Digoxin (Lanoxin) is a well known cardiac glycoside and has been used for many years to treat several cardiovascular problems, such as heart failure and rate control in patients with atrial arrhythmias who experience rapid ventricular response.1,2 As it relates to heart failure, it is important to note that this is in the context of systolic heart failure, not diastolic heart failure where digoxin could potentially worsen that condition.1 This distinction is not only important clinically, but forms the context for the question presented. As a quick review, patients with systolic heart failure will usually have reductions in cardiac output (CO). This reduction in CO primarily occurs from a reduction in stroke volume (SV). Stroke volume is influenced by a number of factors such as 1) inotropy (force of ventricular contraction), 2) preload (volume of blood returning back to the heart or filling the ventricles during diastole), and 3) afterload (resistance to forward blood flow during systole). Therefore, anything that increases any one or more of these factors will increase SV and thus, ultimately increases CO (assuming the pulse does not change or decrease).

Most clinicians recognize that digoxin's role in helping to control symptoms associated with systolic heart failure has to do with its inotropic effect or ability to increase the force of contraction.3 Some of those clinicians will go on to say that it does this by increasing the intracellular calcium (Ca2+) concentrations. While that is all true, the real question that connects this thought process is how does digoxin cause this increase in cytosolic calcium concentrations and how does that ultimately increase inotropy? In order to understand the role of digoxin in systolic heart failure, the clinician must understand the normal physiology of the cardiac cycle that causes ventricular contraction (systole) and relaxation (diastole).

What happens during normal cardiac muscle contraction?
Upon ventricular depolarization (systole), sodium (Na+) moves into the cardiac myocyte (during phase 0 of the cardiac action potential; see figure below). Shortly thereafter, potassium (K+) will start to move out of the cardiac myocyte to be placed in the extracellular environment (this is phase 1 in the action potential). During this time, the cytosolic concentrations of Ca2+ are known to increase rapidly through a number of mechanisms (representing phase 2 of the action potential).4 As shown in the second figure, Ca2+ comes into the cardiac myocyte via the L-type voltage gated Ca2+ channels that line the T-tubule of the sarcomere (this channel has also been called the DHPR = dihydropyridine receptor and is the receptor that the "dihydropyridine" type calcium channel blockers (i.e., diltiazem and verapamil) inhibit). Once the Ca2+ gets into the cytosol it binds to calmodulin to activate the Ca2+/calmodulin-dependent protein kinase (also known as, myosin light chain kinase II (MLKII or CaMKII).5 Once MLKII has been formed it can do a lot of things, one of which is increasing cytosolic Ca2+. MLKII does this by two mechanisms: 1) it can phosphorylate the ryanodine receptors (RyR) on the sarcoplasmic reticulum, which causes Ca2+ to move from inside the sarcoplasmic reticulum into the cytosol (cytoplasm) and at the same time it can 2) phosphorylate phospholamban, which puts Ca2+ inside the sarcoplasmic reticulum via Ca2+-ATPase (SERCA2) during repolarization in preparation for being pushed out via the RyR upon the next cardiac depolarization.6,7 In most situations these are working together, however, sympathetic stimulation (as seen in heart failure) can also increase the activity of phospholamban during repolarization, thereby putting more Ca2+ into the sarcoplasmic reticulum that is now ready for the next repolarization or action potential. This is the attempt by the human body to increase inotropy with sympathetic stimulation especially during left ventricular systolic heart failure where cardiac output is compromised.

What happens to this physiologic process if the patient is given digoxin?
Once distributed to the heart, digoxin binds to the phosphorylated form of the alpha subunit of the Na+/K+ ATPase pumps and inhibits their activity (see the figure below).10,11 This causes the intracellular or cytosolic Na+ concentration to remain higher, which in turn disrupts the Na+ gradient needed to operate the Na+/ Ca2+ exchange pump because it works by bringing 3 Na+ from outside of the cardiac myocyte into the myocyte and in exchange it would take a Ca2+ from inside the myocyte and move it outside the cell. Therefore, a greater concentration of cytosolic Ca2+ occurs inside the cell with digoxin, thereby allowing for a greater degree of binding to troponin C and eventually myosin/actin binding thus allowing for a greater force of contraction (or inotropy).

Well unfortunately not as much as it sounds or would be desired. Despite having a unique and useful mechanism of action for patients with lower CO, the Dig Trial failed to show a reduction in mortality in patients with heart failure.12 However, digoxin is known to reduce symptoms and hospitalizations associated to heart failure, which it is why it is recommended in Stage C systolic heart failure per the AHA/ACC guidelines.1,12 Lastly, it is important to keep in mind this small beneficial effect is only seen with therapeutic levels. Since digoxin has a narrow therapeutic index, appropriate monitoring of drug concentrations is necessary, especially in patients with impaired or changing renal function and starting new medications that are known inhibitors of the efflux pump, P-glycoprotein.

References:

1. Jessup M, Abraham WT, Casey WT et al.  2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.  Circulation 2009;119:1977-2016.  
2. Cheng JW, Rybak I.  Use of digoxin for heart failure and atrial fibrillation in elderly patients.  Am J Geriatr Pharmacother  2010;8:419-27.  
3. Little WC, Rossi JR, Freeman GL. Comparison of effects of dobutamine and ouabain on left ventricular contraction and relaxation in closed-chest dogs.  J Clin Invest  1987:80;613-620.  
4. Zhang L, Kelley J, Schmeisser G et al.  Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane.  J Biol Chem  1997;272:23389-97.  
5. Couchonnal LF, Anderson ME.  The role of calmodulin kinase II in myocardial physiology and disease.  Physiology 2008;23:151-9.  
6. Lanner JT, Georgiou DK, Joshi AD et al.  Ryanodine receptors: structure, expression, molecular details, and function in calcium release.  Cold Spring Harb Perspect Biol  2010;2:a003996.  
7. Beard NA, Wei L, Dulhunty AF.  Control of muscle ryanodine receptor calcium release channels by proteins in the sarcoplasmic reticulum lumen.  Clin Exp Pharmacol Physiol 2009;36:340-5.  
8. Kamm KE, Stull JT.  Signalling to myosin regulatory light chain in sarcomeres.  J Biol Chem 2011;286:9941-7.  
9. Ding P, Huang J, Battiprolu PK et al.  Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo.  J Biol Chem 2010;285:40819-29.  
10. Li PW, Ho CS, Swaminathan R  et al. The chronic effects of long-term digoxin administration on Na+/K(+)-ATPase activity in rat tissues. Int J Cardiol  1993;40:95-100.  
11. Eichhorn EJ, Gheorghiade M.  Digoxin.  Prog Cardiovasc Dis  2002;44:251-66.  
12. The Digitalis Investigation Group, The effect of digoxin on mortality and morbidity in patients with heart failure, N Engl J Med  1997;336;525-533.

• Pharmacology: Digoxin and Amiodarone Drug Interaction
• Lab Test: Digoxin Level
• Anatomy: Heart (External)

Digoxin, Lanoxin, Digoxin Mechanism of Action, Inotropy, Force of Contraction