brand digox 250 mcg tablet

Uses

Cardiac glycosides are used principally in the prophylactic management and treatment of heart failure and to control the ventricular rate in patients with atrial fibrillation.

Digoxin is the most commonly used cardiac glycoside, principally because it may be administered by various routes, has an intermediate duration of action, and has been extensively studied in patients with or without renal insufficiency. Some clinicians believe that digitoxin is the cardiac glycoside of choice in patients with renal failure because elimination half-life is unchanged in these patients; however, digitoxin is no longer commercially available in the US. Use of digoxin for maintenance therapy has replaced digitalis because the latter is standardized biologically and not by glycoside content.

Heart Failure

Cardiac glycosides are used, usually in conjunction with other agents, in the management of symptomatic heart failure associated with left ventricular systolic dysfunction. 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. ( and .) Additional agents (e.g., cardiac glycosides, 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. Cardiac glycoside therapy may be initiated in the early development of heart failure in patients who have started but not yet responded symptomatically to an ACE inhibitor or a β-blocker. Alternatively, cardiac glycosides may be withheld until the patient's symptomatic response to the ACE inhibitor or β-blocker has been defined and then used only in those patients who remain symptomatic while receiving ACE inhibitor or β-blocker therapy. In patients with heart failure who are receiving a cardiac glycoside without an ACE inhibitor or β-blocker, the cardiac glycoside should not be withdrawn, but appropriate therapy with an ACE inhibitor and/or a β-blocker should be added. The beneficial effects of cardiac glycosides have been shown to be additive with those of ACE inhibitors and/or diuretics; symptomatic and functional deterioration can occur when cardiac glycosides are withdrawn from patients whose failure was stabilized on a regimen of combined therapy. Use of cardiac glycosides is not recommended in patients with asymptomatic left ventricular systolic dysfunction (New York Heart Association [NYHA] heart failure functional class I) since such patients should only receive treatment to prevent progression of heart failure and cardiac glycosides have not been shown to have demonstrable effect on such progression when used in symptomatic patients.

In patients with heart failure, cardiac glycosides may alleviate symptoms and decrease heart failure-related hospitalizations. Although data demonstrating an overall survival benefit of cardiac glycosides 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 a cardiac glycoside (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). The decision to use a cardiac glycoside 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.

Cardiac glycosides increase cardiac output resulting in diuresis and relief of the symptoms of right-sided heart failure caused by systemic venous congestion (e.g., peripheral edema) and the symptoms of left-sided heart failure caused by pulmonary congestion (e.g., dyspnea, orthopnea, and paroxysmal nocturnal dyspnea). Cardiac glycosides increase left ventricular ejection fraction and improve symptoms of heart failure (as evidenced by exercise capacity, heart failure-related hospitalizations and emergency care), while having no apparent effect on overall mortality. The acute and sustained hemodynamic efficacy of cardiac glycosides is well established, at least in patients with symptomatic heart failure caused by predominant systolic ventricular dysfunction, and the drugs can provide symptomatic and functional improvement. However, some clinicians state that cardiac glycosides generally are not indicated for the stabilization of patients with acutely decompensated heart failure requiring IV inotropic therapy, unless they have rapid atrial fibrillation. Cardiac glycoside therapy may be initiated in these patients in an effort to establish a long-term treatment strategy.

Cardiac glycosides generally are most effective in the management of low-output failure secondary to hypertension, coronary artery or atherosclerotic heart disease, primary myocardial disease, nonobstructive cardiomyopathies, and valvular heart disease. The drugs are less effective in high-output failure caused by bronchopulmonary insufficiency, infection, hyperthyroidism, anemia, fever, arteriovenous fistula, thiamine deficiency, or Paget's disease and heart failure precipitated by complete AV block, 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, arteriovenous shunt) is best treated by addressing the underlying condition rather than by using cardiac glycosides. Cardiac glycosides are 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 cardiac glycosides may have a worsening of outflow obstruction as a result of the inotropic effects of the drugs. Cardiac glycosides should be used concomitantly with other drugs or measures to correct the underlying cause of the heart failure, if possible; the glycoside should be continued after failure is corrected unless the underlying cause has been corrected.

