Mechanism of Action of Digoxin
Digoxin works by inhibiting the sodium-potassium ATPase pump in cardiac myocytes, which increases intracellular sodium and subsequently increases intracellular calcium through sodium-calcium exchange, resulting in enhanced myocardial contractility (positive inotropic effect). 1
Primary Mechanisms
Direct Cardiac Effects
Digoxin's inhibition of Na+-K+ ATPase leads to:
- Increased intracellular calcium concentration - This produces the positive inotropic effect by increasing the force and velocity of myocardial systolic contraction 1
- The calcium increase occurs through stimulation of sodium-calcium exchange after intracellular sodium rises 2, 3
Autonomic Nervous System Effects
Beyond its direct cardiac action, digoxin exerts important indirect effects 1:
- Vagomimetic action - Responsible for effects on sinoatrial (SA) and atrioventricular (AV) nodes, slowing heart rate and decreasing AV nodal conduction velocity 1
- Baroreceptor sensitization - Increases afferent inhibitory activity and reduces sympathetic nervous system and renin-angiotensin system activity 1, 4
The vagomimetic effects occur at low serum concentrations and contribute to slowing sinus and AV nodal conduction. At higher concentrations, paradoxically, the parasympathetic effects actually shorten the refractory period of non-nodal specialized conduction tissue 2.
Therapeutic Consequences
In Heart Failure
The beneficial effects are mediated by 1, 5:
- Positive inotropic action - Direct increase in contractile force
- Neurohormonal deactivation - Decreased activation of sympathetic nervous system and renin-angiotensin system
- Suppression of renin secretion through inhibition of renal tubular Na+-K+ ATPase 4, 5
In Atrial Fibrillation
The rate control effects result from 3:
- Suppression of AV node conduction - Increases effective refractory period and decreases conduction velocity 3
- Vagomimetic effects that slow ventricular response 2
Important Caveats
At toxic doses, digoxin increases sympathetic outflow from the CNS, which may be an important factor in digitalis toxicity 1. This represents a shift from the parasympathetic dominance seen at therapeutic levels.
The drug requires a 6-8 hour tissue distribution phase after administration before steady-state post-distribution serum concentrations equilibrate with tissue concentrations and correlate with pharmacologic effects 1. This explains why early high serum concentrations do not reflect the concentration at the site of action 1.
Digoxin is not dependent on the CYP450 system; metabolism occurs primarily by gut bacteria 3. Approximately 50-70% is excreted unchanged in the urine with an elimination half-life of 36-48 hours 3.