Digoxin: Difference between revisions

{{Short description|Plant-derived medication}}

{{Distinguish|Dioxin|Digitoxin}}

{{About||the genus of plants with the same name|Digitalis}}

{{drugbox

| verifiedrevid = 459476549

| image = Digoxin.svg

| width = 300

| alt =

| image2 = Digon ball-and-stick.png

| alt2 =

| pronounce = {{IPAc-en|d|ᵻ|ˈ|dʒ|ɒ|k|s|ᵻ|n}}<ref name="oxforddict">{{cite dictionary |entry=Digoxin |entry-url=https://www.lexico.com/en/definition/digoxin |dictionary=Lexico |access-date=28 October 2019 |language=en |title=Digoxin &#124; Definition of Digoxin by Lexico |archive-date=27 October 2019 |archive-url=https://web.archive.org/web/20191027122438/https://www.lexico.com/en/definition/digoxin |url-status=dead }}</ref><ref>{{cite web |title=digoxin |website=WordReference |url=https://www.wordreference.com/definition/digoxin |access-date=28 October 2019 }}</ref>

| tradename = Lanoxin, others

| DailyMedID = Digoxin

| pregnancy_AU = A

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy" />

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]], [[Intravenous therapy|intravenous]]

| ATC_prefix = C01

| ATC_suffix = AA05

| ATC_supplemental =

| legal_AU = S4

| legal_UK = POM

| legal_US = Rx-only

| legal_status =

| bioavailability = 60 to 80% (by mouth)

| metabolism = [[Liver]] (16%)

| elimination_half-life = 36 to 48 [[hour]]s <br />(normal [[kidney function]])<br />3.5 to 5 [[day]]s <br />(impaired kidney function)

| excretion = [[Kidney]]

| IUPHAR_ligand = 4726

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| UNII_Ref = {{fdacite|correct|FDA}}

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| NIAID_ChemDB =

| PDB_ligand = DGX

| synonyms =

| IUPAC_name = 3β-[(''O''-2,6-dideoxy-β-D-''ribo''-hexopyranosyl-(1→4)-''O''-2,6-dideoxy-β-D-''ribo''-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-''ribo''-hexopyranosyl)oxy]-12β,14-dihydroxy-5β-card-20(22)-enolide

| C=41 | H=64 | O=14

| SMILES = O=C\1OC/C(=C/1)[C@H]2CC[C@@]8(O)[C@]2(C)[C@H](O)C[C@H]7[C@H]8CC[C@H]6[C@]7(C)CC[C@H](O[C@@H]5O[C@H](C)[C@@H](O[C@@H]4O[C@@H]([C@@H](O[C@@H]3O[C@@H]([C@@H](O)[C@@H](O)C3)C)[C@@H](O)C4)C)[C@@H](O)C5)C6

| StdInChI = 1S/C41H64O14/c1-19-36(47)28(42)15-34(50-19)54-38-21(3)52-35(17-30(38)44)55-37-20(2)51-33(16-29(37)43)53-24-8-10-39(4)23(13-24)6-7-26-27(39)14-31(45)40(5)25(9-11-41(26,40)48)22-12-32(46)49-18-22/h12,19-21,23-31,33-38,42-45,47-48H,6-11,13-18H2,1-5H3/t19-,20-,21-,23-,24+,25-,26-,27+,28+,29+,30+,31-,33+,34+,35+,36-,37-,38-,39+,40+,41+/m1/s1

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

<!-- Definition and medical uses -->

'''Digoxin''' (better known as '''Digitalis'''), sold under the brand name '''Lanoxin''' among others, is a medication used to treat various [[heart disease|heart conditions]].<ref name=AHFS2016/> Most frequently it is used for [[atrial fibrillation]], [[atrial flutter]], and [[heart failure]].<ref name=AHFS2016/> 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 [[Muscle contraction|contraction]].<ref name="sciencedirect.com">{{cite journal | vauthors = Patocka J, Nepovimova E, Wu W, Kuca K | title = Digoxin: Pharmacology and toxicology-A review | journal = Environmental Toxicology and Pharmacology | volume = 79 | pages = 103400 | date = October 2020 | pmid = 32464466 | doi = 10.1016/j.etap.2020.103400 | s2cid = 218950180 | url = https://www.sciencedirect.com/science/article/pii/S1382668920300764 }}</ref> Digoxin is taken by mouth or by [[intravenous|injection into a vein]].<ref name=AHFS2016>{{cite web|title=Digoxin|url=https://www.drugs.com/monograph/digoxin.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221004328/https://www.drugs.com/monograph/digoxin.html|archive-date=21 December 2016}}</ref> 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.

