AHFS Class:

• Cardiotonic Agents 24:04.08

Generic Name(s):

• Digoxin

Digoxin is a cardiac glycoside with positive inotropic and antiarrhythmic effects.398,700,701

Digoxin is a cardiac glycoside that is used principally in the management of heart failure and atrial fibrillation.398,700,701 Cardiac glycosides are a class of drugs that increase force and velocity of myocardial systolic contraction (positive inotropic action) and also decrease conduction velocity through the atrioventricular (AV) node.398 Although several cardiac glycoside preparations were previously available for medicinal use (see Chemistry and Stability: Chemistry), digoxin is currently the only commercially available cardiac glycoside in the US.401

Heart Failure

Digoxin is used in conjunction with other agents in the management of mild to moderate (New York Heart Association [NYHA] class II-III) heart failure associated with left ventricular systolic dysfunction.398,400,402,403,524 Although digoxin has been used extensively in the management of heart failure,12,395,399,401 current use is generally limited because of the lack of demonstrated survival benefit, potential for serious adverse effects, and availability of other drugs that have been shown to substantially reduce morbidity and mortality.395,398,399,401,524

Current guidelines for the management of heart failure in adults generally recommend inhibition of the renin-angiotensin-aldosterone system with a combination of drug therapies, including neurohormonal antagonists (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-adrenergic blocking agents [β-blockers], aldosterone receptor antagonists) to inhibit the detrimental compensatory mechanisms in heart failure and reduce morbidity and mortality.524,703,800,801 (See Uses: Heart Failure, in Enalaprilat/Enalapril 24:32.04 and in Sacubitril and Valsartan 24:32.92.) Additional agents (e.g., digoxin, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement of heart failure and/or reduction in heart failure-related hospitalizations.524,800 Experts state that digoxin therapy may be initiated in severely symptomatic patients with heart failure and reduced left ventricular ejection fraction who have started, but not yet responded to, an ACE inhibitor or a β-blocker.524 Alternatively, digoxin may be withheld until the patient's symptomatic response to the ACE inhibitor or β-blocker has been defined524 and then used only in those patients who remain symptomatic while receiving ACE inhibitor or β-blocker therapy.524 In patients with heart failure who are receiving digoxin without an ACE inhibitor or β-blocker, digoxin should not be withdrawn, but appropriate therapy with an ACE inhibitor and/or a β-blocker should be added.524 The beneficial effects of digoxin have been shown to be additive with those of ACE inhibitors and/or diuretics; symptomatic and functional deterioration can occur when digoxin is withdrawn from patients whose heart failure was stabilized on a regimen of combined therapy.384,388,389,390,391

In patients with heart failure, digoxin may alleviate symptoms and decrease heart failure-related hospitalizations.524 Although data demonstrating an overall survival benefit of digoxin are lacking, a large, controlled study (the Digitalis Investigation Group [DIG] study) showed reductions in hospitalization rates, both overall and for worsening heart failure, as well as a reduction in the combined incidence of death from worsening heart failure and hospitalization for such worsening, when digoxin was added to a regimen of ACE inhibitors and/or diuretics in patients with normal sinus rhythm and chronic left ventricular heart failure (principally mild to moderate).384,386,524 The decision to use digoxin in patients with symptomatic heart failure caused by systolic left ventricular dysfunction should be based not on an anticipated improvement in survival but on potential benefits of less deterioration of the condition and associated improvement in hospitalization rates as well as of improved symptomatic and functional status.384,386,388,389,390,391,392,524

Digoxin increases left ventricular ejection fraction and improves symptoms of heart failure (as evidenced by exercise capacity, heart failure-related hospitalizations and emergency care), while having no apparent effect on overall mortality.384,386,387,390,391,392,398,524 The acute and sustained hemodynamic efficacy of digoxin is well established, at least in patients with symptomatic heart failure caused by predominant systolic ventricular dysfunction.384,386,387,388,389,390,392,524 Digoxin is less effective in the management of high-output heart failure caused by bronchopulmonary insufficiency, infection, hyperthyroidism, anemia, fever, arteriovenous fistula, thiamine deficiency, Paget's disease, cor pulmonale, acute glomerulonephritis, or toxic or infectious myocarditis (e.g., diphtheria, acute rheumatic fever). Heart failure resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, AV shunt) is best treated by addressing the underlying condition rather than by using digoxin.398 In addition, digoxin is of limited value in the management of heart failure caused by mechanical disturbances such as constrictive pericarditis, pericardial tamponade, mitral stenosis with normal sinus rhythm, and pure valvular aortic stenosis. Patients with idiopathic hypertrophic subaortic stenosis receiving digoxin may have a worsening of outflow obstruction as a result of the inotropic effects of the drug.398

Supraventricular Tachyarrhythmias

Atrial Fibrillation

Digoxin is used for controlling rapid ventricular rate in patients with chronic atrial fibrillation; however, the drug is not considered first-line therapy for this use, in part because of its slow onset of action.12,25,28,71,386,398,400,402,403,701 In addition, concerns have been raised regarding possible increased mortality in patients with atrial fibrillation receiving digoxin, particularly when used for long-term therapy.395 In the AFFIRM (AF Follow-up Investigation of Rhythm Management) study, use of digoxin was associated with a 41% increase in mortality in patients with atrial fibrillation;395 however, additional post-hoc analyses have reported conflicting results.396,397

Experts recommend the use of β-blockers or nondihydropyridine calcium-channel blocking agents (e.g., diltiazem, verapamil) as the preferred drugs for ventricular rate control in patients with atrial fibrillation.701 Digoxin may be used in combination with one of these agents to improve heart rate control during exercise and also may be useful in patients with concomitant heart failure.701 (See Uses: Heart Failure.) Choice of therapy should be individualized based on the clinical situation and patient-related factors.701 Digoxin should not be used in patients with preexcited atrial fibrillation because the drug may increase ventricular response and result in ventricular fibrillation.700,701

Other Supraventricular Tachycardias

Digoxin also is used in the management of paroxysmal supraventricular tachycardia (PSVT) due to AV nodal reentry tachycardia (AVNRT) or AV reentry tachycardia (AVRT)†.700 Some experts state that oral digoxin may be reasonable for ongoing management of PSVT in patients who are not candidates for, or prefer not to undergo, catheter ablation.700 Because of the potential for adverse effects, digoxin generally is reserved as a third-line agent for patients who are not responsive to, or are not candidates for, the preferred therapies (e.g., β-blockers, nondihydropyridine calcium-channel blocking agents, flecainide, propafenone).700 If acute treatment of PSVT is necessary, however, measures to increase vagal tone (such as carotid sinus massage and Valsalva maneuver) or administration of adenosine are the treatments of choice.700

Digoxin has been used in the management of regular supraventricular (reciprocating) tachycardia associated with Wolff-Parkinson-White (WPW) syndrome†, but the drug may be potentially harmful if used in patients with WPW syndrome and preexcited atrial fibrillation because acceleration of the ventricular rate may occur.701 Digoxin should therefore not be administered to patients with WPW syndrome and preexcited atrial fibrillation.701 The preferred treatment of choice in hemodynamically compromised patients with WPW syndrome usually is prompt direct-current cardioversion.701

Myocardial Infarction

Use of digoxin in acute myocardial infarction (MI) is controversial.12,386,387,388,389,390 (See Cautions: Precautions and Contraindications.) Because the drug can increase myocardial oxygen demand and exacerbate ongoing ischemia, it is generally not recommended during acute MI.398 However, digoxin may be used in selected patients with left ventricular systolic dysfunction after acute MI.398,524 (See Uses: Heart Failure.)

Administration

Digoxin usually is administered orally.398,402,403 When oral therapy is not feasible or when rapid therapeutic effect is necessary, the drug may be administered parenterally.400 Although digoxin may be given IM or IV, the IV route of administration is preferred because IM injection can cause severe local irritation and pain at the site of injection.98,400 If the drug must be administered by the IM route, injections should be made deep into the muscle followed by massage of the injection site, and no more than 2 mL of the drug should be injected at a single site.400

Oral Administration

Digoxin is administered orally as tablets or oral solution.398,402,403 The manufacturers recommend once-daily dosing in adults and children older than 10 years of a divided daily dosing is recommended in infants and children younger than 10 years of age.398,402,403

The manufacturer recommends that the oral solution be used to obtain the appropriate dose in infants, young children, or patients with very low body weights.398,402 The calibrated dosing syringe supplied by the manufacturer should be used to measure doses of the oral digoxin solution; a separate measuring device should be used to accurately measure doses less than 0.1 mL.402

IV Administration

For IV administration, digoxin injection may be given undiluted or may be diluted with a fourfold or greater volume of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection; use of less than a fourfold volume of diluent may cause precipitation of the drug.400 Diluted IV solutions of digoxin should be used immediately.400

Digoxin should be administered by slow IV infusion (over at least 5 minutes); rapid IV (i.e., bolus) administration may cause systemic and coronary vasoconstriction and should be avoided.400

