Digoxin

Not to be confused with Dioxin or Digitoxin.

ory, the increased force of contraction should lead to improved pumping function of the heart, but its eect on
prognosis is disputable, and other eective treatments
are now available. Digoxin is no longer the rst choice
for congestive heart failure, but can still be useful in patients who remain symptomatic despite proper diuretic
and ACE inhibitor treatment.

Digoxin INN (/ddksn/[1] ) is a puried cardiac glycoside similar to digitoxin extracted from the foxglove
plant, Digitalis lanata.[2] Its corresponding aglycone is
digoxigenin, and its acetyl derivative is acetyldigoxin.
Digoxin is widely used in the treatment of various heart
conditions, namely atrial brillation, atrial utter and Digitalis/digoxin has recently fallen out of favor because
sometimes heart failure that cannot be controlled by other it did not demonstrate a mortality benet in patients with
congestive heart failure; however, it did demonstrate a remedication.
[7]
Digoxin preparations are marketed under the trade duction in hospitalizations for this condition. Because
names Cardigox; Cardiogoxin; Cardioxin; Cardoxin; other therapies have shown a mortality benet in congesCoragoxine; Digacin; Digicor; Digomal; Digon; Digosin; tive heart failure, maximizing other therapies (e.g., beta
Digoxine Navtivelle; Digoxina-Sandoz; Digoxin-Sandoz; blockers) rst is recommended before using digoxin.
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.

2 Adverse eects

Main article: Digoxin toxicity

Digoxin was discovered by physician William Withering, a graduate of the University of Edinburgh Medical
The occurrence of adverse drug reactions is common,
School.
owing to its narrow therapeutic index (the margin beIt is on the World Health Organizations List of Essentween eectiveness and toxicity).
Adverse eects
tial Medicines, a list of the most important medication
are
concentration-dependent,
and
are
rare
when plasma
needed in a basic health system.[3]
digoxin concentration is <0.8 nanograms/l.[8] They are
also more common in patients with low potassium levels (hypokalemia), since digoxin normally competes with
+
K
ions for the same binding site on the Na+ /K+ ATPase
1 Medical use
pump.
Common adverse eects (1% of patients) include loss
of appetite, nausea, vomiting, and diarrhea as gastrointestinal motility increases. Other common eects are
blurred vision, visual disturbances (yellow-green halos and problems with color perception), confusion,
drowsiness, dizziness, insomnia, nightmares, agitation,
and depression, as well as a higher acute sense of sensual activities.[9] Less frequent adverse eects (0.1%
1%) include: acute psychosis, delirium, amnesia,
convulsions, shortened QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with
AV block, ventricular tachycardia or brillation, and
heart block.[8] Rarely, digoxin has been shown to cause
thrombocytopenia.
Gynaecomastia (enlargement of
breast tissue) is mentioned in many textbooks as a side
eect, thought to be due to the estrogen-like steroid
moiety of the digoxin molecule,[10] but when systematically sought, the evidence for this is equivocal.[11]
The pharmacological actions of digoxin usually result in

Derivatives of plants of the genus Digitalis have a long history of medical use. The British physician William Withering is credited with the rst 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.[4]
Today, the most common indications for digoxin are
atrial brillation and atrial utter with rapid ventricular
response, though beta blockers and/or calcium channel
blockers are a better rst choice.[5][6] High ventricular
rate leads to insucient diastolic lling time. By slowing down the conduction in the AV node and increasing
its refractory period, digoxin can reduce the ventricular
rate. The arrhythmia itself is not aected, but the pumping function of the heart improves owing to improved lling.
The use of digoxin in heart problems during sinus rhythm
was once standard, but is now controversial. In the1

