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digoxin (Lanoxin, Lanoxicaps, Digitek)

Tradenames: Lanoxin, Lanoxicaps, Digitek. RECALL: [04/28/2008] nationwide, all strengths of Digitek recalled due to the possibility that tablets may contain twice the approved level of digoxin [13] Indications: 1) atrial fibrillation/flutter* 2) heart failure a) with atrial fibrillation/flutter b) systolic heart failure - reduces hospitalization for systolic heart failure [27,28,29] 3) paroxyxsmal atrial tachycardia * associated with higher mortality among patients with atrial fibrillation (RR= 1.2) [21,22,25] Contraindications: 1) cardioversion in the setting of digoxin toxicity is contraindicated - potentially fatal arrhythmias may be precipitated 2) Wolff-Parkinson-White (WPW) syndrome 3) idiopathic hypertrophic subaortic stenosis (IHSS) 4) constrictive pericarditis 5) ventricular tachycardia 6) ventricular fibrillation Cautions: 1) discontinuation of digoxin in patients with CHF on an ACE inhibitor, diuretics & digoxin may result in clinical deterioration 2) digoxin may increase myocardial oxygen demand in the setting of an acute myocardial infarction 3) conduction through accessory AV pathways may be potentiated by digoxin Dosage: - rapid atrial fibrillation/flutter (AF): a) loading dose: 0.25 mg IV every 6 hours up to 1 mg b) maintenance dose* 0.125-0.25 mg IV/PO QD-QOD - CHF: start 0.125 mg QOD-QD; no loading dose; max 0.250 mg QD * 0.125 mg PO QD is enough for most patients [10] 0.125 mg PO QOD is enough for most patients with therapeutic range of 0.5-0.9 ng/mL [12] Lanoxin: 0.125, 0.25, 0.5 mg. Elixir: 0.05 mg/mL. Lanoxicaps: 0.05, 0.1, 0.2 mg. No role for IV digoxin if patient can take oral meds [4] Pharmacokinetics: 1) bioavailability: a) tablet: 60-85% b) liquid-capsules: 90-100% c) elixir 75-80% 2) onset of action: a) IV: 15-30 minutes b) oral: 2 hours. c) 6 hours for adequate distribution to myocardium [4] 3) maximum effect: a) IV: 1-4 hours b) oral: 2-8 hours (absorption delayed by food [8]) 4) drug is metabolized by liver & excreted in kidney 5) steady state levels achieved in 6-8 days 6) therapeutic plasma levels 0.5-2.0* ng/mL, although higher levels may be required for control of certain arrhythmias 7) serum trough level a) 4-6 hours after IV dose b) 6-8 hours after PO dose 8) volume of distribution 130-310 L (geriatrics) 9) 1/2 life 38-48 hours (adults), 70 hours (geriatrics) ESRD > 4.5 days 10) protein binding 25% * 0.5-1.0 ng/mL may be more appropriate range (see serum digoxin) Monitor: - serum digoxin levels (see Laboratory:) a) suspected toxicity b) suspected non-compliance c) diseases or physiologic changes - renal failure, thyroid disease d) starting or stopping an interacting drug e) change in drug dose (check after 5-7 days) [14] - serum creatinine periodically or every 6 months - serum electrolytes periodically every 6 months [14] Dosage adjustment in renal failure: - monitor serum digoxin level; adjust dose accordingly [14] Adverse effects: incidence: (toxicity) - 5-15% of patients at some time during therapy precipitating factors: - drug interactions, electrolyte abnormalities (esp hypokalemia, hypomagnesemia, hypercalcemia), hypoxia, hypothyroidism, renal failure, volume depletion manifestations: 1) gastrointestinal: nausea, vomiting, diarrhea, anorexia 2) neurologic: confusion, delirium, seizures, headache, hallucinations, blurred vision, disturbed color perception (yellow vision), photophobia, vertigo, dizziness, apathy 3) cardiac: a) all types of arrhythmias b) all types of AV block - a regular ventricular rate in a patient with atrial fibrillation suggests complete AV block with a junctional escape