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.

Digoxin and HF

CHF is a myocardial dysfunction caused by the contractile performance of the heart, ventricular relaxation/filling of the heart, or both. In CHF, contractility is decreased, which in turn reduces cardiac output. Digoxin is effective in patients with CHF because of its positive inotropic properties. Although studies have shown that digoxin reduces hospitalizations and improves symptoms of HF, it has not been proven to decrease mortality.

Digoxin's role in HF has been assessed in numerous trials. One double-blind, controlled trial of digoxin for CHF treatment randomized subjects with cardiac dysfunction to digoxin or placebo for 7 weeks.^[8] Placebo subjects deteriorated more quickly than those taking digoxin. Cardiac function, as measured by ejection fraction (EF), was significantly improved in digoxin patients.^[8] Many other clinical trials showed that digoxin's positive inotropic effects were useful in the management of CHF.

According to the 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline on managing HF, digoxin improves symptoms, quality of life, and exercise tolerance in patients with mild-to-moderate HF, regardless of the underlying rhythm (normal sinus rhythm or AF).^[5] Therefore, digoxin may be considered as add-on therapy for patients who have persistent symptoms of HF despite treatment with ACEI/ARBs and/or beta-blockers. Digoxin may also be considered in patients with stage C HF (structural heart disease with prior or current symptoms of HF) or stage D HF (HF symptoms at rest and recurrent hospitalizations despite therapy). HF patients should not take digoxin without an ACEI or beta-blocker. Although digoxin is prescribed for patients with HF and AF, concomitant beta-blocker therapy is usually more effective at controlling ventricular response, particularly during exercise.^[5,6]

The initial dosage of digoxin is 0.125 mg to 0.25 mg by mouth daily. The dosage must be adjusted based on renal function and age (Table 1). The target serum level of digoxin in HF is 0.5 ng/mL to 0.9 ng/mL.^[5]

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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

Digoxin and HF

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