Digoxin

Drug interaction

Drugs that increase serum digoxin concentrations

Drug/conditionPharmacodynamic interactionPharmacokinetic interaction
ACE inhibitors Angiotensin receptor blockersThey cause hyperkalaemia which reduces cardiac binding of digoxin and increase SDC.Decrease renal excretion
Antiarrhythmics:
- Disopyramide, Quinidine
- Flecainide, Propafenone
- β-blockers
- 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
Antibiotics:
- Aminoglycosides (Amikacin, Gentamycin, Kanamycin, Roxithromycin, Tobramycin)
- Cephalosphorines
- Macrolides (Azithromycin, Clarithromycin, Erythromycin, Roxithromycin, Telithromycin)
- Tetracyclines
- 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.
Antimalarials:
- Choroquine
- Hydroxychloroquine
- Quinine
Decrease non-renal clearance
Atorvastatin Decrease the Vd and the renal clearance of digoxin
Anticholinergic drugs:
- Propantheline
- Diphenoxylate
Increase digoxin absorption by decreasing gut motility
Antidepressants:
- Nefazodone
- Trazodone
May increase digoxin toxicity
Nonsteroidal anti-inflammatory agents (indomethacin), including COX-2 inhibitorsThey increase serum potassiumNSAIDs reduce the renal clearance of digoxin.
Atazanavir Increase the risk of AV block
β-blockersβ-blockers increase the risk of bradycardia and AV block . They also increase serum potassiumCarvedilol enhances GI absorption and decreases renal clerance
Benzodiazepines:
- Alprazolam
- Diazepam
Decrease digoxin clearance
Calcium channel blockers
- Felodipine, Nicardipine, Nifedipine, Nitrendipine
Decrease the Vd and renal clearance of digoxin
- Diltiazem
- Verapamil
Increase the risk of bradycardia, and AV blockVerapamil inhibits P-gp and the active tubular secretion and non-renal clearance of digoxin
CanagliflozinUnknownUnknown
Calcium saltsIncrease 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
- Cobicistat
- Crizotinib
- Lomitapide
- Loratadine
- Tyrosine kinase inhibitors: Lapatinib, Neratinib
- Ranolazine
- Tacrolimus
- Ticagrelor
- Vasopressin receptor antagonists : Conivaptan, Tolvaptan
- Vemurafenib
Inhibit P-gp, increase digoxin absorption and increase SDC
Non-potassium-sparing diuretics - Azetazolamide
- Loop diuretics
- Thiazides
Produce hypokalemia and potentiates the cardiac effects of digoxin. Increase the risk of arrhythmiasThey may also reduce the renal tubular secretion of digoxin.
Prazosin Decreases digoxin binding to plasma and tissue proteins
Potassium-sparing diuretics
- Amiloride
- Spironolactone
- Triamterene
These diuretics and digoxin increase serum potassium levelsDecrease digoxin clearance
Proton pump inhibitorsCause hypomagnesemia and increase the risk for digoxin toxicityIncrease the absorption and inhibit the metabolism and of digoxin.
Sympathomimetic agentsCan increase the risk of cardiac arrhythmias
TeriparideIncrease the risk of arrhythmias
Vitamin D and analogs (Paricalcitol)Increase the risk of arrhythmiasVitamin D analogues can also increase DSC

Clinical implications

  • 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.

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Drugs that decrease serum digoxin concentrations

Drug/condition Pharmacodynamic interaction Pharmacokinetic interaction
Aldosterone antagonistsMay protect against digoxin-induced arrhythmiasProduce hyperkalemia
Anticancer drugs:
- Carmustine, Cyclophosphamide, Cytarabine, Doxorubicin, Methotrexate, Vincristine
Alter the intestinal epithelium. Decrease GI absorption
ClotrimazoleInduces P-gp
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
Gastrointestinal drugs:
- Antiacids
- Acarbose
- Activated charcoal
- Carbenoxolone
- Carbimazole
- Cimetidine
- Eribulin
- Kaolin-pectin
- Metoclopramide
- Neomycin
- Resins: Cholestyramine, Cholestipol
- Sulfacrate
- Sulfasalazine
Decrease digoxin absorption from the gastrointestinal tract
Drugs that produce hypokalemia**:
- Amphotericin B
- Selective β2-adrenergic agonists (albuterol, salbutamol, Terbutaline)
- Carbenoxolone
- Glucocorticoids
- Laxatives
- Insulin
- 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
TizanidineExcessive bradycardia and atrioventricular block
Topiramate Reduces the bioavailability of digoxin
Vasodilators:
- Hydralazine, Nitroprusside
Increase renal clearance of digoxin

Clinical implications

  • 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

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Factors predisposing to digoxin toxicity

ConditionPharmacodynamic interaction Pharmacokinetic interactionClinical Implications
Acute hypoxemia
Acute myocardial infarction
Cardiac amyloidosis
Hypercalcemia
Hyperthyroidism
Hypokalemia
Hypomagnesemia
Increase in sympathetic tone
Severe myocarditis
Severe respiratory disease
Sensitizes the heart to the effects of cardiac glycosides. Increase the risk of cardiac arrhythmiasHyperthyroidism: increases the Vd and renal elimination of digoxin resulting in lower SDCTherapy 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.
Hypothyroidism
Obesity
Decrease the Vd and renal excretion of digoxinReduce the dose of digoxin
Hypocalcemia
Hyperkalemia
Decrease sensitivity to cardiac glycosides Monitor SDC, serum potassium and ECG
HypothyroidismDecreases the Vd and plasma clearance of digoxinDigoxin should be initiated at lower dosages monitoring SDC. Treatment of hypothyroidism may increase the dose requirements of digoxin.
Renal impairmentIncreased risk for digoxin toxicity, including ventricular arrhythmias and AV conduction disturbancesDecreases digoxin excretionDigoxin should be administered cautiously in patients with impaired renal function. Dosage increments should be made very gradually. Monitor SDC and ECG
ChildrenChildren are especially sensitive.Increase the Vd and renal clearance of digoxinDecrease the dose of digoxin. Monitor SDC
Elderly Increased risk of digoxin toxicityDecreased renal function and low lean body mass leadsReduce the dose

Cautions/notes

  • 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.

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Abbreviations

AF: atrial fibrillation
COX2:  Cyclooxygenase 2
DC: electrical. GI: gastrointestinal
HF: heart failure
IV: intravenous
MI: myocardial infarction
P-gp: glycoprotein P
Vd: volume of distribution