|Systematic (IUPAC) name|
|Pregnancy cat.||A (Au), C (U.S.)|
|Legal status||S4 (Au), POM (UK), ℞-only (U.S.)|
|Bioavailability||60 to 80% (Oral)|
|Half-life||36 to 48 hours
(patients with normal renal function)
3.5 to 5 days
(patients with impaired renal function)
|Mol. mass||780.938 g/mol|
|Melt. point||249.3 °C (481 °F)|
|Solubility in water||0.0648 mg/mL (20 °C)|
|(what is this?)|
Digoxin INN (//) is a purified cardiac glycoside similar to Digitoxin extracted from the foxglove plant, Digitalis lanata, which was discovered by William Withering. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin. Digoxin is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication.
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.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
Derivatives of plants of the genus Digitalis have a long history of medical use. The British 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".
Today, 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 a better first choice. 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.
The use of digoxin in heart problems during sinus rhythm was once standard, but is now controversial. In theory, the increased force of contraction should lead to improved pumping function of the heart, but its effect on prognosis is disputable, and other effective treatments are now available. Digoxin is no longer the first choice for congestive heart failure, but can still be useful in patients who remain symptomatic despite proper diuretic and ACE inhibitor treatment.
Digitalis/digoxin has recently fallen out of favor because it did not demonstrate a mortality benefit in patients with congestive heart failure; however, it did demonstrate a reduction in hospitalizations for this condition. Because other therapies have shown a mortality benefit in congestive heart failure, maximizing other therapies (e.g., beta blockers) first is recommended before using digoxin.
The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index (the margin between effectiveness and toxicity). Adverse effects are concentration-dependent, and are rare when plasma digoxin concentration is <0.8 μg/l. They are also more common in patients with low potassium levels (hypokalemia), since digoxin normally competes with K+ ions for the same binding site on the Na+/K+ ATPase pump.
Common adverse effects (≥1% of patients) include loss of appetite, nausea, vomiting and diarrhea as gastrointestinal motility increases. Other common effects are blurred vision, visual disturbances (yellow-green halos and problems with color perception), confusion, drowsiness, dizziness, insomnia, nightmares, agitation, and depression, as well as a higher acute sense of sensual activities. Less frequent adverse effects (0.1%–1%) include: acute psychosis, delirium, amnesia, convulsions, shortened QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or fibrillation, and heart block. Rarely, digoxin has been shown to cause thrombocytopenia. 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. The pharmacological actions of digoxin usually result in electrocardiogram changes, including ST depression or T wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca2+ may cause a type of arrhythmia called bigeminy (coupled beats), eventually ventricular tachycardia or fibrillation. 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.
An often described, but rarely seen, adverse effect of digoxin is a disturbance of color vision (mostly yellow and green) called xanthopsia. Vincent van Gogh's "Yellow Period" may have somehow been influenced by concurrent digitalis therapy. Other oculotoxic effects of digoxin include generalized blurry vision, as well as seeing a "halo" around each point of light. The latter effect can also be seen in van Gogh's Starry Night. Evidence of van Gogh's digoxin use is supported by multiple self-portraits that include the foxglove plant, from which digoxin is obtained. (e.g. Portrait of Dr. Gachet)
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). Toxicity can also be treated with higher than normal doses of potassium. Digoxin is not removed by hemodialysis or peritoneal dialysis with enough effectiveness to treat toxicity.
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.
In patients with decreased kidney function, the half-life is considerably longer, along with decrease in Vd, 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, elimination is mainly by renal excretion and involves P-glycoprotein which leads to significant clinical interactions with other drugs commonly used in patients with heart problems. These include: spironolactone, verapamil and amiodarone. ( Inhibit P-glycoprotein that is mainly responsible for Digoxin Clearance )
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 1.0 and 2.0 ng/ml. 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 increases plasma levels of digoxin (by displacing tissue binding sites and depressing renal digoxin clearance), so plasma digoxin must be monitored carefully.
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.
Digoxin is also used as a standard control substance to test for p-glycoprotein inhibition.
Mechanisms of action
|This section does not cite any references or sources. (April 2012)|
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 effects as it increases myocardial contractility; however, the duration of the contractile response is just slightly increased. Overall, the heart rate is decreased, while blood pressure is increased resulting in an net increase in stroke volume, leading to increased tissue perfusion. This causes the myocardium to work more efficiently, with optimised haemodynamics and the ventricular function curve is improved.
Other electrical effects include an initial brief increase in action potential, followed by a decrease as the K+ conductance increases due to an 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. Other, more indirect effects are cholinomimetic because of vagal stimulation, giving rise to AV nodal delay.
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 patient taking digoxin include increased PR interval (due to decreased AV conduction) and a decreased 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.
Mechanism of action
The mechanism of action is not completely understood; however, the current hypothesis is outlined below.
Digoxin is a Cardiac Glycoside that acts as an inotropic agent, it decreases the action of the Na+/K+ ATPase channel by binding to an allosteric site. Normally 3 X Na+ moves out of the cardiac cell and 2 X K+ moves into the cardiac cell. As a result,Na+ concentration in myocyte increases and inactivates the NCX antiporter protein, which Na+ will no longer be pumped into the myocyte. On the other hand, inactivation of NCX causes Ca2+ concentration to increase inside the cell as Ca2+ cannot be pumped out. Increase in Ca2+ concentration thus aid contraction in the heart. Digoxin also acts as a vagal agonist. Hence, its secondary effect of decreased heart rate. Toxicity is marked by Atrial Tachycardia due to ectopy and AV block due to its vagal stimulating properties.
The benefits of Digoxin is an increased stroke volume, increased ejection fraction and decreased heart rate.
Society and culture
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 16-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".
This March 31 press release from Caraco, a generic pharmaceutical company, states:
[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 movie Once Upon a Time in Anatolia the prosecutor tells the doctor a story of a 'gorgeous woman' who died on the date she predicted she would die, well after delivering the baby. The doctor speculates she may have taken high doses of Dogoxin 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.
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- Lanatoside C (isolanid, Cedilanid - four glycoside analog), Digoxigenin (aglycone analog)
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Practice". JAMA Internal Medicine.
- U.S. National Library of Medicine: Drug Information Portal — Digoxin
- Commonly used website to calculate empiric digoxin doses for medical purposes for heart problems
- Protein Data Bank entry (useful for computational molecular dynamics): http://www.rcsb.org/pdb/explore.do?structureId=3B0W