"Cardiac glycosides"-quo vaditis?-past, present, and future?

Abstract

Up to date, digitalis glycosides, also known as "cardiac glycosides", are inhibitors of the Na⁺/K⁺-ATPase. They have a long-standing history as drugs used in patients suffering from heart failure and atrial fibrillation despite their well-known narrow therapeutic range and the intensive discussions on their raison d'être for these indications. This article will review the history and key findings in basic and clinical research as well as potentially overseen pros and cons of these drugs.

Keywords: Atrial fibrillation; Cancer; Cardiac glycosides; Digitalis glycosides; Digitoxin; Digoxin; Heart failure; Metabolism; NKA inhibitors; Na+/K+-ATPase; Toxicity.

Fig. 1

Cardiovascular and non-cardiovascular effects of DG. The Na⁺/K⁺-ATPase (NKA) is crucial for maintaining ion gradient across cell membranes by pumping Na⁺ (red circles) out of the cell and K⁺ (yellow triangles) into the cell against their concentration gradient by hydrolyzing adenosine triphosphate (ATP). Digitalis glycosides (DG) target NKA, resulting in various tissue-specific effects. In the cardiovascular system, DG inhibit NKA, causing intracellular Na⁺ accumulation, which impedes the Na⁺/Ca²⁺ exchanger (NCX) and increases intracellular Ca²⁺ (green hexagons). The excess Ca²⁺ is stored in the sarcoplasmic reticulum (SR) resulting in an increased amount of Ca²⁺ released during systole, enhancing myocardial contractility (positive inotropic effect). DG also stimulate baroreceptors and the vagus nerve, enhancing parasympathetic tone and thereby reducing sympathetic tone, leading to a lower heart rate (negative chronotropic effect) and slower atrioventricular conduction (negative dromotropic effect). In non-cardiac tissues, DG influence NKA signaling through activation of pathways such as SRC-EGFR-MAPK and PI3K-Akt. DG treatment also leads to recruitment of phospholipase C (PLC) to NKA, generating inositol trisphosphate (IP3), which triggers Ca²⁺ release from the endoplasmic reticulum (ER) by the IP3 receptor (IP3R). The activation of these signaling pathways by NKA after DG treatment leads to increased cytosolic Ca²⁺ levels, generation of reactive oxygen species (ROS), activation of nuclear factor-κB (NF-κB), and overall affects gene transcription. Created with BioRender.com. ADP adenosine diphosphate, EGFR epidermal growth factor receptor, Raf rapidly accelerated fibrosarcoma, MEK mitogen-activated protein kinase kinase, ERK extracellular-signal regulated kinase, PI3K phosphoinositide 3-kinase