Difference between revisions of "Digoxin"

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Digoxin (INN) (pronounced /dɨˈdʒɒksɨn/^[1]), also known as digitalis, is a purified cardiac glycoside 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 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 injectable solution. It is marketed by GlaxoSmithKline.

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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). It has mechanical effects as it increases myocardial contractility, however, the duration of the contractile response is just slightly increased. Overall, the heart rate is decreased, while blood pressure increases as the stroke volume is increased, leading to increased tissue perfusion. Myocardial efficiency improves due to improved hemodynamics, and the ventricular function curve is improved.

Other, electrical effects are an initial brief increase in action potential, followed by a decrease as the K⁺ conductance increases due to an increased intracellular amounts of Ca²⁺ ions. The refractory period of the atria and ventricles is decreased, while it increases in the sinoatrial and AV nodes. A less negative resting membrane potential is made, leading to increased excitability. Other, more indirect effects are cholinomimetic because of vagal stimulation, giving rise to AV nodal delay.

The conduction velocity increases in the atria, but decreases in the AV node. The effect upon Purkinje fibers and ventricles is negligible. Automaticity is also increased, in the atria, AV node, Purkinje fibers and ventricles.

EKG changes are increased PR interval, due to decreased AV conduction, and a decreased QT interval because of the altered duration of decreased action potential. Also, the T wave is inverted, accompanied by ST depression. It may cause AV junctional rhythm and ectopic beats (bigemminy) resulting in ventricular tachycardia and fibrillation.

Slight vasodilation is seen in heart failure. This effect is contrary to effects that should be seen as a result of increased intracellular calcium levels, but this occurs since digoxin improves hemodynamics, which leads to restored angiotensin levels and decreased sympathetic discharge, causing indirect vasodilation.

Digoxin also affects the kidney by increased renal blood flow and increased GFR. A mild diuretic effect is seen only in heart failure.

Mechanism of action

The mechanism of action is not completely understood; however the current hypothesis is outlined below.

Digoxin binds to a site on the extracellular aspect of the α-subunit of the Na⁺/K⁺ ATPase pump in the membranes of heart cells (myocytes) and decreases its function. This causes an increase in the level of sodium ions in the myocytes, which then leads to a rise in the level of calcium ions. Because there is a sodium/calcium exchanger which depends on sodium gradient to pump out calcium, digoxin reduces such concentration gradient and subsequently calcium efflux, thus increasing calcium concentration in myocardiocytes and pacemaker cells. The proposed mechanism is the following: inhibition of the Na⁺/K⁺ pump leads to increased intracellular Na⁺ levels, which in turn slows down the extrusion of Ca²⁺ by the sodium-calcium exchanger that relies on the high Na⁺ 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, leads to a decrease in heart rate.^{[citation needed]} Increased amounts of Ca²⁺ 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.

Digoxin also increases vagal activity via its action on the central nervous system, thus decreasing the conduction of electrical impulses through the AV node ^[3]. This negatively chronotropic effect is important for its clinical use in different arrhythmias (see below).

Clinical use

Today, the most common indications for digoxin are probably atrial fibrillation and atrial flutter with rapid ventricular response, but beta- or calcium channel- blockers should be the first choice [1] [2]. 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.

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 mortality in congestive heart failure. It is shown to increase quality of life, however.

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).

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).

Quinidine, verapamil, and amiodarone increases plasma levels of digoxin (by displacing tissue binding sites and depressing renal digoxin clearance) so plasma digoxin must be monitored carefully.

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. 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 placebo 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.

Digoxin is also used as a standard control substance to test for p-glycoprotein inhibition.

Adverse effects

The occurrence of adverse drug reactions 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.^[4] 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 pump.

Common adverse effects (≥1% of patients) include: loss of appetite, nausea, vomiting and diarrhea as the gastrointestinal motility increase. Other common effects 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.^{[5][unreliable source?]} Less frequent adverse effects (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 fibrillation, and heart block^[4] Rarely, digoxin has been shown to cause thrombocytopenia. Gynaecomastia (enlargement of breast tissue) is mentioned in many textbooks as a side-effect – thought to be due to the estrogen-like steroid moiety of the digoxin molecule^[6] but when systematically sought, the evidence for this is equivocal.^[7] 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 Ca²⁺ 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.^[8]

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. Other oculotoxic effects of digoxin include generalized blurry vision as well as seeing a "halo" around each point of light.^[9] The latter effect can also be seen in van Gogh's Starry Night. Evidence of van Gogh's digoxin use is supported by multiple self portraits that include the foxglove plant, from which digoxin is obtained.

Digoxin plasma concentrations may increase while on antimalarial medication hydroxychloroquine (based on two case reports from 1982)^[10].

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).^[11] 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.

Digoxin has potentially dangerous interactions with verapamil,^[12] amiodarone, erythromycin, and epinephrine (as would be injected with a local anesthetic).

In the news

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.^[13]

On April 25, 2008 the FDA issued a press release^[14] alerting the public to a Class I recall of Digitek, a brand of digoxin produced by Mylan.^[15] It was found that 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.^[16]

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".

This March 31 press release from Caraco, a generic pharmaceutical company, states that:

[A]ll 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.

On May 6, the Public Radio program Health in a Heartbeat, produced by the University of Florida, discussed a recent study of the National Academy of Sciences, which suggests that digoxin has beneficial effects not only for the heart but also in reducing the risk of certain kinds of cancer.^[17]

References

Further reading

• Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology, 5th edition. Edinburgh: Churchill Livingstone; 2003. ISBN 0-443-07145-4
• Summary of Product Characteristics, Digoxin 0,125 mg, Zentiva a.s.
• Lüllmann. Pharmakologie und Toxikologie (15th edition), Georg Thieme Verlag, 2003. ISBN 3-13-368515-5

External links

• U.S. National Library of Medicine: Drug Information Portal - Digoxin

de:Digoxin et:Digoksiin es:Digoxina fa:دیگوکسین fr:Digoxine he:דיגוקסין nl:Digoxine ja:ジゴキシン pl:Digoksyna pt:Digoxina ru:Дигоксин sk:Digoxín sr:Digoksin fi:Digoksiini sv:Digoxin uk:Дигоксин vi:Digoxin

1. ↑ OED
2. ↑ A. Hollman (1996). "Digoxin comes from Digitalis lanata" (letter). British Medical Journal. 312 (7035): 912. 
3. ↑ DJ Goodman; et al. (1975). "Effect of digoxin on atioventricular conduction. Studies in patients with and without cardiac autonomic innervation". Circulation. 51 (2): 251–256. CS1 maint: Explicit use of et al. (link)
4. ↑ ^{4.0 4.1} Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
5. ↑ http://www.digitekrecallinformation.com/
6. ↑ 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 db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16019364&query_hl=14&itool=pubmed_docsum
7. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
8. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
9. ↑ Goldfrank, LW. Goldfrank's Toxicologic Emergencies, 8th Edition. New York: McGraw-Hill, 2006.
10. ↑ [3]
11. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
12. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
13. ↑ "Victims' families set to confront killer". USA Today. 2006-01-01. 
14. ↑ http://www.fda.gov/oc/po/firmrecalls/actavis04_08.html
15. ↑ "Urgent Digitek Digoxin Recall". U.S. Recall News. 28 April 2008. Retrieved 25 July 2009. 
16. ↑ "Patients Sue Icelandic Drugmaker Over Recalled Heart Drug". Wall Street Journal. 9 May 2008. Retrieved 25 July 2009. 
17. ↑ http://www.news.health.ufl.edu/heartbeat/heartbeat.aspx?ID=8724