Supraventricular Tachyarrhythmias

Atrial Fibrillation

Digoxin is used for controlling rapid ventricular rate in patients with atrial fibrillation; however, the drug usually is not considered first-line therapy for this use, in part because of its slow onset of action. 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. 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. Choice of therapy should be individualized based on the clinical situation and patient-related factors. Digoxin should not be used in patients with preexcited atrial fibrillation because the drug may increase ventricular response and result in ventricular fibrillation.

Other Supraventricular Tachycardias

Cardiac glycosides are used in the management of paroxysmal supraventricular tachycardia (PSVT) due to AV nodal reentry tachycardia (AVNRT) or AV reentry tachycardia (AVRT). Although cardiac glycosides (e.g., digoxin) are not as effective in the treatment of PSVT as they are in the treatment of chronic atrial fibrillation, some experts state that use of oral digoxin may be reasonable for ongoing management of PSVT in patients who are not candidates for, or prefer not to undergo, catheter ablation. Because of the potential for adverse effects, use of digoxin generally is reserved for patients who fail or cannot take preferred therapies (e.g., β-adrenergic blocking agents, nondihydropyridine calcium-channel blocking agents, flecainide, propafenone). 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. Cardiac glycosides should not be used for the management of chaotic (multifocal) atrial tachycardia.

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 preexcited atrial fibrillation because acceleration of the ventricular rate may occur. Digoxin should not be administered to patients with WPW syndrome and preexcited atrial fibrillation. The preferred treatment of choice in hemodynamically compromised patients with WPW syndrome usually is prompt direct-current cardioversion.

Myocardial Infarction

Use of cardiac glycosides in acute myocardial infarction is controversial.(See Cautions: Precautions and Contraindications.) Most clinicians believe that mild left ventricular dysfunction after acute myocardial infarction should be treated with modest diuresis (e.g., with a parenteral loop diuretic) and afterload and preload reduction (e.g., with parenteral nitroglycerin); institution of ACE inhibitor therapy also may be appropriate. The precise role of cardiac glycosides is less clear. Empiric information from observational studies has shown equivocal results with cardiac glycosides in terms of mortality, and concern about increased mortality associated with long-term milrinone therapy has prompted reexamination of this empiric information. Although a recent large, controlled study (the Digitalis Investigation Group [DIG]) in patients with normal sinus rhythm and chronic heart failure (principally mild to moderate) showed no reduction in total mortality when a cardiac glycoside (digoxin) was added to a regimen of ACE inhibitors and/or diuretics, reductions in hospitalization rates both overall and for worsening heart failure, as well as in the combined incidence of death from worsening heart failure and hospitalization for such worsening, were observed in cardiac glycoside-treated patients. In addition, other recent studies have shown that cardiac glycoside therapy can improve symptomatic and functional status and favorably affect the neurohormonal system in patients with definite systolic left ventricular dysfunction and sinus rhythm who are receiving diuretics and/or ACE inhibitors. Therefore, because of this and other evidence of potential beneficial effects of cardiac glycosides on morbidity, the drugs can be used selectively in patients recovering from an acute myocardial infarction, generally reserving their use for patients with a supraventricular arrhythmia and for those with systolic left ventricular heart failure that is refractory to first-line agents.