<!-- Side effects -->

Common side effects include [[gynecomastia|breast enlargement]] with other side effects generally due to an excessive dose.<ref name=AHFS2016/><ref name=WHO2008/> These side effects may include loss of appetite, nausea, trouble seeing, confusion, and an [[Heart arrhythmia|irregular heartbeat]].<ref name=WHO2008/> Greater care is required in older people and those with poor [[kidney function]].<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | page=270 }}</ref> It is unclear whether use during [[pregnancy]] is safe.<ref name="Drugs.com pregnancy">{{cite web|title=Digoxin Use During Pregnancy |url=https://www.drugs.com/pregnancy/digoxin.html|website=Drugs.com|access-date=14 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221004656/https://www.drugs.com/pregnancy/digoxin.html|archive-date=21 December 2016}}</ref>

<!-- Class, history, use -->

Digoxin is in the [[cardiac glycoside]] family of medications.<ref name=AHFS2016/> It was first isolated in 1930 from the [[foxglove]] plant, ''[[Digitalis lanata]]''.<ref name=cartwright>{{cite book| vauthors = Cartwright AC |title=The British Pharmacopoeia, 1864 to 2014: Medicines, International Standards and the State|date=2016|publisher=Routledge|isbn=9781317039792|page=183|url=https://books.google.com/books?id=gI21CwAAQBAJ&pg=PA183|language=en|url-status=live|archive-url=https://web.archive.org/web/20170908135429/https://books.google.com/books?id=gI21CwAAQBAJ&pg=PA183|archive-date=2017-09-08}}</ref><ref name=hollman>{{cite journal | vauthors = Hollman A | title = Drugs for atrial fibrillation. Digoxin comes from Digitalis lanata | journal = BMJ | volume = 312 | issue = 7035 | pages = 912 | date = April 1996 | pmid = 8611904 | pmc = 2350584 | doi = 10.1136/bmj.312.7035.912 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 2021, it was the 241st most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Digoxin - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Digoxin | access-date = 14 January 2024}}</ref>

== Medical uses ==

=== Irregular heartbeat ===

The most common indications for digoxin are [[atrial fibrillation]] and [[atrial flutter]] with rapid [[ventricle (heart)|ventricular]] response,<ref>{{cite journal | vauthors = Sticherling C, Oral H, Horrocks J, Chough SP, Baker RL, Kim MH, Wasmer K, Pelosi F, Knight BP, Michaud GF, Strickberger SA, Morady F | display-authors = 6 | title = Effects of digoxin on acute, atrial fibrillation-induced changes in atrial refractoriness | journal = Circulation | volume = 102 | issue = 20 | pages = 2503–8 | date = November 2000 | pmid = 11076824 | doi = 10.1161/01.CIR.102.20.2503 | s2cid = 127927 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hallberg P, Lindbäck J, Lindahl B, Stenestrand U, Melhus H | title = Digoxin and mortality in atrial fibrillation: a prospective cohort study | journal = European Journal of Clinical Pharmacology | volume = 63 | issue = 10 | pages = 959–71 | date = October 2007 | pmid = 17684738 | doi = 10.1007/s00228-007-0346-9 | s2cid = 30951337 }}</ref> especially in older or less active patients,<ref>{{cite book |title=Kumar and clark's clinical medicine |date=2017 |publisher=Elsevier |location=Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto |isbn=9780702066009 |page=972 |edition=9th}}</ref> though [[beta blocker]]s and/or [[calcium channel blocker]]s may be preferred in some patients, such as younger more active ones, or those without heart failure or hemodynamic instability.<ref name=Craig2019>{{cite journal | vauthors = January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW | display-authors = 6 | title = 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons | journal = Circulation | volume = 140 | issue = 2 | pages = e125–e151 | date = July 2019 | pmid = 30686041 | doi = 10.1161/CIR.0000000000000665 | s2cid = 59304609 | doi-access = free }}</ref>

