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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.
Last updated: September 1, 2022
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
CONTENTS
Chemistry and Pharmacodynamics
Pharmacokinetics
Indications
Adverse Effects
Overdose
References
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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:
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+.
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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
Typical “scooped” ST-depression resulting from digoxin use.
Image: “F15: An ECG with characteristic scooping ST segment depressionin a patient taking Digoxin.” by Christopher
Yates and Alex F Manini. License: CC BY 2.5
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:
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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
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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
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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
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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
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heart