Digoxin toxicity precipitated by clarithromycin use: case presentation and concise review of the literature

Canadian Journal of Cardiology 27 (2011) 870.e15– 870.e16 www.onlinecjc.ca Case Report
Digoxin Toxicity Precipitated by Clarithromycin Use: Case Presentation and Concise Review of the Literature Candace Y.W. Lee, MD, PhD,a François Marcotte, MD,a Geneviève Giraldeau, MD,a Gideon Koren, MD,b Martin Juneau, MD,a and Jean-Claude Tardif, MDa a Montreal Heart Institute, Université de Montréal, Montreal, Québec, Canada b University of Toronto, Toronto, Ontario, Canada We present a case of digoxin toxicity in the context of dehydration, Nous présentons un cas d’intoxication à la digoxine dans un contexte renal dysfunction and concomitant use of the macrolide antibiotic, de déshydratation, de dysfonction rénale et d’utilisation concomitante clarithromycin, which is known to inhibit P-glycoprotein–mediated ef- d’antibiotiques macrolides, la clarithromycine, qui est connue pour flux mechanisms of digoxin. A focused review of the literature is pre- inhiber les mécanismes d’efflux de la digoxine par l’intermédiaire de la sented. Health care providers need to be vigilant of this mechanism of glycoprotéine P. Une analyse documentaire ciblée est présentée. Les drug– drug interaction, which is also relevant to other commonly used dispensateurs de soins doivent être vigilants à ce mécanismed’interactions médicamenteuses, qui est aussi applicable à d’autres médicaments cardiovasculaires communément utilisés.
A previously well-functioning 83-year-old man with a past his- tion of 99% (room air). Cardiorespiratory examination did not tory of hypertension, dyslipidemia, myocardial infarction, left show signs of decompensated heart failure (HF). Blood tests ventricular dysfunction, and chronic obstructive pulmonary demonstrated a white cell count of 13.6 ϫ 109/L, potassium disease presented to hospital with a recent history of fatigue, 5.2 mM, urea 15.8 mM, creatinine 184 ␮M (3 weeks earlier: dyspnea on exertion, cough, nausea, loss of appetite, and light- urea 12.3 [reference 2.5– 8.2] mM, and creatinine 116 [refer- headedness. Three days prior to his presentation, the patient ence 65–120] ␮M), and digoxin levels of 4.6 nM (5 hours had been started on clarithromycin 500 mg PO twice daily for postdose) and 4.7 nM (18 hours postdose). His electrocardio- the treatment of possible pneumonia. His cardiac medications gram showed normal sinus rhythm, complete right bundle included digoxin 0.125 mg PO daily, spironolactone 25 mg branch, and left anterior hemiblock and evidence of prior an- PO once daily, captopril 25 mg PO twice daily, pravastatin 40 teroseptal and inferior infarctions (no significant changes from mg PO daily, isosorbide mononitrate 30 mg PO daily, furo- semide 60 mg PO daily, bisoprolol 2.5 mg PO daily, and po- The presentation of this patient was consistent with digoxin tassium 20 mmol PO daily. Due to severe nausea, the patient toxicity in the context of dehydration, a recent onset of renal presented to the emergency department following completion dysfunction, and concomitant use of the macrolide antibiotic of his fifth dose of clarithromycin. On examination, he ap- clarithromycin, which is known to inhibit P-glycoprotein–me- peared unwell. He was afebrile. His blood pressure and heart diated efflux mechanisms of Both drugs were stopped rate were 124/50 mm Hg and 68 beats per minute (supine) and immediately. In addition, medications that could raise serum 105/40 mm Hg and 82 beats per minute (standing), respec- potassium levels, including spironolactone, captopril, and po- tively. His respiratory rate was 16/min with an oxygen satura- tassium supplements, were discontinued on a temporary basis.