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-called [[propensity score matching]]).<ref>{{cite journal | vauthors = Ouyang AJ, LvYN, Zhong HL, Wen JH, Wei XH, Peng HW, Zhou J, Liu LL | display-authors = 6 | title = Meta-analysis of digoxin use and risk of mortality in patients with atrial fibrillation | language = English | journal = The American Journal of Cardiology | volume = 115 | issue = 7 | pages = 901–906 | date = April 2015 | pmid = 25660972 | doi = 10.1016/j.amjcard.2015.01.013 | doi-access = free }}</ref><ref name=Vamos2015>{{cite journal | vauthors = Vamos M, Erath JW, Hohnloser SH | title = Digoxin-associated mortality: a systematic review and meta-analysis of the literature | journal = European Heart Journal | volume = 36 | issue = 28 | pages = 1831–1838 | date = July 2015 | pmid = 25939649 | doi = 10.1093/eurheartj/ehv143 | doi-access = free }}</ref> However, systematic reviews focusing on [[randomised controlled trial|randomised controlled trials]] of digoxin (which ensured similarity between patients on digoxin, and those not on it) showed no difference in mortality.<ref>{{cite journal | vauthors = Sethi NJ, Nielsen EE, Safi S, Feinberg J, Gluud C, Jakobsen JC | title = Digoxin for atrial fibrillation and atrial flutter: A systematic review with meta-analysis and trial sequential analysis of randomised clinical trials | journal = PLOS ONE | volume = 13 | issue = 3 | pages = e0193924 | date = 2018-03-08 | pmid = 29518134 | pmc = 5843263 | doi = 10.1371/journal.pone.0193924 | bibcode = 2018PLoSO..1393924S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, Steeds RP, Townend J, Kotecha D | display-authors = 6 | title = Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data | journal = BMJ | volume = 351 | pages = h4451 | date = August 2015 | pmid = 26321114 | pmc = 4553205 | doi = 10.1136/bmj.h4451 }}</ref> Evidence suggested the increased mortality in patients taking digoxin was due to their having worse heart disease than those not taking it.<ref name="Ziff_2015">{{cite journal | vauthors = Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, Steeds RP, Townend J, Kotecha D | display-authors = 6 | title = Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data | journal = BMJ | volume = 351 | issue = | pages = h4451 | date = August 2015 | pmid = 26321114 | pmc = 4553205 | doi = 10.1136/bmj.h4451 }}</ref> Cardiac arrhythmias may also occur when patients are prescribed digoxin alongside thiazides and loop diuretics.<ref name="Kumar & Clark">{{cite book |title=Kumar and Clark's clinical medicine |date=2017 |publisher=Elsevier |location=Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto |isbn=9780702066009 |page=24 |edition=9th}}</ref>

=== Heart failure ===

[[Digitalis]] (i.e. extracts, including digoxin, from the plant genus ''Digitalis'') was the first drug used to treat [[dropsy]] (swollen ankles—a symptom of heart failure) following its discovery by [[William Withering]].<ref>{{cite book | vauthors = Withering W | url = https://archive.org/details/b21517356 | title = An Account of the Foxglove and some of its Medical Uses | location = Birmingham, England | publisher = M. Swinney | date = 1785 }}</ref> Alongside [[diuretics]], 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.<ref name="ESC2021">{{cite journal | vauthors = McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JG, Coats AJ, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CS, Lyon AR, McMurray JJ, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GM, Ruschitzka F, Kathrine Skibelund A | display-authors = 6 | title = 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure | journal = European Heart Journal | volume = 42 | issue = 36 | pages = 3599–3726 | date = September 2021 | pmid = 34447992 | doi = 10.1093/eurheartj/ehab368 | publisher = European Society of Cardiology | doi-access = free }}</ref> In certain circumstances it may be used under specialist guidance in addition to, or instead of, the recommended first-line treatments of [[ACE inhibitor]], [[beta blocker]], [[Antimineralocorticoid|mineralocorticoid antagonist]], and [[SGLT-2 inhibitor]], where they are not effective or not tolerated. <ref>{{cite journal | vauthors = Ezekowitz JA, O'Meara E, McDonald MA, Abrams H, Chan M, Ducharme A, Giannetti N, Grzeslo A, Hamilton PG, Heckman GA, Howlett JG, Koshman SL, Lepage S, McKelvie RS, Moe GW, Rajda M, Swiggum E, Virani SA, Zieroth S, Al-Hesayen A, Cohen-Solal A, D'Astous M, De S, Estrella-Holder E, Fremes S, Green L, Haddad H, Harkness K, Hernandez AF, Kouz S, LeBlanc MH, Masoudi FA, Ross HJ, Roussin A, Sussex B | display-authors = 6 | title = 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure | journal = The Canadian Journal of Cardiology | volume = 33 | issue = 11 | pages = 1342–1433 | date = November 2017 | pmid = 29111106 | doi = 10.1016/j.cjca.2017.08.022 | doi-access = free }}</ref><ref name="ESC2021"/>

=== 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.<ref>{{cite book |url= https://books.google.com/books?id=iK7xrRr2p9sC |title=Management of Unintended and Abnormal Pregnancy: Comprehensive Abortion Care | vauthors = Paul M, Lichtenberg S, Borgatta L, Grimes DA, Stubblefield PG, Creinin MD |date=2011-08-24|publisher=John Wiley & Sons|isbn=9781444358476 |url-status=live|archive-url= https://web.archive.org/web/20170908135429/https://books.google.com/books?id=iK7xrRr2p9sC |archive-date=2017-09-08 }}</ref>

