Digoxin

From Anvita Health Wiki

Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Dosage-adjustment-in-renal-failure 6 Pharmacokinetics 7 Monitor 8 Adverse-effects 9 Drug-interactions 10 Laboratory 11 Mechanism-of-action 12 Notes 13 More General Terms 14 Additional Terms 15 Internet Database 16 References

Introduction

• 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

• atrial fibrillation/ flutter
• heart failure

• with atrial fibrillation/ flutter
• congestive heart failure

• paroxyxsmal atrial tachycardia

Contraindications

• cardioversion in the setting of digoxin toxicity is contraindicated. Potentially fatal arrhythmias may be precipitated
• Wolff-Parkinson-White ( WPW) syndrome
• idiopathic hypertrophic subaortic stenosis ( IHSS)
• constrictive pericarditis
• ventricular tachycardia
• ventricular fibrillation Cautions:
• discontinuation of digoxin in patients with CHF on an ACE inhibitor, diuretics & digoxin may result in clinical deterioration
• digoxin may increase myocardial oxygen demand in the setting of an acute myocardial infarction
• conduction through accessory AV pathways may be potentiated by digoxin
  

• pregnancy category = c
• safety in lactation = ?

Dosage

• rapid atrial fibrillation/ flutter ( AF):

• loading dose: 0.25 mg IV every 6 hours up to 1 mg
• 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]

Dosage-adjustment-in-renal-failure

• monitor serum digoxin level; adjust dose accordingly [14]

Pharmacokinetics

• bioavailability:

• tablet: 60-85%
• liquid- capsules: 90-100%
• elixir 75-80%

• onset of action:

• IV: 15-30 minutes
• oral: 2 hours.
• 6 hours for adequate distribution to myocardium [4]

• maximum effect:

• IV: 1-4 hours
• oral: 2-8 hours ( absorption delayed by food [8])

• drug is metabolized by liver & excreted in kidney
• steady state levels achieved in 6-8 days
• therapeutic plasma levels 0.5-2.0* ng/mL, although higher levels may be required for control of certain arrhythmias
• serum trough level

• 4-6 hours after IV dose
• 6-8 hours after PO dose

• volume of distribution 130-310 L ( geriatrics)
• 1/2 life 38-48 hours (adults), 70 hours ( geriatrics) ESRD > 4.5 days
• protein binding 25%

• * 0.5-1.0 ng/mL may be more appropriate range (see serum digoxin)
  
• elimination via liver
• elimination via kidney
• 1/2life = 1.4-1.8 days
• protein binding = 23 %
• elimination by hemodialysis = -
• elimination by hemoperfusion = +
• elimination by peritoneal dialysis = -

Monitor

• serum digoxin levels (see Laboratory:)

• suspected toxicity
• suspected non-compliance
• diseases or physiologic changes

• renal failure, thyroid disease

• starting or stopping an interacting drug
• change in drug dose (check after 5-7 days) [14]

• serum creatinine periodically or every 6 months
• serum electrolytes periodically every 6 months [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:

• gastrointestinal: nausea, vomiting, diarrhea, anorexia
• neurologic: confusion, delirium, seizures, headache, hallucinations, blurred vision, disturbed color perception (yellow vision), photophobia, vertigo, dizziness, apathy
• cardiac:

• all types of arrhythmias
• all types of AV block
• the combination of supraventricular tachycardia ( SVT) & AV block suggests digitalis toxicity
• inversion of T waves
• ST segment depression
• increase in PR interval
• increased outflow obstruction in patients with hypertrophic obstructive cardiomyopathy

• digoxin associated with 28% increased in mortality in patients with ESRD on hemodialysis

• higher serum digoxin levels* lowers serum potassium levels at the start of dialysis correlated with mortality [15]

• laboratory findings:

• hypokalemia is common with chronic intoxication
• hyperkalemia occurs with acute overdoses

• treatment:

• GI elimination done carefully to avoid vagal stimulation, activated charcoal (repeated doses), treatment of hyperkalemia with kayexalate, insulin & glucose.
• symptomatic bradycardia may be controlled with atropine & electrical pacing.
• symptomatic tachyarrhythmias may be controlled with phenytoin or lidocaine.
• avoid sympathomimetics; they may precipitate or worsen ventricular arrhythmias.
• 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

• drugs that increase digoxin levels

• quinidine
• Ca+2 channel blockers
• verapamil
• diltiazem
• flecainide
• amiodarone
• propafenone
• bepridil
• antibiotics

• macrolides

• erythromycin
• clarithromycin

• tetracycline

• quinine

• drugs that impair absorption of digoxin

• cholestyramine
• kaolin- pectin
• antacids

• concurrent administration of Ca+2 channel blockers or beta blockers may result in complete AV block
• concurrent IV Ca+2 may result in serious arrhythmias
  
• drug interaction(s) of antiarrhythmic agents in combination with diuretics

Laboratory

• (see serum digoxin)
• specimen:

• serum, plasma ( heparin, EDTA)
• collect at least 12 hours after last dose

• methods: RIA, HPLC, EIA, FPIA
• interferences:

• RIA: using beta emitters, interference with quenching of chemiluminescence with uremic serum or by color of hyperbilirubinemia
• RIA: using gamma emitters; coadminstration of gamma emitter diagnositc agents
• RIA: coadminstration of spironolactone may increase apparent concentration due to canrenone ( metabolite of spironolactone)
• digoxin-like immunoreactive substance with renal failure, hepatic failure or pregnancy
• RIA: Digi- kit: fosinopril
• Digibind may increase digoxin levels by immunoassay; measure free digoxin with Digibind
• digoxin cannot be accurately measured by immunoassay in patients switched from digitoxin

Mechanism-of-action

• vagomimetic actions

• depression of the SA node
• prolonged conduction to the AV node
• baroreceptor sensitization

• increased carotid sinus activity
• enhanced sympathetic withdrawal

• inhibition of sarcolemal membrane-bound Na+/K+ ATPase

• alters Ca+2 flux & increases the concentration of Ca+2 in the sarcoplasmic reticulum
• increases myocardial contractility
• increased refractory period of AV node

• digitalis glycosides induce vasoconstriction in coronary & mesenteric vascular beds
• in patients with high sympathetic outflow, digitalis is often ineffective in controlling ventricular rate

Notes

• in mice, digoxin suppresses production of IL-17 & onset of experimental autoimmune encephalitis [16]

More General Terms

• cardenolide
• cardiac glycoside (digitalis glycoside)
• antiarrhythmic agent

Additional Terms

• digoxin immune Fab (Digibind)
• digoxin in serum/plasma

Internet Database

PubChem: 30322
PubChem: 3062
PubChem: 108057
PubChem: 2724385

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
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: [1]
13. FDA MedWatch [2]
14. Anvita Health guideline :id 1535 Anvita Health guideline :id 1537
    - Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: [3] (subscription needed) [4]
15. Chan KE et al Digoxin Associates with Mortality in ESRD J Am Soc Nephrol. 2010 Jun 24. [Epub ahead of print] <PubMed> PMID: [5] <Internet> [6]
16. Huh JR et al Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORt activity. Nature 2011 Apr 28; 472:486 PMID: [7]
    - Solt LA et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011 Apr 28; 472:491 PMID: [8]
    - Jetten AM. A helping hand against autoimmunity. Nature 2011 Apr 28; 472:421 PMID: [9]

digoxin (Lanoxin, Lanoxicaps, Digitek)