Cardiac glycosides are effective in the treatment of persistent supraventricular tachyarrhythmias in patients with acute myocardial infarction. Rapid digitalization can be used to slow a rapid ventricular response and improve left ventricular function in patients with supraventricular tachyarrhythmias, especially in those with atrial fibrillation. Atrial fibrillation following acute myocardial infarction most often occurs within the initial 24 hours postinfarction and usually is transient but may recur. The incidence of atrial fibrillation and flutter appears to be decreased in patients receiving thrombolytic therapy for acute myocardial infarction. Cardiac glycosides may be particularly useful for slowing a rapid ventricular response in patients with coexisting left ventricular dysfunction. For patients without clinical evidence of left ventricular dysfunction and in whom there are no other risks of β-blockade (e.g., bronchospastic disease, AV block), an IV β-blocker (e.g., atenolol, metoprolol) can be used as an alternative to a cardiac glycoside to slow a rapid ventricular response.

Cardiogenic Shock

Cardiac glycosides have been used in the treatment of cardiogenic shock; however, most clinicians consider these drugs to have little benefit in this situation because they have a positive inotropic effect only on the noninfarcted part of the ventricle and do not increase cardiac output. In patients with cardiogenic shock and atrial fibrillation or flutter with rapid ventricular rate, cardiac glycosides are used to improve left ventricular function.

Angina Pectoris

Cardiac glycosides may be useful, especially in conjunction with a β-blocker, in the treatment of angina pectoris in patients with cardiomegaly and heart failure; however, cardiac glycosides alone are not beneficial in the treatment of angina pectoris in patients without cardiomegaly and heart failure.

Dosage and Administration

Administration

Cardiac glycosides usually are administered orally. When oral therapy is not feasible or when rapid therapeutic effect is necessary, cardiac glycosides may be administered by IV injection. Although cardiac glycosides may also be given IM, this route of administration is rarely justified because these drugs frequently cause severe local irritation, pain, and muscle fasciculation at the site of injection and because IV administration produces more rapid, predictable effects. Cardiac glycosides should not be given subcutaneously. Therapy with an oral cardiac glycoside should replace IM or IV administration as soon as possible.

ECG monitoring of cardiac function should be performed during cardiac glycoside therapy, especially when the drugs are given IV, when they are given orally for prolonged periods, and when they are given in patients with increased risk of adverse reactions to cardiac glycosides, such as those with severe heart or renal disease. Differences in pharmacokinetics and/or bioavailability should be considered when patients are changed from one cardiac glycoside to another or one route of administration to another.

Dosage

Cardiac glycosides have a low therapeutic index;therefore, cautious dosage determination is essential. Usual dosages are averages that may require considerable modification as determined by individual requirements and response; the general condition, cardiovascular status, and renal function of the patient; and cardiac glycoside plasma concentrations. Cardiac glycoside dosage should be based on ideal body weight. Determination of optimal cardiac glycoside dosage is complex because readily measurable therapeutic objectives usually are absent (except in supraventricular arrhythmias), individual response is not predictable, and the difference between the full therapeutic and toxic dose is small.

Although the manufacturers of cardiac glycosides state that dosage of these drugs must be reduced in patients with renal impairment, most clinicians believe that the digitalizing dose of any cardiac glycoside should not be reduced in these patients, but that maintenance dosage of digoxin usually should be reduced in patients with creatinine clearances of less than 50 mL/minute.

Cardiac glycosides must be administered with extreme caution and dosage carefully adjusted in premature and full-term neonates and in geriatric patients since delayed excretion and systemic accumulation may occur in these patients. Cardiac glycoside dosage in neonates, infants, and children is substantially larger than that required in adults when calculated on the basis of mcg/kg or mcg/m.

Cardiac glycosides, especially injections of these drugs, should be administered with caution and usually in reduced dosage in patients who have recently received (usually within the previous 2-3 weeks) or are presently receiving other cardiac glycosides.

Administration of a cardiac glycoside (either rapidly or slowly) until sufficient amounts of the drug have accumulated in the body to produce a therapeutic response without signs and symptoms of toxicity is called digitalization. The estimated total digitalizing dosage is given in divided doses at time intervals sufficient to allow the full effect of each dose to occur before subsequent doses are administered. A positive inotropic effect occurs even with low dosages of cardiac glycosides and before digitalization is complete, but higher maintenance and digitalizing dosages usually are required to slow the ventricular rate in patients with atrial tachyarrhythmias. Slow digitalization is preferred for most patients without life-threatening conditions.