== Side effects ==

{{Main|List of side effects of digoxin}}

{{See|Digoxin toxicity}}

The occurrence of [[adverse drug reaction]]s 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 (chemistry)|moiety]] of the digoxin molecule,<ref name=Moscovitz>{{cite journal | vauthors = Moscovitz T, Aldrighi JM, Abrahanshon PA, Zorn TM, Logullo AF, Gebara OC, Rosano GG, Ramires JF | display-authors = 6 | title = Repercussions of digoxin, digitoxin and estradiol on the endometrial histomorphometry of oophorectomized mice | journal = Gynecological Endocrinology | volume = 20 | issue = 4 | pages = 213–20 | date = April 2005 | pmid = 16019364 | doi = 10.1080/09513590400021219 | s2cid = 22855158 }}</ref> but when systematically sought, the evidence for this is equivocal {{as of|2005|lc=1}}.<ref name=Ptherapy1993>{{cite journal | vauthors = Thompson DF, Carter JR | title = Drug-induced gynecomastia | journal = Pharmacotherapy | volume = 13 | issue = 1 | pages = 37–45 | year = 1993 | pmid = 8094898 | doi = 10.1002/j.1875-9114.1993.tb02688.x | s2cid = 30322620 }}</ref>

The combination of increased ([[atrial]]) [[arrhythmia|arrhythmogenesis]] and inhibited [[atrioventricular node|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.<ref name=Doering1977>{{cite journal | vauthors = Doering W, König E, Sturm W | title = [Digitalis intoxication: specifity and significance of cardiac and extracardiac symptoms. part I: Patients with digitalis-induced arrhythmias (author's transl)] | language = de | journal = Zeitschrift für Kardiologie | volume = 66 | issue = 3 | pages = 121–8 | date = March 1977 | pmid = 857452 | trans-title = ''Digitalis'' intoxication: specificity and significance of cardiac and extracardiac symptoms. Part I: Patients with ''[[Digitalis]]''-induced [[Heart arrhythmia|arrhythmia]]s }}</ref>

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.<ref>{{cite book | vauthors = Ritter J, Lewis L, Mant T, Ferro A |title=A Textbook of Clinical Pharmacology and Therapeutics |date=2008 |publisher=Hodder Arnold |location=London |isbn=978-0-340-90046-8 |page=75 |edition=5th}}</ref> It can also cause visual disturbances as well as dizziness or fainting.

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

==Overdose==

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).<ref name=Flanagan2004>{{cite journal | vauthors = Flanagan RJ, Jones AL | title = Fab antibody fragments: some applications in clinical toxicology | journal = Drug Safety | volume = 27 | issue = 14 | pages = 1115–33 | year = 2004 | pmid = 15554746 | doi = 10.2165/00002018-200427140-00004 | url = http://drugsafety.adisonline.com/pt/re/drs/fulltext.00002018-200427140-00004.htm | archive-url = https://archive.today/20130116063055/http://drugsafety.adisonline.com/pt/re/drs/fulltext.00002018-200427140-00004.htm | url-status = dead | archive-date = January 16, 2013 | s2cid = 40869324 | access-date = July 16, 2007 }}</ref> 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 ===

[[File:Signal-averaged ECG with digoxin.png|thumb|250px|Signal-averaged [[electrocardiography|ECG]] from a person taking digoxin, explaining ST depressions in mainly [[precordial lead]]s V4 and V5]]

Digoxin's primary mechanism of action involves inhibition of the sodium potassium adenosine triphosphatase ([[Na+/K+ ATPase]]), mainly in the [[myocardium]].<ref name="sciencedirect.com"/> This inhibition causes an increase in intracellular [[sodium]] levels, resulting in decreased activity of the [[sodium-calcium exchanger]], which normally imports three extracellular [[sodium ion]]s 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 [[protein]]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]], which leads to a decrease in heart rate.<ref>{{ cite book | editor = Tripathi |editor-first=K. D. | title = Essentials of Medical Pharmacology | edition = 6th | pages = 498 | publisher = Jaypee Publications | location = New Delhi | isbn = 978-81-8448-085-6 |date=2008-12-01 }}</ref> 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|date=June 2017}}

The inhibition of the [[sodium pump]] may also improve [[baroreceptor]] sensitivity in heart failure and may explain some of the neurohormonal effects of digoxin.<ref name="Wang 1990">{{cite journal | vauthors = Wang W, Chen JS, Zucker IH | title = Carotid sinus baroreceptor sensitivity in experimental heart failure | journal = Circulation | volume = 81 | issue = 6 | pages = 1959–66 | date = June 1990 | pmid = 2344687 | doi = 10.1161/01.cir.81.6.1959 | doi-access = }}</ref>

Digoxin also has important [[parasympathetic]] effects, particularly on the [[atrioventricular node]].<ref name="Gheorghiade 2004">{{cite journal | vauthors = Gheorghiade M, Adams KF, Colucci WS | title = Digoxin in the management of cardiovascular disorders | journal = Circulation | volume = 109 | issue = 24 | pages = 2959–64 | date = June 2004 | pmid = 15210613 | doi = 10.1161/01.cir.0000132482.95686.87 | s2cid = 33752611 | doi-access = free }}</ref> While it does increase the magnitude of [[myocardium|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 [[hemodynamic]]s and an improved ventricular function curve.

