Alternative actions of clinical antimuscarinics on the urinary bladder

Abstract

Antimuscarinics are the first-line pharmaceutical treatment for overactive bladder (OAB). However, more than 70% of patients prescribed antimuscarinics cease their treatment regimen, due to lower-than-expected treatment benefits or adverse side effects. The reason for this is not entirely known, but evidence identifies the potential for some antimuscarinics to have alternative mechanisms of action on bladder tissue. The overall aim of this research is to assess the muscarinic actions of commonly prescribed clinical antimuscarinics on urothelium and lamina propria (U&LP) and detrusor contractions and identify any alternative mechanisms of the actions that clinical antimuscarinics have.

For experimental chapters, strips of adult or juvenile porcine U&LP or detrusor smooth muscle were mounted in isolated tissue baths. Carbachol concentration-response curves were performed on paired tissues in the absence or presence of the six most commonly prescribed antimuscarinics: darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine and trospium. Estimated affinities were calculated for each curve from pEC50 values, and for each antimuscarinic, estimated affinities were compared between detrusor and U&LP, as well as the juvenile and adult (paired Student's two-tailed t-test). Maximum contraction was also compared between paired control and intervention tissues (paired Student's two-tailed t-test). Single-dose experiments were then conducted in the presence and absence of darifenacin with serotonin, prostaglandin E2, histamine, αβ-methylene-ATP, angiotensin II, neurokinin A and carbachol(paired Student's two-tailed t-test).

A systematic review and meta-analysis was conducted on the adverse effects and discontinuations of OAB patients prescribed darifenacin and reported under PRISMA guidelines. The primary outcome was OAB patient discontinuation and adverse events in darifenacin and placebo groups. Randomised control trials were searched in PubMed, Embase, and Cochrane CENTRAL. A risk of bias assessment and a Grading of Recommendations Assessment, Development and Evaluation were used for study appraisal and to assess the certainty of evidence.

In all juvenile and adult detrusor and U&LP samples (p < 0.001 for all), a right parallel shiftfrom the control was observed in response to oxybutynin (1 µM), solifenacin (1 µM), tolterodine (1 µM), darifenacin (100 nM), trospium (100 nM) and fesoterodine (100 nM). These shifts were consistent, with no significant differences observed between the layers or differently aged tissues for each antimuscarinic. Darifenacin significantly inhibited juvenile and adult, U&LP and detrusor maximum contraction responses. Darifenacin inhibited maximum contractions significantly in adult detrusor preparations to carbachol by 46%, αβ-methylene-ATP by 50%, prostaglandin E2 by 73%, histamine by 64%, and serotonin by 53%. Maximum contraction was significantly reduced by darifenacin in adult U&LP preparations to carbachol by 49% and αβ-methylene-ATP by 35%.

An identified non-muscarinic action was found across both tissue layers and differently aged bladder tissues with darifenacin, but not from fesoterodine, oxybutynin, solifenacin, tolterodineor trospium. While antimuscarinics remain an effective front-line pharmaceutical therapy for urinary bladder contractile disorders, there appears to be a unique action of darifenacin that warrants further investigation. Its ability to exhibit actions on non-muscarinic receptors presents a consideration within clinical settings, but also highlights a potential for its use in non-muscarinic pathology of OAB.

Date of Award	3 Dec 2025
Original language	English
Supervisor	Christian Moro (Supervisor) & Russ Chess-Williams (Supervisor)