The pharmacokinetic, pharmacodynamic and haemodynamic effects of acute and chronic alpha-adrenoceptor blockade in chronic heart failure.

Pharmacokinetic and haemodynamic studies with the alpha-1 adrenoceptor antagonist prazosin were made in 20 patients disabled by chronic ischaemic heart failure. In eight patients given doubling doses of oral prazosin in successive days, the peak plasma concentration and area under the concentration-time curve were linearly reated to the oral dose. The pharmacodynamic response was a dose-related fall in the systemic arterial pressure, both supine and standing; dose-response effects were most evident in the upright posture. Severe hypotension occurred unpredictably, and was unrelated to co-existing clinical or radiographic features. There was a reciprocal relationship between the reduction in systemic blood pressure and the increase in heart rate. The immediate and long-term haemodynamic effects were determined during sitting, standing and walking in 12 patients before and after their first dose of prazosin (2 mg) and in 6 of these patients after a further 12 weeks of sustained treatment (2 mg t.d.s.). When first added to treatment with digoxin and frusemide, prazosin was followed by substantial reductions in systemic arterial, pulmonary arterial and pulmonary venous pressures in both postures at rest and also during walking. These changes were significantly attenuated after continued treatment. Cardiac output sitting and standing at rest was reduced in both instances but the response to exercise was unchanged. The pharmacodynamic effects of prazosin in heart failure are explicable in terms of blockade of alpha-1 adrenoceptors in arterial resistance and venous capacitance vessels; the cause of the attenuation of the acute haemodynamic effects of the drug during sustained treatment is less clearly defined.