Clinical Geriatrics

Plants of the genus Digitalis are the source of digoxin. Historical evidence of pharmacological use of purple foxglove (Digitalis purpurea) is documented as early as 1250, when it was used as a recipe for headache. Its topical form was used in 1466 for wound healing. In 1785, Dr. William Withering, an English physician and botanist, analyzed approximately 200 cases, mostly with “dropsy” in his An Account of the Foxglove and Some of its Medical Uses: With Practical Remarks on Dropsy and Other Diseases. Dr. Withering considered digitalis to be a diuretic.

Digoxin is the most frequently used digitalis glycoside in the United States. It is the fifth most frequently prescribed medication, particularly in the elderly due to increased prevalence of its indications.

For the purpose of this discussion, only studies that included patients more than 70 years of age are presented.

Mechanism of Action
Digoxin inhibits the Na,K-ATPase pump in myocardial cells. Therefore, the transmembrane sodium gradient is reduced. This reduction in turn raises intracellular calcium concentration, which leads to enhanced isolated myocyte contractile performance (positive inotropic effect).This effect is more pronounced in decompensated heart failure (HF) and systolic dysfunction. Digoxin reduces plasma renin-angiotensin system activity (neurohormonal deactivation effect) and decreases norepinephrine levels.1,2

Digoxin increases parasympathetic tone (via central and peripheral effects) and slows conduction through the sinoatrial and atrioventricular (AV) nodes. It increases baroreceptor sensitivity, which results in decrease of sympathetic activation. This sympatholytic activity of digoxin diminishes systemic vascular resistance (SVR) and venous tone. Digoxin increases contractility without increasing heart rate.2

With lower doses (serum level of 1-2 ng/mL), digoxin decreases automaticity, decreases AV nodal velocity, and prolongs the effective refractory period.

Digoxin has positive inotropic effect at higher serum levels (eg, usually achieved by doses of 0.25 mg/day or more), but at the lower serum levels (eg, doses less than 0.25 mg/day) it has more neurohormonal effect and negligible inotropic effect. Digoxin improves renal perfusion (thus renal function) via increasing cardiac inotropic effect. It directly inhibits renal tubular sodium reabsorption due to the inhibition of renal Na,K-ATPase pump.

Pharmacokinetics
Digoxin is rapidly absorbed from the gastrointestinal tracts (70-80% oral bioavailability). When oral route cannot be used, it should be administered intravenously. Due to erratic absorption and local pain, its intramuscular administration should be avoided.

Age-related changes in the gastrointestinal tract (increase in gastric pH, decrease in gastrointestinal motility and blood flow) do not appear to alter the absorption of digoxin significantly. Its extent of absorption may be increased in elderly patients with hypochlorhydria. Digoxin is converted into inactive metabolite by intestinal bacteria Eubacterium lentum. This bacterium is found in 10% of the general population and is responsible for “resistance” to standard oral doses of digoxin.

Digoxin has a large volume of distribution in young healthy individuals. With advancing age and accompanying decrease in lean body mass and increase in adipose tissue, its volume of distribution is reduced. The result is increased half-life and higher serum concentration for hydrophilic medications (eg, digoxin, ethanol). Hence, the average half-life of digoxin in the geriatric population is longer (70 hr), but can range between 24 to 129 hours.