Since a fixed percentage of the amount of cardiac glycoside in the body is excreted daily, the daily maintenance dosage must be adjusted to replace the percentage of glycoside eliminated from the body and sustain the desired response.

Long-term administration of cardiac glycosides is indicated in most infants digitalized for acute heart failure. In infants with paroxysmal atrial tachycardia or heart failure, cardiac glycosides generally are administered at least until the child is 2 years of age. Infants with myocarditis require cardiac glycoside therapy for at least 18 months. Children with severe, inoperable, congenital cardiac disorders usually require cardiac glycoside therapy throughout childhood and often for life. Dosage is adjusted as the child grows older and larger.

Cautions

In addition to toxicity, other adverse effects may occur in patients receiving cardiac glycosides.

Other Adverse Effects

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. Unilateral and bilateral gynecomastia and enlargement of the mammary glands in women have been reported after chronic therapy with cardiac glycosides; these effects are reversible when the drugs are withdrawn. The glycosides commonly produce vaginal cornification in postmenopausal women and may 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. Cardiac glycosides 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, particularly digitoxin (no longer commercially available in the US). An individual cardiac glycoside is contraindicated in patients who have demonstrated hypersensitivity to it. Cross-sensitivity among the drugs may occur.

Precautions and Contraindications

Cardiac glycosides should be used with caution in patients with severe pulmonary disease, hypoxia, myxedema, acute myocardial infarction, severe heart failure, acute myocarditis (including rheumatic carditis) or an otherwise damaged myocardium, since the likelihood of cardiac glycoside-induced arrhythmias is increased in these patients. The possibility that use of cardiac glycosides in some patients with acute myocardial infarction may result in an undesirable increase in oxygen demand and associated ischemia should be considered. In patients with rheumatic carditis, dosage should be low initially and increased gradually until a beneficial effect is obtained or, if improvement does not occur in these patients, the drug should be discontinued. Cardiac glycosides should be used with caution in patients with chronic constrictive pericarditis since these patients may respond unfavorably. Cardiac glycosides should be administered with extreme caution in patients with acute glomerulonephritis and heart failure; if the drugs are necessary, total daily dosage must be reduced and given in divided doses with constant ECG monitoring. These patients should be treated concomitantly with diuretics and hypotensive agents and the glycoside should be discontinued as soon as possible. Cardiac glycosides also should be used with extreme caution, if at all, in patients with idiopathic hypertrophic subaortic stenosis because increased obstruction to left ventricular outflow may result. 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 be particularly susceptible to the toxicity of cardiac glycosides.

Cardiac glycosides should be given IV with caution in hypertensive patients, since IV administration of these drugs may increase blood pressure transiently.

Cardiac glycosides should not be administered to patients with substantial sinus or atrioventricular (AV) block, unless the conduction block has been addressed with a permanent pacemaker. The drugs should be used cautiously with other drugs that can depress sinus or AV nodal function.

Cardiac glycosides generally should not be used alone in the management of Wolff-Parkinson-White (WPW) syndrome since it may enhance conduction via the accessory AV pathway and, in the presence of atrial fibrillation or flutter, result in extremely rapid ventricular rates and even ventricular fibrillation. Cardiac glycosides generally are not used in the treatment of tachyarrhythmias, especially atrial fibrillation or flutter, in patients with anomalous AV conduction unless it has been shown that the glycosides will not result in an increased ventricular rate via an effect on anomalous AV pathway conduction. (See Other Supraventricular Tachycardias under Uses: Supraventricular Tachyarrhythmias.)

