Cardiac Glycosides

Cardiac glycosides are a class of drugs reversibly inhibiting the sodium-potassium ATPase pump in myocardial cells and increasing vagal tone, which results in increased cardiac contractility and slowed conduction through the atrioventricular node. Digoxin is the only medically used drug in the cardiac glycoside class. Digoxin can be used for rate control in atrial fibrillation/flutter and for systolic heart failure. However, the medication needs to be used with caution due to a very narrow therapeutic window. Digoxin toxicity can result in life-threatening arrhythmias as well as GI and neurologic symptoms; an antidote is available.

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Chemistry and Pharmacodynamics

Chemical structure

Digoxin is the prototype drug of the cardiac glycoside class and the only drug in the class used for medicinal purposes.

  • Steroid nucleus with 4 fused rings
  • Lactone ring 
  • Glycoside attachment composed of 3 sugars
Chemical structure of digoxin cardiac glycosides

The chemical structure of digoxin:
Notice the steroid nucleus (4 fused rings) with an attached lactone ring (far right) and glycoside attachment (left).

Image: “The chemical structure of digoxin” by Edgar181. License: Public Domain

Mechanism of action

  • Digoxin reversibly inhibits the Na+-K+ ATPase of myocytes, resulting in:
    • ↑ Intracellular Na+ → ↓ Na+-calcium (Ca2+) antiporter exchange → ↓ Ca2+ efflux 
    • ↑ Intracellular Ca2+ → ↑ Ca2+ binding to contractile proteins → ↑ cardiac contractility 
  • ↑ Vagal tone: 
    • ↑ Refractory period → ↓ conduction velocity in the atrioventricular (AV) node
    • ↓ Sinoatrial (SA) node automaticity
Mechanism of action of digoxin

Mechanism of action of digoxin:
Inhibition of sodium (Na+)-potassium (K+) ATPase leads to increased intracellular Na+, which lowers the exchange of the Na+-calcium (Ca2+) antiporter and inhibits the efflux of Ca2+.
More intracellular Ca2+ can bind to contractile proteins (such as troponin (TN-C)), resulting in increased cardiac contractility.

Image by Lecturio. License: CC BY-NC-SA 4.0

Physiologic effects

  • ↑ Cardiac contractility (positive inotropy) → ↑ cardiac output
  • AV and SA node slowing → ↓ heart rate
  • Blood pressure is not significantly impacted.
  • May cause characteristic changes to a resting ECG (“digitalis effect”): 
    • ↑ PR interval (due to ↓ AV conduction)
    • ↓ QT interval
    • Classic finding: “scooped” ST-segment depressions
    • Flattened or inverted T wave
ECG Typical “scooped” ST-depression resulting from digoxin use

Typical “scooped” ST-segment depression resulting from digoxin use

Image: “Typical for digoxin intoxication is the oddly shaped ST-depression” by I.A.C. van der Bilt, MD. License: CC BY-NC-SA 3.0

Pharmacokinetics

Absorption

  • Oral and IV forms are available.
  • Oral absorption:
    • Passive, nonsaturable diffusion in the proximal small intestine
    • Food may delay, but not impact, the extent of absorption.

Distribution

  • Extensive in peripheral tissues:
    • Distribution phase: 6–8 hours
    • Higher concentrations in heart, liver, kidney, and skeletal muscle
  • Protein binding:
    • Approximately 25% is protein bound.
    • Uremic patients: Digoxin is displaced from plasma protein binding sites.

Metabolism and excretion

  • Minimal hepatic metabolism:
    • Approximately 16% of an absorbed dose is metabolized to active metabolites.
    • Does not interact with the cytochrome P450 system
  • Predominantly excreted in the urine (50%–70% as an unchanged drug)

Indications

Congestive heart failure

  • 2nd-line therapy for heart failure with reduced ejection fraction:
    • Provides a positive inotropic effect
    • ↓ Symptoms of heart failure and the need for hospitalization
    • Not shown to improve mortality
  • 1st-line choice in patients with heart failure with reduced ejection fraction complicated by atrial fibrillation.

