Drugs Currently Undergoing Preclinical or Clinical Trials for the Treatment of Overactive Bladder: A Review

Silvia Joseph, Steffi A Maria, Jacob Peedicayil, Silvia Joseph, Steffi A Maria, Jacob Peedicayil

Abstract

Background: Overactive bladder (OAB) is a common clinical condition for which current drug treatment comprises drugs blocking the cholinergic nerve supply, or augmenting the adrenergic nerve supply, to the detrusor muscle of the urinary bladder. Current treatments have drawbacks, including lack of efficacy and the development of adverse effects in some patients. Hence, new and better drugs for treating OAB will be clinically useful.

Objective: This review is meant to provide information on drugs currently undergoing preclinical or clinical trials for the treatment of OAB published in journal articles or elsewhere.

Methods: The cited articles were retrieved from PubMed and Google Scholar from January 1, 1990, to December 31, 2021. The search terms used were contraction or contractility, detrusor, inhibition, isolated or in vitro, in vivo, overactive bladder, and relaxant effect or relaxation.

Results: There are 4 classes of new drugs under various stages of development for the treatment of OAB. These are drugs acting on the autonomic nerve supply to the detrusor muscle of the urinary bladder that include the anticholinergics tarafenacin and afacifenacin and the β3 adrenoceptor agonists solabegron and ritobegron; drugs acting on ion channels in the detrusor muscle (eg, potassium channel openers and calcium channel blockers), drugs acting on cellular enzymes like phosphodiesterase-5 inhibitors and Rho kinase inhibitors, and drugs acting on miscellaneous targets (eg, pregabalin and trimetazidine).

Conclusions: Drugs currently used to treat OAB target only the cholinergic and adrenergic cellular signalling pathways. There are many other drugs under trial targeting other cellular pathways that may be useful for treating OAB. Their approval for clinical use might improve the treatment of patients with OAB. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Keywords: contractility; detrusor; new drugs; overactive bladder; pharmacodynamics.

© 2022 The Author(s).

Figures

Figure 1
Figure 1
Diagrammatic representation of how activation of muscarinic M3 receptors stimulates, and stimulation of adrenergic β3 receptors inhibits, contractility of the detrusor muscle of the urinary bladder. Myosin light chain kinase (MLCK) activity is needed for contraction. Activation of muscarinic M3 receptors activates phospholipase C (PLC) leading to increased levels of inositol triphosphate (IP3), which leads to raised levels of Ca2+. Ca2+binds to the protein calmodulin and the Ca2+-calmodulin complex activates MLCK, causing muscle contraction. Stimulation of β3 receptors activates adenylyl cyclase, which catalyzes the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate, which activates cAMP-dependent protein kinase (PKA). PKA inhibits MLCK leading to muscle relaxation. Phosphodiesterase-4 (PDE-4) catalyzes the metabolism of cAMP. AC = adenylyl cyclase; Ach = acetyl choline; β3 = beta adrenergic receptor 3 subtype; DAG = diacylglycerol; M3 = muscarinic 3 receptor subtype; MLCP = myosin light chain phosphatase; NA = noradrenaline. + = Stimulation; – = Inhibition; X = site of antagonism.
Figure 2
Figure 2
Diagrammatic representation of how blockade of voltage-gated calcium channels (VGCC) by calcium channel blockers (CCBs) can inhibit contractility of the detrusor muscle of the urinary bladder. Normally, when VGCC are activated, calcium ions (Ca2+) pass from exterior into the detrusor muscle cell. Inside the cell, Ca2+ combines with the protein calmodulin. The Ca2+- calmodulin complex activates myosin light chain kinase (MLCK), which contracts the muscle. MLCP = myosin light chain phosphatase; + = Stimulation; – = Inhibition; X = site of antagonism.
Figure 3
Figure 3
Diagrammatic representation of how activation of soluble guanylyl cyclase (sGC) or inhibition of phosphodiesterase-5 (PDE-5) inhibits contractility of the detrusor muscle of the urinary bladder. Activation of sGC as occurs after addition of nitric oxide (NO) donors catalyzes the metabolism of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) which activates cGMP-dependent protein kinase or protein kinase G (PKG). PKG inhibits myosin light chain kinase (MLCK). Phosphodiesterase-5 (PDE-5) catalyzes the metabolism of cGMP. The RhoA kinase pathway is also involved in smooth muscle contraction. When inactive RhoA is phosphorylated it is activated to active RhoA, which stimulates Rho kinase, a serine/threonine kinase which phosphorylates the myosin-binding subunit of myosin light chain phosphatase (MLCP), thereby inactivating it and promoting muscle contraction. + = stimulation; – = Inhibition.

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