4 MECHANISMS OF ACTION

electrocardiogram changes, including ST depression or T

wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca2+ may cause
a type of arrhythmia called bigeminy (coupled beats),
eventually ventricular tachycardia or brillation. The
combination of increased (atrial) arrhythmogenesis and
inhibited atrioventricular conduction (for example paroxysmal atrial tachycardia with A-V block - so-called PAT
with block) is said to be pathognomonic (i.e. diagnostic)
of digoxin toxicity.[12]

for a reduction in dose or a switch to a dierent glycoside, such as digitoxin (not available in the United States),
which has a much longer elimination half-life of around
seven days, elimination is mainly by renal excretion and
involves P-glycoprotein which leads to signicant clinical
interactions with other drugs commonly used in patients
with heart problems. These include: spironolactone, verapamil and amiodarone. ( Inhibit P-glycoprotein that is
mainly responsible for Digoxin Clearance )
Eective plasma levels vary depending on the medical indication. For congestive heart failure, levels between 0.5
and 1.0 ng/ml are recommended.[19] This recommendation is based on post hoc analysis of prospective trials,
suggesting higher levels may be associated with increased
mortality rates. For heart rate control (atrial brillation),
plasma levels are less dened and are generally titrated
to a goal heart rate. Typically, digoxin levels are considered therapeutic for heart rate control between 1.0 and 2.0
ng/ml. In suspected toxicity or ineectiveness, digoxin
levels should be monitored. Plasma potassium levels also
need to be closely controlled (see side eects below).

An often described, but rarely seen, adverse eect of

digoxin is a disturbance of color vision (mostly yellow
and green) called xanthopsia. Vincent van Gogh's Yellow Period may have somehow been inuenced by concurrent digitalis therapy. Other oculotoxic eects of
digoxin include generalized blurry vision, as well as seeing a halo around each point of light.[13] The latter effect can also be seen in van Goghs Starry Night. Evidence of van Goghs digoxin use is supported by multiple
self-portraits that include the foxglove plant, from which
digoxin is obtained. (e.g. Portrait of Dr. Gachet)
Quinidine, verapamil, and amiodarone increases plasma
Digoxin plasma concentrations may increase while on levels of digoxin (by displacing tissue binding sites and
antimalarial medication hydroxychloroquine (based on depressing renal digoxin clearance), so plasma digoxin
two case reports from 1982).[14]
must be monitored carefully.
In overdose, the usual supportive measures are needed.
If arrhythmias prove troublesome, or malignant hyperkalaemia occurs (inexorably rising potassium level
due to paralysis of the cell membrane-bound, ATPasedependent Na/K pumps), the specic antidote is antidigoxin (antibody fragments against digoxin, trade
names Digibind and Digifab).[15] . Digoxin is not removed
by hemodialysis or peritoneal dialysis with enough eectiveness to treat toxicity.

Researchers at Yale University looked at data from an

earlier study to see if digoxin aected men and women
dierently. That study determined digoxin, which has
been used for centuries and makes the heart contract more
forcefully, did not reduce deaths overall, but did result in
less hospitalization. Researcher Dr. Harlan Krumholz
said they were surprised to nd women in the study who
took digoxin died more frequently (33%) than women
who took a placebo pill (29%). They calculated digoxin
Digoxin has potentially dangerous interactions increased the risk of death in women by 23%. There was
with verapamil,[16] amiodarone, erythromycin, and no dierence in the death rate for men in the study.
epinephrine (as would be injected with a local anes- Digoxin is also used as a standard control substance to test
for p-glycoprotein inhibition.
thetic).
Patients taking
hawthorn.[17][18]

digoxin

should

avoid

taking

Pharmacokinetic properties

Digoxin is usually given orally, but can also be given by IV

injection in urgent situations (the IV injection should be
slow, and heart rhythm should be monitored). While IV
therapy may be better tolerated (less nausea), digoxin has
a very long distribution half-life into the cardiac tissue,
which will delay its onset of action by a number of hours.
The half-life is about 36 hours for patients with normal
renal function, digoxin is given once daily, usually in 125g or 250-g doses.
In patients with decreased kidney function, the half-life
is considerably longer, along with decrease in Vd, calling

