Mechanism of action of digitalis glycosides

It appears well established that the inotropic effect of digitalis is due initially to inhibition of the sodium pump (Na-K-ATPase), initiating a cascade effect which in turn increases "diastolic" intracellular Ca2+, which then increases "systolic" intracellular Ca2+ responsible for the inotropic effect.     

Direct cardiac mechanism of action of digitalis glycosides

The direct cardiac mechanism of action of digitalis remains obscure. The inhibition of membrane ATP-ase seems to correlate with the increase in free intracellular calcium at the contractile sites during membrane depolarization. Two mechanisms may explain this phenomenon: increase in the sodium-calcium exchange or labilisation of the calcium pool bound to the internal wall of the sarcoplasmic reticulum. Digitalis toxicity occurs when the sodium pump is inhibited to such an extent that cellular homeostasis cannot be maintained. The intracellular calcium overload is responsible for the increased automaticity of the automatic fibres by oscillations of the membrane potential, added to the spontaneous slope of diastolic depolarisation.     

Effect of digitalis on skeletal muscle in man

Although an inotropic effect of digitalis on skeletal muscle has been demonstrated in animals, it has not been shown in man. Digitalis, in previous studies, has failed to improve voluntary exercise performance. In this investigation the strength of nerve-stimulated involuntary thumb adduction was measured before, during and after infusion of ouabain into the brachial artery. With this experimental design, the many uncontrolled factors that govern ordinary exercise tolerance were avoided. Large doses of ouabain (0.5 mg) produced significant augmentation of peak strength of thumb adduction whereas smaller doses (75 μg) more likely to reach the thumb during systemic digitalization produced only suggestive increases in peak contraction strength. In patients previously digitalized for heart failure, the large doses of ouabain did not significantly change contractility. The findings suggest that skeletal muscle is less sensitive than cardiac muscle to ouabain, and that systemic digitalization has a minor effect on skeletal muscle. When the differences between skeletal and cardiac muscle in excitation-contraction coupling are considered, the reduced effect of ouabain on skeletal muscle contraction is compatible with a cell membrane locus of action in both tissues.     

Effects of digitalis on cardiopulmonary baroreflex in man

We examined whether digitalis augments cardiopulmonary baroreflex control of forearm vascular resistance in normal young men. Cardiopulmonary baroreceptor input was reduced with lower body negative pressure (LBNP) at 10 and 20 mmHg which decreased central venous pressure (CVP) but did not alter blood pressure (BP) or heart rate (HR). Decreases in forearm blood flow and increases in forearm vascular resistance with LBNP were greater after cedilanid than before and the slope of the regression line relating changes in central venous pressure and those in forearm vascular resistance was steeper after cedilanid. Vasoconstrictor responses to a cold pressor test did not differ before and after cedilanid, which suggested that augmented responses to LBNP after cedilanid were not due to a generalized change in reflex control. These results suggest that cedilaniid augments the tonic inhibitory influence of cardiopulmonary baroreceptors in normal men.     

Use of digitalis glycosides in severe disorders of intra-ventricular conduction]

The use of digitalis in severe disorders of intra-ventricular conduction is debatable, and some consider it contra-indicated. Once it had been shown that the latter attitude is at best based on contraversial theoretical arguments, two types of study were undertaken: 1. Nine patients with bilateral bundle branch block had intracavitary recordings made of the HV interval both before and for one hour after the administration of lanatoside C (0.8 to 1.6 mg). In no case was this interval found to be increased, indicating that there was no increase in the original conduction defect. 2. Thirty four patients with complete right bundle branch block and associated left antero-superior hemiblock were digitalised, and followed up for an average of 16 months; only 2 complete atrio-ventricular blocks occurred (5.9%). The risk of complete atrio-ventribular block occurring within a year (4.5% in our series) does not differ significantly from that in an identical control group of 38 patients with the same conduction defect, but who were not digitalised (6%). Three patients had a therapeutic overdose of digitalis with no observed increase in their atrio-ventricular block. The authors conclude that it is perfectly in order to digitalise a patient with a severe intra-ventricular conduction defect.