rhythm [18] c) the combination of supraventricular tachycardia (SVT) & AV block suggests digitalis toxicity d) inversion of T waves e) ST segment depression f) increase in PR interval g) increased outflow obstruction in patients with hypertrophic obstructive cardiomyopathy 4) long-term digoxin use neither increases or decreases mortality [9] - if serum digoxin maintained < 0.9 ng/mL - digoxin associated with 28% increased in mortality in patients with ESRD on hemodialysis - higher serum digoxin levels & lower serum potassium levels at the start of dialysis correlated with mortality [15] laboratory findings: 1) hypokalemia is common with chronic intoxication 2) hyperkalemia occurs with acute overdoses treatment: 1) GI elimination done carefully to avoid vagal stimulation, activated charcoal (repeated doses), treatment of hyperkalemia with kayexalate, insulin & glucose. 2) symptomatic bradycardia may be controlled with atropine & electrical pacing. 3) symptomatic tachyarrhythmias may be controlled with phenytoin or lidocaine. 4) avoid sympathomimetics; they may precipitate or worsen ventricular arrhythmias. 5) digoxin antibodies are available to treat severe poisoning (Dosage in 40 mg vials calculated by dividing the ingested dose of digoxin in mg by 0.6 mg/vial. Give empirically 5-10 vials to an adult if serum levels & ingested dose unknown). Drug interactions: 1) drugs that increase digoxin levels a) quinidine b) Ca+2 channel blockers a) verapamil b) diltiazem c) flecainide d) amiodarone e) propafenone f) bepridil g) antibiotics 1] macrolides a] erythromycin b] clarithromycin c] azithromycin [9] 2] tetracycline h) quinine i) mirabegron (Myrbetriq) 2) drugs that impair absorption of digoxin a) cholestyramine b) kaolin-pectin c) antacids 3) concurrent administration of Ca+2 channel blockers or beta blockers may result in complete AV block 4) concurrent IV Ca+2 may result in serious arrhythmias Laboratory: (see serum digoxin) 1) specimen: a) serum, plasma (heparin, EDTA) b) collect at least 12 hours after last dose 2) methods: RIA, HPLC, EIA, FPIA 3) interferences: a) RIA: using beta emitters, interference with quenching of chemiluminescence with uremic serum or by color of hyperbilirubinemia b) RIA: using gamma emitters; coadministration of gamma emitter diagnostic agents c) RIA: coadministration of spironolactone may increase apparent concentration due to canrenone (metabolite of spironolactone) d) digoxin-like immunoreactive substance with renal failure, hepatic failure or pregnancy e) RIA: Digi-Tab kit: fosinopril f) Digibind may increase digoxin levels by immunoassay; measure free digoxin with Digibind g) digoxin cannot be accurately measured by immunoassay in patients switched from digitoxin 4) serum pro-BNP may be elevated with digoxin toxicity [26] Mechanism of action: 1) vagomimetic actions a) depression of the SA node b) prolonged conduction to the AV node c) baroreceptor sensitization 1] increased carotid sinus activity 2] enhanced sympathetic withdrawal 2) inhibition of sarcolemal membrane-bound Na+/K+ ATPase a) alters Ca+2 flux & increases the concentration of Ca+2 in the sarcoplasmic reticulum b) increases myocardial contractility c) increased refractory period of AV node 3) digitalis glycosides induce vasoconstriction in coronary & mesenteric vascular beds 4) in patients with high sympathetic outflow, digitalis is often ineffective in controlling ventricular rate Notes: - digoxin use not associated with all-cause mortality [24] - associated with small reduction in hospital admission [24] Comparative biology: - in mice, digoxin suppresses production of IL-17 & onset of experimental autoimmune encephalitis [16]

