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Digitek

Digitek

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 ar terial 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 activit y 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) or 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 Absolute Bio- availability Equivalent Doses(mcg)* Among Dosage Forms
Digoxin Tablets 60-80% 62.5 125 250 500
Digoxin Pediatric Elixir 70-85% 62.5 125 250 500
Digoxin Solution in Capsules 90-100% 50 100 200 400
Digoxin Injection/IV 100% 50 100 200 400
*For example, 125-mcg Digoxin Tablets equivalent to 125 mcg Digoxin Pediatric Elixir equivalent to 100 mcg Digoxin Solution in Capsules equivalent to 100 mcg Digoxin Injection/IV.

In some patients, orally administered digoxin is conver ted 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 3 β-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 propor tional 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 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 cardiopulmonar y 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. A table 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 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 to Peak Effect*
Digoxin Tablets 0.5-2 hours 2-6 hours
Digoxin Pediatric Elixir 0.5-2 hours 2-6 hours
Digoxin Solution in Capsules 0.5-2 hours 2-6 hours
Digoxin Injection/IV 5-30 minutes 1-4 hours
*Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.
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.

Chronic Heart Failure: Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II or III heart failure previously treated with digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with digoxin. Both trials demonstrated better preservation of exercise capacit y in patients randomized to digoxin. Continued treatment with digoxin reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy. The larger study also showed treatment-related benefits in NYHA class and patients' global assessment. In the smaller trial, these trended in favor of a treatment benefit.

The Digitalis Investigation Group (DIG) main trial was a multicenter, randomized, double-blind, placebo-controlled mortalit y study of 6,801 patients with heart failure and left ventricular ejection fraction ≤ 0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or digoxin, the dose of which was adjusted for the patient's age, sex, lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION), and followed for up to 58 months (median 37 months). The median daily dose prescribed was 0.25 mg. Overall all-cause mortality was 35% with no difference between groups (95% confidence limits for relative risk of 0.91 to 1.07). Digoxin was associated with a 25% reduction in the number of hospitalizations for heart failure, a 28% reduction in the risk of a patient having at least one hospitalization for heart failure, and a 6.5% reduction in total hospitalizations (for any cause).

Use of digoxin was associated with a trend in reduction in time to all-cause death or hospitalization. The trend was evident in subgroups of patients with mild heart failure as well as more severe disease, as shown in Table 3. Although the effect on all-cause death or hospitalization was not statistically significant, much of the apparent benefit derived from effects on mor tality and hospitalization attributed to heart failure.

Table 3: Subgroup Analyses of Mortality and Hospitalization During the First Two Years Following Randomization.

  n Risk of All Cause Mortality or All Cause Hospitalization*
Placebo Digoxin Relative risk
All Patients (EF ≤ 0.45) 6801 604 593 0.94
(0.88-1.00)
NYHA I/II 4571 549 541 0.96
(0.89-1.04)
EF 0.25-0.45 4543 568 571 0.99
(0.91-1.07)
CTR ≤ 0.55 4455 561 563 0.98
(0.91-1.06)
NYHA III/IV 2224 719 696 0.88
(0.80-0.97)
EF < 0.25 2258 677 637 0.84
(0.76-0.93)
CTR > 0.55 2346 687 650 0.85
(0.77-0.94)
EF > 0.45 987 571 585 1.04
(0.88-1.23)
  n Risk of HF Related Mortality or HF Related Hospitalization*
Placebo Digoxin Relative risk
All Patients (EF ≤ 0.45) 6801 294 217 0.69
(0.63-0.76)
NYHA I/II 4571 242 178 0.70
(0.62-0.80)
EF 0.25-0.45 4543 244 190 0.74
(0.66-0.84)
CTR ≤ 0.55 4455 239 180 0.71
(0.63-0.81)
NYHA III/IV 2224 402 295 0.65
(0.57-0.75)
EF < 0.25 2258 394 270 0.61
(0.53-0.71)
CTR > 0.55 2346 398 287 0.65
(0.57-0.75)
EF > 0.45 987 179 136 0.72
(0.53-0.99)
*Number of patients with an event during the first 2 years per 1000 randomized patients.
Relative risk (95% confidence inter val).
DIG Ancillary Study.

In situations where there is no statistically significant benefit of treatment evident from a trial's primary endpoint, results pertaining to a secondar y end-point should be interpreted cautiously.

Chronic Atria Fibrillation: In patients with chronic atrial fibrillation, digoxin slows rapid ventricular response rate in linear dose-response fashion from 0.25 to 0.75 mg/day. Digoxin should not be used for the treatment of multifocal atrial tachycardia.

Last reviewed on RxList: 4/14/2008
This monograph has been modified to include the generic and brand name in many instances.

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