Mixing of digoxin injection with other drugs in the same container or simultaneous administration in the same IV line is not recommended.400

Dosage

General Considerations

Digoxin has a narrow therapeutic index; therefore, cautious dosage determination is essential and dosage must be carefully individualized based on clinical assessment and therapeutic drug monitoring.398,400,402,403 Dosage guidelines provided are based upon average patient response and substantial patient variation can be expected.398,400,402,403 When selecting an appropriate dosage, the patient's renal function, body weight, age, concomitant disease states, concurrent drugs, and other factors likely to alter serum concentrations of digoxin should be considered.398,399,400,402,403 Because the drug is largely distributed into tissues, lean body weight should be used for dosage calculations.399 Serum digoxin concentrations can be used to guide dosing, but should always be interpreted in the overall clinical context.400

Digoxin dosage may be initiated with or without a loading dose depending on whether rapid titration or a more gradual titration is desired; the different approaches vary in dosage and frequency of administration but achieve the same total amount of digoxin accumulated in the body.398,400,402,403 Loading doses may be used to reach adequate and effective drug concentrations for control of ventricular response in patients with atrial fibrillation.399 However, in patients with heart failure, experts state there is no reason to use loading doses and maintenance dosing can be initiated immediately.399,524

Loading doses of digoxin are administered in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose and additional fractions (usually 25%) usually administered every 6-8 hours with careful assessment of the patient's clinical response (including possible toxicity) before each additional dose.398,400,402,403 If a change from the calculated loading dose is required, then the maintenance dosage should be calculated based upon the amount (i.e., total loading dose) actually administered.402

More gradual attainment of digoxin concentrations can be achieved by initiating therapy with a maintenance dosage without a loading dose.402 Steady-state serum digoxin concentrations will be achieved in about 5 half-lives of the drug for the individual patient; depending on the patient's renal function, this may take approximately 1-3 weeks.402

Differences in the bioavailability of parenteral and oral preparations of digoxin should be considered when patients are switched from one dosage form to another. 398,400,402,403 Because the absolute bioavailability of digoxin tablets and solution are similar, equivalent dosages may be used.402 (See Pharmacokinetics: Absorption.) When switching from oral to IV therapy, dosage of digoxin should be reduced by about 20-25%.402

Since daily maintenance digoxin dosage is a replacement of daily digoxin loss from the body, an alternative dosing method has been used where the maintenance dosage for a particular patient is estimated by multiplying the daily percentage loss (see Pharmacokinetics: Elimination) by the peak body stores (i.e., loading dose) that produced a satisfactory response.398,400,403 The percentage of digoxin eliminated from the body daily can be estimated by the following equation:398,400,403

daily % loss = 14 + (creatinine clearance [in mL/minute] / 5)

Heart Failure in Adults

Loading doses are generally not required in patients with heart failure.399,524 If a loading dose is to be given, the manufacturers recommend an oral loading dose of 10-15 mcg/kg or an IV loading dose of 8-12 mcg/kg in adults, administered in divided doses.398,400,402,403 (See General Considerations under Dosage and Administration: Dosage.)

Experts state that digoxin is commonly initiated and maintained at a dosage of 125-250 mcg (0.125-0.25 mg) daily for the management of heart failure in adults.524 The manufacturers recommend an initial oral digoxin maintenance dosage of 3.4-5.1 mcg/kg once daily as tablets or 3-4.5 mcg/kg once daily as the oral solution in adults with normal renal function; dosage may be increased every 2 weeks according to clinical response, serum digoxin concentrations, and toxicity.398,402,403 If IV administration is necessary, the manufacturer recommends an initial IV maintenance dosage of 2.4-3.6 mcg/kg once daily in adults with normal renal function; dosage may be increased every 2 weeks according to clinical response, serum digoxin concentrations, and toxicity.400 The manufacturer's prescribing information should be consulted for recommended maintenance oral and IV dosages based on renal function.398,400,402,403

Atrial Fibrillation in Adults

If a loading dose is to be given for rate control in patients with atrial fibrillation, the manufacturers recommend an oral loading dose of 10-15 mcg/kg or an IV loading dose of 8-12 mcg/kg in adults, administered in divided doses.398,400,402,403 (See General Considerations under Dosage and Administration: Dosage.) Some experts recommend an initial IV dose of 250 mcg (0.25 mg) with repeat dosing to a maximum of 1500 mcg (1.5 mg) over 24 hours.701 These experts state that the usual oral maintenance dosage of digoxin for ventricular rate control in adults with atrial fibrillation is 125-250 mcg (0.125-0.25 mg) daily.701

Heart Failure in Pediatric Patients

Dosage should be carefully titrated in neonates, especially in premature infants, because renal clearance of digoxin is reduced in such patients.398,402,403 Infants and young children (up to 10 years of age) generally require proportionally larger doses than children older than 10 years of age and adults when calculated on the basis of lean body weight or body surface area.402 Children older than 10 years of age require adult dosages in proportion to the child's body weight.402

Loading doses and maintenance dosages recommended by the manufacturers for the treatment of heart failure in pediatric patients are given in the tables that follow based on the dosage form administered.398,400,402,403 (See General Considerations under Dosage and Administration: Dosage.)

Geriatric Dosage

Dosage of digoxin should be selected carefully in geriatric patients since they are more likely to have impaired renal function.398,399,400,402,403,524 (See Dosage in Renal Impairment under Dosage and Administration: Dosage.) Lower dosages (125 mcg [0.125 mg] daily or every other day) are recommended for the management of heart failure in geriatric patients older than 70 years of age.399,524

Dosage in Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment; however, serum digoxin concentrations may be used to guide dosing in such patients.398,400,402,403

Dosage in Renal Impairment

Renal function should be considered during dosage selection.398,400,402,403 Digoxin is principally excreted by the kidneys and impaired renal function may predispose patients to digoxin toxicity.398,400,402,403 Dosage should be reduced and titrated carefully in patients with renal impairment based on clinical response and serum digoxin concentrations as appropriate.398,400,402,403

In addition to toxicity (see Acute Toxicity and also see Chronic Toxicity), other adverse effects may occur in patients receiving digoxin.

Adverse Effects

GI effects, including nausea, vomiting, abdominal pain, and intestinal ischemia and hemorrhagic necrosis, have occurred in patients receiving digoxin.398 CNS effects associated with digoxin include headache, weakness, dizziness, apathy, confusion, and mental disturbances (e.g., anxiety, depression, delirium, hallucinations).398

Estrogen-like effects may occur with chronic administration of cardiac glycosides, especially in geriatric men and women whose endogenous concentrations of sex hormones are low. Cardiac glycosides increase plasma estrogen and decrease serum luteinizing hormone in men and postmenopausal women and decrease plasma testosterone in men. Gynecomastia and enlargement of the mammary glands in women have been reported after chronic therapy with digoxin and were reversible when the drug was withdrawn. Digoxin also may produce vaginal cornification in postmenopausal women and result in the incorrect diagnosis of endometrial carcinoma. The estrogen-like effects of cardiac glycosides also cause reduced excretion of pituitary gonadotropin in postmenopausal women. Digoxin may cause an increase in urinary 17-hydroxycorticosteroids.

Hypersensitivity reactions to cardiac glycosides are rare but may occur, usually within 6-10 days after initiating therapy. Skin reactions may be erythematous, scarlatiniform, papular, vesicular, or bullous. Rashes usually are accompanied by eosinophilia; eosinophilia also may occur without skin reactions. Urticaria; fever; pruritus; facial, angioneurotic, or laryngeal edema; alopecia of the scalp; shedding of finger and toe nails; and desquamation have been reported. Rarely, thrombocytopenic purpura has been reported to occur during administration of cardiac glycosides.

