What is the action of digoxin?

The most common indications for digoxin are atrial fibrillation and atrial flutter with rapid ventricular response,[12][13] though beta blockers and/or calcium channel blockers may be preferred in some patients, such as those without heart failure or hemodynamic instability.[14]

One 2015 review found that digoxin increases the risk of death,[15] while another reported no change in mortality.[16] It has been suggested that the effect on mortality seen in some studies was due to inappropriately high doses of digoxin and that the low doses often used in practice (levels <0.9 ng/ml) may not increase mortality.[17] Cardiac arrythmias may also occur when patients are prescribed digoxin alongside thiazides and loop diuretics.

Heart failure

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.[15] Currently, the recommendation for heart failure is a triple therapy of ACE inhibitor, beta blocker and mineralocorticoid antagonists. Digoxin is a third-line therapy.[18]

Abortion

Digoxin is also used intrafetally or amniotically during abortions in the late second trimester and third trimester of pregnancy. It typically causes fetal demise (measured by cessation of cardiac activity) within hours of administration.[19]

Main article: List of side effects of digoxin

Further information: Digoxin toxicity

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,[20] but when systematically sought, the evidence for this is equivocal as of 2005[update].[21] The combination of increased (atrial) arrhythmogenesis and inhibited atrioventricular (AV) conduction (for example paroxysmal atrial tachycardia with AV block – so-called "PAT with block") is said to be pathognomonic (that is, diagnostic) of digoxin toxicity.[22]

Digoxin can lead to cardiac arrhythmias when given with thiazides and loop diuretics. This is because co-administration of Digoxin with drugs such as thiazides and loop diuretics which can cause hypokalemia, low serum levels of potassium in the blood. This exacerbates the potential for cardiac arrythmias because the low levels of potassium reduces the amount of K+ at the ATPase pump and increase calcium levels too much which leads to these arrythmias. It can also cause visual disturbances as well as dizziness or fainting.

Several other drugs associated with ADRs in concommitant use include verapamil, amiodarone, quinidine, tetracycline, and erythromycin.

In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant hyperkalemia 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).[23] The mechanism of action for drugs such as Digibind and Digifab, used when adverse events occur with the use of digoxin, is that the FAB regions on the antibodies created against digoxin expedite the excretion of the drug into urine. Therefore, the amount of Digoxin in the body decreases quickly as it gets excreted rapidly.

Digoxin's primary mechanism of action involves inhibition of the sodium potassium adenosine triphosphatase (Na+/K+ ATPase), mainly in the myocardium.[5] 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 reversal of this exchanger, triggered by the increase in intracellular sodium, results in an increase in the intracellular calcium concentration that is available to the contractile proteins. The increased calcium concentrations lead to the binding of Calcium to Troponin, and the formation of the Ca+2 troponin complex results in increased inotrophy. Increased intracellular calcium lengthens phase 4 and phase 0 of the cardiac action potential, which leads to a decrease in heart rate.[24] 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.[citation needed]

The inhibition of the sodium pump may also improve baroreceptor sensitivity in heart failure and may explain some of the neurohormonal effects of digoxin.[25]

Digoxin also has important parasympathetic effects, particularly on the atrioventricular node.[26] While it does increase the magnitude of myocardial contractility, the duration of the contraction is only slightly increased. Its use as an antiarrhythmic drug, then, comes from its direct and indirect parasympathetic stimulating properties. Vagus nerve stimulation slows down conduction at the AV node by increasing the refractory period of cardiac myocytes. The slowed AV node gives the ventricles more time to fill before contracting. This negative chronotropic effect is synergistic with the direct effect on cardiac pacemaker cells. 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 stroke volume is increased, resulting in a net increase in blood pressure, 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.

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.[27]

ECG changes seen in people 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.

