Digitalis: new actions for an old drug

Abstract

The mechanisms by which digitalis causes its therapeutic and toxic actions have been studied for nearly a half century, revealing a great deal about cardiac cell regulation of intracellular ions via the Na-K-ATPase (NKA) and how it is altered by cardiac glycosides. However, recent observations suggest that digitalis may have additional effects on cardiac cell function in both the short and long term that include intracellular effects, interactions with specific NKA isoforms in different cellular locations, effects on intracellular (including nuclear) signaling, and long-term regulation of intracellular ionic balances through circulating ouabain-like compounds. The purpose of this review is to examine the current status of a number of the newest and most interesting developments in the study of digitalis with a particular focus on cardiac function, although we will also discuss some of the new advances in other relevant cardiovascular effects. This new information has important implications for both our understanding of ionic regulation in normal and diseased hearts as well as for potential avenues for the development of future therapeutic interventions for the treatment of heart failure.

Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

“…Consistently, i.v. administration of the Digibind antibody reverses digitoxin toxicity in humans within the same limited time frame (14)(15)(16). We interpret the latter data to mean that the toxic mechanism for digitoxin action is equally available to an extracellular inhibitory antibody in a cultured cell system, a planar lipid bilayer system, and in vivo in humans.…”

“…As mentioned in the Introduction, an overdose of digitoxin or digoxin in humans treated for heart failure can be quickly reversed over a 15-to 30-min time period by administering specific anti-digitoxin/ digoxin antibodies (14)(15)(16). Therefore, we hypothesized that if digitoxin channel activity contributed to cytotoxic adverse events, anti-digitoxin antibodies might quickly block both channel activity in vitro and digitoxin-dependent calcium uptake into cells.…”

“…Digibind is an inactivating Fab fragment antibody against the digitalis pharmacophore, which is widely available in all poison control centers. In fact, the NaKATPase hypothesis for the regulation of positive inotropic effects of cardiac glycosides has been under continuous questioning by investigators for many years without compelling resolution (11)(12)(13)(14)(15)(16). Non-NaKATPase effects also have been observed.…”

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

“…However, it has to be considered that the effect of Na + on the cytosolic Ca 2+ transient is most pronounced at very low stimulation rates and diminishes at higher rates [16]. Furthermore, digitalis can elevate cytosolic Ca 2+ transients in the absence of Na + , indicating that at least part of the inotropic effect of digitalis is Na + -independent [17,18].…”

Endogenous digitalis: pathophysiologic roles and therapeutic applications

“…18,19 These issues, particularly the last, have been reviewed in a series of excellent papers. [16][17][18][19][20][21][22][23] The main purpose of the present Review is to emphasize the roles of endogenous cardiotonic steroids in human health and disease-in particular with regard to the renal and cardiovascular systems-and to highlight potential therapeutic targets that have arisen as a result of research in this area. In short, we hope to establish that endogenous cardiotonic steroids have begun their journey from bench to bedside.…”