Precautions and Contraindications

The possibility that use of digoxin in patients with acute myocardial infarction (MI) may increase oxygen demand and associated ischemia should be considered.398 Patients with idiopathic hypertrophic subaortic stenosis may experience worsening of their condition because of the inotropic effects of digoxin.398 Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction (e.g., restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale) may experience decreased cardiac output with digoxin.398 Digoxin should not be administered to patients with substantial sinus or atrioventricular (AV) block, unless the conduction block has been addressed with a permanent pacemaker.524,700 Digoxin should be used cautiously with other drugs that can depress sinus or AV nodal function.524

Digoxin should be used with caution in patients with Wolff-Parkinson-White (WPW) syndrome and atrial fibrillation since the drug may enhance conduction via the accessory pathway and result in extremely rapid ventricular rates and ventricular fibrillation.398,700 (See Other Supraventricular Tachycardias under Uses: Supraventricular Tachyarrhythmias.) Carotid sinus massage has caused ventricular fibrillation in patients receiving cardiac glycosides.109

Since digoxin can induce ventricular arrhythmias, it is recommended that dosage of the drug be reduced or therapy discontinued for 1-2 days before elective cardioversion in patients with atrial fibrillation; however, clinicians should consider the consequences of increasing the ventricular response if digoxin is decreased or withdrawn.398 Elective cardioversion should be postponed in patients with signs and symptoms of cardiac glycoside toxicity.398 If it is not possible to delay cardioversion, the lowest possible energy level should be used to avoid provoking ventricular arrhythmias.398

Digoxin is contraindicated in patients with ventricular fibrillation.398

Digoxin is contraindicated in patients who have demonstrated hypersensitivity to the drug or to other forms of digitalis.398,400,402,403

Pediatric Precautions

Safety and efficacy of digoxin in controlling ventricular rate have not been established in pediatric patients with atrial fibrillation.398,400

The manufacturer states that safety and efficacy of digoxin in pediatric patients with heart failure have not been established in adequate and well-controlled studies; however, improvements in hemodynamics and clinical manifestations have been reported in pediatric patients with heart failure of various etiologies in the published literature.398,400

Neonates exhibit considerable variability in their tolerance to digoxin.398,400 Premature and immature infants are particularly sensitive to the drug, and dosage must be reduced and individualized according to maturity.398,400 The adverse effect profile of digoxin differs in infants and children, particularly in regard to initial signs of toxicity.398,400 Cardiac arrhythmias, including sinus bradycardia, usually occur earliest and most frequently.398,400 In children, any arrhythmia can occur.398,400 Therefore, any arrhythmia or alteration in cardiac conduction in a child should be considered a sign of toxicity.398,400

Pregnancy and Lactation

Pregnancy

Available data from retrospective clinical studies and case reports have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal and fetal effects with digoxin.400 However, the underlying maternal condition (e.g., heart failure, atrial fibrillation) may increase the risk of adverse pregnancy outcomes during digoxin therapy.400 Animal reproduction studies have not been conducted with the drug.400

Dosage requirements for digoxin may increase during pregnancy and decrease during the postpartum period; serum digoxin concentrations should be monitored.400

Because digoxin crosses the placenta and is found in amniotic fluid, neonates should be monitored for signs and symptoms of digoxin toxicity (e.g., vomiting, cardiac arrhythmias).400

Lactation

Although digoxin is distributed into milk, the quantities present are unlikely to be clinically important.400 The effects of digoxin on the breast-fed infant or on milk production are not known.400

Because digoxin has a narrow therapeutic window, increased monitoring of serum digoxin concentrations and for possible clinical manifestations of digoxin toxicity is necessary when initiating, adjusting, or discontinuing therapy with any drugs that may interact with digoxin.398,400 Clinicians should also consult the prescribing information for any drugs that are concurrently administered with digoxin for potential drug interaction information.398,400

Concomitant use of certain drugs may increase serum concentrations of digoxin by interfering with absorption of the cardiac glycoside via P-glycoprotein (P-gp) interaction or other mechanisms.398,399 Drugs that have been shown to increase serum digoxin concentrations by more than 50% include amiodarone, captopril, clarithromycin, dronedarone, gentamicin, erythromycin, itraconazole, lapatinib, propafenone, quinidine, ranolazine, ritonavir, tetracycline, and verapamil.398 Serum digoxin concentrations should be measured prior to initiating these drugs and dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency and continuing monitoring.398

Drugs that have been shown to increase digoxin concentrations by less than 50% include atorvastatin, carvedilol, conivaptan, diltiazem, indomethacin, mirabegron, nefazodone, nifedipine, propantheline, quinine, rabeprazole, saquinavir, spironolactone, telmisartan, ticagrelor, tolvaptan, and trimethoprim.398 Serum digoxin concentrations should be measured prior to initiating these drugs and dosage of digoxin should be adjusted by either decreasing the dose by approximately 15-30% or modifying the dosing frequency and continuing monitoring.398

Drugs that have been shown to increase serum digoxin concentrations with unclear magnitude include alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, and omeprazole.398 Serum digoxin concentrations should be measured prior to initiating these drugs; monitoring should be continued and dosage of digoxin should be reduced as necessary.398

Drugs or therapies that have been shown to decrease serum digoxin concentrations include acarbose, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, exenatide, kaolin-pectin, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's wort ( Hypericum perforatum ), sucralfate, and sulfasalazine.398 Serum digoxin concentrations should be measured prior to initiating these drugs or therapies; monitoring should be continued and dosage of digoxin should be increased by approximately 20-40% as necessary.398

Drugs Affecting P-glycoprotein Transport

Digoxin is a substrate of the P-gp transport protein at the level of intestinal absorption, renal tubular secretion, and biliary-intestinal secretion.381,398,399 Clinically important interactions may occur when digoxin is used concomitantly with drugs that induce (e.g., rifampin, neomycin, penicillamine) or inhibit (e.g., amiodarone, dronedarone, verapamil, propafenone, quinidine, cyclosporine, atorvastatin, simvastatin, darunavir, saquinavir, ritonavir) P-gp.381,398,399

Drugs Affecting GI Absorption of Digoxin

A number of drugs are capable of binding digoxin and/or inhibiting the absorption of the cardiac glycoside from the GI tract, which may result in low serum concentrations of the glycoside.

Single-dose studies indicate that aluminum hydroxide, magnesium hydroxide, magnesium trisilicate, kaolin-pectin, aminosalicylic acid, metoclopramide, and sulfasalazine reduce GI absorption of digoxin (resulting in low serum digoxin concentrations), especially when these drugs are administered at the same time as digoxin; therefore, doses of these drugs should be spaced as far apart as possible from doses of digoxin.

Orally administered neomycin may cause malabsorption of digoxin, which may result in low serum digoxin concentrations, but administration of neomycin to digitalized patients apparently does not affect the terminal half-life of digoxin.112

Macrolide antibiotics (e.g., clarithromycin, erythromycin) may increase oral bioavailability of digoxin by altering the GI flora that metabolize digoxin, possibly resulting in increased serum concentrations of digoxin and risk of digoxin toxicity.380,524 (See Drug Interactions: Anti-infective Agents.)

GI absorption of oral digoxin tablets may be substantially reduced in patients receiving radiation therapy,300,398 certain antineoplastic agents,398 or various combination chemotherapy regimens,301 possibly as a result of temporary damage to intestinal mucosa caused by the radiation or cytotoxic agents.300,301,309 Colestipol and cholestyramine may bind digoxin in the GI tract and impair its absorption (resulting in low serum digoxin concentrations), particularly if the glycoside and colestipol or cholestyramine are administered simultaneously or close together. Digoxin should be given at least 1.5-2 hours before cholestyramine or colestipol. Drugs that alter GI transit time and/or motility of the GI tract, such as antimuscarinics and diphenoxylate, may alter the rate of absorption of digoxin. Patients receiving an antimuscarinic and digoxin should be closely observed for signs of digitalis toxicity.

Drugs Affecting Electrolyte Balance

In patients receiving digoxin, electrolyte disturbances produced by diuretics such as ethacrynic acid, furosemide, and thiazides (primarily hypokalemia but also hypomagnesemia and, with the thiazides, hypercalcemia) predispose the patient to digoxin toxicity. Fatal cardiac arrhythmias may result. Periodic electrolyte determinations must be performed in patients concurrently receiving digoxin and a diuretic, and corrective measures undertaken if warranted. Other drugs that deplete body potassium (e.g., amphotericin B, corticosteroids, corticotropin, edetate disodium, laxatives, sodium polystyrene sulfonate) or that reduce extracellular potassium (e.g., glucagon, large doses of dextrose, dextrose-insulin infusions) also may predispose digitalized patients to toxicity.

Drugs Affecting Renal Function

Drugs that affect renal function (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]) may impair elimination of digoxin, and thus predispose patients to digoxin toxicity.398

Calcium Salts

The inotropic and toxic effects of digoxin and calcium are synergistic and arrhythmias may occur if these drugs are given together (particularly when calcium is administered rapidly IV).398 IV administration of calcium should be avoided in patients receiving digoxin; if necessary, calcium should be given slowly in small amounts.

Antiarrhythmic Agents

Although quinidine, procainamide, disopyramide, phenytoin, propranolol, and lidocaine have been used effectively in conjunction with digoxin to treat arrhythmias and also alone to treat cardiac glycoside-induced arrhythmias, these antiarrhythmic agents may have negative inotropic effects with larger than usual doses, especially in patients with cardiac glycoside toxicity (propranolol has negative inotropic effects with usual doses).28

Amiodarone

Concomitant administration of digoxin and amiodarone may result in increased serum digoxin concentrations and subsequent digoxin toxicity. Serum digoxin concentrations generally increase by an average of 70-100% in adults, but substantial variability exists in the magnitude of the increase. Limited data suggest that the magnitude of the increase may be much greater in children than in adults (i.e., 70-800%).

