Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction

Abstract

Several disorders of the human upper and lower urinary tract, such as urinary stone disease, lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and detrusor overactivity, can be therapeutically addressed by influencing the function of the smooth musculature of the ureter, prostate or urinary bladder, respectively. In order to ensure a drug effect without significant adverse events, a certain degree of tissue selectivity is mandatory. The treatment of said conditions aims to focus on orally available drugs acting via intracellular signalling pathways. Specifically, the cyclic nucleotide monophosphate cyclic GMP represents an important mediator in the control of the outflow region (bladder, urethra). The use of phosphodiesterase (PDE) inhibitors, such as sildenafil, tadalafil, vardenafil, avanafil or udenafil, known to restrain the degradation of the second messenger cyclic GMP, offers great opportunities in the treatment of lower urinary tract dysfunction. PDE inhibitors are regarded as efficacious, have a rapid onset of action and favourable effect‐to‐side‐effect ratio. The role of PDE5 inhibitors in the treatment of BPH/LUTS and the overactive bladder has already been addressed in randomized, double‐blind, placebo‐controlled trials, as well as preliminary open‐label studies enrolling either several hundreds or only 20 patients. The purpose of this review is to focus on the potential use and clinical significance of PDE inhibitors in the treatment of storage and voiding dysfunctions of the lower urinary tract. The strategy of modulating the activity of PDE isoenzymes might represent a novel approach in patients with lower urinary tract dysfunction (LUTD).

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

“…Clinically, there is now good level 1 evidence of a beneficial effect of PDE5is on urinary symptoms, especially for men with LUTS and significant ED (42). To note, as mentioned previously, PDE5is provided only limited improvement in urinary flow rate, which gave rise to controversy regarding this therapy, although mounting and consistent evidence is showing their significant benefits in treating BPH/ LUTS (39,68). According to the American Urological Association guidelines, ␣ 1 -adrenergic blockers combined with 5␣-reductase inhibitors are considered the most effective therapy for the treatment of BPH, especially for larger prostates.…”

Control of Urinary Drainage and Voiding

“…Neuronal release of NO primarily elicits relaxation responses at the level of the neck and urethra to facilitate micturition (71). In the cytoplasm, it activates guanylate cyclase and thus increases cGMP, which then activates protein kinase G. In the clinical setting, this pathway has been targeted through use of phosphodiesterase inhibitors, such as sildenafil, which result in elevated levels of intracellular cGMP and enhanced relaxation of bladder neck and urethra (72). In one study, a group of healthy male volunteers, given a NO donor sublingually and studied urodynamically, exhibited lowered bladder outlet resistance characterized by reduced detrusor pressure during voiding and a lower maximal flow rate (73).…”

Urethral dysfunction due to alloxan-induced diabetes. Urodynamic evaluation and action of sildenafil citrate

“…There was also demonstrated increased urinary frequency associated with bladder hyperactivity in the initial phase of the disease 5 .…”