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| Pronunciation | /dɪˈdʒɒksɪn/[1][2] |
| Trade names | Lanoxin, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682301 |
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| Routes of administration | By mouth,intravenous |
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| Pharmacokinetic data | |
| Bioavailability | 60 to 80% (by mouth) |
| Protein binding | 25% |
| Metabolism | Liver (16%) |
| Eliminationhalf-life | 36 to 48hours (normalkidney function) 3.5 to 5days (impaired kidney function) |
| Excretion | Kidney |
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| ECHA InfoCard | 100.040.047 |
| Chemical and physical data | |
| Formula | C41H64O14 |
| Molar mass | 780.949 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 249.3 °C (480.7 °F) |
| Solubility in water | 0.0648 mg/mL (20 °C) |
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Digoxin (better known asdigitalis), sold under the brand nameLanoxin among others, is a medication used to treat variousheart conditions.[4] Most frequently it is used foratrial fibrillation,atrial flutter, andheart failure.[4] Digoxin is one of the oldest medications used in the field ofcardiology. It works by increasingmyocardial contractility, increasingstroke volume andblood pressure, reducingheart rate, and somewhat extending the time frame of thecontraction.[5] Digoxin is taken by mouth or byinjection into a vein.[4] 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 includebreast enlargement with other side effects generally due to an excessive dose.[4][6] These side effects may include loss of appetite, nausea, trouble seeing, confusion, and anirregular heartbeat.[6] Greater care is required in older people and those with poorkidney function.[6] It is unclear whether use duringpregnancy is safe.[3]
Digoxin is in thecardiac glycoside family of medications.[4] It was first isolated in 1930 from Grecian foxglove (Digitalis lanata).[7][8] It is on theWorld Health Organization's List of Essential Medicines.[9] In 2021, it was the 241st most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10][11]
The most common indications for digoxin areatrial fibrillation andatrial flutter with rapidventricular response,[12][13] especially in older or less active patients,[14] thoughbeta blockers and/orcalcium channel blockers may be preferred in some patients, such as younger more active ones, or those without heart failure or hemodynamic instability.[15]
Early observational studies showed an increased risk of death in patients taking digoxin, despite an attempt to allow for other risk factors for death (so-calledpropensity score matching).[16][17] However, systematic reviews focusing onrandomised controlled trials of digoxin (which ensured similarity between patients on digoxin, and those not on it) showed no difference in mortality.[18][19] Evidence suggested the increased mortality in patients taking digoxin was due to their having worse heart disease than those not taking it.[20] Cardiac arrhythmias may also occur when patients are prescribed digoxin alongsidethiazides andloop diuretics.[21]
Digitalis (i.e. extracts, including digoxin, from the plant genusDigitalis) was the first drug used to treatdropsy (swollen ankles—a symptom of heart failure) following its discovery byWilliam Withering.[22] Alongsidediuretics, it was the mainstay of treatment for heart failure for over a century. Since the introduction of other drugs with better outcomes and fewer adverse effects, it is generally now only used where heart failure is associated with atrial fibrillation and or a rapid ventricular rate.[23] In certain circumstances it may be used under specialist guidance in addition to, or instead of, the recommended first-line treatments ofACE inhibitor,beta blocker,mineralocorticoid antagonist, andSGLT-2 inhibitor, where they are not effective or not tolerated.[24][23]
Digoxin is also used intrafetally or amniotically duringabortions in the late second trimester and third trimester of pregnancy. It typically causesfetal demise (measured by cessation of cardiac activity) within hours of administration.[25]
The occurrence ofadverse drug reactions is common, owing to its narrowtherapeutic index (the margin between effectiveness andtoxicity).Gynaecomastia (enlargement ofbreast tissue) is mentioned in many textbooks as a side effect, thought to be due to theestrogen-like steroidmoiety of the digoxin molecule,[26] but when systematically sought, the evidence for this is equivocal as of 2005[update].[27] The combination of increased (atrial)arrhythmogenesis and inhibitedatrioventricular (AV) conduction (for exampleparoxysmal atrial tachycardia with AV block – so-called "PAT with block") is said to bepathognomonic (that is, diagnostic) of digoxin toxicity.[28]
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 causehypokalemia, low serum levels of potassium in the blood. This exacerbates the potential for cardiac arrhythmias 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 arrhythmias.[29] It can also cause visual disturbances as well as dizziness or fainting.
Several other drugs associated with adverse drug reactions in concomitant use includeverapamil,amiodarone,quinidine,tetracycline, anderythromycin.
In overdose, the usual supportive measures are needed. Ifarrhythmias prove troublesome, or malignanthyperkalemia occurs (inexorably risingpotassium level due to paralysis of the cell membrane-bound,ATPase-dependent Na/K pumps), the specificantidote is antidigoxin (antibody fragments against digoxin, trade names Digibind and Digifab).[30] 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 themyocardium.[5] This inhibition causes an increase in intracellularsodium levels, resulting in decreased activity of thesodium-calcium exchanger, which normally imports three extracellularsodium ions into the cell and transports one intracellularcalcium 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 contractileproteins. The increased calcium concentrations lead to the binding of more calcium totroponin C, which results in increasedinotropy. Increased intracellular calcium lengthens phase 4 and phase 0 of thecardiac action potential, which leads to a decrease in heart rate.[31] Increased amounts of Ca2+ also leads to increased storage of calcium in thesarcoplasmic 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 improvebaroreceptor sensitivity in heart failure and may explain some of the neurohormonal effects of digoxin.[32]
Digoxin also has importantparasympathetic effects, particularly on theatrioventricular node.[33] While it does increase the magnitude ofmyocardial contractility, the duration of the contraction is only slightly increased. Its use as anantiarrhythmic 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 negativechronotropic 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 whilestroke volume is increased, resulting in a net increase inblood pressure, leading to increased tissueperfusion. This causes the myocardium to work more efficiently, with optimizedhemodynamics and an improved ventricular function curve.