Arrhythmia

Digoxin is indicated for rate control when other therapies are ineffective or contraindicated:

  • Atrial fibrillation
  • Atrial flutter
  • Supraventricular tachycardia

Adverse Effects

Adverse effects

Digoxin has a very narrow therapeutic window and several signs of toxicity:

  • Arrhythmias can occur through multiple mechanisms:
    • ↑ Intracellular Ca2+ → delayed afterdepolarizations and ↑ automaticity
    • Slowed conduction
  • GI symptoms:
    • Nausea
    • Vomiting
    • Diarrhea
    • Anorexia
  • Neurologic symptoms:
    • Confusion
    • Weakness
    • Yellow vision (xanthopsia)

Warnings and precautions

  • As with all AV node-blocking agents, digoxin should not be used in supraventricular tachyarrhythmias caused by an accessory pathway (e.g., Wolff-Parkinson-White syndrome).
  • Avoid in sinus node disease and AV block
  • Acute coronary syndrome: 
    • Use caution in patients with an acute MI.
    • May ↑ myocardial oxygen demand → ischemia
  • Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction:
    • Outflow obstruction may worsen.
    • Due to digoxin’s positive inotropic effects
  • Thyroid disease: 
    • Use caution in patients with hypothyroidism or hyperthyroidism.
    • May cause significant changes in digoxin clearance

Drug interactions

Drug interactions may lead to:

  • ↑ AV blocking/bradycardic effect:
    • Calcium channel blockers
    • Beta blockers
    • Dronedarone
    • Lacosamide
  • ↑ Risk of toxicity due to:
    • ↑ Digoxin concentration:
      • Amiodarone
      • Quinidine
      • Spironolactone
    • Hypokalemia and/or hypomagnesemia:
      • Loop diuretics
      • Thiazide diuretics

Overdose

Risk factors

  • Factors affecting digoxin levels:
    • Advanced age
    • Low lean body mass
    • Renal impairment
    • Certain medications
  • Potential triggers for toxicity:
    • Hypokalemia
    • Hypomagnesemia
    • Hypercalcemia

Clinical presentation

  • Arrhythmia:
    • The most serious manifestation of digoxin overdose
    • May be any type of arrhythmia (except rapidly-conducted atrial arrhythmias)
    • May be life-threatening
  • GI symptoms:
    • Anorexia
    • Nausea
    • Vomiting
    • Abdominal pain
  • Neurologic symptoms:
    • Confusion
    • Weakness
    • Vision changes

Laboratory evaluation

  • Serum digoxin concentration: 
    • ↑ Level is indicative of toxicity.
    • Draw 4–6 hours after the dose to avoid false elevation.
    • Level does not always correlate with toxicity.
  • ↑ Serum K+ level:
    • Due to Na+-K+ ATPase inhibition
    • Degree of elevation correlates with mortality risk
    • Note: Hypokalemia is a potential trigger for digoxin toxicity.
  • BUN and creatinine → renal dysfunction may be a precipitating factor
  • ECG:
    • Evaluate for arrhythmia
    • Note: The “digitalis effect” does not correlate with toxicity.

Management

  • Antidote: digoxin-specific antibody (Fab) fragments
  • Supportive treatment:
    • Bradyarrhythmias: atropine or temporary pacemaker
    • Hypotension: bolus IV fluids
    • Correct electrolyte abnormalities.
    • Life-threatening arrhythmia treatment
  • Activated charcoal can be given for acute digoxin intoxication within 1–2 hours.

References

  1. Katzung, B.G. (2012). Drugs used in heart failure. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 211-225). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  2. Kumar, K., and Zimetbaum, P. (2021). Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials. In Knight, B. (Ed.), UpToDate. Retrieved July 6, 2021, from https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials
  3. Makielski, J., and Eckhardt, L. (2021). Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs. In Levy, S. (Ed.), UpToDate. Retrieved July 7, 2021, from https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs
  4. Levine, M., and O’Connor, A. (2021). Digitalis (cardiac glycoside) poisoning. In Traub, S. and Burns, M. (Ed.), UpToDate. Retrieved July 7, 2021, from https://www.uptodate.com/contents/digitalis-cardiac-glycoside-poisoning
  5. Giardina, E., and Sylvia, L. (2021). Treatment with digoxin: Initial dosing, monitoring, and dose modification. In Dardas, T. (Ed.), UpToDate. Retrieved July 7, 2021, from https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification
  6. Wyse D.G., Waldo A.L., DiMarco J.P., et al. (2002). A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med; 347:1825. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/abstract/1
  7. Falk R.H. (2001). Atrial fibrillation. N Engl J Med; 344:1067. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/abstract/3
  8. Dan G.A., Martinez-Rubio A., Agewall S., et al. (2018). Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/abstract/4 
  9. Busti, A.J. (2015). The mechanism of digoxin’s increase in inotropy (force of contraction of the heart). In Evidence-Based Medicine Consult. Retrieved July 22, 2021, from https://www.ebmconsult.com/articles/mechanism-of-action-digoxin-inotropy-force-contraction-heart

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