Pharmacokinetics

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.[citation needed]

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.[citation needed]

Effective plasma levels vary depending on the medical indication. For congestive heart failure, levels between 0.5 and 1.0 ng/ml are recommended.[28] 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).[29] 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.[citation needed]

A study which looked to see if digoxin affected men and women differently found that digoxin did not reduce deaths overall, but did result in less hospitalization. Women who took digoxin died "more frequently" (33%) than women who took placebo (29%). Digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.[30]

Digoxin is also used as a standard control substance to test for P-glycoprotein inhibition.[citation needed]

Pharmacomicrobiomics

The bacteria Eggerthella lenta has been linked to a decrease in the toxicity of Digoxin.[31] These effects have been studied through comparisons of North Americans and Southern Indians, in which a reduced digoxin metabolite profile correlates with E. lentum abundance.[32] Further studies have also revealed an increase in digoxin toxicity when used alongside erythromycin or tetracycline, the researches attributed this to the decrease in the E. lentum population.[33]

Overall, bacterial inactivation of Digoxin, as in Digoxin being inactivated by bacteria in the gut microbiome occurs often. This is why Digoxin is given as a capsule or as a solution in capsule.

Derivatives of plants of the 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.[34] Its effects were first explained by Arthur Robertson Cushny. The name is derived from that of digitoxin,[1] which explains its pronunciation.

In 1930, Digoxin was first isolated by Dr. Sydney Smith from the foxglove plant, Digitalis lanata.[7][8][35] Initially, the digoxin was purified by dissolving the dried plant material in acetone and boiling the solution in chloroform. The solution was then reacted with acetic acid and small amount of ferric chloride and sulfuric acid (Keller reaction). Digoxin was distinguishable from other glucosides by the olive-green colored solution produced from this reaction, completely free of red.[35]

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.[36]

On April 25, 2008, the U.S. Federal Drug Administration (FDA) issued a press release[37] alerting the public to a Class I recall of Digitek, a brand of digoxin produced by Mylan.[38] 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.[39]

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.[citation needed]

A 2008 study suggested digoxin has beneficial effects not only for the heart, but also in reducing the risk of certain kinds of cancer.[40] However, comments on this study suggested that digoxin is not effective at reducing cancer risk at therapeutic concentrations of the drug,[41] so the results need further investigation.[42]

Brand names

Digoxin preparations are marketed under the brand 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.[citation needed]

Cardiac glycosides particularly digoxin has been conventionally used for treatment of common cardiac problems mainly heart failure and cardiac arrhythmias. As it is clear, the mechanism of action of this medication involve inhibition of Na+/K+-ATPases as well as secondary activation of Na+/Ca2+ membrane exchangers. Despite existence of numerous preclinical studies that investigated the anticancer effects of digoxin, there are no solid and conclusive results so far. Several studies suggested that cardiac glycosides may have anticancer properties, others have reported that they aggravate cancer risk in clinical studies. The reason behind that thought is the similarity in the basic structure between cardiac glycosides and that of estradiol. Focusing on digoxin, it has the ability to bind oestrogen receptors and increases the risk of oestrogen-sensitive breast and uterine cancers. Therefore, the effect of cardiac glycosides in cancer remains controversial.[43]

A study analyzed the possible correlation between digoxin administration and the risk of cancer development. The researchers in this study used two big databases; The US Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japan Medical Data Center claims database (JMDC) as clinical databases to evaluate reporting odds ratios and adjusted sequence ratios, respectively. The BaseSpace Correlation Engine and Connectivity Map bioinformatics databases were used to investigate molecular pathways related to digoxin anticancer mechanisms. Significant inverse associations were found between digoxin and four types of cancers; gastric (stomach), colorectal (colon and rectum), prostate cancer and haematological malignancy. Consistent findings suggested that digoxin use is inversely associated with the risks of these cancers. With regard to the molecular mechanisms by which digoxin suppresses the proliferation of cancer cells, it was indicated that these mechanisms include the caspase cascade in apoptosis and peroxisome proliferator-activated receptor α (PPARα) pathways.[44] In conclusion, these data suggest that digoxin may have potential anticancer effects against several cancers.