Other electrical effects include a brief initial increase inaction potential, followed by a decrease as theK+ conductance increases due to increasedintracellular amounts ofCa2+ ions. Therefractory period of theatria andventricles is decreased, while it increases in thesinoatrial 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 uponPurkinje fibers and ventricles is negligible.Automaticity is also increased in theatria, AV node, Purkinje fibers, and ventricles.[34]
ECG changes seen in people taking digoxin include increased PR interval (due to decreased AV conduction) and a shortened QT interval. Also, theT wave may be inverted and accompanied by ST depression. It may cause AV junctional rhythm andectopic beats (bigeminy) resulting inventricular tachycardia andfibrillation.
Digoxin is also anM2 receptormuscarinic agonist.[35]
Digoxin is usually given orally, but can also be given byIV 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. Thehalf-life is about 36 hours for patients with normalrenal function, digoxin is given once daily, usually in 125 μg or 250 μg doses.[citation needed]
Digoxin elimination is mainly byrenal excretion and involvesP-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 inVd (volume of distribution), calling for a reduction in dose or a switch to a differentglycoside, such asdigitoxin (not available in the United States), which has a much longerelimination half-life of around seven days and is eliminated by the liver.[citation needed]
Effectiveplasma levels vary depending on the medical indication. Forcongestive heart failure, levels between 0.5 and 1.0 ng/mL are recommended.[36] This recommendation is based onpost hoc analysis of prospective trials, suggesting higher levels may be associated with increasedmortality rates. For heart rate control (atrial fibrillation), plasma levels are less defined and are generallytitrated 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).[37] 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 tookplacebo (29%). Digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.[38]
Digoxin is also used as a standard control substance to test forP-glycoprotein inhibition.[39]
Digoxin appears to be aperipherally selective drug due to limitedbrain uptake caused by binding to P-glycoprotein.[40][41]
The bacteriaEggerthella lenta has been linked to a decrease in the toxicity of digoxin.[42] These effects have been studied through comparisons of North Americans and Southern Indians, in which a reduced digoxin metabolite profile correlates withE. lenta abundance.[43] Further studies have also revealed an increase in digoxin toxicity when used alongside erythromycin or tetracycline, the researches attributed this to the decrease in theE. lenta population.[44]
Derivatives of plants of the genusDigitalis have a long history of medical use.Nicholas Culpeper referred to various medical uses for foxglove in his 1652 publicationThe English physician.[45]William Withering is credited with the first published description of the systematic use ofDigitalis derivatives in his 1785 bookAn Account of the Foxglove and some of its Medical Uses With Practical Remarks onDropsy and Other Diseases.[46] Its use was somewhat sporadic untilSir James Mackenzie identified the phenomenon ofatrial fibrillation, and the actions of digitalis on this.[47] Its effects were first explained byArthur Robertson Cushny.[48] The name is aportmanteau, derived fromDigitalis lanata andtoxin.[49]
In 1930, digoxin was first isolated by Dr. Sydney Smith from the foxglove plant,Digitalis lanata.[7][8][50] Initially, the digoxin was purified by dissolving the dried plant material in acetone and boiling the solution in chloroform. The solution was then reacted withacetic acid and small amount offerric chloride andsulfuric acid (Keller reaction). Digoxin was distinguishable from otherglucosides by the olive-green colored solution produced from this reaction, completely free of red.[50]
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 forparole.[51]
On April 25, 2008, the U.S.Food and Drug Administration (FDA) issued a press release[52] alerting the public to aClass I recall of Digitek, a brand of digoxin produced byMylan.[53] Some tablets had been released at double thickness and therefore double strength, causing some patients to experience digoxin toxicity. Aclass-action lawsuit against the Icelandicgeneric drug makerActavis was announced two weeks later.[54]
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 fromCaraco, 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.[55] However, comments on this study suggested that digoxin is not effective at reducing cancer risk at therapeutic concentrations of the drug,[56] so the results need further investigation.[57]
Digoxin preparations are marketed under thebrand names Cardigox; Cardiogoxin; Cardioxin; Cardoxin; Coragoxine; Digacin; Digicor; Digitek; 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.[58][59]
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,[60] others not.[61]
Digoxin, as a cardiac glycoside, has a chemical structure basically similar to that ofestradiol. 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.[62] A large Danish study found a complicated picture, with slightly increased risk of breast cancer amongst women taking digoxin, but better prognostic features.[63] The Nurses' Health Study found a similar slight increase of risk.[64]
Digoxin inhibits the proliferation of many cancerous cell linesin vitro,[65][66] but its relevance to cancerin vivo remains unclear.
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