Other electrical effects include a brief initial increase in [[action potential]], followed by a decrease as the [[potassium|K⁺]] conductance increases due to increased [[intracellular]] amounts of [[calcium|Ca²⁺]] ions. The [[refractory period (physiology)|refractory period]] of the [[atrium (heart)|atria]] and [[Ventricle (heart)|ventricles]] is decreased, while it increases in the [[sinoatrial node|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]]s and ventricles is negligible. [[Automaticity]] is also increased in the [[atrium (heart)|atria]], AV node, [[Purkinje fiber]]s, and ventricles.<ref>{{cite book | vauthors = Cunningham L |date=2018 |title=Cardiology Secrets |url=https://www.sciencedirect.com/book/9780323478700/cardiology-secrets |location= |publisher=Elsevier |pages=241–252 |isbn=978-0-323-47870-0 |access-date=2021-03-28 |archive-date=2021-04-20 |archive-url=https://web.archive.org/web/20210420043214/https://www.sciencedirect.com/book/9780323478700/cardiology-secrets |url-status=live }}</ref>

[[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 beat]]s (bigeminy) resulting in [[ventricular tachycardia]] and [[ventricular fibrillation|fibrillation]].

Digoxin is also an [[M2 receptor]] [[muscarinic agonist]].<ref>{{cite book | vauthors = King GS, Goyal A, Grigorova Y, Hashmi MF | chapter = Antiarrhythmic Medications | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK482322/ |title = StatPearls | location = Treasure Island (FL) |publisher=StatPearls Publishing |access-date=7 May 2023 |date=2023 | pmid = 29493947 }}</ref>

=== Pharmacokinetics ===

Digoxin is usually given orally, but can also be given by [[Intravenous injection|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&nbsp;μg or 250&nbsp;μg doses.{{citation needed|date=June 2017}}

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 [[Volume of distribution|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|date=June 2017}}

Effective [[Blood plasma|plasma]] levels vary depending on the medical indication. For [[congestive heart failure]], levels between 0.5 and 1.0&nbsp;ng/mL are recommended.<ref>{{cite journal | vauthors = Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B | display-authors = 6 | title = ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society | journal = Circulation | volume = 112 | issue = 12 | pages = e154-235 | date = September 2005 | pmid = 16160202 | doi = 10.1161/CIRCULATIONAHA.105.167586 | doi-access = free }}</ref> This recommendation is based on ''post hoc'' analysis of prospective trials, suggesting higher levels may be associated with increased [[mortality rate]]s. For heart rate control ([[atrial fibrillation]]), plasma levels are less defined and are generally [[titrate]]d to a goal heart rate. Typically, digoxin levels are considered therapeutic for heart rate control between 0.5 and 2.0&nbsp;ng/mL (or 0.6 and 2.6&nbsp;nmol/L).<ref>{{cite book|title=Medical Toxicology| vauthors = Dart RC |publisher=Lippincott Williams & Wilkins|year=2004|chapter=Digoxin and Therapeutic Cardiac Glycosides|chapter-url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA700|page=700|isbn=978-0-7817-2845-4|url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA700|access-date=2016-12-15|archive-url=https://web.archive.org/web/20170908135429/https://books.google.com/books?id=BfdighlyGiwC&pg=PA700|archive-date=2017-09-08|url-status=dead}}()</ref> 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|date=April 2016}}

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.<ref>{{cite journal | vauthors = Rathore SS, Wang Y, Krumholz HM | title = Sex-based differences in the effect of digoxin for the treatment of heart failure | journal = The New England Journal of Medicine | volume = 347 | issue = 18 | pages = 1403–11 | date = October 2002 | pmid = 12409542 | doi = 10.1056/NEJMoa021266 | doi-access = free }}</ref>

Digoxin is also used as a standard control substance to test for [[P-glycoprotein]] inhibition.<ref>{{cite journal | vauthors = Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L | display-authors = 6 | title = Membrane transporters in drug development | journal = Nature Reviews. Drug Discovery | volume = 9 | issue = 3 | pages = 215–236 | date = March 2010 | pmid = 20190787 | pmc = 3326076 | doi = 10.1038/nrd3028 }}</ref>

Digoxin appears to be a [[peripherally selective drug]] due to limited [[brain]] uptake caused by binding to P-glycoprotein.<ref name="pmid10706193">{{cite journal | vauthors = Fromm MF | title = P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs | journal = Int J Clin Pharmacol Ther | volume = 38 | issue = 2 | pages = 69–74 | date = February 2000 | pmid = 10706193 | doi = 10.5414/cpp38069 | url = }}</ref><ref name="pmid10837715">{{cite journal | vauthors = Schinkel AH | title = P-Glycoprotein, a gatekeeper in the blood-brain barrier | journal = Adv Drug Deliv Rev | volume = 36 | issue = 2–3 | pages = 179–194 | date = April 1999 | pmid = 10837715 | doi = 10.1016/s0169-409x(98)00085-4 | url = }}</ref>

