Digoxin Lanoxin

Structural Formula Ball-and-Stick Model Space-filling Model

Other brand names: Digitek; Therapeutic use: Approximately since 1500 B.C.; Drug category: Cardiac glycoside - Na+/K+ ATPase pump inhibitor; Main uses: To treat congestive heart failure, increase cardiac output, and decrease heart rate. Approximate number of people treated annually: 550,000 New patients in the US; Related drugs: Ouabain.

Cardiac failure, which occurs when the heart cannot deliver the required amount of blood to the tissues and organs, is along with ischemia and arrhythmia (irregular heartbeat), a common and major medical problem. This condition is usually caused by damaged and weakened heart muscles (especially the ventricles) that do not contract efficiently. The net effect is reduced circulation, accumulation of blood in the heart, lowered blood pressure and inadequate blood flow to the lungs and kidneys. Digoxin is efficacious in people with heart failure because it increases the contractile force of the heart and improves the blood flow to vital organs. Digoxin remains a useful treatment for this condition despite the fact that the efficacious dose is not far below the toxic dose.1

Cardiac glycosides have a long history in medical practice since their early use in the form of plant extracts as diuretics and heart stimulants which dates back to 1500 B.C. The first modern account of the beneficial effects of cardiac glycosides was made in the late 1700s by a British doctor, William Withering, who described the effect of digitalis (extract from foxglove plants) for the treatment of edema (also known as dropsy). Withering noted that the foxglove extract was both beneficial and toxic and that correct dosing was critical to successful treatment.

We now know that the foxglove extract contains two main components, digoxin and digitoxin that are easily separated. Digoxin proved to be the more effective and less toxic substance. Digoxin works by binding to the a-subunit of the Na+/K+ ATPase pump in the membranes of heart cells (mycocytes). With the inhibition of the Na+/K+ pump, the concentration of Na+ increases in the cells. This also leads to an increase of intracellular Ca2+ concentration and ultimately to an increase in the force of heart muscle contraction (positive inotropic effect). Until recently digoxin was the first-line treatment for individuals with congestive heart failure. However, it is now administered mainly to those who remain symptomatic despite treatment with diuretics and ACE inhibitors. Digoxin can only be used safely with strict medical monitoring since severe side effects, especially heart rhythm disturbances, may occur.2,3

The structure of digoxin is made up of two distinct moieties: the carbohydrate part (the three six-membered rings at the left of the above structural formula) and the steroidal part (the right side). The carbohydrate part improves aqueous solubility, but it is not essential for activity. Numerous cardioactive glycosides occur in plants which share the steroid framework and differ mainly in the carbohydrate units and in the number and location of OH groups attached to the steroid part. The development of safer versions of digoxin would be medically useful.

1. Prog. Cardiovasc Dis 2006. 48. 372-385; 2. Exp. Opin. Drug. Safety 2006, 5, 453-467; 3. Am. J. Cardiovasc. Drugs 2006, 6, 77-86; Refs. p 85

Ligand

Heterotrimeric

G Protein

G Protein Coupled Receptor

Heterotrimeric

G Protein

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