4 Mechanisms of action
Digoxins primary mechanism of action involves inhibition of the Na+/K+ ATPase, mainly in the myocardium.
This inhibition causes an increase in intracellular sodium
levels, resulting in a reversal of the action of the sodiumcalcium exchanger, which normally imports three extracellular sodium ions into the cell and transports one intracellular calcium ion out of the cell. The reversal of
this exchange causes an increase in the intracellular calcium concentration that is available to the contractile proteins, resulting in an increase in the force of myocardial
contraction. The inhibition of the sodium pump may
also improve baroreceptor sensitivity in HF and may explain some of the neurohormonal eects of digoxin.[20]
Digoxin also has important parasympathetic eects, par-

3
ticularly on the atrioventricular node.[21]

causing some patients to experience digoxin toxicity. A

drug
The main pharmacological eects of digoxin are on the class-action lawsuit against the Icelandic generic
[25]
maker
Actavis
was
announced
two
weeks
later.
heart. Extracardiac eects are responsible for some of
the therapeutic and many of the adverse eects (see On March 31, 2009, the FDA announced another generic
above). It exerts a mechanical eect as it increases digoxin pill recall by posting this company press release
myocardial contractility; however, the duration of the on the agencys web site: Caraco Pharmaceutical Labocontractile response is only slightly increased. Overall, ratories, Ltd. Announces a Nationwide Voluntary Recall
the heart rate is decreased while blood pressure is in- of All Lots of Digoxin Tablets Due to Size Variability.
creased, resulting in a net increase in stroke volume, lead- This March 31 press release from Caraco, a generic pharing to increased tissue perfusion. This causes the my- maceutical company, states:
ocardium to work more eciently, with optimized hemodynamics and an improved ventricular function curve.
[All] tablets of Caraco brand Digoxin,
Other electrical eects include a brief initial increase in
USP, 0.125 mg, and Digoxin, USP, 0.25 mg,
+
action potential, followed by a decrease as the K condistributed prior to March 31, 2009, which are
ductance increases due to increased intracellular amounts
not expired and are within the expiration date
2+
of Ca ions. The refractory period of the atria and
of September, 2011, are being voluntarily reventricles is decreased, while it increases in the sinoatrial
called to the consumer level. The tablets are
and AV nodes. A less negative resting membrane potenbeing recalled because they may dier in size
tial is made, leading to increased irritability. Other, more
and therefore could have more or less of the
indirect eects are cholinomimetic because of vagal stimactive ingredient, digoxin.
ulation, giving rise to AV nodal delay.
The conduction velocity increases in the atria, but decreases in the AV node. The eect upon Purkinje bers
and ventricles is negligible. Automaticity is also increased in the atria, AV node, Purkinje bers, and ventricles.

A 2008 study suggested digoxin has benecial eects not

only for the heart, but also in reducing the risk of certain kinds of cancer.[26] However, comments on this study
suggested that digoxin is not eective at reducing cancer
risk at therapeutic concentrations of the drug,[27] so the
ECG changes seen in patient taking digoxin include in- results need further investigation.[28]
creased PR interval (due to decreased AV conduction)
In the Turkish movie Once Upon a Time in Anatolia the
and a decreased QT interval. Also, the T wave may be inprosecutor tells the doctor a story of a 'gorgeous woman'
verted and accompanied by ST depression. It may cause
who died on the date she predicted she would die, well
AV junctional rhythm and ectopic beats (bigeminy) reafter delivering the baby. The doctor speculates she may
sulting in ventricular tachycardia and brillation.
have taken high doses of digoxin to die of heart attack.
Slight vasodilation is seen in heart failure. This eect is There are hints that she may have been the prosecutors
contrary to eects that should be seen as a result of in- wife who committed suicide because she couldn't take his
creased intracellular calcium levels, but this occurs since one time aair.
digoxin improves hemodynamics, which leads to restored
angiotensin levels and decreased sympathetic discharge,
causing indirect vasodilation.

