Digoxin and mexiletine sensitivity in a Collie with the MDR1 mutation.

A 9-year-old, 29.6-kg, female spayed Collie was referred to the University of Wisconsin–Madison Veterinary Medical Teaching Hospital (VMTH) for evaluation of tachycardia. Past history included surgery for patent ductus arteriosus (PDA) at 9 months of age. The ductus remained patent after surgery, although the murmur had changed in quality. The owner elected not to pursue a second surgery or the use of thrombotic coils, and the dog remained asymptomatic until 9 years of age. An ECG was performed at the VMTH; results were consistent with paroxysmal ventricular tachycardia, with a heart rate of 180 beats/min. Lidocaine (2 mg/kg IV) was administered as a bolus to suppress the arrhythmia, and continued as a constant rate infusion at 60 mg/kg/min. Radiographs of the thorax revealed pulmonary edema and pleural effusion with cardiomegaly, aneurysmal dilatation of the descending aorta, enlarged pulmonary vessels, and a bulge of the main pulmonary artery, findings consistent with PDA and biventricular congestive heart failure. Serum biochemistry values and total T4 concentration reported by the referring veterinarian were within the reference range with the exception of total protein (4.8 g/dL, reference range 5.0–7.4 g/dL), consistent with movement of protein into the pleural and alveolar spaces. Additional medications given on the day of admission included furosemide (2.7 mg/kg) IV once, and then 1.7 mg/kg PO q8h, digoxin 0.002 mg/kg PO in the morning and 0.004 mg/kg PO in the evening, and enalapril 0.51 mg/kg PO q12h. Doppler echocardiography, performed after the arrhythmia was controlled, documented continuous flow in the pulmonary artery, moderate to severe mitral valve regurgitation with mitral valve thickening, left atrial and left ventricular dilation, and myocardial failure (fractional shortening 12%, reference range 25– 35%). Lidocaine was tapered and discontinued on the 2nd hospital day, and oral mexiletine was administered at a dosage of 5.1 mg/kg PO q8h. The dog had no interest in eating and vomited immediately after the 2nd mexiletine dose. Oral famotidine and metoclopramide were administered with the cardiac medications, and the dog was discharged on the 3rd hospital day. Seven days after the initial presentation for tachycardia, the dog re-presented to the VMTH for anorexia and abnormal mentation. The owner reported that the dog was being force-fed, and a 3-hour episode of circling had occurred at home. In addition, the dog had not reacted normally to stimuli in the home environment since beginning the medications. On physical examination, the cardiac rhythm was regular and the dog appeared dehydrated. A serum digoxin concentration was obtained 8 hours after dosing, and the dog was administered 500 mL lactated Ringer’s solution SC. The owner was advised to not administer the next dose of furosemide and to discontinue administration of digoxin. The serum digoxin concentration, reported the next day, was 4.5 ng/mL (reference range, 0.8–1.2 ng/ mL). The dog presented again to the VMTH on an emergency basis 3 days later with a history of repeated vomiting and continued anorexia. Current medications included enalapril and mexiletine at the previously prescribed dosages. Subcutaneous fluid administration was repeated, and treatment with metoclopramide and famotidine was again recommended with continuation of the enalapril (0.51 mg/kg q12h) and mexiletine (5.1 mg/kg q8h). One week later, the dog had another episode of confusion and anxiety, characterized by walking into walls, uncontrollable pacing, and attempting to crawl under furniture. The dosage of mexiletine was reduced to q12h on the basis of suspicion of mexiletine toxicosis, and further reduced by the owner to q24h administration after 2 days. The dog was re-examined 20 days after the 1st presentation. The dog had lost 3.4 kg, which was 11.5% of her initial body weight, over 20 days. The owner reported that the dog was no longer anxious or excited since decreasing administration of mexiletine to once daily, and that appetite was returning. An ECG revealed a heart rate of 120 beats/min and sinus rhythm without ventricular arrhythmias. Mexiletine neurotoxicosis was suspected on the basis of the history, and administration of the drug was discontinued. A buccal swab DNA sample was obtained to determine if the dog had a functional defect in Pglycoprotein (P-gp) on the basis of adverse reactions to digoxin and mexiletine. Swabs were submitted for MDR1 genotyping. DNA was extracted using previously published methods and used as a template for polymerase chain reaction amplification. Labeled amplicons were detected using amplified fragment length polymorphism and analyzed. Primers were designed such that they spanned the mutation area, base pairs 294–297 of the canine MDR1 gene (GenBank From the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI (Henik, Kellum); and the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA (Bentjen, Mealey).