When cardiac glycosides are used in patients with atrial fibrillation or flutter prior to administration of antiarrhythmic drugs with anticholinergic activity such as disopyramide, procainamide, and quinidine (see Drug Interactions: Antiarrhythmic Agents), the glycosides may reduce, but do not abolish, the dangers of increased ventricular rates produced by the antiarrhythmic drugs. Cardiac glycosides should not be used for the treatment of multifocal atrial tachycardia. Cardiac glycosides should be used with caution in patients with increased carotid sinus sensitivity, since glycosides cause increased vagal tone. Carotid sinus massage has caused ventricular fibrillation in patients receiving cardiac glycosides.

Cardiac glycosides should be administered with caution in patients with frequent ventricular premature contractions or ventricular tachycardia, especially if these arrhythmias are not caused by heart failure. The drugs are contraindicated in patients with ventricular fibrillation.

Since cardiac glycosides predispose to postcardioversion arrhythmias, most clinicians withhold cardiac glycosides 1-2 days before elective cardioversion in patients with atrial fibrillation and start with initial shocks of 25-50 watt-seconds and increase by 100 watt-second increments until normal sinus rhythm or 400 watt-seconds is reached. Elective cardioversion should be postponed in patients with signs and symptoms of glycoside toxicity. After cardioversion of arrhythmias, subsequent adjustment of cardiac glycoside dosage will be required to avoid provoking ventricular arrhythmias.

Pregnancy and Lactation

Pregnancy

Safe use of cardiac glycosides during pregnancy has not been established. Although the drugs have been used in pregnant women without apparent harm to the mother or fetus, one neonatal death has been reported, allegedly because of digitoxin (no longer commercially available in the US) overdosage in utero.

Lactation

Safe use of cardiac glycosides during lactation has not been established.

Drug Interactions

Drugs Affecting GI Absorption of Cardiac Glycosides

A number of drugs are capable of binding cardiac glycosides and/or inhibiting the absorption of the glycosides from the GI tract, which may result in low plasma 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 plasma 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 plasma digoxin concentrations but administration of neomycin to digitalized patients apparently does not affect the terminal plasma t_½ of digoxin.

GI absorption of oral digoxin tablets may be substantially reduced in patients receiving radiation therapy, certain antineoplastic agents, or various combination chemotherapy regimens, possibly as a result of temporary damage to intestinal mucosa caused by the radiation or cytotoxic agents. Use of digoxin oral elixir or liquid-filled capsules may minimize the potential interaction, since the drug is rapidly and extensively absorbed from these dosage forms. Limited data suggest that the extent of GI absorption of digitoxin (no longer commercially available in the US) is not substantially affected by concomitant administration of combination chemotherapy regimens known to decrease absorption of digoxin.

Colestipol and cholestyramine may bind digoxin in the GI tract and impair its absorption (resulting in low plasma digoxin concentrations), particularly if this glycoside and colestipol or cholestyramine are administered simultaneously or close together. Orally administered cardiac glycosides 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 cardiac glycosides. Concurrent use of propantheline and slow-dissolving tablets of digoxin may result in increased digoxin concentrations. This interaction can be avoided by using digoxin oral solution or tablets that dissolve rapidly (e.g., Lanoxin). Patients receiving an antimuscarinic and digoxin should be closely observed for signs of digitalis toxicity.

Drugs Affecting Electrolyte Balance

In patients receiving cardiac glycosides, 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 cardiac glycoside toxicity. Fatal cardiac arrhythmias may result. Periodic electrolyte determinations must be performed in patients receiving a cardiac glycoside 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.

Calcium Salts

The inotropic and toxic effects of cardiac glycosides and calcium are synergistic and arrhythmias may occur if these drugs are given together (particularly when calcium is given IV). IV administration of calcium should be avoided in patients receiving cardiac glycosides; 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 cardiac glycosides 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). Concomitant use of cardiac glycosides and β-adrenergic blocking agents (β-blockers) can have additive negative effects on AV conduction, which can result in complete heart block. Although such combined therapy may be useful in controlling atrial fibrillation, digoxin dosage in patients receiving such therapy should be carefully individualized given the considerable variability of these interactions.

