Drugs to affect the smooth musculature of the human ureter - an update with integrated information from basic science to the use in medical expulsion therapy (MET)

Abstract

Purpose: Urolithiasis and symptomatic ureterolithiasis represent diseases known to be on the increase in most westernized countries. The present article aims to give an overview on some drug principles assumed to target signalling systems involved in modulating ureter smooth muscle contractility and to present background to their potential use or prospects in ureter stone disease.

Methods: The article reviews drugs that have been evaluated over the last decades in vitro, in vivo and/or in clinical settings with regard to their properties to achieve spontaneous passage of (distal) ureteral stones and relieve colic pain. Among these drugs are alpha- and beta-adrenoceptor antagonists, calcium channel blocking agents, Rho kinase inhibitors, nitric oxide (NO) donor drugs, selective inhibitors of cyclic nucleotide phosphodiesterase enzymes (PDEs), as well as potassium channel openers.

Results: Based on the recent scientific information on agents targeting different pathways, antagonists of alpha 1-adrenoceptors, inhibitors of the PDE isoenzymes PDE4 and PDE5 (affecting cyclic AMP- or NO/cyclic GMP-mediated signals that facilitate relaxation of ureter smooth muscle), as well as the combination of certain drugs (for example, PDE5/PDE4 inhibitor plus alpha 1-AR antagonist) seem to be intriguing pharmacological approaches to medical expulsion therapy (MET) in the overall population of patients.

Conclusion: While NO donors, calcium channel antagonists and potassium channel openers may be limited for further development for medical expulsion therapy (MET) due to their systemic effects and a lack of effect on stone clearance, Rho kinase inhibitors should be explored further as a future pharmacological principle in ureteral stone disease.

Keywords: Pharmacology; Treatment options; Upper urinary tract stone disease; Ureter.

Fig. 1

Structural formulas of some compounds assumed to gain clinical significance in the near future in the treatment of ureteral stone disease by facilitating relaxation of ureter smooth muscle and, thus, promoting the spontaneous expulsion of ureteral calculi and easing episodes of colic pain: alpha 1-adrenoceptor antagonists silodosin and tamsulosin, the PDE4 (cyclic AMP PDE) inhibitors drotaverine and rolipram, PDE5 (cyclic GMP PDE) inhibitor tadalafil (interacting with the signaling pathways mediated via cyclic AMP or NO/cyclic GMP, respectively) and the Rho kinase (ROCK) inhibitor Y 27632