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 Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. 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 Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Overview of Antidotes is available.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

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 ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (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 Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • Oral and IV forms are available.
  • Oral absorption:
    • Passive, nonsaturable diffusion in the proximal small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. 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 Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation.

Arrhythmia

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

  • Atrial fibrillation
  • Atrial flutter Atrial flutter Atrial flutter is a regular supraventricular tachycardia characterized by an atrial heart rate between 240/min and 340/min (typically 300/min), atrioventricular (AV) node conduction block, and a "sawtooth" pattern on an electrocardiogram (ECG). Atrial Flutter
  • Supraventricular tachycardia Supraventricular tachycardia Supraventricular tachycardias are related disorders in which the elevation in heart rate is driven by pathophysiology in the atria. This group falls under the larger umbrella of tachyarrhythmias and includes paroxysmal supraventricular tachycardias (PSVTs), ventricular pre-excitation syndromes (i.e. Wolff-Parkinson-White syndrome), atrial flutter, multifocal atrial tachycardia, and atrial fibrillation. Supraventricular Tachycardias

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 Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block
  • Acute coronary syndrome: 
    • Use caution in patients with an acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction.
    • May ↑ myocardial oxygen demand → ischemia
  • Hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. 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 Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism or hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism.
    • May cause significant changes in digoxin clearance

Drug interactions

Drug interactions may lead to:

  • ↑ AV blocking/bradycardic effect:
    • Calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
    • Beta blockers
    • Dronedarone
    • Lacosamide
  • ↑ Risk of toxicity due to:
    • ↑ Digoxin concentration:
      • Amiodarone
      • Quinidine
      • Spironolactone
    • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia and/or hypomagnesemia:
      • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics
      • Thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics

Overdose

Risk factors

  • Factors affecting digoxin levels:
    • Advanced age
    • Low lean body mass
    • Renal impairment
    • Certain medications
  • Potential triggers for toxicity:
    • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
    • Hypomagnesemia
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia is a potential trigger for digoxin toxicity.
  • BUN and creatinine → renal dysfunction may be a precipitating factor
  • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG):
    • Evaluate for arrhythmia
    • Note: The “digitalis effect” does not correlate with toxicity.

Management

  • Antidote: digoxin-specific antibody (Fab) fragments
  • Supportive treatment:
    • Bradyarrhythmias Bradyarrhythmias Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias: atropine or temporary pacemaker
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension: bolus IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous 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

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details