Cardiac Glycosides

Cardiac Glycosides: Digoxin, Mechanism of Action, Dosage and Toxicity

  • Pharmacology
  • Cardiac Glycosides
  • 2020-08-04 04:19:58
  • 10 minutes, 3 seconds

Cardiac Glycosides: Digoxin, Mechanism of Action, Dosage and Toxicity

Digoxin belongs to a class of drugs known as cardiac glycosides. These are organic compounds derived from a plant known as foxglove and used in the treatment of heart conditions. These compounds are known to have positive inotropy meaning that they have the ability to increase the force of contraction of the heart muscle.

Examples of cardiac glycosides

There are many drugs under the class of cardiac glycosides. The most common ones are

  1. Digoxin
  2. Digitoxin
  3. Ouabain

But for this article, we shall be highly interested in the most commonly used drug among the cardiac glycosides; Digoxin.

Digoxin is an antiarrhythmic drug. This simply means that it is used in treating arrhythmias which are abnormal heartbeats.  Arrhythmias are of various types but digoxin is used in arrhythmias affecting the atria. Atria are the upper chambers of the heart. Examples of arrhythmias affecting the atria are atrial fibrillation and atrial flutter.

Digoxin is also used to treat heart failure(HF).

What are the Mechanisms of action of cardiac glycosides?

When looking at the mechanism of action we need to consider two modes of action by which digoxin works.

We need to look at how, how digoxin works for arrhythmias (atrial fibrillation and atrial flutter) and how it works in cases of heart failure.

How does digoxin work in arrhythmias?

In arrhythmias, digoxin exerts its action by increasing vagal tone. This means that it increases the effects that lead to reduced conduction through the atrioventricular node which is located between the upper and lower chambers of the heart. With a reduced conduction fewer impulses pass through the AV node to the ventricles eventually reducing the ventricular rate. We can say that digoxin has a knock-on effect on the ventricles.

How does digoxin work in heart failure?

For a better understanding of how digoxin works in heart failure, we shall look at the basic physiology of how the heart muscle contracts and how heart failure occurs.

In heart failure, the heart doesn’t completely stop functioning but instead, it is functioning sub-optimally. This means that it is unable to pump blood effectively to need the demands of the body. The muscles contract weakly and in turn, there is low cardiac output. This means that it is unable to pump all the blood that gets in. As more blood gets to the heart and less getting out, the heart becomes congested. This is known as congestive heart failure.

We recommend that you have a look at this article on congestive heart failure.

Having understood what is heart failure, let us look at how the heart muscles work.

For the heart muscle to contract there has to be an interplay between some amount of electrolytes, sodium ions, potassium ions, and calcium ions. These ions are on either side of the cell membranes in the heart muscle cells.

The electrolytes move from either side of the cell membrane of the heart muscle to the other through the sodium-potassium pump (Na/K –ATPase). This ion transport system moves sodium ions out of the cell and brings potassium ions into the cell.

The Na+/K+-ATPase also plays an active role in the membrane potential. This pump is electrogenic because it transports 3 sodium ions out of the cell for every 2 potassium ions that enter the cell. This can add several negative millivolts to the membrane potential depending on the activity of the pump.

Calcium and sodium can move in either direction across the sarcolemma.

Three sodium ions are exchanged for each calcium ion. This causes the generation of an electrogenic potential by this exchanger. The direction of movement of these ions depends upon the membrane potential and the chemical gradient for the ions. We also know that an increase in intracellular sodium concentration competes for calcium through this sodium-calcium exchange mechanism increasing the intracellular calcium concentration.

An increase in intracellular sodium ion concentration reduces the concentration gradient driving sodium into the cell across the exchanger. This reduces the exchanger activity, which decreases the movement of calcium out of the cell.

Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a subsequent accumulation of intracellular calcium because of decreased exchange pump activity.

By inhibiting the Na+/K+-ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This leads to an increase in intracellular calcium concentration through the Na+-Ca++ exchange system.