Regarding the studying of the protective effects of digoxin against prostate cancer risk, a retrospective cohort study evaluated the association between use of digoxin and prostate cancer-specific survival as compared with users of other antiarrhythmic drugs. The study population consisted of 6537 prostate cancer cases from the Finnish Randomized Study of Screening for Prostate Cancer diagnosed during 1996–2009 and 485 of them were among digoxin users.  Information were collected on antiarrhythmic drug purchases from the national prescription database. Both pre-diagnostic and post-diagnostic drug usages were analysed using the Cox regression method. This study found no significant association between prostate cancer survival and digoxin as well as no difference was observed between survival estimates of pre-diagnostic and post-diagnostic digoxin usage. No dose response was found in the risk by the cumulative amount, duration or intensity of digoxin use. Therefore, the results do not support the PCa-protective effects of this antiarrhythmic agent.[45]

Digoxin and breast cancer

A retrospective study examined the association between digoxin use with increased incidence of breast and uterus cancers. They hypothesized that digoxin use might affect tumor characteristics and increase relapse risk in women with breast cancer. Analyses were conducted in Danish women 20 to 74 years old with breast cancer (n= 49.312) in 1995 - 2008. Relapse hazard ratios (HR) were compared in women using and not using digoxin, adjusting for age, calendar period, protocol, tumor size, nodal involvement, histology grade, estrogen-receptor (ER) status, and anti-estrogen therapy in Cox regression models. The study indicated that 45 relapses occurred in women already using digoxin at breast cancer diagnosis in the first year while 24 relapses occurred in women later starting digoxin (384 person-years). The overall relapse risk HR in digoxin users was statistically significantly higher in the first year but not thereafter. First-year relapse hazard was high in digoxin-using women with ER+ tumors but not ER- tumors. It was concluded that although breast cancer incidence is increased in the women taking digoxin, the breast cancers incidence in women taking digoxin had better prognostic features than in women not taking digoxin. After adjustment for prognostic features, women who continued to use digoxin after breast cancer onset had a significantly higher risk of recurrence in the first year but not overall vs. those not using digoxin.[46]

Despite preclinical evidence supporting anti-cancer effects of cardiac glycosides, epidemiologic studies consistently show elevated breast cancer risk in digoxin users. A study investigated this association in the Nurses' Health Study cohort to evaluate influences of screening mammography and lifestyle-related risk factors. The study followed 90,202 postmenopausal women from 1994 until 2010. Self-reported breast cancers were confirmed by medical record review. Fit Cox regression models were used to estimate associations between time-varying digoxin use and breast cancer incidence, overall and by tumor ER status, accounting for mammography screening and established breast cancer risk factors.

There were 5,004 digoxin users over 1.05 million person-years of observation, among whom 144 breast cancer cases occurred. Digoxin users were more likely to undergo mammographic screening. The results indicated that current digoxin use of >4 years' duration was associated with a 45% increased rate of breast cancer compared with never used group. The association appeared stronger for ER-positive disease than for ER-negative disease. Associations were robust to restriction on regular mammography use and to adjustment for established breast cancer risk factors, including lifestyle-related exposures. It was concluded that the positive association between digoxin use and breast cancer occurrence was not attenuated when lifestyle-related breast cancer risk factors and screening practices were accounted for. The researcher assumed that digoxin which is a common cardiac drug worldwide, may promote breast carcinogenesis.[47]

