α1-Adrenoceptor Selectivity: The North American Experience

Abstract

Objective: The recent publication of multicentre US studies raises the possibility that the response to tamsulosin is dose-related and less than maximum at 0.4 mg. The objective of the present study was to calculate pharmacologically equivalent, alpha-blocking doses of doxazosin and tamsulosin in a clinical setting and thereby to examine further the concept of ‘uroselectivity’ and ‘prostate selectivity’. Methods: Healthy male volunteers were monitored in controlled, crossover studies. The effects of placebo or alpha blocker on phenylephrine (PE)-induced urethral and vascular responses, were determined. These were related to plasma drug concentrations and used with in vitro radioligand binding data to derive receptor occupancy. Results: Doxazosin effectively blocked PE-induced vascular and urethral changes over the dose range 1–16 mg. There was no evidence for target organ selectivity. The degree of blockade of the PE-induced responses by tamsulosin was highly dependent on the time of measurement, post drug administration. The degree of observed blockade with tamsulosin at 0.4 mg was substantially less than that observed at 0.8 mg tamsulosin and/or 1 mg doxazosin. Conclusions: These studies provide no evidence of prostate selectivity for tamsulosin. 0.4 mg tamsulosin is a sub-optimal blocking dose and is equivalent to 1 mg of doxazosin and terazosin (1–2 mg). It is recommended that future comparative studies on benefit/risk in patients should include a range of doses encompassing the ED₅₀.