Practice question

Therapeutic use of foxglove extracts containing digoxin and digitoxin dates to Withering eighteenth century for dropsy. Molecular target identified as sodium potassium ATPase, P-type pump maintaining high potassium low sodium intracellular, essential for cardiac electrophysiology. Digitalis glycosides bind extracellular vestibule formed by transmembrane segments of alpha subunit in E2P conformation, competing with potassium and locking enzyme in phosphorylated outward open state, inhibiting cycle. Inhibition fraction modest at therapeutic concentrations about 20 to 40 percent raises submembrane sodium from 8 to approximately 15 millimolar. Reduced sodium gradient impairs forward mode of sodium calcium exchanger NCX1 that normally extrudes calcium using downhill sodium entry with stoichiometry three sodium per calcium. Less calcium extrusion elevates intracellular calcium stores in sarcoplasmic reticulum via SERCA loading, increasing calcium transient amplitude during systole enhancing actin myosin force generation, positive inotropic effect. V-type proton pumps acidifying lysosomes insensitive, calcium ATPases unaffected, CFTR chloride channel ABC family not target, specificity explaining cardiovascular action at nanomolar digoxin concentrations.