What are the potential drug interactions with digoxin?

Digoxin Drug Interactions

Digoxin has numerous clinically significant drug interactions primarily through P-glycoprotein inhibition and renal excretion pathways, with the most critical interactions being amiodarone (requiring 30-50% dose reduction), verapamil (requiring dose reduction), quinidine, clarithromycin, erythromycin, itraconazole, cyclosporine, and propafenone—all of which can substantially increase digoxin levels and precipitate life-threatening toxicity. 1, 2

Major Drug Interactions Requiring Dose Adjustment

Antiarrhythmic Agents

• Amiodarone causes predictable doubling of digoxin levels through P-glycoprotein inhibition and requires a 30-50% reduction in digoxin dose when coadministered 1, 3
• The peak effects of amiodarone-digoxin interaction occur approximately 7 weeks after initiation due to amiodarone's long half-life 1
• Dronedarone requires at least a 50% reduction in digoxin dose 1, 3
• Quinidine markedly increases steady-state serum digoxin levels and is contraindicated in some contexts due to severe interaction 1, 2, 4
• Propafenone and flecainide require close monitoring of digoxin levels when coadministered 1, 3, 2

Calcium Channel Blockers

• Verapamil increases digoxin levels by 50-180% depending on formulation and timing, with the greatest effect when immediate-release verapamil is given 1 hour before digoxin 1, 2
• The interaction becomes negligible if verapamil is taken 2 hours after digoxin when absorption is complete 1
• Verapamil is contraindicated with dofetilide and inhibits both P-glycoprotein and CYP3A4 1
• Diltiazem also increases digoxin levels through P-glycoprotein inhibition, though less dramatically than verapamil 1, 2

Macrolide Antibiotics

• Clarithromycin increases digoxin AUC and Cmax by approximately 19% and 15% respectively through P-glycoprotein inhibition 1, 2
• Erythromycin significantly increases digoxin levels and requires close monitoring 1, 3, 2
• In selected patients, antibiotics may paradoxically enhance digoxin bioavailability by eliminating intestinal flora that metabolize digoxin 2, 4

Antifungal Agents

• Itraconazole, posaconazole, and voriconazole all increase digoxin levels through P-glycoprotein inhibition and require monitoring 1, 3, 2
• Ketoconazole is contraindicated with digoxin due to marked increases in drug exposure 1

Drugs That Decrease Digoxin Levels

Gastrointestinal Absorption Inhibitors

• Antacids, kaolin-pectin, cholestyramine, neomycin, and sulfasalazine interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations 2, 4
• Sucralfate and acarbose can reduce digoxin plasma concentrations through decreased gastrointestinal absorption 5

Enzyme Inducers

• Rifampin may lower steady-state serum digoxin levels, particularly in patients with severe renal disease, by increasing non-renal clearance 2, 5, 4
• St. John's wort significantly decreases digoxin exposure through P-glycoprotein induction and should be avoided 1

Drugs That Potentiate Digoxin Toxicity Without Altering Levels

Electrolyte-Depleting Agents

• Potassium-depleting diuretics are a major contributing factor to digitalis toxicity, particularly when administered rapidly by IV route 2, 5
• Hypokalemia and hypomagnesemia potentiate digoxin's cardiac effects even at therapeutic serum levels 1, 3, 6

Cardiac Conduction Agents

• Beta-blockers and other drugs with SA/AV nodal-blocking properties can cause advanced or complete heart block when combined with digoxin 1, 2, 6
• Concurrent use should be approached cautiously, especially in patients without a pacemaker 1

Other Interactions

• Calcium administration, particularly IV, may produce serious arrhythmias in digitalized patients 2
• Sympathomimetics may cause sudden extrusion of potassium from muscle cells, causing arrhythmias in digitalized patients 2
• Succinylcholine increases the risk of cardiac arrhythmias when used with digoxin 2

Special Populations and Risk Factors

Renal Dysfunction

• Drugs causing renal impairment (NSAIDs, ACE inhibitors, angiotensin II receptor antagonists, cyclosporine) can precipitate digoxin toxicity by reducing renal clearance 2, 5, 7
• Elderly patients with impaired renal function are at greatest risk for elevated digoxin levels and toxicity 1, 7

Other High-Risk Scenarios

• Low lean body mass and advanced age (>70 years) increase risk of toxicity and warrant lower maintenance doses (0.125 mg daily or every other day) 1, 3, 6
• Hypothyroidism increases sensitivity to digoxin, while thyroid hormone administration to a digitalized hypothyroid patient may increase digoxin dose requirements 1, 3, 2

Clinical Monitoring Recommendations

• Serum digoxin levels should be monitored when initiating or discontinuing interacting medications 1, 2
• Target therapeutic range is 0.5-0.9 ng/mL for heart failure, with toxicity commonly occurring at levels >2 ng/mL 1, 3, 6
• Serum electrolytes (particularly potassium and magnesium) and renal function should be assessed periodically 2, 5
• Clinical monitoring for bradycardia, gastrointestinal symptoms, and neurological changes is essential, as toxicity can occur even at therapeutic levels in the presence of risk factors 3, 5, 7

Critical Pitfalls to Avoid

• Never assume digoxin levels alone are sufficient for monitoring—clinical context including renal function, electrolytes, and concurrent medications is essential 5, 7
• Loading doses should be avoided in elderly patients or those with renal impairment to minimize toxicity risk 3, 7
• When amiodarone is added to digoxin therapy, reduce digoxin dose immediately by 30-50% rather than waiting for toxicity to develop 1, 6
• Spironolactone does not inhibit digoxin disposition despite earlier concerns about cross-reactivity in assays 1