Digoxin and risk of cancer development

Research database of Taiwan between January 1, 2000, and December 31, 2000. This study included (1,219 patients) and a comparison cohort. These analytical data suggested that patients taking digoxin are at an increased risk of cancers, including breast, liver, and lung cancers, during the 10-year follow-up period. In contrast to the anti-tumor function of digoxin, the researchers further examined the potential pathway of digoxin via the cell-based strategy using several breast cancer cell lines, including MCF-7, BT-474, MAD-MB-231, and ZR-75-1. Results indicated that digoxin consistently exerted its cytotoxicity to these four cell lines with various range of concentration. However, the proliferation of ZR-75-1 cells was the only cell lines induced by digoxin and the others were dramatically suppressed by digoxin. The responsiveness of SRSF3 to digoxin might be involved with cell-type differences. In summary, data of this cohort study for digoxin treatment for HF patients was combined with a cell-based strategy that addresses the translation issue, which revealed the complexity of personalized medicine.[48]

in vitro anti-proliferate effects of digoxin

A study examined the anti-proliferative effects of Digoxin on small cell lung cancer (SCLC) which is a malignant neuroendocrine tumor with very high mortality using both in vitro and in vivo models. Results showed that digoxin was highly effective in inhibiting SCLC cell growth. Interesting findings showed that NaCl supplement noticeably enhanced the anti-tumor activities of digoxin in both in vitro and in vivo models of SCLC. Subsequent analysis revealed that this novel combination of digoxin/NaCl caused an up-regulation of intracellular Na+ and Ca2+ levels with an induction of higher resting membrane potential of SCLC cells. The researchers also found that this combination lead to morphological shrinking of SCLC cells, together with high levels of cytochrome C release. Lastly, data revealed that NaCl supplement was able to induce the expression of ATP1A1 (a Na+/K+ ATPase subunit), in which contributes directly to the increased sensitivity of SCLC cells to digoxin. Thus, this is the first demonstration that NaCl is a potent supplement necessitating superior anti-cancer effects of digoxin for SCLC. Further, this study suggests that digoxin treatment could need to be combined with NaCl supplement in future clinical trial of SCLC, particularly where low Na+ is often present in SCLC patients.[49]

A retrospective cohort study analyzed patient information retrieved from the National Health Insurance Research database of Taiwan between January 1, 2000, and December 31, 2000. This study included (1,219 patients) and a comparison cohort. These analytical data suggested that patients taking digoxin are at an increased risk of cancers, including breast, liver, and lung cancers, during the 10-year follow-up period. In contrast to the anti-tumor function of digoxin, the researchers further examined the potential pathway of digoxin via the cell-based strategy using several breast cancer cell lines, including MCF-7, BT-474, MAD-MB-231, and ZR-75-1. Results indicated that digoxin consistently exerted its cytotoxicity to these four cell lines with various range of concentration. However, the proliferation of ZR-75-1 cells was the only cell lines induced by digoxin and the others were dramatically suppressed by digoxin. The responsiveness of SRSF3 to digoxin might be involved with cell-type differences. In summary, data of this cohort study for digoxin treatment for HF patients was combined with a cell-based strategy that addresses the translation issue, which revealed the complexity of personalized medicine.[48]

Based on the above data which have been conducted on the association between Digoxin use and various types of cancer, it can be concluded that the findings are controversial and no solid conclusions can be done. Further retrospective as well as in vitro studies are required to find out the possible association between digoxin use and cancer.

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• Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
• Summary of Product Characteristics, Digoxin 0.125 mg, Zentiva.
• Lüllmann (2003). Pharmakologie und Toxikologie (15th ed.). Georg Thieme Verlag. ISBN 3-13-368515-5.
• Lanatoside C (isolanid, Cedilanid – four glycoside analog), Digoxigenin (aglycone analog)
• Goldberger ZD, Alexander GC (January 2014). "Digitalis use in contemporary clinical practice: refitting the foxglove". JAMA Internal Medicine. 174 (1): 151–4. doi:10.1001/jamainternmed.2013.10432. PMID 24217624.

• "Digoxin". Drug Information Portal. U.S. National Library of Medicine.
• Commonly used website to calculate empiric digoxin doses for medical purposes for heart problems

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