1. DIGOXIN USE AND TOXICITY TJ O’Neill 2/5/10

2. Historical Use of Digoxin  Romans used a non-Digoxin cardiac glycoside derived from sea onion  Used sporadically in Middle Ages but popularized in 18 th century  Used for dropsy and recognized to decrease edema and slow HR  Withering in 1785 published an account of 156 patients sucessfully treated including Erasmus Darwin William Withering Foxglove 16- 3 75-60

3. Digoxin Mechanism of Action  Inhibits Cardiac isoform of Na/K ATPase which indirectly increases intracellular Ca concentration  Increased cardiac output in low output states without increased oxygen consumption  Decreases PCWP  Improves baroreceptor sensitivity in the carotid which may decrease RAAS activation  Increases AV node refractory period by increasing vagal tone

4. Evidence for Digoxin  In a series of trials beginning in 1988 Digoxin reduced hospitalization but no effect on mortality.  Largest was Digitalis Investigation Group (DIG) 7788 pts radomized to digoxin vs placebo.  No difference in mortality but 25% reduction in hospital admissions  Subgroup analysis showed significant reduction in deaths attributed to “worsening CHF” and almost identical increase in “cardiac death, not due to CHF”

5. Digoxin Toxicity  Incidence decreasing 2610 reported cases in 2006 compared to 10K for Ca channel blocker and 18K beta blocker toxicity cases  However there were 22 deaths compared to 13 and 4 for CCB and BB during the same year  Increased incidence in elderly as well as decreased renal fxn

6. Digoxin Toxicity  Cardiac disturbances  GI symptoms  Anorexia, N/V/D, abdominal pain  CNS effects  Weakness, blurred vision, halos around light  In severe cases can cause hyper K  Can be difficult to detect clinically  In Dig trial incidence of “Digoxin toxicity” was 11.9% in Digoxin group and 7.9% in placebo group

7. Conduction Defects in Digoxin Toxicity  Slows nodal conduction while increasing automaticity  More likely in patients w/ CAD, particularly active ischemia and are potentiated by low Mg, K  Downward slurring of ST  Heart block  VT/VT  -PAT w/ Block  -Bidirectional VT Dali’s Mustache

8. Pharmacokinetics/dynamics  Half life 36-48 hours in the case of normal renal function (levels stabilize 7 days after dose change  Large reservoir in skeletal muscle  Clearance is primarily renal, but some hepatic metabolism as well  Level should be checked at least 8 hours after dose and may not reflect tissue concentrations if recent dose change.  Level increased by several medications  Verapamil, Diltiazem, amiodarone, itraconazole- decreased clearance  Erythromycin, clarithromycin, tetracycline- decreased gut flora metabolism  Toxicity can be increased by any medication decreasing serum K or potentially affecting renal fxn  Increased level (probably >2.5 but possibly less) + relevant clinical scenario (usually conduction distrubance) = TOXICITY

9. Treatment  If early after intentional overdose, can give activated charcoal  Bradycardia  If asymptomatic keep serum K at least 4.0 (or higher) Potassium will affect affinity for Na/K pump  Symptomatic- Atropine, pacing  Digibind (Humanized sheep Mab)  Symptomatic bradycardia not responsive to Atropine  Malignant arrhythmia (particularly in the setting of hyperkalemia)  Hyperkalemia  Important to give adequate dose initially as digoxin levels will be affected for up to 2 weeks  Plasmapheresis will prevent rebound effect  Neither HD nor PD will decrease serum concentation

10. Prevention  Err on the lower end of dosing, as there is no clear lower end of efficacy. The DIG trial dose of 0.25mg daily is probably not appropriate initial dose for anyone.  Closely monitor drug levels, especially if used with Amio, non DHP CCB, or macrolides  Be particularly cautious following recent hospital discharge

11. References  Eichhorn EJ et al. Prog Cardiovasc Dis. 44 (4): 251-266, 2002.  Shahbudin H et al. Circulation; 109: 2942-6, 2004  Hood WB et al. J Cardiac Failure. 10 (2): 155-164, 2004