Digoxin Use in Modern Medicine

Shan Chen, PharmD Candidate; Troy Khusial, PharmD Candidate; Dipen Patel, PharmD Candidate; Satinder Singh, PharmD Candidate; Tatyana Yakubova, PharmD Candidate; Amy Wang, PharmD, BCPS, MBA; Timothy Nguyen, PharmD, BCPS, CCP, FASCP

Disclosures

US Pharmacist. 2015;40(2):44-48.

Abstract and Introduction

Abstract

Digoxin, a cardiac glycoside, has inotropic effects in addition to effects on cardiac output. It is used to treat heart failure and atrial fibrillation and has other off-label uses. Digoxin has been shown to reduce hospitalization rates without affecting mortality rates in patients with heart failure. Digoxin is effective for rate control in patients with atrial fibrillation, but its influence on mortality rates is a source of controversy. The use of digoxin is limited because the drug has a narrow therapeutic index and requires close monitoring. Digoxin can cause many adverse events, is involved in multiple drug interactions, and can result in toxicity. Despite its limitations, however, digoxin has a place in therapy.

Introduction

Digoxin is a cardiac glycoside derived from the purple foxglove flower. In 1785, the English chemist, botanist, and physician Sir William Withering published his findings that Digitalis purpurea could be used to treat cardiac dropsy (congestive heart failure; CHF).^[1] Digoxin has been in use for many years, but was not approved by the FDA for treatment of heart failure (HF) until the late 1990s.^[2,3] Another FDA indication for digoxin is atrial fibrillation (AF).^[3] Digoxin also has numerous off-label uses, such as in fetal tachycardia, supra-ventricular tachycardia, cor pulmonale, and pulmonary hypertension.^[3]

Digoxin acts by inhibiting the sodium-potassium adenosine triphosphatase pump, promoting sodiumcalcium exchange; this results in an upsurge of intracellular calcium, thereby increasing myocardial contractility. Digoxin also has parasympathomimetic properties. By increasing vagal tone in the sinoatrial and atrioventricular (AV) nodes, it slows the heart rate and AV nodal conduction.^[4] Table 1 provides a brief overview of digoxin.

Digoxin has been around for centuries, but its use has been limited by several factors. Because of its narrow therapeutic window, digoxin requires close monitoring. Also, two major drawbacks of digoxin are its adverse effects (AEs) and multiple drug interactions. Despite these limitations, digoxin still plays a role in therapy for HF, AF, and several off-label uses. It is considered adjunctive therapy, rather than first-line therapy, for these indications.^[5,6]

According to current guidelines, digoxin may be used as additive therapy with beta-blockers and/or ACE inhibitors/angiotensin receptor blockers (ACEIs/ARBs) in the management of CHF.^[5] Digoxin possesses negative chronotropic properties and has been shown to decrease morbidity in patients with AF. It is used mainly as add-on therapy in AF patients whose heart rates are not adequately controlled on beta-blockers alone.^[6] Because of its positive inotropic effects, digoxin may have benefits in pulmonary arterial hypertension (PAH), but more studies are needed to assess long-term effects in this patient population.^[7]

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Table 1. Brief Summary of Digoxin
Dosing	Dosage Adjustment	Target Serum Concentration	Bioavailability	Pharmacokinetics
Heart Failure
LD: not recommended; MD: 0.125–0.2 mg daily	MD: CrCl >120 mL/min—0.25 mg once daily; CrCl 80–120 mL/min—0.25 mg alternating with 0.125 mg once daily; CrCl 30–80 mL/min—0.125 mg once daily; CrCl <30 mL/min—0.125 mg q48h. Patients >70 y should receive 0.125 mg daily or every other day. Reduce by 50% in ESRD	0.5–0.9 ng/mL	Oral: 70%; capsule: 90%; elixir: 80%; IV: 100%	Onset of action: IV—15–30 min; po—30–120 min Peak effect: IV— 1–3 h; po—2–6 h
Atrial Fibrillation
LD: 0.25 mg po/IV q2h (max 1.5 mg/24 h); MD: 0.125–0.375 mg po/IV daily	MD: CrCl >50 mL/min—no adjustment necessary; CrCl 10–50 mL/min—25%-75% of normal daily dosage q36h; CrCl <10 mL/min—10%-25% of normal daily dosage q48h. Continuous RRT: 25%-75% of normal daily dosage q36h	0.8–1.2 ng/mL	NA	NA

CrCl: creatinine clearance; ESRD: end-stage renal disease; LD: loading dose; max: maximum; MD: maintenance dose; min: minute; NA: not applicable; RRT: renal replacement therapy.
Source: References 2, 3, 5, 6.

