Management

Digoxin Toxicity - Emergency Management

Editors: Helen W. Hou PharmD, BCEMP, BCPS; Anita K. Mudan MD; Jacob A. Lebin MD; Rachel Chin MD

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Background Information

Description

  • Digoxin is a commonly prescribed agent used for rate control in atrial fibrillation and heart failure in adults and children
    • Available as digoxin in the United States as well as select European, Scandinavian, and other countries
    • Digitoxin is not approved by the United States Food and Drug Administration for clinical use, but it is still available as a prescription drug in certain countries in Europe
  • Cardioactive steroids are found throughout nature in various plants (such as red squill, foxglove, oleander, yellow oleander, lily of the valley, milkweed, dogbane), animals, (such as the bufo toad) and insects (such as Photinus species of fireflies)
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Pharmacokinetics

  • Digoxin oral dose is absorbed within 1-2 hours with secondary redistribution into tissues within 6 hours
  • Digoxin is renally eliminated
  • Digoxin elimination half-life is 36 hours; elimination half-life may increase with toxic serum concentrations and very elderly patients
  • Many conditions and medications can alter serum digoxin levels
    • Decreased renal function may impair digoxin excretion, leading to higher serum levels and clinical symptoms of toxicity
      • Medications
        • Angiotensin-converting enzyme (ACE) inhibitors
        • Angiotensin receptor blocker
        • Nonsteroidal anti-inflammatory drugs
        • Cyclooxygenase-2 (COX-2) inhibitors
        • Spironolactone
        • Cyclosporine
      • Acute kidney injury or chronic kidney disease
    • Drugs that increase bioavailability within the gastrointestinal (GI) tract may increase serum digoxin levels, leading to toxicity
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      • Antibiotics: macrolides (for example, erythromycin, azithromycin), tetracycline
      • P-glycoprotein inhibitors (for example, clarithromycin, verapamil, amiodarone, quinidine)
    • Conditions and medications that decrease serum digoxin levels
      • Medications that bind directly to digoxin in the GI tract (for example, cholestyramine, antacids)
      • Medications that induce P-glycoprotein in the intestine (for example, rifampin, St. John wort)
  • Digitoxin pharmacokinetics differ from that of digoxin
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    • Digitoxin is primarily eliminated by hepatic metabolism and less dependent on renal function for elimination compared to digoxin
    • Digitoxin has a longer elimination half-life compared to digoxin, ranging from 2.4 to 16.4 days with an average of 7.6 days in contrast to 1 to 2 days for digoxin

Mechanism of Action

  • Digoxin increases myocardial intracellular calcium influx indirectly by interfering with Na+-K+ ATPase function
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    • Increased myocardial cytoplasmic calcium will decrease the heart rate by slowing transmission of impulse through the atrioventricular (AV) node (negative chronotropy)
    • Increased cytosolic calcium causes additional calcium release from the sarcoplasmic reticulum leading to increased interaction of actin-myosin, which results in increased cardiac contractile force (positive inotropy)

Additional Information

  • Risk factors for digoxin toxicity
    • Extremes of age
    • Acute kidney injury
    • Decompensation of underlying cardiovascular disease (for example, heart failure, atrial fibrillation)
    • Co-ingestion of medications that also cause hypotension and bradycardia (such as beta-blockers, calcium channel blockers, clonidine)
    • Intentional overdose
    • Hypokalemia
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