Digoxin (better known as Digitalis), 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 Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

. Digoxin is one of the oldest medications used in the field of cardiology. It works by increasing myocardial contractility, increasing stroke volume and blood pressure, reducing heart rate, and somewhat extending the time frame of the contraction. Digoxin is taken by mouth or by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

. Digoxin has a half life of approximately 36 hours given at average doses in patients with normal renal function. It is excreted mostly unchanged in the urine. 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 Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

. Greater care is required in older people and those with poor kidney function. It is unclear whether use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

is safe. Digoxin is in the cardiac glycoside family of medications. It was first isolated in 1930 from the foxglove plant, '' Digitalis lanata''. It is on the World Health Organization's List of Essential Medicines. In 2020, it was the 237th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Irregular heartbeat

The most common indications for digoxin are atrial fibrillation and atrial flutter with rapid ventricular response, though beta blockers and/or calcium channel blockers may be preferred in some patients, such as those without heart failure or hemodynamic instability. Some reviews suggest that digoxin increases the risk of death, while others suggest no change in mortality. 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. Cardiac arrhythmias may also occur when patients are prescribed digoxin alongside thiazides and loop diuretics.

Heart failure

Digoxin is no longer the first choice for

; it has fallen out of favor in people with heart failure because it may increase the risk of death. Currently, the recommendation for heart failure is a triple therapy of ACE inhibitor, beta blocker and mineralocorticoid antagonists. Digoxin is a third-line therapy.

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.

Side effects

The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index (the margin between effectiveness and

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

Gynaecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...

(enlargement of

breast tissue The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

) is mentioned in many textbooks as a side effect, thought to be due to the

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

-like steroid

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

of the digoxin molecule, but when systematically sought, the evidence for this is equivocal . 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. 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.

Overdose

In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant

hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...

occurs (inexorably rising

potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...

level due to paralysis of the cell membrane-bound,

ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...

-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names Digibind and Digifab). 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.

Pharmacology

Pharmacodynamics

Digoxin's primary mechanism of action involves inhibition of the sodium potassium adenosine triphosphatase ( Na+/K+ ATPase), mainly in the

myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

. This inhibition causes an increase in intracellular

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

levels, resulting in decreased activity of the

sodium-calcium exchanger The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by al ...

, which normally imports three extracellular sodium ions into the cell and transports one intracellular

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

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

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s. The increased calcium concentrations lead to the binding of more calcium to troponin C, which results in increased inotropy. Increased intracellular calcium lengthens phase 4 and phase 0 of the

cardiac action potential The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins ...

, 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 Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable is ...

may also improve

baroreceptor Baroreceptors (or archaically, pressoreceptors) are sensors located in the carotid sinus (at the bifurcation of external and internal carotids) and in the aortic arch. They sense the blood pressure and relay the information to the brain, so that ...

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. 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 The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and righ ...

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 Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...

, leading to increased tissue perfusion. This causes the myocardium to work more efficiently, with optimized

hemodynamic Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously mo ...

s and an improved ventricular function curve. Other electrical effects include a brief initial increase in

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells ...

, 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 fiber The Purkinje fibers (; often incorrectly ; Purkinje tissue or subendocardial branches) are located in the inner ventricular walls of the heart, just beneath the endocardium in a space called the subendocardium. The Purkinje fibers are specia ...

s and ventricles is negligible. Automaticity is also increased in the atria, AV node,

s, and ventricles. 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 In electrocardiography, the T wave represents the repolarization of the ventricles. The interval from the beginning of the QRS complex to the apex of the T wave is referred to as the ''absolute refractory period''. The last half of 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 Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...

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 Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

is about 36 hours for patients with normal

renal function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's flui ...

, 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 Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood press ...

, 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 In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...

, such as

digitoxin Digitoxin is a cardiac glycoside used for the treatment of heart failure and certain kinds of heart arrhythmia. It is a phytosteroid and is similar in structure and effects to digoxin, though the effects are longer-lasting. Unlike digoxin, wh ...

