Editing Digoxin (section)

==Pharmacology==

=== Pharmacodynamics ===
[[File:Signal-averaged ECG with digoxin.png|class=skin-invert-image|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 Ca<sup>2+</sup> 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<sup>+</sup>]] conductance increases due to increased [[intracellular]] amounts of [[calcium|Ca<sup>2+</sup>]] 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 fibers, 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>