Editing Cardiac glycoside (section)

== Mechanism of action ==
Cardiac glycosides affect the [[Na+/K+-ATPase|sodium-potassium ATPase pump]] in [[cardiac muscle cell]]s to alter their function.<ref name=Pate2016/> Normally, these sodium-potassium pumps move potassium ions in and sodium ions out. Cardiac glycosides, however, inhibit this pump by stabilizing it in the E2-P transition state, so that sodium cannot be extruded: intracellular sodium concentration therefore increases. With regard to potassium ion movement, because both cardiac glycosides and potassium compete for binding to the ATPase pump, changes in extracellular potassium concentration can potentially lead to altered drug efficacy.<ref name=Bullock>{{Cite book|url=https://books.google.com/books?id=ODjiBAAAQBAJ&pg=PA615|title=Fundamentals of Pharmacology| vauthors = Bullock S, Manias E |date=2013-10-15|publisher=Pearson Higher Education AU|isbn=9781442564411|language=en}}</ref> Nevertheless, by carefully controlling the dosage, such adverse effects can be avoided. Continuing on with the mechanism, raised intracellular sodium levels inhibit the function of a second membrane ion exchanger, [[Sodium-calcium exchanger|NCX]], which is responsible for pumping calcium ions out of the cell and sodium ions in at a ratio of {{chem2|3Na+/Ca(2+)}}. Thus, calcium ions are also not extruded and will begin to build up inside the cell as well.<ref name=Babula2013rev>{{cite journal | vauthors = Babula P, Masarik M, Adam V, Provaznik I, Kizek R | title = From Na+/K+-ATPase and cardiac glycosides to cytotoxicity and cancer treatment | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 13 | issue = 7 | pages = 1069–1087 | date = September 2013 | pmid = 23537048 | doi = 10.2174/18715206113139990304 | s2cid = 1537056 }}</ref><ref>{{Cite web|url=http://cvpharmacology.com/cardiostimulatory/digitalis|title=CV Pharmacology {{!}} Cardiac Glycosides (Digitalis Compounds)|website=cvpharmacology.com|access-date=2017-06-08}}</ref>

The disrupted calcium homeostasis and increased cytoplasmic calcium concentrations cause increased calcium uptake into the [[sarcoplasmic reticulum]] (SR) via the SERCA2 transporter. Raised calcium stores in the SR allow for greater calcium release on stimulation, so the myocyte can achieve faster and more powerful contraction by cross-bridge cycling.<ref name=Pate2016/> The refractory period of the [[Atrioventricular node|AV node]] is increased, so cardiac glycosides also function to decrease heart rate. For example, the ingestion of digoxin leads to increased cardiac output and decreased heart rate without significant changes in blood pressure; this quality allows it to be widely used medicinally in the treatment of cardiac arrhythmias.<ref name=Pate2016/>

=== Non-cardiac uses ===
Cardiac glycosides were identified as [[senolytic]]s: they can selectively eliminate [[senescent]] cells which are more sensitive to the ATPase-inhibiting action due to cell membrane changes.<ref>{{cite journal | vauthors = L'Hôte V, Courbeyrette R, Pinna G, Cintrat JC, Le Pavec G, Delaunay-Moisan A, Mann C, Thuret JY | display-authors = 6 | title = Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy | journal = Aging Cell | volume = 20 | issue = 9 | pages = e13447 | date = September 2021 | pmid = 34355491 | pmc = 8564827 | doi = 10.1111/acel.13447 }}</ref><ref>{{cite journal | vauthors = Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, Wolter K, Pombo J, Irvine EE, Innes AJ, Birch J, Glegola J, Manshaei S, Heide D, Dharmalingam G, Harbig J, Olona A, Behmoaras J, Dauch D, Uren AG, Zender L, Vernia S, Martínez-Barbera JP, Heikenwalder M, Withers DJ, Gil J | display-authors = 6 | title = Cardiac glycosides are broad-spectrum senolytics | journal = Nature Metabolism | volume = 1 | issue = 11 | pages = 1074–1088 | date = November 2019 | pmid = 31799499 | pmc = 6887543 | doi = 10.1038/s42255-019-0122-z }}</ref><ref>{{cite journal | vauthors = Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, Collado M | display-authors = 6 | title = Identification and characterization of Cardiac Glycosides as senolytic compounds | journal = Nature Communications | volume = 10 | issue = 1 | pages = 4731 | date = October 2019 | pmid = 31636264 | pmc = 6803708 | doi = 10.1038/s41467-019-12888-x | bibcode = 2019NatCo..10.4731T }}</ref>