Prospective pharmacologic therapies for the overactive bladder

Abstract

Lower urinary tract symptoms (LUTS), overactive bladder syndrome (OAB) and detrusor overactivity (DO) are all conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are first-line treatment-they often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium, the spontaneous myocyte activity during bladder filling, and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of LUTS/OAB/DO pathophysiology. There may be several new possibilities to treat LUTS/OAB/DO. 3 -AR agonists (YM178), PDE 5 inhibitors (sildenafil, tadalafil, vardenafil), vitamin D analogs (elocalcitol), combinations ( 1 -AR antagonist þ antimuscarinic), and drugs with a central mode of action (tramadol, aprepitant) all have Randomized controlled trial (RCT) documented efficacy. Which of these therapeutic principles will be developed to clinically useful treatments remains to be established.

Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double‐blind, placebo‐controlled, phase III studies

“…In animal models, activation of the b-adrenoceptor in the bladder facilitates urine storage through flattening and lengthening of the bladder base (16). Furthermore, stimulation of the b 3 -adrenoceptor is associated with increased bladder capacity, without change in micturition pressure, residual volume or voiding contraction (17)(18)(19). As a consequence, targeting the b 3 -adrenoceptor increases the storage capacity of the bladder without affecting the amplitude of the voiding contraction.…”

The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis

“…Unlike antimuscarinics, mirabegron mediates relaxation of the detrusor muscle during the storage phase of the micturition cycle, thus increasing bladder storage capacity [10,11]. …”

Insights into the Management of Overactive Bladder: What Difference Can Mirabegron Make?

“…Animal studies suggest that the myorelaxant action of mirabegron occurs during the storage phase. Hence, mirabegron does not significantly influence micturition pressure, PVR volume, or detrusor contraction during voiding (33,34,35). In a 12-week phase II study, which included male patients with LUTS and bladder outlet obstruction, mirabegron did not adversely affect maximum urinary flow rate and detrusor pressure at maximum urinary flow compared with placebo (60).…”

“…When activated by the ligand (epinephrine, norepinephrine), the receptor couples to a specific G protein (G s ) which in turn stimulates adenylate cyclase, resulting in increased intracellular levels of cyclic adenosine monophosphate (cAMP) (30). Elevated cAMP levels lead to detrusor smooth muscle relaxation and improved storage capacity without significant changes in bladder contraction during voiding or post-void residual (PVR) volume (31,32,33,34,35). There is additional evidence showing that acetylcholine-containing nerve fibers of the human bladder express immunoreactivity for the β3adrenoreceptor (36).…”