===Pharmacomicrobiomics===

The bacteria ''[[Eggerthella lenta]]'' has been linked to a decrease in the toxicity of Digoxin.<ref>{{Cite web|title=PharmacoMicrobiomics|url=http://pharmacomicrobiomics.com/select/?q=2|access-date=2020-08-13|website=pharmacomicrobiomics.com|archive-date=2021-06-02|archive-url=https://web.archive.org/web/20210602212845/https://c.statcounter.com/6166637/0/607d5329/0/|url-status=live}}</ref> These effects have been studied through comparisons of North Americans and Southern Indians, in which a reduced digoxin metabolite profile correlates with ''E. lenta'' abundance.<ref>{{cite journal | vauthors = Mathan VI, Wiederman J, Dobkin JF, Lindenbaum J | title = Geographic differences in digoxin inactivation, a metabolic activity of the human anaerobic gut flora | journal = Gut | volume = 30 | issue = 7 | pages = 971–7 | date = July 1989 | pmid = 2759492 | pmc = 1434295 | doi = 10.1136/gut.30.7.971 }}</ref> 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. lenta'' population.<ref>{{cite journal | vauthors = Lindenbaum J, Rund DG, Butler VP, Tse-Eng D, Saha JR | title = Inactivation of digoxin by the gut flora: reversal by antibiotic therapy | journal = The New England Journal of Medicine | volume = 305 | issue = 14 | pages = 789–94 | date = October 1981 | pmid = 7266632 | doi = 10.1056/NEJM198110013051403 }}</ref>

== History ==

Derivatives of plants of the genus ''[[Digitalis]]'' have a long history of medical use. [[Nicholas Culpeper]] referred to various medical uses for Foxglove in his 1652 publication ''The English physician''.<ref>{{cite book | vauthors = Culpeper N |title=The English Physician, Etc |date=1652 |publisher=William Bentley |location=London |pages=97–98 |edition=1st |url=https://books.google.com/books?id=WuyUw_5Hd8cC&pg=RA1-PA173 |access-date=22 January 2023 |language=en}}</ref> [[William Withering]] is credited with the first published description of the systematic use of ''Digitalis'' derivatives in his 1785 book ''An Account of the Foxglove and some of its Medical Uses With Practical Remarks on [[Edema|Dropsy]] and Other Diseases''.<ref>{{cite book| vauthors = Withering W |title=An Account of the Foxglove and some of its Medical Uses With Practical Remarks on Dropsy and Other Diseases|year=1785|url=http://www.gutenberg.org/ebooks/24886|url-status=live|archive-url=https://web.archive.org/web/20170908000000/http://www.gutenberg.org/ebooks/24886|archive-date=2017-09-08}}</ref> Its use was somewhat sporadic until [[James_Mackenzie_(cardiologist)|Sir James Mackenzie]] identified the phenomenon of [[atrial fibrillation]], and the actions of digitalis on this.<ref>{{cite book | vauthors = Aronson JK |title=An Account of the Foxglove and its Medical Uses 1785–1985 |date=1985 |publisher=Oxford University Press |location=London |isbn=0192615017 |pages=Chapters 5–7 |edition=1st}}</ref> Its effects were first explained by [[Arthur Robertson Cushny]].<ref>{{cite journal | vauthors = Cushny AR |title=The Action and Uses in Medicine of Digitalis and its Allies |journal=Nature |date=1925 |volume=116 |issue=2905 |pages=8–9 |publisher=Longmans, Green and Co |location=London |doi=10.1038/116008a0 |bibcode=1925Natur.116....8. |hdl=2027/uc1.b3846609 |s2cid=9025850 |edition=1st |url=https://www.nature.com/articles/116008a0 |language=en|hdl-access=free }}</ref> The name is a [[portmanteau]], derived from ''Digitalis lanata'' and ''toxin''.<ref>{{cite web |title=digoxin |url=https://en.wiktionary.org/wiki/digoxin |website=Wiktionary |publisher=Wikimedia |access-date=21 January 2023 |language=en |date=16 January 2023}}</ref>

