Development of pharmacodynamic tolerance to prozosin 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.

Positive inotropic effects of hydralazine in human subjects: comparison with prazosin in the setting of congestive heart failure.

Hydralazine possesses positive inotropic properties in animal model preparations. To determine whether this vasodilator elicits a positive inotropic response in the failing human ventricle, hydralazine, 75 or 100 mg, was administered orally to 14 patients with left ventricular dysfunction and congestive heart failure; the results were compared with those of first-dose prazosin at 5 and 10 mg. The duration of the preejection period and the isovolumic developed pressure/duration of isovolumic contraction (delta P/delta t) were used as indexes of inotropy. Prazosin did not effect a significant response in the duration of the preejection period or in the delta P/delta t. Hydralazine significantly shortened the preejection period and increased the delta P/delta t over 8 hours after administration; these data suggest that hydralazine elicits a positive inotropic response in the failing human ventricle.

Electrocardiographic abnormalities in patients with myotonic dystrophy.

In examining the incidence and progression of electrocardiographic abnormalities in 45 patients with myotonic dystrophy, 26 (58%) of whom at entry had at least 1 electrocardiographic abnormality, we found conduction abnormalities in 17 (38%). In 21 patients (47%), new abnormalities developed during follow-up (mean, 4.6 years). The overall incidence of electrocardiographic abnormalities increased to 78%, and the incidence of conduction defects increased to 62%. Second-degree or complete atrioventricular block did not develop in any of the patients. Pseudoinfarction patterns were common at entry and during follow-up and were not correlated with evidence of clinical coronary artery disease. There was no correlation between the presence of electrocardiographic abnormalities and apparent disease severity.

Prazosin and hydralazine in congestive heart failure. Regional hemodynamic effects in relation to dose.

Central hemodynamic variables and regional blood flow and vascular resistances were ascertained in patients with severe congestive heart failure before and after the oral administration of prazosin hydrochloride or hydralazine. Prazosin was administered in doses of 2, 5, and 10 mg and hydralazine, 75 and 100 mg. Although both agents significantly increased cardiac output and decreased vascular resistances, their effects on regional blood flow and vascular resistances were considerably different. Prazosin increased hepatic blood flow and reduced hepatic vascular resistance at lower doses; these changes decreased as prazosin was increased. Hydralazine did not significantly alter mean hepatic blood flow or vascular resistance. Prazosin did not affect renal blood flow or renal vascular resistance. In contrast, hydralazine significantly increased renal blood flow and reduced vascular resistance; the changes were dose related. Both drugs augmented limb blood flow and diminished limb vascular resistance; the magnitude of change was dose dependent.