12.03.6 Digoxin

Digoxin is derived from a plant source (the foxglove) and has been in medical use for dropsy (heart failure) since medieval times. It is much more recently that it was discovered that the mechanism of action of digoxin is inhibition of the Na⁺K⁺ATP-ase that drives sodium and potassium exchange across membranes (Figure 12.3.4). This inhibition leads to an increase in intracellular Na+ (Figure 12.3.4). The cardiac cell has a Na+Ca2+ exchanger, and when there are increased levels of intracellular Na+, this exchanger is inhibit, and this leads to an increase in the level of intracellular Ca2+ (Figure 12.3.4). With an increased intracellular Ca2+, there is an increased force of myocardial contraction.

Figure 12.3.4 Mechanism of action of digoxin (Copyright QUT, Sheila Doggrell)

In heart failure, increasing the force of the heart beat to increase cardiac output, with digoxin, helps reverse the decreased cardiac output in heart failure. However, “Digoxin has a very low therapeutic index, and at least 60% of the toxic dose is required to produce a therapeutic effect. Because of this narrow safety margin, it has been argued, that if digoxin were to be introduced as a new drug today, it would be regarded as too dangerous for clinical use”. But we still use digoxin!

As the Na⁺K⁺ATP-ase is present on all cells, it is not surprising that digoxin has widespread effects, some of which are toxic. On the cardiovascular system, digoxin is pro-arrhythmic i.e. it can cause cardiac arrhythmias. Some of the toxic effects of digoxin help to identify it as the culprit. For instance, digoxin causes visual disturbances such as disturbed colour vision, and halos around objects. Digoxin also causes psychiatric problems such as delirium, fatigue, malaise, confusion, and abnormal dreams. Digoxin can also cause gastro-intestinal toxicity such as anorexia, nausea, vomiting, and abdominal pain. In life threatening digoxin toxicity, anti-digoxin immunotherapy is used intravenously.