What is the mechanism of action for increasing vagal tone with Digoxin (digitalis glycoside)?

From the Guidelines

Digoxin increases vagal tone through its inhibition of the sodium-potassium ATPase pump in cardiac cells, leading to increased intracellular sodium and calcium, which stimulates baroreceptors and enhances parasympathetic outflow to the heart. This mechanism is supported by the most recent study from 2024, which found that digoxin increases cardiac vagal tone, depolarizes atrial resting membrane potential, and slows intraatrial conduction 1. The inhibition of the sodium-potassium ATPase pump by digoxin results in increased intracellular sodium, which affects the sodium-calcium exchanger, leading to higher intracellular calcium levels. The elevated calcium enhances cardiac contractility while simultaneously stimulating baroreceptors in the carotid sinus and aortic arch. These activated baroreceptors signal the central nervous system to increase parasympathetic (vagal) outflow to the heart.

The enhanced vagal tone slows conduction through the atrioventricular (AV) node, decreasing heart rate and prolonging the PR interval on ECG. Key points to consider when using digoxin include:

• Typical dosing ranges from 0.125-0.25 mg daily after an optional loading dose
• Serum levels should be monitored (therapeutic range 0.8-2.0 ng/mL) to avoid toxicity, especially in patients with renal impairment, as digoxin is primarily eliminated by the kidneys
• The vagal effects are most pronounced at the AV node, which explains why digoxin effectively controls ventricular rate without necessarily converting atrial fibrillation to normal sinus rhythm. It is essential to note that while digoxin can increase vagal tone, its use should be carefully considered in the context of atrial fibrillation, as some studies suggest it may predispose to the reinduction of AF or convert paroxysmal AF into permanent AF 1.

From the FDA Drug Label

The autonomic effects include: (1) a vagomimetic action, which is responsible for the effects of digoxin on the sinoatrial and atrioventricular (AV) nodes; and (2) baroreceptor sensitization, which results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system for any given increment in mean arterial pressure The pharmacologic consequences of these direct and indirect effects are: ... (3) slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect).

The mechanism of action for increasing vagal tone with Digoxin is through its vagomimetic action, which slows the heart rate and decreases conduction velocity through the AV node, as well as baroreceptor sensitization, leading to increased afferent inhibitory activity and reduced sympathetic nervous system activity 2.

• The vagomimetic effect is responsible for the effects of digoxin on the sinoatrial and atrioventricular (AV) nodes.
• The baroreceptor sensitization results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system.

From the Research

Mechanism of Action for Increasing Vagal Tone with Digoxin

• The mechanism of action for increasing vagal tone with Digoxin is related to its parasympathomimetic effect on the AV node 3, 4.
• Digoxin, a cardiac glycoside, has been used to treat heart failure and atrial fibrillation due to its cardiotonic and neurohormonal effects 3.
• The parasympathomimetic effect of digoxin on the AV node can help slow the ventricular rate in patients with atrial fibrillation, which may contribute to increasing vagal tone 4.
• However, the evidence on the safety and efficacy of digoxin in patients with atrial fibrillation and heart failure is conflicting, and more trials are needed to fully understand its effects 3, 5.
• Some studies suggest that digoxin may not be effective in converting recent-onset atrial fibrillation to sinus rhythm, and its use may be associated with increased mortality in certain patient populations 6, 5.

Clinical Use of Digoxin

• Digoxin has been used in combination with other medications, such as furosemide, to relieve symptoms of congestive heart failure 7.
• However, the indications for digoxin as a positive inotropic agent in patients with congestive heart failure need to be reevaluated, and its use should be cautious due to the risk of digitalis toxicity 7.
• The role of digoxin in increasing vagal tone is not fully understood and requires further study to determine its potential benefits and risks in different patient populations 3, 5.