Inhibitors of Na+/K+-ATPase: Cardiac glycosides - Effects
The inhibition of Na+/K+-ATPase by cardiac glycosides is responsible of their cardiac, vascular and incidentally diuretic effects.
Dromotropic effect (conduction) and bathmotropic effect (excitability): generally cardiac glycosides reduce the rate of atrioventricular conduction, both by direct effect and indirect effect via acetylcholine. They increase at low-dose the excitability of the myocardium, which can cause ectopic beats.
- Positive inotropic effect: cardiac glycosides increase the force of contraction of the normal and failing myocardium. This reinforcement is accompanied by an increase in the rate of contraction and by a shortening of the duration of the systole with a relative lengthening of the diastole, independently of slowing heart rythm.
- Positive tonotropic effect: cardiac glycosides reduce the size of the heart in diastole both in normal subjects and in patients with heart failure (heart dilated, distended, with a blood residue in the ventricle at the end of the systole). The reduction of the size of the heart in diastole increases cardiac output in heart failure but not in normal heart, because the normal heart has the optimal size and any decrease reduces its efficacy. This partly explains the different effects obtained in normal subjects and in patients with heart failure.
- Negative chronotropic effect: cardiac glycosides slow down the heart rhythm. This bradycardiac effect results from their direct action on the heart and from indirect action on autonomic nervous system:
Cardiac glycosides modify the electrocardiogram: they induce at therapeutic doses, in patients with heart failure, a decrease or an inversion of T wave, a lengthening of PR space, a shortening of QT interval. At toxic dose they induce rhythm disorders.
In patients with heart failure, there is an excessive catecholamine release with a decrease of the density of the cardiac beta-adrenergic receptors and a decrease of the sensitivity of the heart to the beta effects of catecholamines. This adrenergic overstimulation has long-term harmful effects
Cardiac glycosides increase peripheral vascular resistance by acting directly on arterial and venous smooth vascular muscles, in normal subject and in patients with heart failure. The essential difference between normal subjects and patients with heart failure is that there is no overactivity of the adrenergic system in healthy subjects. The reduction of the adrenergic hyperactivity in patients with heart failure induces an indirect vasodilation more important than the direct vasoconstriction.
In addition, cardiac glycosides can in patients with heart failure reduce the requirements of oxygen for the heart because, although reinforcing the force of contraction of the myocardium, which increases the requirements for oxygen, they reduce the size of the heart, slow down its rhythm, decrease peripheral resistances.
Cardiac glycosides have little effect on the blood pressure.
Cardiac glycosides increase diuresis in patients with heart failure, less because of the renal inhibition of Na+/K+-ATPase than because they decrease the sympathetic tone and the stimulation of the renin-angiotensin-aldosterone system.
In addition cardiac glycosides can induce contractions of intestinal muscles by direct effect and indirect effect by bulbar stimulation.
Diagram of the mechanism of action of digoxin