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Review

Digoxin is still useful, but is still causing toxicity

Alejandro Durán Crane, MD, Michael Militello, PharmD, BCPS and Michael D. Faulx, MD
Cleveland Clinic Journal of Medicine August 2024, 91 (8) 489-499; DOI: https://doi.org/10.3949/ccjm.91a.23105
Alejandro Durán Crane
Cardiovascular Medicine Fellow, Cleveland Clinic, Cleveland, OH
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Michael Militello
Cardiology Clinical Pharmacist, Pharmacotherapy Residency Program Director, Cleveland Clinic, Cleveland, OH
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Michael D. Faulx
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
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    Figure 1

    Bidirectional ventricular tachycardia in a patient with digoxin toxicity. The QRS axis alternates with each QRS complex (see rhythm strip for lead II).

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    Figure 2

    Electrocardiogram showing “sagging” ST depressions, most notably in leads V3–V6 and lead II, and ventricular ectopy in a patient with digoxin toxicity with a serum level of 8.0 ng/mL (normal range 0.6–1.2).

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    Figure 3

    Treatment of severe digoxin toxicity with digoxin-fab.

    aThe calculated number of vials should be rounded up to the nearest digit. Each vial contains 38 to 40 mg of digoxin-fab.

    Based on information from reference 29.

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    TABLE 1

    Dosing recommendations for digoxin therapy

    IndicationDosingDesired serum concentrationComments
    Symptomatic heart failure with reduced ejection fraction despite guideline-directed medical therapy0.125–0.25 mg daily, modified according to nomogram of Jelliffe and Brooker60.5–0.9 ng/mLNo need for loading dose
    Low doses (0.125 mg daily or every other day) should be used initially if the patient is > 70 years, has impaired renal function, or has a low lean body mass
    Rate control in atrial fibrillation with decreased left ventricular function or hemodynamic instabilityLoading dose: 0.25 mg intravenously with repeat dosing every 6 hours to a maximum of 1.5 mg over 24 hours
    Maintenance dose: 0.125–0.25 mg daily
    0.5–1.2 ng/mLFor individuals with low body weight (45–70 kg) and renal dysfunction, loading doses should be reduced to 0.7 to 1.0 mg in the first 24 hours
    • Based on information from references 3–5.

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    TABLE 2

    Drug interactions that increase the risk of digoxin toxicity

    MedicationMechanism of interactionComments
    Amiodarone, quinidine, dronedarone, nondihydropyridine calcium channel blockers (diltiazem and verapamil), propafenone, flecainide, clarithromycin, cyclosporine, itraconazoleInhibition of P-glycoprotein, a drug efflux pump that mediates secretion of digoxin in the kidney, liver, and gutDigoxin dose may have to be decreased to half when starting any of these medications
    Check digoxin levels 1 week after starting any P-glycoprotein inhibitor
    Macrolides (azithromycin, clarithromycin, erythromycin) and tetracyclineDecreased initial degradation of digoxin by gut microflora, leading to increased drug absorptionMonitor levels closely when co-administering digoxin with these antibiotics
    Diuretics, amphotericin BDecreased glomerular filtration rate and hypokalemia can increase digoxin toxicityMonitor potassium levels to avoid hypokalemia
    Nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, cyclosporineDecreased glomerular filtration rate and acute kidney injuryTelmisartan increases digoxin concentration by about 50%
    Beta-blockers, nondihydropyridine calcium channel blockersSlowing of atrioventricular conduction can lead to bradycardia compounding on digoxin’s vagotonic effectsIncreased risk of bradycardia; carvedilol can increase digoxin concentration
    Amiodarone, sotalol, quinidine, procainamide, dofetilide, ibutilide, quinolones, macrolides, azole antifungals, tricyclic antidepressants, antipsychotics, methadoneQT-prolonging agents increase risk of life-threatening arrhythmias as digoxin increases early afterdepolarizations, which can lead to R-on-T phenomenon and torsade de pointesMonitor QT closely when adding any of these medications
    • Based on information from references 17 and 18.

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    TABLE 3

    Risk factors for digoxin toxicity

    Risk factorComments
    Advanced ageReduced volume of distribution due to lower muscle mass and reduced renal drug clearance can lead to higher serum concentrations of digoxin in the elderly
    Digoxin use has been linked to higher mortality in patients age 65 and older with atrial fibrillation and heart failure19
    Renal dysfunctionDigoxin is primarily excreted by the kidneys and its clearance is directly proportional to the glomerular filtration rate
    Reduced renal clearance results in higher serum digoxin concentration, and dose should be reduced in patients with renal dysfunction
    Any condition that leads to acute renal injury (eg, dehydration, sepsis, glomerular or tubular disease, or decompensated heart failure) can predispose to toxicity
    Digoxin use in patients with end-stage kidney disease undergoing hemodialysis is associated with a 28% increase in mortality and is therefore not recommended20
    If needed in end-stage kidney disease, a loading dose of 3 to 5 μg/kg (0.25–0.375 mg) is recommended, followed by a maintenance dose of 0.0625 mg every 48 hours
    HypokalemiaDecreased potassium levels result in decreased competition for the binding spot of digoxin in sodium-potassium adenosine triphosphatase, favoring binding of digoxin to the ionic pump17
    Drug interactionsDiuretics, antiarrhythmic drugs, and antibiotics can increase serum digoxin concentration or enhance digoxin action17,18
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    TABLE 4

    Clinical manifestations of digoxin toxicity

    Cardiac
    Tachyarrhythmias
     Bidirectional ventricular tachycardia
     Ventricular tachycardia
     Ventricular fibrillation
     Atrial fibrillation
     Supraventricular tachycardia
    Bradyarrhythmias
     Sinus bradycardia
     Atrioventricular block
     Asystole
    Increased ectopy
     Atrial ectopy
     Ventricular ectopy
     Ventricular bigeminy
    Gastrointestinal
    Nausea
    Vomiting
    Abdominal pain
    Mesenteric ischemia and diarrhea (rare)
    Central nervous system
    Color perception disturbances (xanthochromia)
    Visual disturbances (halos)
    Headaches
    Confusion
    Apathy
    Electrolyte abnormalities
    Hyperkalemia
    Constitutional
    Fatigue
    Anorexia
    • Based on information from references 15,19,20,22,23.

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Cleveland Clinic Journal of Medicine: 91 (8)
Cleveland Clinic Journal of Medicine
Vol. 91, Issue 8
1 Aug 2024
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Digoxin is still useful, but is still causing toxicity
Alejandro Durán Crane, Michael Militello, Michael D. Faulx
Cleveland Clinic Journal of Medicine Aug 2024, 91 (8) 489-499; DOI: 10.3949/ccjm.91a.23105

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Digoxin is still useful, but is still causing toxicity
Alejandro Durán Crane, Michael Militello, Michael D. Faulx
Cleveland Clinic Journal of Medicine Aug 2024, 91 (8) 489-499; DOI: 10.3949/ccjm.91a.23105
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  • Article
    • ABSTRACT
    • DIGOXIN’S CLINICAL USES
    • DIGOXIN HAS INOTROPIC AND OTHER EFFECTS
    • PHARMACOKINETICS AND DOSING
    • MANY DRUGS INCREASE DIGOXIN LEVELS
    • INTERACTIONS WITH CATIONS
    • CLINICAL PRESENTATION OF TOXICITY
    • MEASURING DIGOXIN LEVELS
    • MANAGEMENT OF DIGOXIN TOXICITY
    • A CHANGING LANDSCAPE
    • DISCLOSURES
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