DIGOXIN USE AND TOXICITY

TJ O’Neill 2/5/10

Historical Use of Digoxin Romans used a non-

Digoxin cardiac glycoside derived from sea onion

Used sporadically in Middle Ages but popularized in 18th 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

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 -PAT w/ Block -Bidirectional VT

Dali’s Mustache

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

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