Editing Digoxin (section)

=== 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>