Quinidine

Concomitant administration of quinidine and digoxin produces increased plasma concentrations of digoxin (in 90% or more of patients) which may result in GI and cardiac toxicity. Although variability exists in the magnitude of the increase, plasma digoxin concentrations usually increase twofold to threefold when quinidine therapy is initiated in patients digitalized with digoxin. Plasma 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 plasma digoxin concentration. The magnitude of the increase appears to depend on the serum quinidine concentration. 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.

When quinidine therapy is initiated in a patient receiving digoxin, serum digoxin concentrations should be carefully monitored and the digoxin dosage reduced as needed; the patient should be observed closely for signs of toxicity. Many clinicians recommend that digoxin dosage be reduced by one-half when quinidine therapy is initiated; however, because of the variability in magnitude of the interaction, additional dosage adjustments are likely to be necessary. If severe toxicity occurs or if digoxin dosage adjustment is difficult, an alternative antiarrhythmic drug (if possible, one that does not interact with digoxin) should be used instead of quinidine (e.g., procainamide). If digoxin therapy is initiated in a patient receiving quinidine, lower than usual dosages of digoxin may be sufficient to produce desired plasma concentrations of the cardiac glycoside. 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.

Flecainide

Studies in healthy individuals indicate that plasma digoxin concentrations may be increased by an average of about 15-25% when flecainide and digoxin are administered concomitantly. The increase in plasma digoxin concentration may occur within a few days of initiating flecainide therapy in patients receiving digoxin and may result from a decrease in the volume of distribution of digoxin. 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. Flecainide has been administered concomitantly with cardiac glycosides in patients with ventricular arrhythmias without unusual adverse effects. Additional studies to determine the potential importance of an interaction in patients with heart failure are needed. Flecainide-induced increases in plasma 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, plasma digoxin concentrations in the upper end of the therapeutic range, and/or high plasma flecainide concentrations may be at increased risk of digoxin toxicity. Pending further accumulation of data, patients receiving flecainide and digoxin should be monitored for signs of digoxin toxicity.

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 cardiac glycoside therapy should be reassessed, and digoxin discontinued if appropriate; if concomitant therapy is considered necessary in patients receiving digoxin, a 50% reduction in digoxin dosage is recommended when amiodarone therapy is begun. Serum digoxin concentrations should be monitored carefully and digoxin dosage reduced as necessary in patients receiving digoxin and amiodarone concomitantly; 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.

Propafenone

Concomitant administration of digoxin and propafenone may result in increased serum digoxin concentrations; possible digoxin toxicity may occur.

Calcium-Channel Blocking Agents

Diltiazem

There are conflicting reports on whether diltiazem substantially affects the pharmacokinetics of digoxin when the drugs are administered concomitantly. In some studies, diltiazem reportedly increased average steady-state serum digoxin concentrations by about 20-50%, possibly by decreasing the renal and nonrenal clearance of the glycoside; however, in other studies, diltiazem did not substantially alter serum digoxin concentrations. 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; digoxin dosage should be reduced if necessary. Digoxin does not appear to affect the pharmacokinetics of diltiazem.

Concomitant use of cardiac glycosides and calcium-channel blocking agents can have negative effects on AV conduction, which can result in complete heart block. Although such combined therapy may be useful in controlling atrial fibrillation, digoxin dosage should be carefully individualized when such therapy is used because of the considerable variability of these interactions.

Nifedipine

Most evidence indicates that nifedipine does not substantially affect the pharmacokinetics of digoxin when the drugs are administered concomitantly; however, some data suggest that serum digoxin concentrations may increase by about 15-45% during concomitant therapy. Further evaluation of this potential interaction is needed. Since there have been isolated reports of increased serum digoxin concentrations during concomitant administration, serum digoxin concentrations should be monitored when nifedipine therapy is initiated or discontinued or dosage of nifedipine is adjusted in patients receiving digoxin. Patients receiving the drugs concomitantly should be monitored for signs and symptoms of digoxin toxicity and dosage of the cardiac glycoside reduced if necessary.

