DIGOXIN

DIGOXIN — digoxin tablet
DEPT HEALTH CENTRAL PHARMACY

CLINICAL PHARMACOLOGY


MECHANISM OF ACTION

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 neu-rohormonal 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 SECTION: ABSORPTION

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) or LANOXICAPS® [Digoxin Solution in Capsules] (relative 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 are shown in Table 1.
Table 1: Comparisons of the Systemic Availability and Equivalent Doses for Oral Preparations of Digoxin
Product AbsoluteBioavailability Equivalent Doses (mcg)*Amoung Dosage Forms
Digoxin Tablets60-80%62.5 125 250 500
Digoxin Elixir Pediatric70-85%62.5 125 250 500
Digoxin Solution in Capsules90-100%50 100 200 400
Digoxin Injection/IV100%50 100 200 400

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 3b-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.

PHARMACODYNAMICS SECTION

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
Product Time to Onset of Effect* Time toPeak Effect
Digoxin Tablets0.5 — 2 hours2 — 6 hours
Digoxin Elixir Pediatric0.5 — 2 hours2 — 6 hours
Digoxin Soultion in Capsules0.5 — 2 hours2 — 6 hours
Digoxin Injection/IV5-30 minutes1 — 4 hours

† Depending upon rate of infusion.

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.

DIGOXIN Indications and Usage

INDICATIONS AND USAGE:

Heart Failure: Digoxin is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection

fraction and improves heart failure symptoms as evidenced by exercise capacity and heart failure-related hospitalizations and

emergency care, while having no effect on mortality. Where possible, digoxin should be used with a diuretic and an angiotensinconverting

enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified.

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