(not available in the United States), which has a much longer

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...

of around seven days and is eliminated by the liver. Effective plasma levels vary depending on the medical indication. For

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

, 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 rate Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of d ...

s. For heart rate control ( atrial fibrillation), plasma levels are less defined and are generally

titrate Titration (also known as titrimetry and volumetric analysis) is a common laboratory method of quantitative chemical analysis to determine the concentration of an identified analyte (a substance to be analyzed). A reagent, termed the ''titrant' ...

d 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. 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 A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

(29%). 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. Digoxin appears to be a peripherally selective drug due to limited

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

uptake caused by binding to P-glycoprotein.

Pharmacomicrobiomics

The bacteria Eggerthella lenta has been linked to a decrease in the toxicity of Digoxin. 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. 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. 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.

History

Derivatives of plants of the genus '' Digitalis'' have a long history of medical use. The English physician

William Withering William Withering FRS (17 March 1741 – 6 October 1799) was an English botanist, geologist, chemist, physician and first systematic investigator of the bioactivity of digitalis. Withering was born in Wellington, Shropshire, the son of a surg ...

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''. Its effects were first explained by Arthur Robertson Cushny. The name is derived from that of

, which explains its pronunciation. In 1930, Digoxin was first isolated by Dr. Sydney Smith from the foxglove plant, '' Digitalis lanata''. 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 Iron(III) chloride is the inorganic compound with the formula . Also called ferric chloride, it is a common compound of iron in the +3 oxidation state. The anhydrous compound is a crystalline solid with a melting point of 307.6 °C. The col ...

and

sulfuric acid Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular fo ...

( Keller reaction). Digoxin was distinguishable from other glucosides by the olive-green colored solution produced from this reaction, completely free of red.

Society and culture

Charles Cullen Charles Edmund Cullen (born February 22, 1960) is an American serial killer. Cullen, a nurse, murdered dozens – possibly hundreds – of patients during a 16-year career spanning several New Jersey medical centers, until being arrested in 20 ...

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 Parole (also known as provisional release or supervised release) is a form of early release of a prison inmate where the prisoner agrees to abide by certain behavioral conditions, including checking-in with their designated parole officers, or ...

. On April 25, 2008, the U.S.

Federal Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

(FDA) issued a press release alerting the public to a Class I recall of Digitek, a brand of digoxin produced by

Mylan Mylan N.V. was a global generic and specialty pharmaceuticals company. In November 2020, Mylan merged with Upjohn, Pfizer's off-patent medicine division, to form Viatris. Previously, the company was domiciled in the Netherlands, with principal ...

. Some tablets had been released at double thickness and therefore double strength, causing some patients to experience digoxin toxicity. A

class-action lawsuit A class action, also known as a class-action lawsuit, class suit, or representative action, is a type of lawsuit where one of the parties is a group of people who are represented collectively by a member or members of that group. The class actio ...

against the Icelandic

generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active c ...

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: 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.

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.

Digoxin and cancer

Cardiac glycosides, particularly digoxin, have been conventionally used for treatment of common cardiac problems, mainly heart failure and cardiac arrhythmias. The interaction of digoxin and cancer has also been studied. Despite existence of numerous preclinical studies that investigated the anticancer effects of digoxin, there are no solid and conclusive results so far. Several studies have suggested that digoxin may have anticancer properties, others not. Digoxin, as a cardiac glycoside, has a chemical structure basically similar to that of estradiol. Digoxin has the ability to bind oestrogen receptors, and therefore it has been proposed that it might increase the risk of oestrogen-sensitive breast and uterine cancers. A large Danish study found a complicated picture, with slightly increased risk of breast cancer amongst women taking digoxin, but better prognostic features. The Nurses' Health Study found a similar slight increase of risk. Digoxin inhibits the proliferation of many cancerous cell lines ''in vitro'', but its relevance to cancer ''in vivo'' remains unclear.

References

External links

*
Commonly used website to calculate empiric digoxin doses for medical purposes for heart problems
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