Interactions

drug interactions

Related

digoxin immune Fab (Digibind) digoxin in serum/plasma

General

antiarrhythmic agent cardenolide cardiac glycoside (digitalis glycoside)

Properties

MISC-INFO: elimination route LIVER KIDNEY 1/2life 1.4-1.8 DAYS therapeutic-range 0.8-2.0 NG/ML toxic-range >2.5 NG/ML >3.0 NG/ML protein-binding 23% elimination by hemodialysis - hemoperfusion + peritoneal dialysis - pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. Advanced Cardiac Life Support, The American Heart Association 1994
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 132.
  3. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 120-21, 163-64
  4. Paul Goebel UCSF Fresno Dept of Medicine, personal communication
  5. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  6. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  7. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  8. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 470
  9. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  10. Prescriber's Letter 9(12):68 2002 Journal Watch 22(24):181, 2002 Rathore SS et al, N Engl J Med 347:1402, 2002
  11. Prescriber's Letter 10(4):22 2003
  12. Bauman JL, DiDomenico RJ, Viana M, Fitch M. A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med. 2006 Dec 11-25;166(22):2539-45. PMID: 17159022
  13. FDA MedWatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#Digitek
  14. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  15. Chan KE et al Digoxin Associates with Mortality in ESRD J Am Soc Nephrol. 2010 Jun 24. [Epub ahead of print] PMID: 20576808 http://jasn.asnjournals.org/cgi/content/abstract/ASN.2009101047v1
  16. Huh JR et al Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORt activity. Nature 2011 Apr 28; 472:486 PMID: 21441909 - Solt LA et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011 Apr 28; 472:491 PMID: 21499262 - Jetten AM. A helping hand against autoimmunity. Nature 2011 Apr 28; 472:421 PMID: 21525918
  17. Vivo RP, Krim SR, Perez J et al Digoxin: current use and approach to toxicity. Am J Med Sci. 2008 Nov;336(5):423-8 PMID: 19011400
  18. Medical Knowledge Self Assessment Program (MKSAP) 16, 18 American College of Physicians, Philadelphia 2012, 2018
  19. Heckman GA, McKelvie RS. Necessary cautions when considering digoxin in heart failure. CMAJ. 2007 Feb 27;176(5):644-5. No abstract available. PMID: 17325330
  20. Pita-Fernandez S, Lombardia-Cortina M, Orozco-Veltran D et al Clinical manifestations of elderly patients with digitalis intoxication in the emergency department. Arch Gerontol Geriatr. 2011 Sep-Oct;53(2):e106-10 PMID: 20705347
  21. Husten L Study Offers Little Support for Digoxin in Atrial Fibrillation. Physician's First Watch, Aug 12, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org article appeas in Journal of the American College of Cardiology (JACC) in August 2014
  22. Washam JB et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: A retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet 2015 Mar 5; PMID: 25749644
  23. Ziff OJ et al Safety and efficacy of digoxin: systematic review and meta- analysis of observational and controlled trial data. BMJ 2015;351:h4451 PMID: 26321114 http://www.bmj.com/content/351/bmj.h4451
  24. See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency department visits and hospitalizations for digoxin toxicity: United States, 2005 to 2010. Circ Heart Fail. 2014 Jan;7(1):28-34. PMID: 24300242 Free PMC Article
  25. Lopes RD, Rordorf R, De Ferrari GM et al Digoxin and Mortality in Patients With Atrial Fibrillation. J Am Coll Cardiol. 71(10) March 2018 PMID: 29519345 http://www.onlinejacc.org/content/71/10/1063 - Turakhia MP Digoxin in Atrial Fibrillation? Leave it Out of the Medicine Cabinet. J Am Coll Cardiol. 71(10) March 2018 PMID: 29519346 http://www.onlinejacc.org/content/71/10/1075
  26. Mattison MLP, Muse VV, Simmons LH Case 15-2018: An 83-Year-Old Woman with Nausea, Vomiting, and Confusion. N Engl J Med 2018; 378:1931-1938. May 17, 2018. PMID: 29768145 https://www.nejm.org/doi/full/10.1056/NEJMcpc1800339 - Rothaus C A Woman with Nausea, Vomiting, and Confusion. NEJM. Resident 360. May 16, 2018 https://resident360.nejm.org/content_items/a-woman-with-nausea-vomiting-and-confusion
  27. Adams KF Jr, Butler J, Patterson JH et al Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial. Eur J Heart Fail. 2016 Aug;18(8):1072-81. PMID: 27492641 Free Article
  28. Ambrosy AP, Butler J, Ahmed A et al The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions. J Am Coll Cardiol. 2014 May 13;63(18):1823-32. Review. PMID: 24613328 Free Article
  29. Dooley DJ, Lam PH, Ahmed A, Aronow WS. The Role of Positive Inotropic Drugs in the Treatment of Older Adults with Heart Failure and Reduced Ejection Fraction. Heart Fail Clin. 2017 Jul;13(3):527-534. Review. PMID: 28602370