In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum making more calcium ions to be available to bind to troponin-C, which increases contractility (inotropy) of the heart muscle.

Inhibition of the Na+/K+-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction.

Some cardiac arrhythmias occur because of malfunctioning of this sodium-potassium pump, resulting in calcium levels being too low on the inside of the cell to cause a contraction. Digoxin then interferes with the action of the sodium-potassium pump leading to an increase of sodium inside the cell.

When sodium concentration in the cardiac myocyte increases, another electrolyte mover known as sodium-calcium exchanger pushes the excess sodium ions out of the cell. This then pushes calcium into the cell increasing actin-myosin interaction and eventually causing stronger heart muscle contractions.

Na+-Ca++ exchanger is essential for maintaining sodium and calcium homeostasis.

The parasympathomimetic action of digitalis reduces the sinoatrial node (SA) firing rate decreasing heart rate; negative chronotropy and reducing conduction velocity of electrical impulses through the atrioventricular node; negative dromotropy.

An indirect effect of digoxin is the inhibition of neuronal Na+-K+ ATPase resulting in increased vagal activity.


The long half-life of digitalis compounds necessitates special considerations when dosing. With a half-life of 40 hours, digoxin would require several days of constant dosing to reach steady-state, therapeutic plasma levels.

Digoxin can be administered via the oral and IV routes.

Effects from oral use present within 2 hours, whereas they take effect at 30 minutes after IV use.

Due to digoxin’s large volume of distribution, loading doses are often administered

Therefore, when initiating treatment, a special dosing regimen involving "loading doses" is used to rapidly increase digoxin plasma levels. This process is termed "digitalization."

For digoxin, the therapeutic plasma concentration range is 0.5 - 1.5 ng/ml. It is very important that therapeutic plasma levels are not exceeded because digitalis compounds have a relatively narrow therapeutic safety window.

Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity, which is manifested as arrhythmias, some of which may be life-threatening.

Digoxin is cleared from the body via renal clearance, therefore, caution should be taken in its use in patients with renal impairment

Tissue protein binding (large Vd) and can be displaced by other drugs (verapamil, quinidine).

Digoxin toxicity

Due to a very narrow therapeutic margin of digoxin, meaning the difference between therapeutic and toxic doses is small, its use may be complicated by digoxin toxicity.

The early signs include anorexia, nausea, electrocardiogram changes

Later signs include disorientation, visual effects known as halos.

In toxic doses, there may be life-threatening cardiac arrhythmias.

If toxicity occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels because of the long half-life. There is an antibody available for digoxin toxicity known as an immune Fab antibody (Digibind) that can be used to rapidly reduce plasma digoxin levels.

Potassium electrolyte supplementation can also reverse the toxic effects of digoxin if the toxicity is related to hypokalemia.

Read about the relationship between potassium and digoxin here

Supportive therapy with antiarrhythmics class IB can also be used.

Drug Interactions

A number of commonly used drugs interact with cardiac glycosides.

Quinidine which is a class 1A antiarrhythmic drug, Propafenone, calcium channel blockers and NSAIDs competes with digoxin for binding sites and depresses renal clearance of digoxin. This increases digoxin levels and can produce toxicity.

Amiodarone (Class III antiarrhythmic) and beta-blockers.

Diuretics indirectly interact with digoxin because of their ability to cause hypokalemia (low potassium levels).

Verapamil and diltiazem also increase the levels of digoxin. These alter the amount of fluids in the blood and are harsh on the kidneys.

Tolvaptan works to decrease the amount of sodium in your body. If you can realize something here. Both digoxin and tolvaptan are increasing sodium concentration. Taking both of these drugs concurrently increases the amount of digoxin in the body as well

Precautions and Considerations

Hypokalemia results in increased digoxin binding to the Na+/K+-ATPase through increased phosphorylation of the enzyme and thereby enhances digoxin's therapeutic and toxic effects.