The amiodarone-induced increase in serum digoxin concentrations usually begins within 1-7 days and progresses gradually over a period of several weeks or even months. The exact mechanism(s) of this interaction appears to be complex and remains to be fully established, but data indicate that amiodarone may decrease the renal and/or nonrenal clearance of digoxin. It also has been suggested that amiodarone may increase the oral bioavailability of digoxin or displace digoxin from tissue binding sites. When initiating amiodarone therapy in patients receiving digoxin, the need for continued digoxin therapy should be reassessed, and digoxin discontinued if appropriate; if concomitant therapy is considered necessary, serum digoxin concentrations should be measured prior to initiating amiodarone and dosage of digoxin adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398 Patients should be observed closely for signs of cardiac glycoside toxicity. In addition, thyroid function should be monitored carefully in patients receiving concurrent amiodarone and digoxin therapy, since amiodarone-induced changes in thyroid function may increase or decrease serum digoxin concentrations or alter sensitivity to the therapeutic and toxic effects of the cardiac glycoside.

Dofetilide

Concomitant use of dofetilide and digoxin was associated with an increased risk of torsades de pointes.398 Dosage of digoxin should be individualized when used concomitantly with dofetilide.398

Dronedarone

Concomitant use of digoxin and dronedarone (a P-gp inhibitor) may result in a substantial increase (150%) in systemic exposure to digoxin; possible digoxin toxicity may occur.398 In clinical studies, baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in patients receiving dronedarone.398,405 Because digoxin can potentiate the electrophysiologic effects of dronedarone and dronedarone can increase exposure to digoxin, concomitant use of these drugs is not recommended.405 If concomitant use of dronedarone is necessary in a patient receiving digoxin, serum digoxin concentrations should be determined prior to initiating dronedarone and dosage of digoxin should be reduced by decreasing the dose by approximately 30-50% or modifying the dosing frequency.398,399,405

Flecainide

Studies in healthy individuals indicate that serum digoxin concentrations may be increased by an average of about 15-25% when flecainide and digoxin are administered concomitantly.304,305,306,307,308 The increase in serum digoxin concentration may occur within a few days of initiating flecainide therapy in patients receiving digoxin305,306 and may result from a decrease in the volume of distribution of digoxin.304 Although the PR interval was substantially prolonged in most healthy individuals during concomitant administration of flecainide and digoxin, it was not determined whether this resulted from an additive effect of the drugs or mainly from flecainide.305,306 Flecainide has been administered concomitantly with cardiac glycosides in patients with ventricular arrhythmias without unusual adverse effects.307 Additional studies to determine the potential importance of an interaction in patients with heart failure are needed.305,306 Flecainide-induced increases in serum digoxin concentration generally appear to be of a small magnitude and are unlikely to be clinically important in most cases; however, patients with AV nodal dysfunction,306 serum digoxin concentrations in the upper end of the therapeutic range, and/or high plasma flecainide concentrations may be at increased risk of digoxin toxicity.305,306 Pending further accumulation of data, patients receiving flecainide and digoxin should be monitored for signs of digoxin toxicity.305,306

Quinidine

Concomitant administration of quinidine and digoxin increases serum concentrations of digoxin (in 90% or more of patients), which may result in digoxin toxicity.303,308,311,312,398,524 Although variability exists in the magnitude of the increase, serum digoxin concentrations usually increase twofold to threefold when quinidine therapy is initiated in patients digitalized with digoxin.303,308,311,398 Serum digoxin concentrations may begin to increase within a few hours after initiating quinidine therapy, but at least 5-7 days are usually required to achieve a new steady-state serum digoxin concentration.303,308,311 The magnitude of the increase appears to depend on the serum quinidine concentration.303 Both the clearance (principally renal clearance) and volume of distribution of digoxin generally are decreased, but serum half-life of the drug may be unaffected.302,303,308,311

When quinidine therapy is initiated in a patient receiving digoxin, serum digoxin concentrations should be carefully monitored and digoxin dosage reduced (by decreasing dose by approximately 30-50% or modifying dosing frequency) as needed; the patient should be observed closely for signs of toxicity.302,303,308,398 Because of the variability in magnitude of the interaction, additional dosage adjustments are likely to be necessary.303,308 If digoxin therapy is initiated in a patient receiving quinidine, lower than usual dosages of digoxin may be sufficient to produce desired serum concentrations of the cardiac glycoside.302,303,308 If quinidine is discontinued in a patient stabilized on therapy with both drugs, the patient should be observed for signs of decreased response to digoxin and dosage of the cardiac glycoside adjusted as necessary.302,303,308

Sotalol

In clinical studies, proarrhythmic events were more common in patients receiving sotalol and digoxin concomitantly than when either drug was used alone.398 It is not known if this represents an adverse drug interaction or is related to the presence of heart failure, which is a known risk factor for proarrhythmia, in patients receiving digoxin.398 Dosage of digoxin should be individualized when used concomitantly with sotalol.398

Beta-Adrenergic Blocking Agents

Concomitant use of digoxin and β-adrenergic blocking agents (β-blockers) can have additive negative effects on AV conduction, which can result in complete heart block.398 Although such combined therapy may be useful in controlling ventricular rate in patient with atrial fibrillation and/or flutter, digoxin dosage in patients receiving such therapy should be carefully individualized given the considerable variability of these interactions.398,701

Calcium-channel Blocking Agents

Although combination therapy with digoxin and calcium-channel blocking agents may be useful in controlling atrial fibrillation, such concomitant use can have negative effects on AV conduction, which can result in complete heart block.398,701 Digoxin dosage should be carefully individualized when used in conjunction with calcium-channel blocking agents because of the considerable variability of these interactions.398,701

Diltiazem

There are conflicting reports on whether diltiazem substantially affects the pharmacokinetics of digoxin when the drugs are administered concomitantly.313,314,315,316,317,318,319,320,321 In some studies, diltiazem reportedly increased average steady-state serum digoxin concentrations by about 20-50%,313,315,316,317,398 possibly by decreasing the renal and nonrenal clearance of the glycoside;313,314,315,317 however, in other studies, diltiazem did not substantially alter serum digoxin concentrations.318,319,320,321 Despite conflicting reports, serum digoxin concentrations should be carefully monitored and the patient observed closely for signs of digoxin toxicity when diltiazem and digoxin are administered concomitantly, especially in geriatric patients, patients with unstable renal function, or those with serum digoxin concentrations in the upper therapeutic range before diltiazem is administered.313,315,317,318,322 Dosage of digoxin should be reduced by either decreasing the dose by approximately 15-30% or modifying the dosing frequency.398 Digoxin does not appear to affect the pharmacokinetics of diltiazem.314,315,318

Nifedipine

Most evidence indicates that nifedipine does not substantially affect the pharmacokinetics of digoxin when the drugs are administered concomitantly;303,324,325,326,327 however, some data suggest that serum digoxin concentrations may increase by about 15-45% during concomitant therapy.328,329,398 Further evaluation of this potential interaction is needed.303,324,325,326,327,328,329 Patients receiving the drugs concomitantly should be monitored for signs and symptoms of digoxin toxicity.303,328 Serum digoxin concentrations should be determined prior to initiating nifedipine and dosage of digoxin should be reduced by either decreasing the dose by approximately 15-30% or modifying the dosing frequency.398

Verapamil

Verapamil, a potent P-gp inhibitor,399 may increase serum digoxin concentrations by 50-75% during the first week of verapamil therapy. This effect may be more substantial in patients with underlying hepatic disease (e.g., cirrhosis). When verapamil is administered to a patient receiving digoxin, serum digoxin concentrations should be measured and dosage of digoxin adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398 The patient should be monitored closely for clinical response and digoxin toxicity. Combined therapy with the drugs (e.g., for control of ventricular rate in patients with atrial fibrillation and/or flutter) usually is well tolerated if dosage of digoxin is properly adjusted.

Other Cardiovascular Drugs

Sympathomimetics (e.g., dopamine, epinephrine, norepinephrine) should be used with caution in patients receiving digoxin, since the risk of arrhythmias may be increased in patients receiving these drugs concomitantly.398

Altered responses to digoxin therapy have occurred in patients receiving digoxin and amiloride concomitantly.331 In healthy individuals in one study, amiloride increased the renal clearance but decreased the extrarenal clearance of digoxin, resulting in slight increases in serum digoxin concentration.331 Inhibition of the positive inotropic effect of digoxin has also been observed in healthy individuals receiving amiloride.331 Patients receiving amiloride and digoxin concurrently should be carefully observed for altered responses to digoxin therapy.303,331 Further studies are needed to determine the clinical importance of the potential drug interaction between amiloride and digoxin.303,331

Concomitant use of captopril and digoxin has been reported to increase serum concentrations and systemic exposure to digoxin by about 58 and 39%, respectively.366,367,368,398 Such increases may result from decreased renal clearance (probably both glomerular filtration and tubular secretion) of digoxin366,368 and, possibly, displacement of the glycoside from tissue-binding sites by captopril-induced increases in serum potassium.366 Captopril has been administered concomitantly with digoxin in patients with congestive heart failure without unusual adverse effects366,367 or apparent increased risk of cardiac glycoside toxicity.366,367,368 It has been postulated that captopril-induced increases in serum potassium may offset the potential toxic effects of increased serum digoxin concentrations.366,368 If captopril is initiated in a patient receiving digoxin, serum digoxin concentrations should be measured prior to initiating captopril and dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398