6 Predecessors

Digoxin also aects the kidney by increased renal blood

ow and increased glomerular ltration rate. A mild Ouabain (g-strophanthin)
diuretic eect is seen only in heart failure.

Society and culture

Charles Cullen admitted in 2003 to killing as many as

40 hospital patients with overdoses of heart medication
usually digoxinat hospitals in New Jersey and Pennsylvania over his 16-year career as a nurse. On March 10,
2006, he was sentenced to 18 consecutive life sentences
and is not eligible for parole.[22]
On April 25, 2008, the FDA issued a press release[23]
alerting the public to a Class I recall of Digitek, a brand of
digoxin produced by Mylan.[24] Some tablets had been released at double thickness and therefore double strength,

7 References
[1] OED
[2] Hollman A (1996). Digoxin comes from Digitalis
lanata". British Medical Journal 312 (7035): 912.
doi:10.1136/bmj.312.7035.912.
[3] WHO Model List of EssentialMedicines. World Health
Organization. October 2013. Retrieved 22 April 2014.
[4] Withering, William (1785). An Account of the Foxglove
and some of its Medical Uses With Practical Remarks on
Dropsy and Other Diseases.

REFERENCES

[5] Sticherling C, Oral H, Horrocks J et al. (November 2000).

Eects of digoxin on acute, atrial brillation-induced
changes in atrial refractoriness (pdf). Circulation 102
(20): 25032508. doi:10.1161/01.CIR.102.20.2503.
PMID 11076824.

[18] Tankenow, Roberta; Tamer, Helen R.; Streetman, Daniel

S.; Smith, Scott G.; Welton, Janice L.; Annesley, Thomas;
Aaronson, Keith D.; Bleske, Barry E. Interaction Study
between Digoxin and a Preparation of Hawthorn (Crataegus oxyacantha), J Clin Pharmacol 2003;43:637-642

[6] Hallberg P, Lindbck J, Lindahl B, Stenestrand U, Melhus H (October 2007). Digoxin and mortality in
atrial brillation: a prospective cohort study. European Journal of Clinical Pharmacology 63 (10): 959971.
doi:10.1007/s00228-007-0346-9. PMID 17684738.

[19] Hunt SA, Abraham, WT, Chin, MH et al. (September 2005). 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 (pdf). Circulation 112 (12): e154e235.
doi:10.1161/CIRCULATIONAHA.105.167586. PMID
16160202.

[7] The eect of digoxin on mortality and morbidity in patients with heart failure.
The Digitalis
Investigation Group.
The New England Journal
February 1997.
of Medicine 336 (8): 525533.
doi:10.1056/NEJM199702203360801. PMID 9036306.
[8] Rossi S, ed. (2006). Australian Medicines Handbook
2006. Adelaide. ISBN 0-9757919-2-3.
[9] Tripathi KD (ed.). Essentials of Medical Pharmacology
(6th ed.). New Delhi: Jaypee Publications. ISBN 818448-085-7.
[10] Moscovitz T, Aldrighi JM, Abrahanshon PA et al. (April
2005). Repercussions of digoxin, digitoxin and estradiol on the endometrial histomorphometry of oophorectomized mice. Gynecology and Endocrinology 20 (4):
213220. doi:10.1080/09513590400021219. PMID
16019364.
[11] Thompson DF, Carter JR (1993). Drug-induced gynecomastia. Pharmacotherapy 13 (1): 3745. PMID
8094898.
[12] Doering W, Knig E, Sturm W (1977). "(title in German)" [Digitalis intoxication: specicity and signicance of cardiac and extracardiac symptoms. part I: Patients with digitalis-induced arrhythmias (authors transl)].
Zeitschrift fr Kardiologie (in German) 66 (3): 121128.
PMID 857452.
[13] Goldfrank LW (2006). Goldfranks Toxicologic Emergencies (8th ed.). New York: McGraw-Hill.
[14] Leden I (1982). Digoxin-hydroxychloroquine interaction?". Acta Medica Scandinavica 211 (5): 411
412. doi:10.1111/j.0954-6820.1982.tb01971.x. PMID
7113754.
[15] Flanagan RJ, Jones AL (2004). Fab Antibody Fragments: Some Applications in Clinical Toxicology. Drug
Safety 27 (14): 11151133. doi:10.2165/00002018200427140-00004. PMID 15554746.
[16] Kaplanski J, Weinhouse E, Topaz M, Genchik G (1983).
Verapamil and digoxin: interactions in the rat. Research
Communications in Chemical Pathology and Pharmacology 42 (3): 377388. PMID 6665298.
[17] Dasgupta A, Kidd L, Poindexter BJ, Bick RJ. Interference
of hawthorn on serum digoxin measurements by immunoassays and pharmacodynamic interaction with
digoxin. Arch Pathol Lab Med. 2010 Aug;134(8):118892.

