Development of pharmacodynamic tolerance to prazosin in congestive heart failure

In order to determine and compare the pharmacodynamic responses to single and multiple dose prazosin therapy in cardiac failure, 14 patients with severe low-output heart failure underwent central and regional hemodynamic measurements after random placement in one of two prazosin dosing schedules. A single 5 mg oral dose of prazosin (Group A, no. = 7) significantly increased the cardiac index and stroke volume index while significantly decreasing systemic, pulmonary and pulmonary capillary wedge pressures and vascular resistances. Hepatic plasma flow and limb blood flow increased after the single dose. Striking attenuation of these hemodynamic effects occurred when the same dose was administered after 24 hours of pretreatment with oral prazosin, 2 mg every 8 hours (Group B, no. = 7). The plasma prazosin levels of the two groups, drawn 2 hours after administration, were 24.5 and 30.5 ng/ml, respectively. Repeated administration of prazosin in patients with congestive heart failure results in rapid attenuation of its beneficial central and regional hemodynamic effects. The usefulness of this vasodilator as a preload-and afterload-reducing agent in the clinical setting of chronic congestive heart failure may be limited by the development of pharmacodynamic tolerance.