Digoxin, sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is taken by mouth or by injection into a vein.
|Pronunciation||//, with a soft gee|
|Trade names||Lanoxin, others|
|by mouth, intravenous|
|Bioavailability||60 to 80% (by mouth)|
|Elimination half-life||36 to 48 hours |
(normal kidney function)
3.5 to 5 days
(impaired kidney function)
|Chemical and physical data|
|Molar mass||g·mol−1 780.949|
|3D model (JSmol)|
|Melting point||249.3 °C (480.7 °F)|
|Solubility in water||0.0648 mg/mL (20 °C)|
Common side effects include breast enlargement with other side effects generally due to an excessive dose. These side effects may include loss of appetite, nausea, trouble seeing, confusion, and an irregular heartbeat. Greater care is required in older people and those with poor kidney function. It is unclear whether use during pregnancy is safe. Digoxin is in the cardiac glycoside family of medications.
Digoxin was first isolated in 1930 from the foxglove plant, Digitalis lanata. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about US$0.21–6.60 a month. In the United States it generally costs less than $25 per month, as of 2015.
Irregular heart beatEdit
The most common indications for digoxin are atrial fibrillation and atrial flutter with rapid ventricular response, though beta blockers and/or calcium channel blockers are often preferred.
Digoxin is no longer the first choice for heart failure; it has fallen out of favor in people with heart failure because it may increase the risk of death. Currently recommendations for heart failure is a triple therapy of ACE inhibitor, Beta-blocker and mineralocorticoid antagonists. Digoxin is a 3rd line therapy.
Digoxin is also used intrafetally or amniotically during abortions in the late second trimester and third trimester of pregnancy, often to comply with the federal Partial-Birth Abortion Ban Act . It typically causes fetal demise (measured by cessation of cardiac activity) within hours of administration.
The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index (the margin between effectiveness and toxicity). Gynaecomastia (enlargement of breast tissue) is mentioned in many textbooks as a side effect, thought to be due to the estrogen-like steroid moiety of the digoxin molecule, but when systematically sought, the evidence for this is equivocal.[as of 2005] The combination of increased (atrial) arrhythmogenesis and inhibited atrioventricular conduction (for example paroxysmal atrial tachycardia with A-V block – so-called "PAT with block") is said to be pathognomonic (i.e., diagnostic) of digoxin toxicity.
In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant hyperkalaemia occurs (inexorably rising potassium level due to paralysis of the cell membrane-bound, ATPase-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names Digibind and Digifab).[as of 2004]
Digoxin is usually given orally, but can also be given by IV injection in urgent situations (the IV injection should be slow, and heart rhythm should be monitored). While IV therapy may be better tolerated (less nausea), digoxin has a very long distribution half-life into the cardiac tissue, which will delay its onset of action by a number of hours. The half-life is about 36 hours for patients with normal renal function, digoxin is given once daily, usually in 125-μg or 250-μg doses.
Digoxin elimination is mainly by renal excretion and involves P-glycoprotein, which leads to significant clinical interactions with P-glycoprotein inhibitor drugs. Examples commonly used in patients with heart problems include spironolactone, verapamil and amiodarone. In patients with decreased kidney function the half-life is considerably longer, along with decrease in Vd (volume of distribution), calling for a reduction in dose or a switch to a different glycoside, such as digitoxin (not available in the United States), which has a much longer elimination half-life of around seven days and is eliminated by the liver.
Effective plasma levels vary depending on the medical indication. For congestive heart failure, levels between 0.5 and 1.0 ng/ml are recommended. This recommendation is based on post hoc analysis of prospective trials, suggesting higher levels may be associated with increased mortality rates. For heart rate control (atrial fibrillation), plasma levels are less defined and are generally titrated to a goal heart rate. Typically, digoxin levels are considered therapeutic for heart rate control between 0.5 and 2.0 ng/ml (or 0.6 and 2.6 nmol/l). In suspected toxicity or ineffectiveness, digoxin levels should be monitored. Plasma potassium levels also need to be closely controlled (see side effects, below).
Quinidine, verapamil, and amiodarone increase plasma levels of digoxin (by displacing tissue binding sites and depressing renal digoxin clearance), so plasma digoxin must be monitored carefully when coadministered.
Researchers at Yale University looked at data from an earlier study to see if digoxin affected men and women differently. That study determined digoxin, which has been used for centuries and makes the heart contract more forcefully, did not reduce deaths overall, but did result in less hospitalization. Researcher Dr. Harlan Krumholz said they were surprised to find women in the study who took digoxin died "more frequently" (33%) than women who took a placebo pill (29%). They calculated digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.
Mechanisms of actionEdit
Digoxin's primary mechanism of action involves inhibition of the sodium potassium adenosine triphosphatase (Na+/K+ ATPase), mainly in the myocardium. This inhibition causes an increase in intracellular sodium levels, resulting in decreased activity of the sodium-calcium exchanger, which normally imports three extracellular sodium ions into the cell and transports one intracellular calcium ion out of the cell. The inaction of this exchanger causes an increase in the intracellular calcium concentration that is available to the contractile proteins. Increased intracellular calcium lengthens phase 4 and phase 0 of the cardiac action potential, which leads to a decrease in heart rate. Increased amounts of Ca2+ also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility (the force of contraction) of the heart without increasing heart energy expenditure.