Hypercalcemia enhances digitalis-induced increases in intracellular calcium, which can lead to calcium overload and increased susceptibility to digitalis-induced arrhythmias.

Hypomagnesemia also sensitizes the heart to digitalis-induced arrhythmias.

Therapeutic Use of Digitalis Compounds

  • These drugs are used in heart Failure to increase inotropy and ejection fraction while reducing preload and pulmonary congestion/edema
  • They are also used in arrhythmias to reduce atrioventricular nodal conduction by their parasympathomimetic effect and reducing ventricular rate in atrial flutter and fibrillation

Apart from heart failure, digoxin can be used in supraventricular tachycardias, except Wolff-Parkinson-White syndrome

Digoxin use in heart failure

Clinical studies in heart failure patients have shown that digoxin, when used in conjunction with diuretics and vasodilators, improves cardiac output and ejection fraction, and reduces filling pressures and pulmonary capillary wedge pressure (this reduces pulmonary congestion and edema); heart rate changes very little.

These effects are to be expected for a drug that increases inotropy. Although the direct effect of digoxin on blood vessels is vasoconstriction, when given to patients in heart failure, the systemic vascular resistance falls.

This most likely results from the improvement in cardiac output, which leads to withdrawal of compensatory vasoconstrictor mechanisms (e.g., sympathetic adrenergic activity and angiotensin II influences). Digitalis compounds have a small direct diuretic effect on the kidneys, which is beneficial in heart failure patients.

Digoxin use in Atrial fibrillation and flutter

Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output. Furthermore, chronic ventricular tachycardia can lead to heart failure.

Digitalis compounds, such as digoxin, are useful for reducing ventricular rate when it is being driven by a high atrial rate. The mechanism of this beneficial effect of digoxin is its ability to activate vagal efferent nerves to the heart (parasympathomimetic effect).

Vagal activation can reduce the conduction of electrical impulses within the atrioventricular node to the point where some of the impulses will be blocked. When this occurs, fewer impulses reach the ventricles and the ventricular rate falls. Digoxin also increases the effective refractory period within the atrioventricular node.

Side Effects of cardiac glycosides

The major side effect of digitalis compounds is cardiac arrhythmia, especially atrial tachycardias and atrioventricular block. Other effects include;

  • Breast enlargement
  • Bradycardia
  • Gastrointestinal effects such as nausea, vomiting, diarrhea, abdominal pain
  • Loss of appetite
  • Skin rash
  • Visual disturbances including blurred /yellowed vision
  • Central nervous system effects such as dizziness, drowsiness, headache
  • Arrhythmias may also occur, though they are more likely in cases of digoxin toxicity.

Given that digoxin has a narrow therapeutic window, the incidence of arrhythmias is not an unlikely one.


Digitalis compounds are contraindicated in patients who are hypokalemic, or who have atrioventricular or Wolff-Parkinson-White (WPW) syndrome.

Impaired renal function leads to enhanced plasma levels of digoxin because digoxin is eliminated by the kidneys.

Lean, elderly patients are more susceptible to digitalis toxicity because they often have reduced renal function, and their reduced muscle mass increases plasma digoxin levels at a given dose because muscle Na+/K+-ATPase acts as a large binding reservoir for digitalis.

Digoxin should be avoided in heart block, due to the increased risk of conduction abnormalities.

Because digoxin is eliminated via the renal route, its dose should be reduced in patients with renal failure.

Electrolyte abnormalities increase the risk of digoxin toxicity these include hypokalemia, hypercalcemia and hypomagnesemia therefore care should be taken when used in patients with electrolyte imbalances.

Due to the development of hypokalemia, thiazide and loop diuretics increase the risk of digoxin toxicity therefore its concurrent use isn’t recommended.


Daniel Ogera

Medical educator, passionate about simplifying difficult medical concepts for easier understanding and mastery by nursing and medical students.

Article details

About this article:
  • Topic:Pharmacology
  • Duration:10 minutes, 3 seconds
  • Subtopic:Cardiac Glycosides

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