Drugs that increase serum digoxin concentrations
|Drug/condition||Pharmacodynamic interaction||Pharmacokinetic interaction|
|ACE inhibitors Angiotensin receptor blockers||They cause hyperkalaemia which reduces cardiac binding of digoxin and increase SDC.||Decrease renal excretion|
- Disopyramide, Quinidine
- Flecainide, Propafenone
- Amiodarone, Dronedarone
|Increase the risk of proarrhythmia. Some antiarrhythmics antagonize the inotropic effect of digoxin.
Dofetilide increases the risk of torsades de pointes.
The combination of digoxin and dronedarone increases the risk of sudden death
|Reduce both renal and non-renal excretion and Vd of digoxin
Amiodarone, Dronedarone and Quinidine increase SDC by reducing P-gp-mediated efflux of digoxin into the gut and kidneys, resulting in increased absorption and decreased elimination of digoxin. Amiodarone and propafenone reduce clearance of digoxin and increase SC (25–75%);
Reduce the dose of digoxin by 50% and closely monitor SDC Avoid the combination with dronedarone
- Aminoglycosides (Amikacin, Gentamycin, Kanamycin, Roxithromycin, Tobramycin)
- Macrolides (Azithromycin, Clarithromycin, Erythromycin, Roxithromycin, Telithromycin)
- Quinolones (Gemifloxacin, Levofloxacin)
- Sulfonamides: Sulfadiazine, Sulfisoxazole
- Aztreonam, Dapsone, Fosfomycin, Metronidazone, Nafcillin, Paromomycin, Trimethoprim, Vancomyn
|Itraconazole may also oppose the positive inotropic effects of digoxin.||Increase digoxin absorption by inactivating the Eubacterium lentum.
Trimethoprim decreases the renal excretion of digoxin.
|Decrease non-renal clearance|
|Atorvastatin||Decrease the Vd and the renal clearance of digoxin|
|Increase digoxin absorption by decreasing gut motility|
|May increase digoxin toxicity|
|Nonsteroidal anti-inflammatory agents (indomethacin), including COX-2 inhibitors||They increase serum potassium||NSAIDs reduce the renal clearance of digoxin.|
|Atazanavir||Increase the risk of AV block|
|β-blockers||β-blockers increase the risk of bradycardia and AV block . They also increase serum potassium||Carvedilol enhances GI absorption and decreases renal clerance|
|Decrease digoxin clearance|
|Calcium channel blockers
- Felodipine, Nicardipine, Nifedipine, Nitrendipine
|Decrease the Vd and renal clearance of digoxin|
|Increase the risk of bradycardia, and AV block||Verapamil inhibits P-gp and the active tubular secretion and non-renal clearance of digoxin|
|Calcium salts||Increase the risk of arrhythmias|
|Cyclosporine||Inhibits P-gp, decreases renal clearance of digoxin|
|- Antifungals: Itraconazole, Ketoconazole
- Antiretroviral treatment: Etravirine, Indinavir, Ritonavir, Saquinavir,
- Antihepatitis C: Boceprevir, Daclatasvir, Sofosbuvir/Velpatasvir, Simeprevir
- BCR-Abl tyrosine kinase inhibitors: Bosutinib, Nilotinib, Ponatinib
- Tyrosine kinase inhibitors: Lapatinib, Neratinib
- Vasopressin receptor antagonists : Conivaptan, Tolvaptan
|Inhibit P-gp, increase digoxin absorption and increase SDC|
- Loop diuretics
|Produce hypokalemia and potentiates the cardiac effects of digoxin. Increase the risk of arrhythmias||They may also reduce the renal tubular secretion of digoxin.|
|Prazosin||Decreases digoxin binding to plasma and tissue proteins|
|These diuretics and digoxin increase serum potassium levels||Decrease digoxin clearance|
|Proton pump inhibitors||Cause hypomagnesemia and increase the risk for digoxin toxicity||Increase the absorption and inhibit the metabolism and of digoxin.|
|Sympathomimetic agents||Can increase the risk of cardiac arrhythmias|
|Teriparide||Increase the risk of arrhythmias|
|Vitamin D and analogs (Paricalcitol)||Increase the risk of arrhythmias||Vitamin D analogues can also increase DSC|
- The increase in SDC increases the risk toxicity and the proarrhythmic effects of digoxin.
- Measure SDC when the dose of concomitant drugs is initiated, changed or discontinued.
- Reduce SDC by decreasing the starting and/or maintenance dose (30-50%) or by modifying the dosing frequency.
