Digoxin
Cardiac glycosides such as digoxin increase myocardial contractility by blocking sodium-potassium adenosine triphosphatase pump (Na + -K + ATPase) [73] , which is present in the cell membrane of myocardial cells. In patients who have PAH and RHF, a single intravenous administration of digoxin has been shown to increase cardiac output and decrease circulating norepinephrine levels in a small, short-term, uncontrolled study ( Table 2) [23]. This study included 17 patients who received a single dose of 1 mg IV digoxin over a 30-minute infusion; hemodynamic measurements were made 2 hours after the infusion and were compared with baseline hemodynamic values. A prospective, randomized, double-blind, placebo-controlled study [74] of 15 patients who had COPD and RHF and no clinical LV failure found that 8 weeks administration of digoxin did not improve RV ejection fraction in any patient who did not have reduced left ventricular ejection fraction (LVEF) on baseline equilibrium radionuclide angiography (see Table 2) [23,74]. The safety, efficacy, and impact on morbidity or mortality with long-term use of digoxin in patients who have PAH and RVF are not known. It should be noted that in patients with systolic LV dysfunction and NYHA class II and III symptoms, treatment with digoxin for 2 to 5 years did not have any impact on mortality [75] ; there was some beneficial effect on rate of congestive heart failure-related hospitalizations, however.
Currently, digoxin is used in patients who have PAH and signs of RHF and in patients who have atrial rhythm abnormalities (eg, multifocal atrial tachycardia, atrial flutter, or atrial fibrillation). Some experts advocate using digoxin with calcium channel antagonists to counteract negative ionotropic effects of CCBs. Because most patients who have PAH and RHF are on digoxin and diuretics, it is important to take extreme caution to monitor digoxin levels and promptly recognize toxicity, especially in association with electrolyte disturbances that result from the use of diuretics. Paroxysmal atrial tachycardia with variable atrioventricular block and bidirectional tachycardia are well-known arrhythmias associated with digoxin toxicity. The half-life of digoxin is prolonged with worsening of renal function. Digoxin is renally cleared and is used in most US centers, whereas digitoxin is hepatically cleared and is mostly used in European centers.
There are no specific recommendations regarding how to monitor digoxin therapy in patients who have PAH, so guidelines developed for monitoring of digoxin therapy in patients with LV failure are relied upon [68]. Digoxin therapy may be started at 0.125 to 0.25 mg orally daily; however, many centers only use low-dose (ie, 0.125 mg/d) therapy. In patients with normal renal function the digoxin levels may be first checked after 1 week. In patients above age 70 with impaired renal function or low body weight, a reduced starting dose [76] (0.125 mg every other day) is more appropriate. When digoxin is used for positive ionotropic effect, it is generally recommended to keep the digoxin trough level between 0.5 and 1.0 ng/mL [68]. At a plasma concentration above 1.0 ng/mL, the risk-adjusted mortality increases, as shown by the Digitalis Investigation Group Trial [77]. In the absence of hypokalemia, hypomagnesemia, or hypothyroidism, digitalis toxicity is generally not seen below a plasma digoxin concentration of 2.0 ng/mL (although digoxin toxicity may rarely be seen at lower concentrations) [78,79]. Digoxin should not be used in cases of suspected coronary ischemia or in patients with recent acute coronary syndrome because of increased risk of death from arrhythmia or myocardial infarction [68,75,80,81]. Concurrent use of clarithromycin, amiodarone, itraconazole, cyclosporine, and many other drugs can increase digoxin levels and increase the potential for toxicity [82–84].
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