In 1930, Digoxin was first isolated by Dr. Sydney Smith from the [[foxglove]] plant, ''[[Digitalis lanata]]''.<ref name=cartwright/><ref name=hollman/><ref name=smith>{{cite journal| vauthors = Smith S |date=1930|publisher=The Royal Society of Chemistry|title=LXXII.—Digoxin, a new digitalis glucoside|url=https://pubs.rsc.org/en/content/articlepdf/1930/jr/jr9300000508|journal=J. Chem. Soc.|pages=508–510|doi=10.1039/JR9300000508|access-date=2020-10-22|archive-date=2021-06-02|archive-url=https://web.archive.org/web/20210602212903/https://pubs.rsc.org/en/content/articlelanding/1930/jr/jr9300000508/unauth|url-status=live}}</ref> 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's reagent|Keller reaction]]). Digoxin was distinguishable from other [[glucosides]] by the olive-green colored solution produced from this reaction, completely free of red.<ref name=smith/>

== 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 19-year career as a nurse. On March 10, 2006, he was sentenced to 18 consecutive life sentences and is not eligible for [[parole]].<ref>{{cite news | work=[[USA Today]] | title = Victims' families set to confront killer | url = http://usatoday.com/news/nation/2006-01-01-patient-deaths_x.htm | date = 2006-01-01 | url-status = live | archive-url = https://web.archive.org/web/20060104040313/http://www.usatoday.com/news/nation/2006-01-01-patient-deaths_x.htm | archive-date = 2006-01-04 }}</ref>

On April 25, 2008, the U.S. [[Food and Drug Administration]] (FDA) issued a press release<ref>{{ cite web | url = https://www.fda.gov/oc/po/firmrecalls/actavis04_08.html | title = Recalls, Market Withdrawals & Safety Alerts | publisher = Federal Drugs Administration | date = 2008-10-15 | access-date = 2011-11-08 | url-status = live | archive-url = https://web.archive.org/web/20080502160007/https://www.fda.gov/oc/po/firmrecalls/actavis04_08.html | archive-date = 2008-05-02 }}</ref> alerting the public to a [[Class I recall]] of Digitek, a brand of digoxin produced by [[Mylan]].<ref>{{ cite news | url = http://www.usrecallnews.com/2008/04/urgent-digitek-digoxin-recall.html | title = Urgent Digitek Digoxin Recall | work = U.S. Recall News | date = 2008-04-28 | access-date = 2009-07-25 | url-status = live | archive-url = https://web.archive.org/web/20080504060554/http://www.usrecallnews.com/2008/04/urgent-digitek-digoxin-recall.html | archive-date = 2008-05-04 }}</ref> 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.<ref>{{ cite news | url = https://blogs.wsj.com/health/2008/05/09/patients-sue-icelandic-drugmaker-over-recalled-heart-drug/ | title = Patients Sue Icelandic Drugmaker Over Recalled Heart Drug | work =[[The Wall Street Journal]] | date = 2008-05-09 | access-date = 2009-07-25 | url-status = live | archive-url = https://web.archive.org/web/20090413213712/http://blogs.wsj.com/health/2008/05/09/patients-sue-icelandic-drugmaker-over-recalled-heart-drug/ | archive-date = 2009-04-13 }}</ref>

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:

{{blockquote|[All] tablets of Caraco brand Digoxin, USP, 0.125&nbsp;mg, and Digoxin, USP, 0.25&nbsp;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|date=June 2017}}}}

A 2008 study suggested digoxin has beneficial effects not only for the heart, but also in reducing the risk of certain kinds of cancer.<ref>{{cite journal | vauthors = Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, Semenza GL | display-authors = 6 | title = Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 50 | pages = 19579–86 | date = December 2008 | pmid = 19020076 | pmc = 2604945 | doi = 10.1073/pnas.0809763105 | type = re: [[glycoside]]s | doi-access = free | bibcode = 2008PNAS..10519579Z }}</ref> However, comments on this study suggested that digoxin is not effective at reducing cancer risk at therapeutic concentrations of the drug,<ref>{{cite journal | vauthors = Lopez-Lazaro M | title = Digoxin, HIF-1, and cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 9 | pages = E26; author reply E27 | date = March 2009 | pmid = 19240208 | pmc = 2651277 | doi = 10.1073/pnas.0813047106 | doi-access = free | bibcode = 2009PNAS..106E..26L }}</ref> so the results need further investigation.<ref>{{cite journal | vauthors = Dal Canto MC | title = AIDS and the nervous system: current status and future perspectives | journal = Human Pathology | volume = 20 | issue = 5 | pages = 410–8 | date = May 1989 | pmid = 2651280 | doi = 10.1016/0046-8177(89)90004-x }}</ref>

=== Brand names ===

Digoxin preparations are marketed under the [[brand name]]s 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.<ref>{{Cite web |date=2021-09-15 |title=Digoxin: a medicine to treat heart problems |url=https://www.nhs.uk/medicines/digoxin/ |access-date=2024-01-24 |website=nhs.uk |language=en}}</ref><ref>{{Cite web |title=Digoxin Tablets: Uses & Side Effects |url=https://my.clevelandclinic.org/health/drugs/19363-digoxin-tablets |access-date=2024-01-24 |website=Cleveland Clinic |language=en}}</ref>

