Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure.

Sequential doses of 5 mg of oral prazosin hydrochloride were administered to eight patients with severe chronic congestive heart failure refractory to conventional therapy.Initial doses of the drug produced marked increases in cardiac index (+0.87I/min/m2) associated with substantial decreases in left ventricular filling pressure (-10.7 mm Hg), total systemic vascular resistance (2118 to 1154 dyn-sec-cm-5), and heart rate (89 to 76 beats/min).However, serial administration of the same dose at 12-24-hour intervals was accompanied by the rapid development of tachyphylaxis, such that the magnitude of hemodynamic effects with second doses was less than 50% of the magnitude of effects seen with first doses (p < 0.01), and third doses produced no overall significant hemodynamic responses.Diuresis with furosemide failed to restore the circulatory effects of prazosin, and the use of 10-mg doses improved cardiovascular performance to only a small extent.Only two of eight patients had sustained hemodynamic responses large enough to justify chronic oral ambulatory therapy.Administration of oral hydralazine caused hemodynamic improvement superior to even high-dose prazosin therapy (p < 0.02).THE BENEFICIAL HEMODYNAMIC and clinical effects of peripheral vasodilators in patients with severe heart failure are well established,' 5 but the search continues for a well-tolerated oral agent which is chronically effective for the therapeutic reduction of preload and afterload.Although nitrates are orally active, their duration of action is short, and they have minimal effects on cardiac output.6' 7The use of hydralazine results in marked increases in cardiac output (CO), significant reductions in left ventricular fill- ing pressure (LVFP),4 and amelioration of clinical symptoms,3 but is often accompanied by poorly tolerated adverse effects.8'9 Therefore, the recent demonstration of balanced preload and afterload reduction with prazosin'0' 1' has stimulated interest in its use in chronic ambulatory therapy.Prazosin exerts a peripheral vasodilator action by producing a-sympathetic blockade;21-6 some have proposed an additional direct smooth muscle relaxant effect mediated by increased intracellular levels of cyclic AMP due to drug-induced phosphodiesterase inhibition.'7Despite extensive experience in antihypertensive therapy, previous work with prazosin in heart failure has involved hemodynamic monitoring of only initial doses of the drug;10 as a result, the ability of maintenance therapy to produce sustained reduc- tion of preload and afterload has not been