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| __NOTOC__
| | #REDIRECT [[Digoxin#Pharmacology]] |
| {{drugbox |
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| | IUPAC_name = 4-[(3S,5R,8R,9S,10S,12R,13S,14S)-3-<br>[(2S,4S,5R,6R)-5-[(2S,4S,5R,6R)-5-<br>[(2S,4S,5R,6R)-4,5-dihydroxy-6-methyl-<br>oxan-2-yl]oxy-4-hydroxy-6-methyl-oxan-<br>2-yl]oxy-4-hydroxy-6-methyl-oxan-2-yl]<br>oxy-12,14-dihydroxy-10,13-dimethyl-1,<br>2,3,4,5,6,7,8,9,11,12,15,16,17-tetra<br>decahydrocyclopenta[a]phenanthren-<br>17-yl]-5H-furan-2-one
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| | image = Digoxin structure.png
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| | CAS_number = 20830-75-5
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| | ATC_prefix = C01
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| | ATC_suffix = AA02
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| | ATC_supplemental = {{ATC|C01|AA05}} {{ATC|C01|AA08}}
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| | PubChem = 30322
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| | DrugBank = APRD00098
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| | C = 41 |H = 64 |O = 14
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| | molecular_weight = 780.938 g/mol
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| | solubility = 64.8
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| | melting_point = 249.3
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| | bioavailability = 60 to 80% (Oral)
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| | protein_bound = 25%
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| | metabolism = [[Liver|Hepatic]] (16%)
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| | elimination_half-life = 36 to 48 hours <br><small>(patients with normal [[renal function]])</small><br>3.5 to 5 days <br><small>(patients with impaired renal function)</small>
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| | excretion = [[Renal|Renal]]
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| | pregnancy_category = A <small>([[Australia|Au]])</small>, C <small>([[United States|U.S.]])</small>
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| | legal_status = S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>
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| | routes_of_administration = [[Route of administration#Enteral|Oral]], [[Intravenous therapy|Intravenous]]
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| }}
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| {{SI}}
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| {{CMG}}
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| ==[[Digoxin (patient information)|For patient information, click here]]==
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| '''Digoxin''' ([[International Nonproprietary Name|INN]]) ({{IPAEng|dɨˈdʒɒksɨn}}<ref>OED</ref>) is a purified [[cardiac glycoside]] extracted from the [[foxglove]] plant, ''[[Digitalis lanata]].''<ref>{{cite journal | author = A. Hollman | title = Digoxin comes from Digitalis lanata | year = 1996 | journal = [[British Medical Journal]] | format = letter | volume = 312 | issue = 7035 | pages = 912 | url = http://www.bmj.com/cgi/content/full/312/7035/912}}</ref> Its corresponding [[aglycone]] is [[digoxigenin]]. Digoxin is widely used in the treatment of various [[heart condition]]s, namely [[atrial fibrillation]], [[atrial flutter]] and sometimes [[heart failure]] that cannot be controlled by other [[medication]]. Digoxin preparations are commonly marketed under the trade names '''Lanoxin''', '''Digitek''', and '''Lanoxicaps'''. It is also available as a 0.05 mg/mL oral solution and 0.25 mg/mL or 0.5 mg/mL injectible solution.
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| ==Actions==
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| The main pharmacological effects of digoxin are on the [[heart]]. Extracardiac effects are responsible for many of the adverse effects (see below).
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| Its main cardiac effects are
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| * A decrease of conduction of electrical impulses through the [[AV node]], making it a commonly used drug in controlling the [[heart rate]] during [[atrial fibrillation]] or [[atrial flutter]].
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| * An increase of force of [[contraction]] via inhibition of the [[NaKATPase|Na<sup>+</sup>/K<sup>+</sup> ATPase]] pump (see below).
