrent use of these P-glycoprotein–
• The MDR1 mutation is a 4–base pair dele- inhibiting drugs with macrocyclic lactones
ASSOCIATED DISORDERS tion mutation that results in dysfunction of (high dose), vinca alkaloids, and doxorubicin
Relative adrenal insufficiency (MDR1 mutant/ P-glycoprotein, the product of the MDR1 should be avoided.
mutant genotype) gene.
• Normally functioning P-glycoprotein protects PROGNOSIS & OUTCOME
Clinical Presentation an individual from a number of drugs by
HISTORY, CHIEF COMPLAINT restricting their access to the brain and • Clinical signs tend to be milder, and clinical
• Depends on the particular drug to which enhancing their export from the body. outcome better, in dogs heterozygous for the
the dog is exposed MDR1 mutation (MDR1 mutant/normal).
○ Exposure to macrocyclic lactones (e.g., DIAGNOSIS • For dogs homozygous for the MDR1 muta-
ivermectin, milbemycin, selamectin, tion (MDR1 mutant/mutant), the prognosis
moxidectin) may result in neurologic Diagnostic Overview is guarded for those exposed to doses of
toxicosis. NOTE: use of these drugs as Screening for the MDR1 mutation can be per- ivermectin used for treating mange (300-600
labeled for heartworm prevention is safe formed preemptively in a dog of a high-prevalence mcg/kg or higher) and customary doses of
2
even for dogs with the MDR1 mutation. breed. Otherwise, the mutation is suspected when vincristine 0.5-0.7 mg/m and doxorubicin
2
Neurologic toxicosis occurs only with signs of drug toxicosis have occurred despite the 30 mg/m (p. 609).
higher doses (e.g., treatment of mange, use of normal drug dosages. In either situation,
accidental overdose). confirmation is done by genotyping. PEARLS & CONSIDERATIONS
○ Exposure to loperamide may result in
neurologic toxicosis. Differential Diagnosis Comments
○ Exposure to some chemotherapeutic drugs • Idiopathic drug sensitivity • The MDR1 mutation and exposure to a
(vinca alkaloids, anthracyclines such as doxo- • Overdose macrocyclic lactone or loperamide should
rubicin) can result in severe gastrointestinal be considered in any herding-breed dog that
signs and/or severe myelosuppression. Initial Database develops unexplained signs of neurologic
○ Exposure to vincristine has been docu- Initial diagnostic tests are those performed for toxicosis.
mented to cause central neuropathy. any suspected case of toxicosis for the particular • Before treatment with chemotherapeutic
○ Exposure to some antiemetics (ondanse- agent (e.g., CBC for chemotherapeutic drugs agents and/or off-label (i.e., anti-mange)
tron, possibly maropitant) may result in with myelosuppressive potential). doses of macrocyclic lactones, mixed-breed
neurologic toxicosis. dogs or breeds listed above should be tested
○ Exposure to some preanesthetic agents Advanced or Confirmatory Testing for the MDR1 mutation.
(acepromazine, butorphanol) may result Definitive diagnosis consists of genotyping • The MDR1 mutation may explain the
in more profound and prolonged sedation the dog. A DNA sample (cheek swab, using intolerance to stress and illness anecdotally
than expected for the dose administered. purpose-made kit or EDTA blood) can be observed in some breeds. In collies, the
○ Exposure to emodepside has resulted in submitted to the Veterinary Clinical Phar- mutation is associated with lower plasma
neurotoxicosis. macology Laboratory at Washington State cortisol concentrations at baseline and after
○ Exposure to apomorphine has resulted in University. A DNA swab kit can be obtained ACTH stimulation. Because P-glycoprotein
central nervous system (CNS) depression. at www.vetmed.wsu.edu/vcpl. limits glucocorticoid passage into the brain,
• Onset of signs occurs in hours to days after MDR1 mutation may favor such passage,
drug exposure. TREATMENT increasing feedback inhibition and creating
• Exposure to macrocyclic lactones can occur a state of relative adrenal insufficiency.
through ingestion of feces of animals, par- Treatment Overview • A similar mutation has been identified in the
ticularly livestock, recently treated with these There is no treatment that can alter the dog’s feline MDR1 gene and likely contributes to
agents. Several pesticides contain avermectins MDR1 genotype, and treatment of clinical signs drug sensitivity in this species. Research is
and have caused neurologic toxicosis in dogs resulting from drug exposure should be aimed ongoing in the author’s laboratory.
that were inadvertently exposed. at the particular drug involved.
Prevention
PHYSICAL EXAM FINDINGS Acute and Chronic Treatment Treatment planning for dogs identified as
Determined by drug to which the dog has been • For macrocyclic lactones, supportive care having the MDR1 mutation (heterozygous or
exposed (see above): is indicated (p. 152). Administration of homozygous) depends on the drug involved.
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