The inhibition of the sodium pump may also improve baroreceptor sensitivity in heart failure and may explain some of the neurohormonal effects of digoxin. Digoxin also has important parasympathetic effects, particularly on the atrioventricular node.
The main pharmacological effects of digoxin are on the heart. Extracardiac effects are responsible for some of the therapeutic and many of the adverse effects (see above). It exerts a mechanical effect as it increases myocardial contractility; however, the duration of the contractile response is only slightly increased. High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves, owing to improved filling.
Overall, the heart rate is decreased while blood pressure is increased, resulting in a net increase in stroke volume, leading to increased tissue perfusion. This causes the myocardium to work more efficiently, with optimized hemodynamics and an improved ventricular function curve.
Other electrical effects include a brief initial increase in action potential, followed by a decrease as the K+ conductance increases due to increased intracellular amounts of Ca2+ ions. The refractory period of the atria and ventricles is decreased, while it increases in the sinoatrial and AV nodes. A less negative resting membrane potential is made, leading to increased irritability.
There is also evidence that digoxin increases vagal activity, thereby decreasing heart rate by slowing depolarization of pacemaker cells in the AV node. This negative chronotropic effect would therefore be synergistic with the direct effect on cardiac pacemaker cells. Digoxin is used widely in the treatment of various arrhythmias.
The conduction velocity increases in the atria, but decreases in the AV node. The effect upon Purkinje fibers and ventricles is negligible. Automaticity is also increased in the atria, AV node, Purkinje fibers, and ventricles.
ECG changes seen in a patient taking digoxin include increased PR interval (due to decreased AV conduction) and a shortened QT interval. Also, the T wave may be inverted and accompanied by ST depression. It may cause AV junctional rhythm and ectopic beats (bigeminy) resulting in ventricular tachycardia and fibrillation.
Slight vasodilation is seen in heart failure. This effect is contrary to effects that should be seen as a result of increased intracellular calcium levels, but this occurs since digoxin improves hemodynamics, which leads to restored angiotensin levels and decreased sympathetic discharge, causing indirect vasodilation.
Derivatives of plants of genus Digitalis have a long history of medical use. The English physician William Withering is credited with the first published description of the use of digitalis derivatives in his 1785 book An Account of the Foxglove and some of its Medical Uses With Practical Remarks on Dropsy and Other Diseases. It effects were first explained by Arthur Robertson Cushny.
Society and cultureEdit
Charles Cullen admitted in 2003 to killing as many as 40 hospital patients with overdoses of heart medication—usually digoxin—at hospitals in New Jersey and Pennsylvania over his 19-year career as a nurse. On March 10, 2006, he was sentenced to 18 consecutive life sentences and is not eligible for parole.
On April 25, 2008, the FDA issued a press release alerting the public to a Class I recall of Digitek, a brand of digoxin produced by Mylan. Some tablets had been released at double thickness and therefore double strength, causing some patients to experience digoxin toxicity. A class-action lawsuit against the Icelandic generic drug maker Actavis was announced two weeks later.
On March 31, 2009, the FDA announced another generic digoxin pill recall by posting this company press release on the agency's web site: "Caraco Pharmaceutical Laboratories, Ltd. Announces a Nationwide Voluntary Recall of All Lots of Digoxin Tablets Due to Size Variability". A March 31 press release from Caraco, a generic pharmaceutical company, stated:
[All] tablets of Caraco brand Digoxin, USP, 0.125 mg, and Digoxin, USP, 0.25 mg, distributed prior to March 31, 2009, which are not expired and are within the expiration date of September, 2011, are being voluntarily recalled to the consumer level. The tablets are being recalled because they may differ in size and therefore could have more or less of the active ingredient, digoxin.
A 2008 study suggested digoxin has beneficial effects not only for the heart, but also in reducing the risk of certain kinds of cancer. However, comments on this study suggested that digoxin is not effective at reducing cancer risk at therapeutic concentrations of the drug, so the results need further investigation.
In the Turkish film Once Upon a Time in Anatolia the prosecutor tells the doctor a story of a woman who died on the date she predicted she would die, well after delivering the baby. The doctor speculates that she may have taken high doses of digoxin to die of heart attack. There are hints that she may have been the prosecutor's wife who committed suicide because she couldn't take his one time affair.
Digoxin preparations are marketed under the trade names Cardigox; Cardiogoxin; Cardioxin; Cardoxin; Coragoxine; Digacin; Digicor; Digomal; Digon; Digosin; Digoxine Navtivelle; Digoxina-Sandoz; Digoxin-Sandoz; Digoxin-Zori; Dilanacin; Eudigox; Fargoxin; Grexin; Lanacordin; Lanacrist; Lanicor; Lanikor; Lanorale; Lanoxicaps; Lanoxin; Lanoxin PG; Lenoxicaps; Lenoxin; Lifusin; Mapluxin; Natigoxin; Novodigal; Purgoxin; Sigmaxin; Sigmaxin-PG; Toloxin.
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