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| ==Mechanism of action==
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| Digoxin binds to a site on the extracellular aspect of the α-subunit of the [[NaKATPase|Na<sup>+</sup>/K<sup>+</sup> ATPase]] pump in the [[cell membrane|membranes]] of heart cells (myocytes). This causes an increase in the level of [[sodium]] [[ion]]s in the myocytes, which then leads to a rise in the level of [[calcium]] ions. The proposed mechanism is the following: inhibition of the Na<sup>+</sup>/K<sup>+</sup> pump leads to increased intracellular Na<sup>+</sup> levels, which in turn slows down the extrusion of Ca<sup>2+</sup> by the [[Sodium-calcium exchanger|Na<sup>+</sup>/Ca<sup>2+</sup> exchange pump]] that relies on the high Na<sup>+</sup> gradient. This effect causes an increase in the length of Phase 4 and Phase 0 of the Cardiac Action Potential, which when combined with the effects of Digoxin on the parasympathetic nervous system, lead to a decrease in heart rate. Increased amounts of Ca<sup>2+</sup> are then stored in the [[sarcoplasmic reticulum]] and released by each action potential, which is unchanged by digoxin. This leads to increased contractility of the heart. This is a different mechanism from that of [[catecholamines]].
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| Digoxin also increases vagal activity via its action on the central nervous system, thus decreasing the conduction of electrical impulses through the [[AV node]]. This is important for its clinical use in different arrhythmias (see below).
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| ==Clinical use==
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| Today, the most common indications for digoxin are probably [[atrial fibrillation]] and [[atrial flutter]] with rapid ventricular response. High ventricular rate leads to insufficient diastolic filling 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 affected, but the pumping function of the heart improves owing to improved filling.
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| The use of digoxin in heart problems during [[sinus rhythm]] was once standard, but is now controversial. In theory the increased force of contraction should lead to improved pumping function of the heart, but its effect on prognosis is disputable and other effective treatments are now available. Digoxin is no longer the first choice for [[congestive heart failure]], but can still be useful in patients who remain symptomatic despite proper [[diuretic]] and [[ACE inhibitor]] treatment. It has fallen out of favor because it was proven to be ineffective at decreasing [[morbidity]] and [[death|mortality]] in Congestive Heart Failure. It is shown to increase quality of life, however.
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| Digoxin is usually given by mouth, but can also be given by IV injection in urgent situations (the IV injection should be slow, heart rhythm should be monitored). The half life is about 36 hours, digoxin is given once daily, usually in 125 μg or 250 μg dosing. In patients with decreased kidney function the half life is considerably longer, calling for a reduction in dosing or a switch to a different glycoside (such as [[digitoxin]] which although having a much longer [[elimination half-life]] of around 7 days, is mainly eliminated from the body via the liver, and thus not affected by changes in renal function).
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| Effective plasma levels are fairly well defined, 1-2.6 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).
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| ==Adverse effects==
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| The occurrence of [[adverse drug reaction]]s is common, owing to its narrow [[therapeutic index]] (the margin between effectiveness and toxicity). Adverse effects are concentration-dependent, and are rare when plasma digoxin concentration is <0.8 μg/L.<ref name=Rossi> Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> They are also more common in patients with low potassium levels ([[hypokalemia]]), since digoxin normally competes with K<sup>+</sup> ions for the same binding site on the [[NaKATPase|Na<sup>+</sup>/K<sup>+</sup> ATPase]] pump.
