Influence of verapamil on the inotropism and pharmacokinetics of digoxin

Abstract

Verapamil has been demonstrated to inhibit the elimination of digoxin and to increase its steady state plasma level by 60-80%. Animal studies suggest that verapamil abolishes the intropic action of other drugs such as ouabain and dopamine. The clinical consequences of this drug interaction were investigated by examining the inotropic activity of single doses of digoxin (assessed from systolic time intervals), with and without coadministration of verapamil. Verapamil decreased total-body clearance of digoxin from 4.68 +/- 0.41 to 3.29 +/- 0.26 ml/min/kg (p less than 0.001) and increased the plasma half-life of the drug from 33.50 +/- 2.38 to 41.31 +/- 2.27 h (p less than 0.01). Verapamil had no influence on the base-line values of the systolic time intervals. Both in the absence and presence of verapamil, digoxin caused significant shortening of the total electromechanical systole and the left ventricular ejection time. However, compared to control conditions, the decay of these changes was slower in the presence of verapamil, in parallel with the prolongation of the plasma half-life of digoxin. A linear relationship was established between reductions in the systolic time intervals and the computer-derived concentration of digoxin in the deep compartment. These regression lines, which represent the concentration-effect relationships of the inotropism of digoxin, were not affected by verapamil. Thus, verapamil per se had no measurable effect either on base-line contractile function of the heart or on digoxin-induced inotropism. The elevated plasma digoxin concentration induced by verapamil appears cardioactive in terms of inotropism.

Influence of nisoldipine on haemodynamic effects and plasma levels of digoxin.

“…Comparable to results found for other calcium channel blockers like verapamil, gallopamil, nifedipine and nitrendipine, in the present study the new calcium antagonist nisoldipine also increased significantly plasma levels of digoxin (Belz et al, 1983;Kirch et al, 1984Kirch et al, , 1986aPedersen et al, 1983). The rise of the digoxin plasma concentrations with concomitant therapy with calcium channel blockers has been speculated to be due to a reduction of renal excretion of digoxin caused by these drugs (Belz et al, 1983;Pedersen et al, 1981).…”

Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein

“…Modulation of P-gp function by P-gp inhibitors or inducers was associated with clinically significant drug-drug interactions (Ayrton and Morgan 2001). Drug-drug interactions resulting from inhibition of P-gp in the gastrointestinal tract have been observed with P-gp inhibitors such as ketoconazole (Kageyama et al 2005), clarithromycin (Tanaka et al 2003), verapamil (Pedersen et al 1983a;Verschraagen et al 1999), quinidine (Dahlqvist et al 1980;Pedersen et al 1983b;Angelin et al 1987), and itraconazole (Partanen et al 1996;Jalava et al 1997). Clinically significant drug-drug interactions at the BBB have been difficult to demonstrate when we rely on pharmacodynamic and toxicodynamic changes.…”

P-Glycoprotein and Bioavailability-Implication of Polymorphism

“…A decreased total body clearance of an intravenously administered P-gp substrate drug has been observed frequently after co-treatment of patients with a reversal agent. For example, the total body clearance of digoxin and paclitaxel were found to decrease substantially after co-treatment of human subjects with verapamil (25,26). Similarly, co-administration of the reversal agent nifidipine reduced the total body clearBrought to you by | University of Arizona Authenticated Download Date | 6/9/15 6:17 PM ance of vincristine (27), and co-treatment of patients with cyclosporin A resulted in a decreased renal and non-renal clearance of etoposide (28).…”