Verapamil

Oral verapamil 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, dosage of the glycoside should generally be reduced and the patient monitored closely for clinical response and cardiac glycoside 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 dosages of the glycoside are properly adjusted. Whenever cardiac glycoside toxicity is suspected, dosage of the glycoside should be further reduced and/or the glycoside temporarily withheld. If verapamil is discontinued in a patient stabilized on digoxin, the patient should be monitored closely and dosage of the glycoside increased as necessary to avoid underdigitalization.

Concomitant use of cardiac glycosides and calcium-channel blocking agents can have additive negative effects on AV conduction.(See Calcium-Channel Blocking Agents: Diltiazem, in Drug Interactions.)

Other Cardiovascular Drugs

Sympathomimetics (e.g., ephedrine, epinephrine, isoproterenol) should be used with caution in digitalized patients, since the risk of arrhythmias may be increased in patients receiving these drugs concomitantly with cardiac glycosides.

Concomitant administration of rauwolfia alkaloids and cardiac glycosides may predispose some patients to the development of cardiac arrhythmias. Although these drugs are frequently administered together safely, the possibility of this interaction should be kept in mind in patients prone to arrhythmias and large parenteral doses of reserpine should be avoided in patients receiving cardiac glycosides.

Altered responses to digoxin therapy have occurred in patients receiving digoxin and amiloride concomitantly. 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. Inhibition of the positive inotropic effect of digoxin has also been observed in healthy individuals receiving amiloride. Patients receiving amiloride and digoxin concurrently should be carefully observed for altered responses to digoxin therapy. Further studies are needed to determine the clinical importance of the potential drug interaction between amiloride and digoxin.

Studies in patients with congestive heart failure indicate that serum digoxin concentrations may increase by about 15-30% when captopril and digoxin are used concomitantly. Such increases may result from decreased renal clearance (probably both glomerular filtration and tubular secretion) of digoxin and, possibly, displacement of the glycoside from tissue-binding sites by captopril-induced increases in serum potassium. Captopril has been administered concomitantly with digoxin in patients with congestive heart failure without unusual adverse effects or apparent increased risk of cardiac glycoside toxicity. It has been postulated that captopril-induced increases in serum potassium may offset the potential toxic effects of increased serum digoxin concentrations. Reduction in digoxin dosage does not appear to be necessary when captopril is initiated; however, serum digoxin concentrations should be monitored and the patient observed for signs of glycoside toxicity when the drugs are used concomitantly. Further studies are needed to determine the clinical importance of this potential interaction.

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. The extent of such metabolism following oral administration appears to vary inversely with the bioavailability of the preparation. 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. The clinical importance of this interaction remains to be determined. The interaction is limited to a minority of patients and would likely be of most consequence in patients receiving oral digoxin preparations with poor bioavailability; in patients who do form substantial amounts of reduced metabolites, use of the liquid-filled digoxin capsules may minimize the potential interaction, since the drug is rapidly and extensively absorbed from this dosage form. 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. Since the effect of anti-infective therapy on the enteric bacteria that inactivate digoxin may persist for at least 9 weeks, anti-infective therapy prior to digitalization may temporarily decrease digoxin requirements; subsequent return of the original bacterial flora might result in underdigitalization.

Concomitant administration of digoxin and itraconazole may result in increased serum digoxin concentrations; digoxin toxicity may occur. A decrease in digoxin dosage may be required. Patients receiving concomitant digoxin and itraconazole therapy should have serum digoxin concentrations monitored and such patients should be observed for clinical signs and symptoms of digoxin toxicity.