- Regular monitoring for signs and symptoms of digoxin toxicity, clinical response and ECG. Monitor SDC more frequently if renal function is impaired and in the elderly
* Patients should be monitored for hypokalemia and given potassium supplements when necessary.
Drugs that decrease serum digoxin concentrations
|Drug/condition||Pharmacodynamic interaction||Pharmacokinetic interaction|
|Aldosterone antagonists||May protect against digoxin-induced arrhythmias||Produce hyperkalemia|
- Carmustine, Cyclophosphamide, Cytarabine, Doxorubicin, Methotrexate, Vincristine
|Alter the intestinal epithelium. Decrease GI absorption|
|Inducers of drug metabolism*:
- Barbiturates, Phenytoin, Rifabutin, Rifampicin, St John’s wort
|Rifampicin and St John’s wort induce P-gp and thereby decrease SDC. Increase nonrenal clearance of digoxin|
- Activated charcoal
- Resins: Cholestyramine, Cholestipol
|Decrease digoxin absorption from the gastrointestinal tract|
|Drugs that produce hypokalemia**:
- Amphotericin B
- Selective β2-adrenergic agonists (albuterol, salbutamol, Terbutaline)
- Lithium salts
|They increase cardiac sensitivity to cardiac glycosides.
Corticosteroids cause sodium and water retention increasing the risk of digoxin toxicity and heart failure.
|Salbutamol increases SDC|
|Neuromuscular blocking drugs*:
- Atracuronium, Pacuronium, Suxamethonium
|Increase potassium efflux from the cardiac cell causing cardiac arrhythmias|
|Tizanidine||Excessive bradycardia and atrioventricular block|
|Topiramate||Reduces the bioavailability of digoxin|
- Hydralazine, Nitroprusside
|Increase renal clearance of digoxin|
- Increase the dose of digoxin. Monitor ECG and SDC.
- The interaction with resins can be prevented by separating the doses of digoxin and anion exchange resin by about 2 hours.
* Avoid concomitant use.
** Give potassium supplements when necessary
Factors predisposing to digoxin toxicity
|Condition||Pharmacodynamic interaction||Pharmacokinetic interaction||Clinical Implications|
Acute myocardial infarction
Increase in sympathetic tone
Severe respiratory disease
|Sensitizes the heart to the effects of cardiac glycosides. Increase the risk of cardiac arrhythmias||Hyperthyroidism: increases the Vd and renal elimination of digoxin resulting in lower SDC||Therapy with digoxin should be administered cautiously. Decrease the dose of digoxin and monitor SDC, serum electrolytes and renal function periodically during the treatment with digoxin.
During the treatment of thyrotoxicosis, digoxin dosage should be gradually reduced as thyroid function comes under control.
|Decrease the Vd and renal excretion of digoxin||Reduce the dose of digoxin|
|Decrease sensitivity to cardiac glycosides||Monitor SDC, serum potassium and ECG|
|Hypothyroidism||Decreases the Vd and plasma clearance of digoxin||Digoxin should be initiated at lower dosages monitoring SDC. Treatment of hypothyroidism may increase the dose requirements of digoxin.|
|Renal impairment||Increased risk for digoxin toxicity, including ventricular arrhythmias and AV conduction disturbances||Decreases digoxin excretion||Digoxin should be administered cautiously in patients with impaired renal function. Dosage increments should be made very gradually. Monitor SDC and ECG|
|Children||Children are especially sensitive.||Increase the Vd and renal clearance of digoxin||Decrease the dose of digoxin. Monitor SDC|
|Elderly||Increased risk of digoxin toxicity||Decreased renal function and low lean body mass leads||Reduce the dose|
- Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information.
- Patients with malabsorption syndrome or gastrointestinal reconstructions may require larger doses of digoxin.
- Digoxin should be withheld for 24 h before cardioversion and the lowest effective energy should be applied when attempting DC cardioversion. DC cardioversion is inappropriate in the treatment of digitalis-induced arrhythmias.
- Rapid IV digoxin can cause vasoconstriction and hypertension. Administer digoxin at a slow injection rate in hypertensive patients with HF and acute MI
- Avoid digoxin in patients with HF associated with beri-beri, cardiac amyloidosis, myocarditis or constrictive pericarditis
- Avoid digoxin in hypertrophic obstructive cardiomyopathy or constrictive pericarditis unless it is used to control the ventricular rate in AF or to improve systolic dysfunction.
AF: atrial fibrillation
COX2: Cyclooxygenase 2
DC: electrical. GI: gastrointestinal
HF: heart failure
MI: myocardial infarction
P-gp: glycoprotein P
Vd: volume of distribution