Anti-infective Agents

Data suggest that, in about 10% of patients receiving digoxin, substantial amounts of the drug are metabolized by bacteria within the lumen of the large intestine to cardioinactive compounds (reduced metabolites) following oral and possibly parenteral administration.253,254 The extent of such metabolism following oral administration appears to vary inversely with the bioavailability of the preparation.253,255 In patients who form substantial amounts of reduced metabolites, alteration of enteric bacterial flora by some anti-infective agents (e.g., oral erythromycin or tetracycline hydrochloride) may result in an increase in the bioavailability of active drug and as much as a twofold increase in serum digoxin concentrations.254 When concomitant therapy with a systemic anti-infective agent is administered in patients receiving digoxin, the possibility that serum digoxin concentrations may increase should be considered and dosage of the cardiac glycoside should be reduced if necessary.256

Concomitant administration of digoxin and itraconazole may result in increased serum digoxin concentrations (by 80%);377,378 digoxin toxicity may occur.377,378 If itraconazole is initiated in a patient receiving digoxin, serum digoxin concentrations should be measured prior to initiating itraconazole and dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398 Such patients should be observed for clinical manifestations of digoxin toxicity.377,378,398

Other Drugs

Succinylcholine appears to potentiate the effects of digoxin on conduction and ventricular irritability. Cardiac arrhythmias have occurred in patients receiving these drugs concomitantly and, therefore, succinylcholine should be administered with caution in patients receiving digoxin. Dosage of digoxin should be individualized when used concomitantly with neuromuscular blocking agents such as succinylcholine.398

Teriparatide can transiently increase serum calcium concentrations, which may predispose patients to digoxin toxicity.398

Thyroid supplements may increase dosage requirements of digoxin.398

Indomethacin may prolong the elimination half-life and increase serum concentrations of digoxin;372,373,374,398 the mechanism of this interaction requires further elucidation.374,375 (See Drug Interactions: Digoxin, in Indomethacin 28:08.04.92.) Serum digoxin concentrations should be monitored carefully in patients receiving the drugs concomitantly.372 The manufacturer states that dosage of digoxin should be reduced by either decreasing the dose by approximately 15-30% or modifying the dosing frequency.398

Laboratory Test Interferences

Digoxin may cause false-positive ST-T changes during exercise testing.398

Acute Toxicity

The widespread use of digoxin and the very narrow margin between effective therapeutic and toxic dosages contribute to the high incidence of toxicity and the relatively high associated mortality rate.250,251,257,258,259,260,270,295

Toxic effects of digoxin are mainly GI, CNS, biochemical, and cardiac in origin.46,107,257,261,264,265,266,398,404 The minimum toxic and lethal doses of digoxin are not well established.258,267 Based on both accidental and suicidal ingestions, the single oral lethal dose in otherwise healthy individuals is approximately 20-50 times the usual daily maintenance dose.258,268,296 However, patients with predisposing factors (e.g., preexisting heart disease)23,53,66,77,258,295 and patients receiving chronic digoxin therapy may tolerate lesser amounts.258,267,295 Infants and children appear to be more tolerant to the therapeutic and toxic actions of digoxin;51,258,267,270,277,278,283,285 children without underlying cardiac problems can usually tolerate an acute dose of several milligrams of the drug without potentially life-threatening cardiac toxicity.267

Serum digoxin concentrations are useful in confirming the diagnosis of intoxication; however, clinical diagnosis and management should not be based on serum concentrations alone but should always be interpreted in the overall clinical context with all other relevant information.232,257,265,270,274,277,395 At least 6-10 hours usually are necessary for digoxin to equilibrate between plasma and tissue; plasma specimens drawn prior to this time may show digoxin concentrations greater than those present after equilibration.275,295,360,361 Many factors, including adequacy of tissue oxygenation,23,53,54,66,102,270,278 electrolyte23,52,53,54,66,225,228,270,295 and acid-base balance,23,53,270,278 thyroid function,23,53,66,270,278 autonomic nervous system tone,23,53,270,278 age of the patient,66,77,270,278 renal function,53,66,77,270,278 other concurrently administered drugs,23,270,278 and the nature and severity of the underlying cardiac disease,53,66,77,270,278 influence whether a patient manifests toxicity with a given dosage or serum concentration. There is some concern that therapeutic serum concentrations of digoxin (e.g., less than 2 ng/mL) may exert deleterious cardiovascular effects in the long term, although such concentrations appear to be well tolerated in the short term.395

Manifestations

Overdosage of digoxin is manifested by a wide variety of signs and symptoms that are difficult to distinguish from effects associated with cardiac disease (e.g., adverse GI effects, arrhythmias).12,266,270,273,274,275,276,278,398 Before additional doses of the drug are administered, attempts should be made to determine whether the patient's manifestations are glycoside induced.266,276,277,398 However, this may be difficult since signs of intoxication do not occur in regular sequence,48,50,51,266 and subjective signs of toxicity are frequently less easily recognized in infants and children than in adults.51,269,295

Extracardiac Effects

The extracardiac manifestations of digoxin intoxication are similar in both acute and chronic intoxication.261,274 However, GI effects and, to a lesser extent, CNS and visual disturbances may be more pronounced following acute overdosage.261,274 Acute toxicity may cause hyperkalemia, whereas patients with chronic toxicity may be hypokalemic or normokalemic.261,274 In addition, patients receiving chronic digoxin therapy may be hyperkalemic, normokalemic, or hypokalemic if acute intoxication occurs.225,265,295 In pediatric patients, drowsiness52,258,269 and vomiting51,269 are often the most prominent extracardiac effects.281 However, life-threatening cardiac arrhythmias have developed suddenly in children without evidence of any extracardiac signs of intoxication.269,282

Anorexia,46,260,265,398 nausea,46,260,265,267,398 and vomiting46,260,265,267,398 are common early signs of toxicity and may precede or follow evidence of cardiotoxicity.50,277,398 Clinical evaluation of the cause of these symptoms should be attempted before further administration of digoxin; determination of serum digoxin concentrations may aid in deciding whether or not toxicity is present. GI effects probably are at least partially mediated by the area postrema of the medulla260,270,276,277,279 since they occur following administration by all routes.53,274 Large doses of cardiac glycosides may also produce emesis by direct GI irritation.258,270 Episodes of nausea and vomiting may start and stop abruptly.270 Other GI effects include salivation, epigastric or abdominal pain,46,266,267,270 abdominal distention,38,286,287 diarrhea,46,66,266,270,274,284 constipation,66,266 and weight loss.267 Acute hemorrhage and intestinal, esophageal, and gastric necrosis have occurred rarely in patients receiving cardiac glycosides.38,266,276,286,287,288

Headache,38,46,48,66,261,265,266,267,268,270,398 fatigue,46,48,66,261,266,270,276 malaise,46,48,261,266,270,276 drowsiness,38,46,48,52,125,261,265,266,269,270 and generalized muscle weakness38,46,48,266,267,269,270 are common nervous system signs of cardiac glycoside toxicity. Dizziness,46,48,289,398 vertigo,38,48,66,266 syncope,46,48 apathy,266,398 lethargy,38,267,269 excitement,38,48 euphoria,38 insomnia,66,266 irritability,38,48 agitation,46,266,289 hiccups,38 restlessness,38,46,48,289 nervousness,46,48,289 seizures,38,48,52,66,265,266,270,276,289 opisthotonos,39,52 stupor,38,48 and coma38,48,58 also have occurred.

Severe facial pain,38,48 simulating trigeminal neuralgia and usually involving the lower third of the face, has occurred in some patients.48,270 The pain usually is characterized by aching of the teeth and lower jaw and sharp stabbing pain throughout the mandible and maxilla.48,270 Neuralgic pain also has occurred in the upper extremities and lumbar area; paresthesias and tremors have accompanied the pain.48,270

Visual disturbances induced by toxic doses of digoxin probably result from a direct effect on the retina38,75,290,363 (cones are affected more than rods).75,363 Transient retrobulbar neuritis has been reported to cause visual changes in digoxin intoxication;46,74,363 however, it is likely that most visual disturbances result from functional changes of the retina in the presence of high concentrations of the drug.258,290,363 Color vision is commonly affected74,363 and objects may appear yellow or green or, less commonly, brown, red, blue, or white.38,270 Blurred vision,38,46,48,66,74 flashes46,74,277 or flickering of light,48,74 photophobia,46,74,257,289 halos or borders on objects (often are white and appear on dark objects),74,270 diplopia,48,270 macropsia,66 and micropsia66 may occur. Transient or permanent amblyopia48,74,270 and scotoma,74,257,270,363 including teichopsia,74,363 also have occurred. Visual disorders generally are reversible after withdrawal of digoxin therapy;38,46,74,105 transient or total blindness is rare.74,105

