A comparison between the effects of diltiazem and isosorbide dinitrate on digoxin pharmacodynamics and kinetics in the treatment of patients with chronic ischemic heart failure

Abstract

Objective: To evaluate the effect of an arteriolar dilator (diltiazem hydrochloride) versus a venodilator (isosorbide dinitrate) on digoxin kinetics and to estimate the efficacy and tolerability of these vasodilators when combined with digoxin for 10 days therapy in patients with congestive heart failure secondary to ischemic heart disease.

Methods: A double blind randomized cross over study was carried out to investigate the effect of an arteriolar dilator (diltiazem hydrochloride 180 mg/day orally) versus a venodilator (isosorbide dinitrate 30 mg/day orally) on digoxin kinetics (0.25 mg/day orally), after 10 days therapy in patients with heart failure due to ischemic heart disease. Also, the effect of these drugs on blood pressure, heart rate, renal functions and serum electrolytes, and their efficacy and tolerability in combination with digoxin were studied. This study was carried out in the Department of Medicine, Main Alexandria University Hospital, Alexandria, Egypt, during the period May 1999 through to May 2000.

Results: Diltiazem caused a significant increase in digoxin maximum serum concentration without significant change in time to reach maximum concentration and the apparent volume of distribution. The total digoxin clearance was significantly reduced and the elimination half life was prolonged. Subsequently the area under time-concentration curve and the steady-state digoxin level were increased, but were still within therapeutic margin. On the other hand isosorbide dinitrate significantly increased digoxin maximum serum concentration but without change in the other digoxin pharmacokinetic parameters. Isosorbide dinitrate, but not diltiazem, caused significant reduction in supine and standing blood pressure, while both drugs did not significantly alter pulse rate, renal functions, serum sodium potassium and electrocardiographic pattern.

Conclusion: Patients who received diltiazem displayed a mean 51% increase in the area under the plasma concentration-time curve, 50% increase in mean steady state serum digoxin concentration, and 37% increase in peak serum digoxin concentration. While patients who received isosorbide dinitrate showed only a 15% increase in digoxin maximum serum concentration and no statistically significant change in mean steady state digoxin concentration or area under the plasma concentration-time curve. The elimination half life during the diltiazem phase was prolonged by 29% while there was no significant change with isosorbide dinitrate. Netiher diltiazem or isosorbide dinitrate significantly altered the time to reach maximum serum digoxin concentration. The addition of a vasodilator such as, diltiazem or isosorbid dinitrate to digoxin could significantly improve the symptoms and signs of heart failure compared to digoxin alone. They were well tolerated and without fear of electrolyte imbalance which potentiate digoxin toxicity.