[20] Wang, W; Chen, JS; Zucker, IH (Jun 1990).

Carotid sinus baroreceptor sensitivity in experimental heart failure.. Circulation 81 (6): 195966.
doi:10.1161/01.cir.81.6.1959. PMID 2344687.
[21] Gheorghiade, M; Adams KF, Jr; Colucci, WS (Jun
22, 2004). Digoxin in the management of cardiovascular disorders.. Circulation 109 (24): 2959
64. doi:10.1161/01.cir.0000132482.95686.87. PMID
15210613.
[22] Victims families set to confront killer. USA Today.
2006-01-01.
[23] Recalls, Market Withdrawals & Safety Alerts. FDA.
2008-10-15. Retrieved 2011-11-08.
[24] Urgent Digitek Digoxin Recall. U.S. Recall News.
2008-04-28. Retrieved 2009-07-25.
[25] Patients Sue Icelandic Drugmaker Over Recalled Heart
Drug. Wall Street Journal. 2008-05-09. Retrieved 200907-25.
[26] Zhang, H.; Qian, D. Z.; Tan, Y. S.; Lee, K.; Gao,
P.; Ren, Y. R.; Rey, S.; Hammers, H.; Chang, D.
(2008). Inaugural Article: Digoxin and other cardiac glycosides inhibit HIF-1 synthesis and block tumor growth. Proceedings of the National Academy
of Sciences (re: glycosides) 105 (50): 1957919586.
doi:10.1073/pnas.0809763105. PMC 2604945. PMID
19020076.
[27] Lopez-Lazaro M (March 2009).
Digoxin,
HIF-1,
and cancer (pdf).
PNAS 106
Bibcode:2009PNAS..106...26L.
(9):
E26.
doi:10.1073/pnas.0813047106.
PMC 2651277.
PMID 19240208.
[28] Zhang, H.; Semenza, G. L. (2009). Reply to LopezLazaro: Evidence that digoxin inhibits human cancer.
Proceedings of the National Academy of Sciences 106 (9):
E27. doi:10.1073/pnas.0900125106.

Further reading
Rang HP, Dale MM, Ritter JM, Moore PK (2003).
Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
Summary of Product Characteristics, Digoxin 0,125
mg, Zentiva a.s.
Lllmann (2003). Pharmakologie und Toxikologie
(15th ed.). Georg Thieme Verlag. ISBN 3-13368515-5.
Lanatoside C (isolanid, Cedilanid - four glycoside
analog), Digoxigenin (aglycone analog)
Goldberger AD, Alexander GC. Retting the Foxglove: Digoxin Use in Contemporary Clinical

Practice. JAMA Internal Medicine.

External links
Lanoxin
U.S. National Library of Medicine: Drug Information Portal Digoxin
Commonly used website to calculate empiric
digoxin doses for medical purposes for heart problems
1. Protein Data Bank entry (useful for computational molecular dynamics): http://www.rcsb.org/
pdb/explore.do?structureId=3B0W

10

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