Prescription Drug Information: Digoxin

DIGOXIN — digoxin tablet
Physicians Total Care, Inc.

Revised 12/11Rx Only

DESCRIPTION:

Digoxin Tablets, USP are one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term “digitalis” is used to designate the whole group of glycosides. The glycosides are composed of two portions: a sugar and a cardenolide (hence “glycosides”).

Digoxin is described chemically as (3β,5β,12β)-3-[(O -2,6-dideoxy-β-Dribo -hexopyranosyl-(1→4)-O -2,6-dideoxy-β-Dribo -hexopyranosyl-(1→4)-2,6-dideoxy-β-Dribo -hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. lts molecular formula is C41 H64 O14 , its molecular weight is 780.95, and its structural formula is:

Structural Formula

Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.

Digoxin Tablets, USP are supplied as 125 mcg (0.125 mg) or 250 mcg (0.25 mg) tablets for oral administration. Each tablet contains the labeled amount of digoxin USP and the following inactive ingredients:

125 mcg (0.125 mg): anhydrous lactose, colloidal silicon dioxide, corn starch, D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake, lactose monohydrate, magnesium stearate and starch 1500.

250 mcg (0.25 mg): anhydrous lactose, colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate and starch 1500.

CLINICAL PHARMACOLOGY:

Mechanism of Action

Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity of sodium and potassium inside cells. Inhibition of the enzyme leads to an increase in the intracellular concentration of sodium and thus (by stimulation of sodium-calcium exchange) an increase in the intracellular concentration of calcium. The beneficial effects of digoxin result from direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system. The autonomic effects include: (1) a vagomimetic action, which is responsible for the effects of digoxin on the sinoatrial and atrioventricular (AV) nodes; and (2) baroreceptor sensitization, which results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system for any given increment in mean arterial pressure. The pharmacologic consequences of these direct and indirect effects are: (1) an increase in the force and velocity of myocardial systolic contraction (positive inotropic action); (2) a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect); and (3) slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect). The effects of digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions. In high doses, digoxin increases sympathetic outflow from the central nervous system (CNS). This increase in sympathetic activity may be an important factor in digitalis toxicity.

Pharmacokinetics

Absorption: Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from digoxin tablets has been demonstrated to be 60% to 80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When digoxin tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparisons of the systemic availability and equivalent doses for oral preparations of digoxin tablets are shown in Table 1.

Table 1: Comparisons of the Systemic Availability and Equivalent Doses for Oral Preparations of Digoxin Tablets

* For example, 125 mcg Digoxin Tablets equivalent to 100 mcg Digoxin Injection/IV.

Product Absolute Equivalent Doses (mcg)*
Bioavailability Among Dosage Forms
Digoxin Tablets 60 — 80% 62.5 125 250 500
Digoxin Injection/IV 100% 50 100 200 400

In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggest that one in ten patients treated with digoxin tablets will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. The magnitude of rise in serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as two-fold in some cases.

Distribution

Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects (see DOSAGE AND ADMINISTRATION: Serum Digoxin Concentrations).

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight.

Metabolism

Only a small percentage (16%) of a dose of digoxin is metabolized. The end metabolites, which include 3β-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system.

Excretion

Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the blood.

Special Populations

Race differences in digoxin pharmacokinetics have not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected.

The clearance of digoxin can be primarily correlated with renal function as indicated by creatinine clearance. The Cockcroft and Gault formula for estimation of creatinine clearance includes age, body weight, and gender. Table 5 that provides the usual daily maintenance dose requirements of digoxin tablets based on creatinine clearance (per 70 kg) is presented in the DOSAGE AND ADMINISTRATION section.

Plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects.

Pharmacodynamic and Clinical Effects

The times to onset of pharmacologic effect and to peak effect of preparations of digoxin tablets are shown in Table 2.

Table 2: Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Digoxin Tablets

* Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.

Depending upon rate of infusion.

Product Time to Time to
Onset of Effect* Peak Effect*
Digoxin Tablets 0.5 — 2 hours 2 — 6 hours
Digoxin Injection/IV 5-30 minutes 1 — 4 hours

Hemodynamic Effects

Digoxin produces hemodynamic improvement in patients with heart failure. Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions.

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