Table 2. Digoxin Drug Interactions
Precipitant	Effect on Digoxin Concentration	Comments
Alprazolam	Increase	Elderly patients are especially likely to have elevated serum digoxin concentrations. Possible mechanism: reduced renal clearance of digoxin. Monitor concentrations and observe patient for digoxin toxicity
Aluminum salts (aluminum hydroxide, magaldrate)	Decrease	Digoxin absorption is decreased. Give digoxin 2 h before administering aluminum salts
Amphotericin B	Increase	Amphotericin B–induced hypokalemia may increase risk of digoxin toxicity
Antiarrhythmics (amiodarone, dronedarone, propafenone, quinidine)	Increase	These agents inhibit Pgp, thereby reducing digoxin clearance. Consider reducing digoxin by 30%-50% upon initiating antiarrhythmic
Anticholinergics	Increase	Decrease in GI motility may cause increased digoxin absorption
Antineoplastics (bleomycin, carmustine, cyclophosphamide, cytarabine, doxorubicin, methotrexate, vincristine)	Decrease	Decreased GI absorption of digoxin may lead to decreased digoxin concentrations. Substitute liquid form or liquid-containing digoxin capsules for tablet form
Azole antifungals (itraconazole, ketoconazole)	Increase	Inhibition of digoxin metabolism and clearance responsible for increased digoxin concentrations. Monitoring and possible dosage reductions of digoxin are warranted
Beta-blockers	Increase	Digoxin and beta-blockers slow AV conduction and decrease HR, increasing risk of bradycardia. Carvedilol may elevate digoxin concentrations, increasing risk of toxicity. Monitor digoxin concentrations and HR. Consider 25% dosage reduction in children
Bile-acid sequestrants	Decrease	These agents bind to digoxin, decreasing GI absorption and enterohepatic recycling. Separate administration of sequestrant and digoxin by as much as possible and adjust digoxin dosage as needed
CCBs (diltiazem, nifedipine, verapamil)	Increase	Non-DHP CCBs (e.g., verapamil, diltiazem) in combination may be helpful in controlling AF, but additive effects on AV-node conduction may result in heart block. Diltiazem, nisoldipine, and verapamil may increase digoxin concentrations by inhibiting renal and/or extrarenal digoxin clearance. Monitor serum digoxin concentrations closely and adjust dosage accordingly
Corticosteroids	Increase	Electrolyte disturbances caused by corticosteroids may predispose patient to digitalis-induced arrhythmia. Monitor potassium and magnesium, supplementing if necessary
Loop diuretics (furosemide)	Increase	Diuretics may cause electrolyte disturbances and predispose patient to digitalis-induced arrhythmia. Monitor potassium and magnesium, supplementing if necessary
Macrolide antibiotics (azithromycin, clarithromycin, erythromycin)	Increase	Antibiotics decrease inactivation of digoxin by bacterial metabolism in lower intestine, increasing digoxin's bioavailability. Effect may persist several wk after antibiotic stopped
Metoclopramide	Decrease	Increase in GI motility may cause decreased digoxin absorption
Potassium-sparing diuretics (amiloride, spironolactone)	Increase/decrease	May decrease positive inotropic effects of digoxin, and digoxin serum concentrations may be elevated. Spironolactone interferes with digoxin assay, resulting in falsely elevated concentrations. Monitor patient closely and watch for potentially false digoxin concentrations
Quinine	Increase	Concomitant use causes decreased biliary clearance of digoxin, which increases digoxin serum concentration and risk of toxicity
Rifamycins (rifampin)	Decrease	May increase digoxin clearance, leading to decreased serum digoxin concentrations
SSRIs (fluoxetine, paroxetine)	Increase	May displace digoxin from protein binding, resulting in increased serum digoxin concentrations
St. John's wort	Decrease	This Pgp inducer speeds up digoxin metabolism, leading to decreased digoxin concentrations
Sucralfate	Decrease	Concomitant use may result in decreased digoxin concentrations and efficacy. Separate administration by ≥2 h
Sympathomimetics (dopamine, epinephrine)	Increase	Coadministration may cause increased risk of cardiac arrhythmias. Mechanism unknown
Telmisartan	Increase	Coadministration leads to ~50% increase in peak digoxin levels and 20% increase in trough digoxin levels, which may cause toxicity
Tetracyclines	Increase	Tetracycline may alter GI flora, allowing for increased digoxin absorption
Thiazide diuretics (hydrochlorothiazide)	Increase	Diuretic-induced electrolyte disturbances may predispose patients to digoxin toxicity. Monitor potassium and magnesium, supplementing if needed
Thioamines (methimazole, propylthiouracil)	Increase	Hyperthyroid patients who become euthyroid have decreased digoxin clearance, leading to increased serum digoxin concentrations
Thyroid hormone (levothyroxine)	Decrease	Hypothyroid patients who become euthyroid develop increased digoxin clearance, resulting in decreased serum digoxin concentrations
Vasopressin receptor antagonists (conivaptan)	Increase	Conivaptan decreases digoxin clearance; this may increase serum digoxin concentrations, causing toxicity

AF: atrial fibrillation; AV: atrioventricular; CCB: calcium channel blocker; DHP: dihydropyridine; GI: gastrointestinal; HR: heart rate; Pgp: P-glycoprotein; SSRI: selective serotonin reuptake inhibitor.
Source: References 2, 3.

Table 3. Common Signs and Symptoms of Digoxin Toxicity
Noncardiac Adverse Effects Anorexia Nausea/vomiting Abdominal pain Visual disturbances: halos, photophobia, red-green or yellow-green vision Fatigue, weakness Confusion, delirium, psychosis	Cardiac Adverse Effects Ventricular arrhythmias Atrioventricular block Atrial arrhythmias Sinus bradycardia

Source: References 2, 3.

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Digoxin Use in Modern Medicine

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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