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INTRODUCTION

In 1785, Sir William Withering first described the leaves from the common foxglove plant, Digitalis purpurea, as a treatment for heart failure (HF) and arrhythmia in his monograph “An Account of the Foxglove and Some of Its Medicinal Uses.”1 More than 200 years later, digoxin remains in contemporary use for the treatment of HF with reduced systolic function, albeit with increasing scrutiny and controversy. In 1997, the landmark Digitalis Investigation Group (DIG) trial showed that while digoxin did reduce total and HF-related hospitalizations, there was no survival benefit.2 Over the next decade, a change in practice patterns would lead to a significant reduction in digoxin use, but ultimately no change in the burden of digoxin-related adverse events.3,4 In patients with persistently symptomatic heart failure with reduced ejection fraction (HFrEF) on guideline-directed medical therapy, the addition of digoxin may help ameliorate signs and symptoms of HF, improve quality of life, and reduce overall and HF-specific hospitalizations. Thus, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the management of HF recommends digoxin as an adjuvant agent in select patient populations.5

MECHANISM OF ACTION

Digoxin is a purified steroid cardiac glycoside. Cardiac glycosides directly and reversibly inhibit the sodium-potassium-activated adenosine triphosphate transporter (Na+K+-ATPase) on the plasma membrane of the cardiac myocyte, preventing the influx of potassium and expulsion of intracellular sodium (Figure 26-1).6 The net increase in intracellular sodium disrupts the sodium-calcium antiporter (Na+-Ca2+ exchange), effectively increasing intracellular calcium concentrations, and as a result, increases cardiac contractility and augments systolic function.6

Figure 26-1

Normal depolarization. Depolarization occurs after the opening of fast Na+ channels; the increase in intracellular potential opens voltage-dependent Ca2+ channels, and the influx of Ca2+ induces the massive release of Ca2+ from the sarcoplasmic reticulum, producing contraction. (Reproduced with permission from Hoffman RS, Howland MA, Lewin NA, et al. Goldfrank’s Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill Education; 2015. Figure 65-1A.)

In addition to augmentation of cardiac inotropy, cardiac glycosides also have an important role in neurohormonal regulation, having effects on both vascular smooth muscle tone and the sympathetic nervous system.6 In patients with advanced systolic HF, digitalis has been shown to reduce plasma renin concentrations and promote peripheral vasodilation, likely due to down-regulation of hypersensitized baroreceptors.7 By increasing vagal tone and attenuating the sympathetic nervous system, cardiac glycosides also work to slow conduction through the SA and AV nodes.7 The increased intracellular calcium levels also work to shorten cardiac repolarization time, increasing the propensity for automaticity and arrhythmias.7 In the setting of cardiac glycoside toxicity, one can see that these dual effects of increased automaticity and nodal block can create dangerous exit blocks and ...

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