Mechanism of action of Cardiac Glycosides

 Cardiac glycosides, such as digoxin and ouabain, are a class of drugs that primarily exert their effects on the heart by increasing the force of cardiac muscle contraction. Their mechanism of action involves inhibition of the sodium-potassium ATPase (Na+/K+-ATPase) pump, an enzyme located on the cell membrane of cardiac cells.

Mechanism of Action:

1. Inhibition of Na+/K+-ATPase:

   • Cardiac glycosides bind to the α-subunit of the Na+/K+-ATPase, inhibiting its function. Normally, this pump actively transports sodium (Na⁺) out of the cell and potassium (K⁺) into the cell.
   • Inhibition leads to an increase in intracellular sodium levels because the pump can no longer expel sodium as efficiently.

2. Increase in Intracellular Calcium:

   • The rise in intracellular sodium affects another membrane protein, the sodium-calcium exchanger (NCX). Normally, this exchanger uses the sodium gradient to pump calcium (Ca²⁺) out of the cell in exchange for sodium entering.
   • Due to increased intracellular sodium, the exchanger becomes less effective at removing calcium from the cell, leading to an accumulation of intracellular calcium.

3. Enhanced Myocardial Contractility:

   • The elevated intracellular calcium is stored in the sarcoplasmic reticulum and is released during cardiac muscle contraction.
   • Increased calcium availability enhances the binding of calcium to troponin, improving the interaction between actin and myosin filaments in the heart muscle, thereby increasing the force of contraction (positive inotropic effect).

4. Electrophysiological Effects:

   • Slower Heart Rate (Negative Chronotropy): Cardiac glycosides exert vagomimetic effects, enhancing vagal tone, which slows the conduction through the atrioventricular (AV) node. This is beneficial in conditions like atrial fibrillation, as it helps control the ventricular rate.
   • Altered Cardiac Electrical Activity: They also affect cardiac excitability and can alter the action potential duration, potentially leading to arrhythmias at high doses.

Clinical Use:

• Cardiac glycosides like digoxin are commonly used to treat heart failure by improving cardiac output through increased contractility. They are also used to control heart rate in supraventricular arrhythmias, particularly atrial fibrillation and atrial flutter.

In summary, cardiac glycosides increase the force of contraction of the heart by inhibiting Na+/K+-ATPase, leading to increased intracellular calcium levels and enhanced contractility. They also exert effects on the heart rate and conduction system.