The patient was rehydrated. Ventricular extrasystoles were ob-served during monitoring. The patient was admitted to hospi- Received for publication May 27, 2011. Accepted June 15, 2011.
tal and improved clinically. Blood tests on day 2 of hospitaliza- Corresponding author: Dr Jean-Claude Tardif, Montreal Heart Institute, tion showed a digoxin level of 3.2 nM, urea 16.9 mM, 5000 Belanger St E, Montreal, Quebéc H1T 1C8, Canada. Tel.: ϩ1-514-376- creatinine 154 ␮M, and potassium 3.9 mM. His serum cre- 3330 ext. 3612; fax: ϩ1-514-593-2500.
atinine level subsequently returned to normal and his med- See page 870.e16 for disclosure information.
ications were optimized. He was discharged from hospital 0828-282X/$ – see front matter 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
doi:10.1016/j.cjca.2011.06.006 uneventfully 10 days later (urea 11.4 mM and creatinine dent on the dose of clarithromycin). Specifically, with an oral dose of clarithromycin 400 mg/day, there was an approxi-mately 70% increase in digoxin concentration.
In a 15-year, population-based, nested case-control study in Ontario, Gomes et evaluated the association between hos- Digoxin is a commonly used cardiac glycoside for the treat- pitalization for digoxin toxicity and recent use of macrolide ment of HF and for controlling ventricular response in atrial antibiotics. These investigators observed that a recent exposure fibrillation. Digoxin is a substrate for P-glycoprotein, which is to clarithromycin was associated with the highest risk of an adenosine triphosphate (ATP)-dependent multidrug efflux digoxin toxicity, with an adjusted odds ratio of 14.8, among transporter located on the luminal surface of epithelial cells of the individual macrolide antibiotics The results of the small intestine, bile canalicular membrane of the liver, renal this study underscore the potentially serious consequences of proximal tubules, and endothelial cells that form the blood- brain and blood-testes Most of the body load of With the advent of newer anticoagulants, in particular, dab- digoxin is eliminated by the kidney unchanged by both glo- igatran, it is anticipated that an increasing number of patients merular filtration and tubular secretion. In this case, the newly will be switched from warfarin to this reversible direct throm- developed renal insufficiency affected glomerular filtration rate bin inhibitor, which is also a substrate of P-glycoprotein with (GFR), whereas the clarithromycin inhibited the tubular secre- moderate affinity and is dependent on transport-mediated re- tion of the cardiac glycoside. When these 2 drugs are com- nal Physicians need to be aware that drugs like cla- bined, it is reasonable to decrease digoxin dose by half with rithromycin, amiodarone, and dronedarone affect the trans- careful therapeutic drug monitoring.
port proteins involved in renal secretion and therefore will Notably, because and the newer antiarrhythmic affect the levels of many drugs, such as digoxin and dabigatran, are both inhibitors of P-gly-coprotein, they share the same mechanism of interaction withdigoxin. In addition, spironolactone The authors have no conflicts of interest to disclose.
digoxin levels by reducing tubular secretion and might have beena contributing factor to digoxin toxicity in our patient, although the disproportional increase in creatinine vs urea would suggest areduced GFR being a prominent factor other than drug– drug 1. Dresser GK, Bailey DG. A basic conceptual and practical overview of in- interactions. The interaction between digoxin and clarithromycin, teractions with highly prescribed drugs. Can J Clin Pharmacol 2002;9: as well as other macrolide antibiotics, has been reported.
In 7 elderly patients who received chronic digoxin therapy, 2. Zapater P, Reus S, Tello A, et al. A prospective study of the clarithromycin- Zapater et conducted a prospective observational study to digoxin interaction in elderly patients. J Antimicrob Chemother 2002;50: evaluate potential interaction between digoxin and clarithro- mycin. These investigators measured digoxin levels before and 3. Tanaka H, Matsumoto K, Ueno K, et al. Effect of clarithromycin on steady- after concurrent clarithromycin use and observed a significant state digoxin concentrations. Ann Pharmacother 2003;37:178-81.
reduction in calculated digoxin clearance following 4-7 days ofclarithromycin therapy, with an elimination half-life that was 4. Gomes T, Mamdani MM, Juurlink DN. Macrolide-induced digoxin tox- 82% longer.In 8 digoxin-treated HF patients, Tanaka et al.
icity: a population-based study. Clin Pharmacol Ther 2009;86:383-6.
studied the effect of clarithromycin on steady-state digoxin 5. Pradax: dabigatran etexilate mesilate. Compendium of Pharmaceuticals levels and reported an increase in digoxin level during concom- and Specialties (e-CPS). Revised October 26, 2010. Available at: itant administration of clarithromycin (which was also depen-

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