Patients with digoxin toxicity are often hypokalemic or normokalemic.261,274 However, severe intoxication may cause hyperkalemia, presumably secondary to inhibition of the Na⁺-K⁺-ATPase pump.77,97,139,261,274 Hyperkalemia may develop rapidly and can result in life-threatening cardiac manifestations, such as AV block and asystole.97,258,261,265,267,274,291 Presence of hyperkalemia during the early stages of intoxication appears to be a poor prognostic indicator; data from clinical studies indicate that mortality correlates better with the severity of initial hyperkalemia than with the dosage of digoxin ingested, initial serum glycoside concentration, or initial ECG changes in patients treated with conventional supportive and symptomatic measures that do not include digoxin immune Fab therapy.97,232,236,247,258,261,265,294

Cardiac Effects

The most well defined and most dangerous toxic actions of digoxin are those affecting the heart.270,274 Cardiac signs of glycoside toxicity may occur with or without other signs of toxicity46,50 and often precede other toxic effects.50 Digoxin has caused almost every kind of cardiac arrhythmia,50,53,54,270 and various combinations of arrhythmias may occur in the same patient.38,50,53,54 In addition, arrhythmias associated with digoxin intoxication may result in worsening of heart failure.47,50,270,295

Since most of the toxic cardiac effects of digoxin also can occur as manifestations of heart disease, it is often difficult to determine whether toxic cardiac effects are caused by an underlying heart disease or the glycoside.38,54,266,270,275,276,398 The type of arrhythmia, presence or absence of other manifestations of toxicity, serum concentrations of the drug, and the patient's age, disease state, renal function, and serum potassium concentration should be considered.38,100,136,157

Cardiac effects occurring in acute overdosage in otherwise healthy individuals often differ from those in patients with underlying heart disease who are receiving chronic digoxin therapy.261,270,274,284,291 Otherwise healthy individuals with acute toxicity frequently present with atrioventricular (AV) conduction disturbances261,270,274,291,292 and supraventricular arrhythmias, such as sinus bradycardia.261,270,274,291 Ventricular arrhythmias are uncommon in these individuals; however, when present, they are associated with severe toxicity and high mortality.261,274,291

Pediatric patients with healthy hearts often present with sinus bradycardia and conduction disturbances; ventricular arrhythmias also occur but are less common than in adults.51,52,222,269,297 In neonates, premonitory signs of toxicity may include sinus bradycardia, sinoatrial (SA) arrest, or prolongation of the PR interval.51,52,222,269,297 Multifocal premature ventricular complexes (PVCs), including bigeminy and trigeminy,24,38,47,50,53,54 and, less commonly, unifocal PVCs24 are common arrhythmias in adults with digoxin toxicity, especially in the presence of heart disease.24,38,47,50,53,54 Patients with glycoside-induced ventricular tachycardia38,50,53,54,258,270 have a high mortality rate,24,25 since ventricular fibrillation38,47,50,53,54,258 or asystole58,258 may result. Bidirectional ventricular tachycardia may occur in severe digoxin toxicity.50,53,54,258,265,270

First-degree AV block is common in patients receiving digoxin25,38,50,53,54 and generally indicates a therapeutic rather than a toxic effect.25,53,106 However, AV block may progressively increase in patients with toxicity.258,398 Mobitz type I (Wenckebach) second-degree AV block12,24,38,50,54,77,270,293 and AV junctional exit block12,24,77,269,270,293 are relatively common AV conduction disorders associated with digoxin toxicity;50,54,269,270,293 complete (third-degree) AV block may occur in advanced intoxication.12,39,293,295

Paroxysmal and nonparoxysmal AV junctional rhythms,12,24,25,38,50,51,54,77,258,270,398 especially nonparoxysmal AV junctional tachycardia,24,25,38,50,54,77,258,270,398 AV dissociation12,50,51,53,54,293 (with or without some degree of AV block),38,53 and paroxysmal atrial tachycardia with variable AV block,24,25,51,53,54,77,258,295 are common in both adults and children and somewhat characteristic of digoxin toxicity.

Digoxin toxicity also may cause various atrial and SA nodal arrhythmias and conduction disorders, including atrial tachycardia,12,24,38,50,258,398 atrial fibrillation,12,38,50,258 atrial flutter,38,50,54,258 atrial premature complexes,38,50,51,54,258 wandering atrial pacemaker,50,52,54 sinus bradycardia,24,38,50,51,52,53,54,258 SA arrest,24,38,50,51,53,54,77,258 SA exit block,12,24,38,50,53,54,77 and sinus tachycardia.50,54 Junctional premature complexes also may occur.24,50,54,258 Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants and children.398

Electrolyte imbalances, especially hypokalemia23,52,53,54,66,225,258,270,398 and, to a lesser extent, hypomagnesemia23,66,224,270,398 or hypercalcemia,23,53,66,270,398 may predispose patients to the cardiotoxic effects of digoxin.23,24,270 Potassium depletion sensitizes the myocardium to digoxin, and calcium has effects similar to digoxin on contractility and excitability of the heart.398 Conversely, hypocalcemia may cause resistance to the effects of digoxin on the AV node, and digoxin may be ineffective until serum calcium is restored to normal.87,398

Treatment

If signs of toxicity appear, digoxin should be discontinued immediately and serum digoxin concentrations obtained; the patient should be placed on a cardiac monitor while possible contributing factors (e.g., electrolyte and thyroid abnormalities, concomitant drugs) are addressed.12,258,277,289,398

Measures to Reduce Absorption or Enhance Elimination of Digoxin

Activated charcoal may be administered if acute ingestion (intentionally or accidently) of a potentially toxic amount of digoxin occurs.398 Administration of activated charcoal appears to be useful in preventing further absorption of the glycoside.261,265 Although activated charcoal is most effective when administered soon after ingestion, doses given later also appear to be effective, presumably because of the prolonged absorption and/or enterohepatic circulation of the drug.227,228,250,251,261,265,276,277,289,295,398 Multiple oral doses of activated charcoal have been used to enhance the elimination of digoxin, especially in patients with substantial renal impairment,230,295 since the drug undergoes enterohepatic circulation.227,228,250,251,265,276,277,289,295,379 Adults have been given 20-60 g of activated charcoal every 4-12 hours until objective evidence and clinical observations indicated that serum glycoside concentration had declined to the subtoxic range.227,228,250,251,252,291

An anion-exchange resin such as cholestyramine or colestipol administered soon after ingestion of digoxin may reduce initial absorption of the glycoside.24,59,230,231,261,265,274,289,291 When administered after onset of toxicity, these resins also may reduce the duration of toxicity by binding digoxin in the GI tract during enterohepatic circulation.59,230,231,265,274,289,291 These agents probably do not have substantial value in the treatment of advanced digoxin toxicity.24,232,291

Although these measures may be used to reduce the absorption or enhance elimination of digoxin, severe digoxin toxicity generally should be treated with digoxin-specific antibody fragments (digoxin immune Fab).24,59,230,231,261,265,274,289,291,379,398,401

Therapeutic Measures

Supportive and symptomatic treatment should be initiated depending on the type of cardiotoxicity;50,258,265 continuous ECG monitoring is recommended398 to monitor for signs of arrhythmias and hyperkalemia.267,277,398 Serum electrolytes, especially potassium, and serum digoxin concentrations should be monitored carefully.267,398 Hypoxia and acid-base and fluid and electrolyte imbalances should be corrected, when necessary.277

Milder forms of cardiotoxicity, such as occasional PVCs,258 AV junctional rhythm with a slow rate,24,54,96 and possibly atrial fibrillation with a slow ventricular rate,24,54,258 usually are treated by temporary withdrawal of digoxin24,51,269 and, if necessary, careful correction of hypokalemia25,28,258 and subsequent adjustment of dosage to prevent recurrence.24,51 However, cardiac irregularities that impair cardiac output because of substantial bradycardia or tachycardia should be treated.24,54,265,269 Ventricular tachycardia,24,25,28,50,54,269 bidirectional ventricular tachycardia,54,269 nonparoxysmal AV junctional rhythm with rapid rate or with exit block,24,28,50,269 and frequent multifocal PVCs24,25,28,50,54,258,269 generally should be treated since these arrhythmias may be forerunners of ventricular fibrillation.24,258,269 In hypokalemic patients, some clinicians believe these ventricular arrhythmias should be treated initially with potassium supplements25,28,50,52,53,54,269,274 and/or IV phenytoin.12,24,25,50,53,54,265,291 In patients with ventricular arrhythmias who are normokalemic or hyperkalemic or in whom potassium is ineffective or contraindicated, phenytoin and/or lidocaine may be used.267,268,270,401 Phenytoin appears to be particularly useful in the treatment of ventricular arrhythmias, especially in the presence of AV block, because the drug improves conduction through the AV node.233,265,267,269,291 Limited data suggest that phenytoin is also occasionally useful in the treatment of supraventricular arrhythmias.261,265,269,270

Although propranolol is effective in the treatment of cardiac glycoside-induced ventricular and supraventricular arrhythmias, the drug should be used with caution because it may compromise conduction through the AV node and also may cause bradycardia.258,265,291 Refractory ventricular53,269 or junctional tachycardia53,269 has been treated with ventricular overdrive pacing,28,53,234,269 but temporary ventricular pacing has been associated with decreased fibrillatory threshold of the ventricle234,265,274 and with mechanical damage to the heart in rare instances.234 Therefore, use of digoxin immune Fab, if available, generally is preferable in the management of ventricular or junctional tachyarrhythmias unresponsive to conventional therapy.234,276

