Interaction Between Digoxin and Amiodarone
Steven Haffa, RPh
Volume IX, Issue 12
Disorders of cardiac rhythm requiring antiarrhythmic therapy generally develop in patients with heart disease for which digoxin is frequently prescribed. Thus concomitant therapy with antiarrhythmic drugs and digoxin is not unusual. Amiodarone, an effective agent in the treatment of supraventricular and ventricular tachyarrhythmias, is often prescribed in patients with congestive heart failure receiving digoxin.1,2 Amiodarone has been found to raise serum digoxin concentrations (SDC).3-6
In 1981 Moysey et. al.3 observed that when amiodarone was added to maintenance digoxin therapy in 7 patients, all showed increases in SDC. When amiodarone 600 mg daily (200mg PO tid) was added to long-term digoxin therapy, SDC increases averaged 69%. Four patients displayed symptoms compatible with digoxin toxicity (primarily nausea and other symptoms not reported). Nademanee et. al.4 found that amiodarone 600 mg to 1,800 mg daily for at least two weeks significantly increased SDC in 20 patients. The increase in digoxin levels was apparent within one to two days of concomitant therapy. Gastrointestinal toxicity, central nervous system toxicity and cardiovascular reactions occurred in several patients. Similarly, Oetgen et. al.5 reported an increase in SDC in 22 patients with stable digoxin dosages and renal function when amiodarone was added to therapy. Amiodarone at doses of 400 mg to 1,400 mg daily caused a mean increase in SDC by 90% (ranges for pre- and post-amiodarone digoxin levels were 0.4 to 1.8 ng/ml and 1.0 to 3.6 ng/ml, respectively).
Two recent cases collected by the MGH Adverse Drug Reaction Reporting system highlight the importance of this drug interaction.
Case Report 1. A 76-year-old white female was admitted for worsening diarrhea, weakness, and decreased oral intake. She had known severe chronic obstructive pulmonary disease, coronary heart disease, and diabetes mellitus along with a significant weight loss from chronic Clostridium difficile colitis. Her hospital course was complex and multifactorial, but her primary problem was felt to be heart failure. She was treated with digoxin, ACE inhibitors, and diuretics. Her diarrhea was controlled with oral vancomycin. Prior to admission, her digoxin dose was 0.125 mg daily with a recent digoxin level of 1.1 ng/ml. She was started on amiodarone 400 mg PO bid for atrial fibrillation. Nine days later her serum digoxin level was noted to be 2.4 ng/ml. Her electrolytes and serum creatinine were within normal limits and glucose was 283 mg/dl. The next day the patient had a junctional bradyarrhythmia with a serum digoxin level of 2.7 ng/ml. Digoxin was held for 2 days until her level returned to less than 2 ng/ml and the junctional rhythm resolved. Her digoxin dose was adjusted and she had no further dysrrythmias.
Case report 2. An 87-year-old white male presented to the MGH ER with a one--week history of fatigue, weakness and a fall with loss of consciousness. In the ER, he had changes in mental status, heart rate in the 40’s (bpm), blood pressure 90-110/40-50 mm Hg. EKG showed atrial fibrillation with a slow ventricular response, alternating with a competing junctional pacemaker. Repeat EKG showed sinus bradycardia and first-degree AV block and a right bundle branch block. His labs showed serum creatinine 1 mg/dl, potassium 4.9 mEq/L, magnesium 2.2 mEq/L, calcium 8 mg/dl, CO2 30.1 mMol/L and blood sugar 254 mg/dl. Medications at home were metoprolol, digoxin, amiodarone, furosemide, ranitidine, warfarin, and aspirin. His digoxin level in the ER was determined to be 4.5 ng/ml. Past medical history included atrial fibrillation, congestive heart failure with an ejection fraction of 30-40%, coronary heart disease, Type 2 diabetes mellitus and recent pneumonia. He had been treated with digoxin 0.25 mg PO daily and was started on amiodarone 400 mg PO tid (loading dose) in the 2 months prior to admission with a taper to maintenance dose. Upon admission his treatment consisted of digoxin 0.25 mg PO daily, amiodarone 400 mg PO daily (maintenance dose), and metoprolol 25 mg PO bid. He was considered to be digoxin toxic and was treated with digoxin immune Fab (Digibind). Six days later his arrhythmias had resolved, digoxin level was 0.9 ng/ml and his CNS symptoms had resolved as well. He was eventually discharged.
These case reports demonstrate the well-documented drug interaction between digoxin and amiodarone and the need to monitor drug levels when given concomitantly. The mechanism of this interaction is complex and not known. It is felt to be a reduction in both renal and nonrenal clearances of digoxin. Another suggested mechanism is the displacement of digoxin from tissue-binding sites or the modification of its bioavailability by altering GI absorption. Amiodarone’s spasmolytic effect on the smooth muscle of the intestinal tract may prolong intestinal transit time, causing a more complete absorption of digoxin.4 Some investigators feel the magnitude of the interaction is dose-related and correlates with amiodarone plasma concentrations1, while others feel the SDC elevations do not seem to relate in any predictable way to the amiodarone dose given.3
When should you expect to see increases in SDC? Increases in SDC were evident within 24 hours and climbed linearly for 6 to 7 days (5 half-lives of digoxin), then reached plateau levels (steady state). The clinical manifestations of digoxin toxicity consist of nausea, anorexia, weakness, malaise, visual disturbances such as yellow halos, sinus bradycardia and sinus arrest 2,3,4.
It is clear that the clinical significance of this drug interaction deserves emphasis and diligence of monitoring SDC throughout combination therapy. Regular determinations of SDC with careful surveillance of clinical features of digoxin toxicity are indicated. We suggest halving the digoxin dose when starting amiodarone therapy. Remember, any adjustment in digoxin dose requires a period of 4 to 5 times the half-life (8-10 days) before new steady state conditions are achieved. To avoid false positive elevations, levels should be taken > 6-8 hours after last digoxin dose. If amiodarone is withdrawn from a regimen including digoxin, SDC decreases progressively over 2 weeks and should be monitored.
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