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| Common adverse effects (≥1% of patients) include: loss of appetite, nausea, vomiting, diarrhea, blurred vision, visual disturbances (yellow-green halos), confusion, drowsiness, dizziness, nightmares, agitation, and/or depression. Less frequent adverse effects (0.1%–1%) include: acute psychosis, delirium, amnesia, shortened QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or fibrillation, heart block<ref name=Rossi>. [[Gynaecomastia]] (enlargement of breast tissue) is mentioned in many textbooks as a side-effect - thought to be due to the oestragen-like steroid moiety of the digoxin molecule<ref name=Moscovitz> Repercussions of digoxin, digitoxin and estradiol on the endometrial histomorphometry of oophorectomized mice. Moscovitz T, et al. ''Gynecol Endocrinol.'' 2005 Apr;20(4):213-20[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16019364&query_hl=14&itool=pubmed_docsum]</ref> but when systematically sought, the evidence for this is equivocal.<ref>{{cite journal | author = Thompson, D.F. | coauthors = Carter, J.R. | year = 1993 | title = Drug-induced gynecomastia. | journal = Pharmacotherapy | volume = 13 | issue = 1 | pages = 37-45 | pmid = 8094898}}</ref>
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| The pharmacological actions of digoxin usually results in [[electrocardiogram]] (ECG) 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 Ca<sup>2+</sup> may cause a type of arrhythmia called [[bigeminy]] (coupled beats), eventually [[ventricular tachycardia]] or [[fibrillation]]. The combination of increased (atrial) arrhythmogenesis and inhibited atrio-ventricular 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.<ref name=Doering1977>{{cite journal | author = Doering, W. | coauthors = Konig, E.; Sturm, W. | year = 1977 | title = Digitalis intoxication: specifity and significance of cardiac and extracardiac symptoms. part I: Patients with digitalis-induced arrhythmias (author's transl) | journal = Z Kardiol | volume = 66 | issue = 3 | pages = 121-8 | pmid = 857452}}</ref>
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| An often described but rarely seen adverse effect of digoxin is a disturbance of colour vision (mostly yellow and green colour) called [[xanthopsia]]. It has been proposed that the painter Vincent Van Gogh's "Yellow Period" may have somehow been influenced by concurrent digitalis therapy.
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| Digoxin has an interaction with the [[antimalarial]] medication [[Hydroxychloroquine]].
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| ==Other information==
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| Digoxin has potentially dangerous interaction with [[verapamil]],<ref name=Kaplanski1983>{{cite journal | author = Kaplanski, J. | coauthors = Weinhouse, E.; Topaz, M.; Genchik, G. | year = 1983 | title = Verapamil and digoxin: interactions in the rat. | journal = Res Commun Chem Pathol Pharmacol | volume = 42 | issue = 3 | pages = 377-88 | pmid = 6665298}}</ref> [[amiodarone]] and [[erythromycin]].
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| 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 ATPase-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names of Digibind® and Digifab®).<ref name=Flanagan2004>{{cite journal | author = Flanagan, R.J. | coauthors = Jones, A.L. | year = 2004 | title = Fab Antibody Fragments: Some Applications in Clinical Toxicology | journal = Drug Safety | volume = 27 | issue = 14
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| | pages = 1115-1133 | url = http://drugsafety.adisonline.com/pt/re/drs/fulltext.00002018-200427140-00004.htm | format = full text (subscription) | pmid = 15554746}}</ref> Toxicity can also be treated with higher than normal doses of [[potassium]]. Digoxin is not removed by hemo or peritoneal dialysis with enough effectiveness to treat toxicity.
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| Researchers at Yale University looked at data from an earlier study to see if digoxin affected men and women differently. That study determined that 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.
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| Researcher Dr. Harlan Krumholz said they were surprised to find that women in the study who took digoxin died more frequently (33%) than women who took a dummy pill (29%). They calculated that digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.
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| ==In the news==
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| 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 16-year career as a nurse. On March 10, 2006 he was sentenced to 18 consecutive life sentences and is not eligible for parole for 397 years.<ref>{{cite news | publisher = USA Today | title = Victims' families set to confront killer | url = http://usatoday.com/news/nation/2006-01-01-patient-deaths_x.htm | date = 1 Jan 2006}}</ref>
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| ==See also==
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| * [[Acetyldigoxin]]
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| * [[Cardiac glycoside]]
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| * [[Digitalis]]
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| * [[Digitoxin]]
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| * [[Digoxigenin]]
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| ==References==
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| <references/>
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| ==Further reading==
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| * Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology, 5th edition. Edinburgh: Churchill Livingstone; 2003. ISBN 0-443-07145-4
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| * Summary of product characteristics, Digoxin 0,125 mg, Zentiva a.s.
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| * Lüllmann. Pharmakologie und Toxikologie (15th edition), Georg Thieme Verlag, 2003. ISBN 3-13-368515-5
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| {{Cardiac glycosides}}
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| {{Antiarrhythmic agents}}
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| [[Category:Antiarrhythmic agents]]
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