Cardiac Glycosides - Function

Function

Therapeutic uses of cardiac glycosides primarily involve the treatment of cardiac failure. Their utility results from an increased cardiac output by increasing the force of contraction. By increasing intracellular calcium as described below, cardiac glycosides increase calcium-induced calcium release and thus contraction.

Drugs such as ouabain and digoxin are cardiac glycosides. Digoxin from the foxglove plant is used clinically, whereas ouabain is used only experimentally due to its extremely high potency.

Normally, sodium-potassium pumps in the membrane of cells (in this case, cardiac myocytes) pump potassium ions in and sodium ions out. Cardiac glycosides inhibit this pump by stabilizing it in the E2-P transition state, so that sodium cannot be extruded: intracellular sodium concentration therefore increases. A second membrane ion exchanger, NCX, is responsible for 'pumping' calcium ions out of the cell and sodium ions in (3Na/Ca); raised intracellular sodium levels inhibit this pump, so calcium ions are not extruded and will also begin to build up inside the cell.

Increased cytoplasmic calcium concentrations cause increased calcium uptake into the sarcoplasmic reticulum via the SERCA2 transporter. Raised calcium stores in the SR allow for greater calcium release on stimulation, so the myocyte can achieve faster and more powerful contraction by cross-bridge cycling. The refractory period of the AV node is increased, so cardiac glycosides also function to regulate heart rate.

Binding of cardiac glycoside to Na-K ATPase is slow, and also, after binding, intracellular calcium increases gradually. Thus, the action of digitalis (even on IV injection) is delayed.

Raised extracellular potassium decreases binding of cardiac glycoside to Na-K ATPase. Consequently, increased toxicity of these drugs is observed in the presence of Hypokalemia.

If SR calcium stores become too high, some ions are released spontaneously through SR ryanodine receptors. Then after-depolarization this effect leads initially to bigeminy: regular ectopic beats following each ventricular contraction. If higher glycoside doses are given, rhythm is lost and ventricular tachycardia ensues, followed by fibrillation.