==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,<ref>{{cite journal | vauthors = Yokoyama S, Sugimoto Y, Nakagawa C, Hosomi K, Takada M | title = Integrative analysis of clinical and bioinformatics databases to identify anticancer properties of digoxin | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 16597 | date = November 2019 | pmid = 31719612 | pmc = 6851125 | doi = 10.1038/s41598-019-53392-y | bibcode = 2019NatSR...916597Y }}</ref> others not.<ref>{{cite journal | vauthors = Kaapu KJ, Murtola TJ, Talala K, Taari K, Tammela TL, Auvinen A | title = Digoxin and prostate cancer survival in the Finnish Randomized Study of Screening for Prostate Cancer | journal = British Journal of Cancer | volume = 115 | issue = 11 | pages = 1289–1295 | date = November 2016 | pmid = 27755533 | pmc = 5129833 | doi = 10.1038/bjc.2016.328 }}</ref>

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.<ref>{{cite journal | vauthors = Biggar RJ, Wohlfahrt J, Oudin A, Hjuler T, Melbye M | title = Digoxin use and the risk of breast cancer in women | journal = Journal of Clinical Oncology | volume = 29 | issue = 16 | pages = 2165–70 | date = June 2011 | pmid = 21422417 | doi = 10.1200/JCO.2010.32.8146 | doi-access = free }}</ref> A large Danish study found a complicated picture, with slightly increased risk of breast cancer amongst women taking digoxin, but better prognostic features.<ref>{{cite journal | vauthors = Biggar RJ, Andersen EW, Kroman N, Wohlfahrt J, Melbye M | title = Breast cancer in women using digoxin: tumor characteristics and relapse risk | journal = Breast Cancer Research | volume = 15 | issue = 1 | pages = R13 | date = February 2013 | pmid = 23421975 | doi = 10.1186/bcr3386 | pmc = 3672748 | doi-access = free }}</ref> The Nurses' Health Study found a similar slight increase of risk.<ref>{{cite journal | vauthors = Ahern TP, Tamimi RM, Rosner BA, Hankinson SE | title = Digoxin use and risk of invasive breast cancer: evidence from the Nurses' Health Study and meta-analysis | journal = Breast Cancer Research and Treatment | volume = 144 | issue = 2 | pages = 427–35 | date = April 2014 | pmid = 24573543 | pmc = 4010120 | doi = 10.1007/s10549-014-2886-x }}</ref>

Digoxin inhibits the proliferation of many cancerous cell lines ''in vitro'',<ref>{{cite journal | vauthors = Deng K, Shen J, Wang W, Li M, Li H, Chen C, Zhao H, Zhang M, Xue T, Liu Q, Lui VW, Hong B, Lin W | display-authors = 6 | title = Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer | journal = Cancer Biology & Therapy | volume = 20 | issue = 1 | pages = 52–64 | date = 2019-01-02 | pmid = 30183476 | pmc = 6343689 | doi = 10.1080/15384047.2018.1504723 }}</ref><ref name="Chung 44203–44216">{{cite journal | vauthors = Chung MH, Wang YW, Chang YL, Huang SM, Lin WS | title = Risk of cancer in patients with heart failure who use digoxin: a 10-year follow-up study and cell-based verification | journal = Oncotarget | volume = 8 | issue = 27 | pages = 44203–44216 | date = July 2017 | pmid = 28496002 | pmc = 5546474 | doi = 10.18632/oncotarget.17410 }}</ref> but its relevance to cancer ''in vivo'' remains unclear.

== References ==

{{Reflist}}

== Further reading ==

{{refbegin}}

* {{cite book | vauthors = Rang HP, Dale MM, Ritter JM, Moore PK | title = Pharmacology | publisher = Churchill Livingstone | location = Edinburgh | year = 2003 | isbn = 0-443-07145-4 | edition = 5th }}

* [[Summary of Product Characteristics]], Digoxin 0.125&nbsp;mg, Zentiva.

* {{cite book | vauthors = Lüllmann H, Kuschinsky G, Mohr K, Wehling M | title = Pharmakologie und Toxikologie | publisher = Georg Thieme Verlag | year = 2003 | isbn = 3-13-368515-5 | edition = 15th }}

* [[Lanatoside C]] (isolanid, Cedilanid – four glycoside analog), [[Digoxigenin]] (aglycone analog)

* {{cite journal | vauthors = Goldberger ZD, Alexander GC | title = Digitalis use in contemporary clinical practice: refitting the foxglove | journal = JAMA Internal Medicine | volume = 174 | issue = 1 | pages = 151–154 | date = January 2014 | pmid = 24217624 | doi = 10.1001/jamainternmed.2013.10432 }}

{{refend}}

{{Cardiac glycosides}}

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