Alfuzosin, a selective α₁‐adrenoceptor antagonist in the lower urinary tract

Abstract

1 Phenylephrine-induced contractions of rabbit isolated trigone and urethra were antagonized in a competitive manner by alfuzosin (pA2 7.44 and 7.30, respectively) and prazosin.2 The characteristics of [3H]-prazosin binding to human prostatic adenoma tissue were evaluated.[3H]-prazosin was potently displaced by al-adrenoceptor specific agents including alfuzosin, its (+ )-and (-)-enantiomers and prazosin (IC5o 0.035, 0.023, 0.019 and 0.00411M, respectively), but only weakly by M2-adrenoceptor selective agents, for example, yohimbine (IC50= 6.0 IM). produced dose-related inhibition of the increases in urethral pressure caused by stimulation of sympathetic hypogastric nerves. Prazosin was approximately 5 fold more potent than alfuzosin. When phenylephrine was employed to induce urethral and vascular al-mediated tone simultaneously, prazosin inhibited both stimuli with similar potency whereas alfusozin was 3-5 fold more potent against elevated urethral pressure. This functional uroselectivity of alfuzosin was more evident by the intraduodenal route, since doses of 0.03 and 0.1 mg kg-' alfuzosin inhibited urethral pressure with minimal effects on arterial blood pressure. 5 Alfuzosin is a potent selective a,-adrenoceptor antagonist in tissues of the lower urinary tract including the human prostate. This provides a pharmacological basis for its use in the treatment of benign prostatic hypertrophy.

Tamsulosin Potently and Selectively Antagonizes Human Recombinant .ALPHA.1A/1D-Adrenoceptors: Slow Dissociation from the .ALPHA.1A-Adrenoceptor May Account for Selectivity for .ALPHA.1A-Adrenoceptor over .ALPHA.1B-Adrenoceptor Subtype

“…The affinity of tamsulosin among α 1 -adrenoceptor subtypes was highest for the α 1A -adrenoceptor, and the selectivity of tamsulosin for the α 1A -adrenoceptor was 11-and 3.4-fold higher compared with α 1B -and α 1D -adrenoceptors, respectively. The drugs 5-methylurapidil and silodosin are selective α 1A -adrenoceptor antagonists, BMY7378 is a selective α 1D -adrenoceptor antagonist, and prazosin, terazosin, alfuzosin, urapidil, and naftopidil are non-selective α 1 -adrenoceptor antagonists, [19][20][21][22][23] consistent with our results. We confirmed tamsulosin as a potent and selectiveH]tamsulosin B max were 71% (α 1A ), 50% (α 1B ) and 83% (α 1D ), respectively.…”

Effects of four different .ALPHA.1-adrenoceptor antagonists on .ALPHA.-adrenoceptor agonist-induced contractions in isolated mouse and hamster ureters

“…The antagonist potency of silodosin in this experiment (pKB value = 9.47) was much greater than those of doxazosin (pKB value = 8.62), terazosin (pKB value = 8.39), and alfuzosin (pKB value = 8.03). The pKB values we obtained for doxazosin, terazosin, and alfuzosin in the mouse ureter were in good agreement with the pA2 values reported for α1A-adrenoceptors in isolated preparations of human prostate, rat vas deferens, and the trigone of the rabbit urinary bladder (Lefèvre-Borg et al, 1993;Kenny et al, 1996;Hancock et al, 2002).…”

Use of drug therapy in the management of symptomatic ureteric stones in hospitalised adults: a multicentre, placebo-controlled, randomised controlled trial and cost-effectiveness analysis of a calcium channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the SUSPEND trial)

“…24 Experiments using animal and human tissue models demonstrate that ureteric smooth muscle contraction can be stimulated by activation of adrenergic receptors, particularly the alpha-1D subtype. [25][26][27][28] Blockade of alpha-1 receptors by specific pharmacological antagonists (alpha-blockers) such as doxazosin, 29 terazosin, 30 alfuzosin 31 and, most typically, tamsulosin 32,33 results in ureteric smooth muscle relaxation. It was hypothesised that this would translate into clinical benefit for people with ureteric colic.…”