The possibility that an interaction similar to that reported with quinidine could occur with concomitant cardiac glycoside and quinine (or another cinchona alkaloid) use should be considered.

Other Drugs

Succinylcholine appears to potentiate the effects of cardiac glycosides on conduction and ventricular irritability. Cardiac arrhythmias have occurred in patients receiving these drugs concomitantly and, therefore, succinylcholine should be administered with caution in digitalized patients.

Indomethacin may prolong the elimination half-life and increase serum concentrations of digoxin; the mechanism of this interaction requires further elucidation. Serum digoxin concentrations should be monitored carefully in patients receiving the drugs concomitantly.

Pharmacokinetics

Absorption

GI absorption of cardiac glycosides presumably occurs by a passive, nonsaturable process; the rate and completeness of absorption decreases with increasing polarity of the cardiac glycoside. Relatively nonpolar cardiac glycosides such as digitoxin (no longer commercially available in the US) are completely absorbed. Digoxin, which is more polar than digitoxin, is absorbed less completely from the GI tract.

There are interindividual variations in plasma concentrations of cardiac glycosides with a specific dose and in plasma concentrations that produce therapeutic and toxic effects. Plasma concentrations of digoxin and digitoxin are the same as their serum concentrations. 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, type, severity and duration of cardiac disorder, thyroid status, autonomic nervous system tone, concurrently administered drugs). Higher plasma concentrations of cardiac glycosides may be required for therapeutic effects in patients with supraventricular tachycardias than in patients with heart failure. Although neonates and infants appear to tolerate higher plasma concentrations of cardiac glycosides than do adults, 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.

IV digoxin is a rapidly acting cardiac glycoside. Orally administered digoxin is an intermediate-acting glycoside, and digitoxin is long-acting. In general, cardiac glycosides that have a rapid onset of action also have a short duration of action and vice versa.

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. Cardiac glycosides cross the placenta and, in pregnant women digitalized with digoxin, fetal and maternal plasma concentrations are equal. Maternal concentrations of digoxin in plasma and milk are similar.

Cardiac glycosides are bound, in varying degrees, to plasma proteins (primarily albumin), and protein binding decreases with increasing polarity. With therapeutic plasma concentrations, 97% of digitoxin and 20-30% of digoxin in the blood are bound to plasma proteins.

Elimination

In patients with normal renal function, the elimination half-life (t_½) of digoxin is 36 hours and the t_½ of digitoxin is usually 5-7 days. The elimination t_½ of digoxin is increased in patients with impaired renal function; elimination t_½ of digitoxin is not prolonged in patients with renal insufficiency. In contrast to digoxin, biliary fistula drainage causes a marked decrease in digitoxin plasma t_½. In undigitalized patients, institution of fixed daily maintenance doses of cardiac glycosides without an initial loading dose results in steady-state plasma concentrations after 4-5 elimination t_½s.

Cardiac glycosides undergo varying degrees of hepatic metabolism, enterohepatic circulation, and renal filtration and reabsorption depending on their polarity and lipid solubility. Digoxin, which is more polar than digitoxin, undergoes less enterohepatic circulation. Highly polar glycosides, such as digoxin, are not metabolized appreciably, but less polar glycosides such as digitoxin are metabolized extensively before they are excreted. Metabolism includes stepwise cleavage of the sugar molecules, hydroxylation, epimerization, and formation of glucuronide and sulfate conjugates.

The glycosides and their metabolites are excreted primarily by the kidneys but vary widely in their rates of excretion. The cardiac glycosides and their metabolites are also excreted in feces. All cardiac glycosides are eliminated from the body by first-order kinetics, with a fixed proportion of the residual drug in the body being eliminated each day. Increased rate of urine flow apparently does not increase elimination of cardiac glycosides from the body. 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. Cardiac glycosides are not appreciably removed by hemodialysis or peritoneal dialysis. Similarly, only minor amounts of digoxin are removed during cardiopulmonary bypass or exchange transfusion.