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
 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”
 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

 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
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
Dali’s Mustache
 -PAT w/ Block
 -Bidirectional VT
 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
 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
 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