In adults with severe sinus bradycardia,24,53,57,267,270,274,276 SA arrest,24,53,57,270 or second- or third-degree AV block,24,53,54,261,268,270 0.6-2 mg of atropine sulfate administered IV or IM may be effective, especially in those without heart disease.139,261 In pediatric patients, recommended dosages of atropine sulfate range from 0.01-0.03 mg/kg per dose.261,267 If atropine is ineffective, administration of digoxin immune Fab, if available, may reverse severe sinus bradycardia and advanced AV block.235,236 Insertion of a transvenous bipolar electrode catheter may be necessary if sinus bradyarrhythmias and/or AV block result in hemodynamic compromise.12,24,50,53,54,58,71,234,274,276

Cardioversion is used only as a last resort for refractory supraventricular or ventricular tachycardia or for ventricular fibrillation caused by cardiac glycosides.12,24,53,258,269,270,277 Cardioversion is potentially hazardous12,55,56,258,269,270,277 in the treatment of ectopic rhythms induced by glycoside toxicity because it may cause ventricular tachycardia or fibrillation that is resistant to further cardioversion.12,25,38,53,55,56,258,265 If cardioversion is mandatory, initial shocks should be at low energy levels53,258,265,269,270,277,289 (e.g., 5, 20, then 40 watt-seconds)258 and gradually increased in successive shocks until the arrhythmia is terminated or evidence of worsened electrophysiologic instability emerges.12,27,53,258,269,277,289 Many clinicians recommend administration of phenytoin53,88,269 or lidocaine88,269 prophylactically before cardioversion and to suppress PVCs if they occur after cardioversion.27,53,55,56

In patients with hypokalemia, potassium supplementation should be given to maintain serum concentrations between 4 and 5.5 mEq/L.398 Potassium generally should not be administered to patients with second- or third-degree AV block caused by cardiac glycosides24,96,258,266,269,276 since excess potassium may further impair AV conduction.12,25,54,261,265,271 Caution should be exercised when using potassium in acute digoxin intoxication since potentially life-threatening hyperkalemia may develop rapidly in advanced toxicity.258 Close ECG monitoring for evidence of hyperkalemia (e.g., tall peaked T-waves) is recommended.265,398

Hypomagnesemia also should be corrected.398,401 Rarely, magnesium sulfate has been used slowly IV as an antiarrhythmic (e.g., to control ventricular arrhythmias unresponsive to other antiarrhythmics)258,364 and to correct demonstrated magnesium deficiency277 in patients with cardiac glycoside toxicity.

Digoxin immune Fab (ovine) is a specific antidote that can be used in the treatment of life-threatening or potentially life-threatening acute or chronic digoxin toxicity.232,235,236,249,280 Specific antigen-binding fragments present in the immune Fab bind to free (unbound) digoxin intravascularly and in extracellular fluid, thereby preventing and reversing the pharmacologic and toxic effects of the glycoside and enhancing its elimination as the bound, inactivated glycoside-Fab fragment complex.235,236,248,249,280 In cases of potentially life-threatening cardiotoxicity or hyperkalemia, digoxin immune Fab should be administered.248,276,401 Clinical trials with the immune Fab have been promising, with complete reversal of toxicity occurring in most cases.235,236,249 Massive glycoside overdosage may cause hyperkalemia,77,97,139,261,274 which can be refractory to conventional therapy.12,24,97,139,232,235,257,269 Prognosis appears to correlate with serum potassium concentration (i.e., the greater the serum potassium concentration, the worse the prognosis) in patients treated by conventional symptomatic and supportive measures that do not include digoxin immune Fab.97,232,236,247,258,261,265,294 Severe hyperkalemia refractory to standard measures is an indication for digoxin immune Fab.248,267 For further information on the immune Fab, see Digoxin Immune Fab 80:04. If digoxin immune Fab is not readily available, emergency measures for the treatment of hyperkalemia have included IV administration of glucose and insulin,261,267,269,291 sodium bicarbonate,267,269 peritoneal dialysis or hemodialysis,257,261,269,274,291 and/or use of exchange resins;269,274 however, these treatments have not been shown to reduce mortality.401 Use of calcium infusions in the treatment of hyperkalemia traditionally has been avoided because calcium may worsen cardiac irregularities.261,401

Forced diuresis does not accelerate the renal elimination of cardiac glycosides180,240,265,269,274,277 and may worsen electrolyte imbalances.240,269,277 Because of the large volume of distribution and extensive protein binding of digoxin, hemodialysis12,100,122,159,265,269 and peritoneal dialysis are ineffective in removing the glycoside from the body and potentially may worsen toxicity because of a reduction in body potassium.100 Hemoperfusion using charcoal241,242,243,365 or extracorporeal resins242,244 or hemofiltration244 may result in limited removal of digoxin from the body. However, because of the risks involved in these procedures, their use cannot be routinely recommended.245,246,276

Chronic Toxicity

Most cases of digoxin toxicity occur following multiple doses and result, at least in part, from the cumulative effects of the drug.265,269,270,274 Administration of digoxin in conjunction with diuretics (see Drug Interactions: Drugs Affecting Electrolyte Balance) is a frequent cause of chronic digoxin toxicity.270,277 Failure to individualize dosage is another contributing factor in many cases of toxicity.258,266,272

Patients with chronic digoxin toxicity commonly present with ventricular arrhythmias, such as PVCs or ventricular tachycardia.139,261,274,284,291 AV conduction disturbances also are frequent in chronic toxicity.261,274,284,291 The extracardiac manifestations of digoxin intoxication are similar in both acute and chronic intoxication.261,274 Neuropsychiatric disturbances are especially likely to develop in geriatric patients with atherosclerotic disease270 and are easily overlooked in patients receiving chronic digoxin therapy.48,289 These effects include disorientation,38,48,107,264,265,267,270 confusion,38,47,48,66,265,266,276,277,398 depression,38,48,266,398 memory impairment,40,48,264 amnesia,38,48 aphasia,38,48,270 bad dreams,46,266,289 delirium,38,40,46,48,66,107,261,266,268,270,276,289,398 delusions,38,48,264,276 illusions,48,264 and hallucinations.38,40,46,47,48,264,265,276,362,398

The initial treatment of chronic overdosage is the same as in an acute overdosage situation.398 (See Acute Toxicity.) If signs of toxicity appear, digoxin should be discontinued immediately and serum digoxin concentrations obtained; the patient should be placed on a cardiac monitor while possible contributing factors (e.g., electrolyte and thyroid abnormalities, concomitant drugs) are addressed.12,258,277,289,398 In patients with hypokalemia, potassium supplementation should be given to maintain serum concentrations between 4 and 5.5 mEq/L.398

Pharmacology

The main pharmacologic property of cardiac glycosides is their ability to increase the force and velocity of myocardial systolic contraction (positive inotropic action) by a direct action on the myocardium both in patients with nonfailing hearts and in those with failing hearts. When the force of contraction is increased in patients with failing hearts, cardiac output is increased, systolic emptying is more complete, and diastolic heart size is decreased. Elevated ventricular end-diastolic pressure also is reduced and, consequently, pulmonary and systemic venous pressures are decreased. However, in normal subjects, cardiac output is unchanged or slightly decreased, and total peripheral resistance is increased by direct constriction of vascular smooth muscle and by CNS-mediated increase in sympathetic tone. In patients with heart failure, cardiac glycosides cause reflex reduction in peripheral resistance by increasing myocardial contractility; this compensates for the direct vasoconstrictor action of the drugs and, therefore, total peripheral resistance usually is reduced.

Digoxin inhibits the activity of sodium-potassium-activated adenosine triphosphatase (Na⁺-K⁺-ATPase), an enzyme required for active transport of sodium across myocardial cell membranes. Inhibition of this enzyme in cardiac cells results in an increase in the contractile state of the heart. Toxic doses of digoxin cause efflux of potassium from the myocardium and concurrent influx of sodium. Toxicity results in part from loss of intracellular potassium associated with inhibition of Na⁺-K⁺-ATPase. With therapeutic doses, augmentation of calcium influx to the contractile proteins with resultant enhancement of excitation-contraction coupling is involved in the positive inotropic action of cardiac glycosides; the role of Na⁺-K⁺-ATPase in this effect is controversial.

In patients with heart failure, increased myocardial contractility and cardiac output reflexly reduce sympathetic tone, thus slowing increased heart rate and causing diuresis in edematous patients. In patients without heart failure, increased myocardial contractility produced by cardiac glycosides is accompanied by increased myocardial oxygen consumption. In patients with heart failure, reduced ventricular end-diastolic pressure and increased myocardial contractility produce a net decrease or no change in myocardial oxygen consumption. Cardiac glycosides do not decrease coronary blood flow, and in patients with heart failure the restoration of efficient heart action may improve coronary circulation. Cardiac glycosides have a minor inotropic effect on skeletal muscle.

Digoxin decreases conduction velocity through the atrioventricular (AV) node and prolongs the effective refractory period (ERP) of the AV node by increasing vagal activity, by a direct effect on the AV node, and by a sympatholytic effect. The effects of the drug on the AV node are not apparent clinically when the atrial rate is slow enough to allow time for the AV node to recover between each beat, but in patients with supraventricular tachyarrhythmias such as atrial flutter or atrial fibrillation, the number of waves of depolarization reaching the ventricles is decreased. With usual doses, conduction velocity and refractoriness of the His-Purkinje system are not directly affected. Digoxin shortens the ERP of the atria and increases conduction velocity by a reflex increase in vagal tone and by a direct effect on the atria. With therapeutic doses, digoxin may cause prolongation of the PR interval and ST segment depression, but these ECG effects are not indicative of toxicity.398

Digoxin-induced slowing of heart rate in patients without heart failure is negligible and is primarily due to vagal (cholinergic) and sympatholytic effects on the sinoatrial (SA) node, but with toxic doses is due to direct depression of SA node automaticity. Therapeutic doses of digoxin apparently have minimal direct effects and do not have cholinergic or sympatholytic effects on the ventricles. Low concentrations of digoxin produce little effect on the action potential, but toxic concentrations cause progressive loss of resting membrane potential, decreased rate of rise of the action potential, and increased rate of spontaneous diastolic depolarization producing increased automaticity and ectopic impulse activity, especially in the ventricles. Therefore, toxic doses of digoxin increase the automaticity (increased spontaneous diastolic depolarization) of all areas of the heart except the SA node.

Anorexia, nausea, and vomiting caused by cardiac glycosides are probably mediated by chemoreceptors located in the area postrema of the medulla.

Pharmacokinetics

Absorption

Absorption of digoxin is mainly from the small intestine, presumably by a passive, nonsaturable process. The presence of food in the GI tract may slow the rate, but not extent, of absorption of orally administered digoxin from the tablet formulation.398,403 Decreased absorption may occur if the drug is administered with a high fiber meal.398,402,403 Gastric pH apparently does not affect the degree of digoxin absorption. Intestinal absorption of the drug may be impaired in patients with certain malabsorption states (e.g., short bowel syndrome, celiac sprue, jejunoileal bypass).398 Digoxin is a substrate of P-glycoprotein (P-gp), a transport protein involved in absorption of the drug.398

There are interindividual variations in plasma concentrations of digoxin with a specific dose and in plasma concentrations of the drug that produce therapeutic and toxic effects. A specific plasma concentration may be therapeutic or toxic in an individual patient depending on factors other than dosage (e.g., serum electrolytes, acid-base balance, concurrently administered drugs, thyroid status, underlying disease states). Plasma concentrations of digoxin are the same as its serum concentrations. If plasma concentrations of digoxin are to be determined, blood samples should be obtained at least 6-8 hours after the daily dose and preferably just prior to the next scheduled daily dose.398,400,402,403 Therapeutic plasma concentrations of digoxin in adults generally are 0.5-2 ng/mL.398,400,402,403 Some experts suggest that plasma concentrations of 0.5-0.9 ng/mL are sufficient for the treatment of heart failure in adults; however, limited data are available.524 In adults, toxicity is usually, but not always, associated with steady-state plasma digoxin concentrations exceeding 2 ng/mL.398,400,402,403,524 Toxicity may also occur with lower digoxin levels, especially if hypokalemia, hypomagnesemia, or hypothyroidism coexists.524 Although neonates and infants appear to tolerate higher plasma concentrations of digoxin than do adults,23,65,76,151,161,182,297,398,400,402,403 evidence suggests that plasma concentrations greater than those in the generally accepted therapeutic ranges for adults are associated with little, if any, additional therapeutic benefit in these patients.297 Serum concentrations of digoxin should be interpreted in the overall clinical context; thus, an isolated serum concentration measurement should not be used alone as the basis for adjusting dosage. 398,400,402,403

Following oral administration of a single dose of digoxin, onset of action occurs in 0.5-2 hours and maximal effects occur in 2-6 hours.398 After IV administration of a single dose of digoxin, the onset of action occurs in 5-30 minutes depending on the rate of infusion and maximal effects occur in 1-4 hours.398

The absolute bioavailability of digoxin tablets is 60-80% and the absolute bioavailability of the oral solution is 70-85%; when switching from IV to oral dosage forms, the differences in bioavailability should be considered.398,400,402

Distribution

Cardiac glycosides are widely distributed in body tissues; highest concentrations are found in the heart, kidneys, intestine, stomach, liver, and skeletal muscle. Lowest concentrations are in the plasma and brain. In the myocardium, cardiac glycosides are found in the sarcolemma-T system bound to a receptor (probably Na⁺-K⁺-ATPase). Only small amounts of digoxin are distributed into fat. Digoxin crosses the placenta and, in pregnant women receiving digoxin, fetal and maternal plasma concentrations are equal. Maternal concentrations of digoxin in plasma and milk are similar.

With therapeutic plasma concentrations, about 20-30% of digoxin in the blood is bound to plasma proteins.

Elimination

In patients with normal renal function, the elimination half-life (t_½) of digoxin is 36 hours. The elimination t_½ of digoxin is increased in patients with impaired renal function. In undigitalized patients, institution of fixed daily maintenance doses of digoxin without an initial loading dose results in steady-state plasma concentrations after 4-5 elimination t_½s.

Digoxin is not metabolized appreciably (only about 13%) prior to excretion. Metabolism includes stepwise cleavage of the sugar molecules, hydroxylation, epimerization, and formation of glucuronide and sulfate conjugates. The cytochrome P-450 (CYP) system is not involved in the metabolism of digoxin.398 Digoxin is also apparently metabolized by bacteria within the lumen of the large intestine following oral administration and possibly after biliary elimination following parenteral administration.398

Digoxin is excreted primarily by the kidneys mainly as unchanged drug. In healthy individuals, about 50-70% of an IV dose of digoxin is excreted unchanged in urine.398 Digoxin is eliminated from the body by first-order kinetics, with a fixed proportion of the residual drug in the body being eliminated each day. Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow.398 Orally administered activated charcoal has been shown to enhance total body clearance and elimination of digoxin, probably by adsorbing the cardiac glycoside in the GI tract with subsequent excretion in feces.250,251 Digoxin is not appreciably removed by hemodialysis or peritoneal dialysis. Similarly, only minor amounts of the drug are removed during cardiopulmonary bypass or exchange transfusion.

Chemistry and Stability

Chemistry

Digoxin is a cardiac glycoside, a class of drugs with common specific effects on the myocardium.398,700,701 Glycosides with positive inotropic actions on the diseased heart occur widely in nature and/or can be prepared synthetically. Cardiac glycosides of medicinal importance have been obtained from Digitalis purpurea Linné (Fam. Scrophulariaceae ) (digitoxin, digitalis, gitalin), Digitalis lanata Ehrhart (Fam. Scrophulariaceae ) (digoxin, digitoxin, lanatoside C, deslanoside, acetyldigitoxin), Strophanthus gratus (ouabain), and Acokanthera schimperi (ouabain). The term “digitalis” is sometimes used to designate the entire class of cardiac glycosides. Currently, digoxin is the only cardiac glycoside commercially available in the US.401

Cardiac glycosides have a characteristic ring structure known as an aglycone (or genin) coupled with one or more types of sugars. The aglycone portion of the glycoside consists of a steroid nucleus (cyclopentanoperhydrophenanthrene nucleus) and an α,β-unsaturated 5- or 6-membered lactone ring at the C 17 position of the steroid nucleus. A β-oriented hydroxyl substitution usually is present at the C 3 and C 14 positions. Increasing the number of hydroxyl groups on the aglycone increases polarity and decreases lipid solubility; additional sugars also may increase polarity. The sugar portion of the glycoside is attached to the steroid nucleus, usually through a hydroxyl group at the C 3 position. The sugar moiety affects in part the activity of the cardiac glycoside by influencing solubility, absorption, distribution, and toxicity.

Digoxin has an hydroxyl group at the C 12 position and a tridigitoxose at the C 3 position.

Digoxin occurs as clear to white crystals or as a white, crystalline powder and has a bitter taste. Digoxin is practically insoluble in water, slightly soluble in diluted alcohol, and very slightly soluble in 40% propylene glycol. The pH of commercially available digoxin injection is 6.8-7.2.400

Stability

Digoxin preparations should be protected from light and stored at 20-25°C.398,400,402,403

Digoxin injection is compatible with most commercially available IV infusion fluids.400 Before IV administration, digoxin injection may be diluted with a fourfold or greater volume of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection; use of less than a fourfold volume of diluent may cause precipitation of digoxin.400 Diluted solutions of digoxin should be used immediately.400

Solutions of digoxin have been reported to be physically incompatible with other drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

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