Two main subtypes of muscarinic receptor (MR) are expressed in the lower urinary tract: M2 and M3 receptors. Their proportions in detrusor membranes are respectively evaluated at 71 % and 22 % [
48]. While M3 are mainly responsible for detrusor contraction in both healthy and pathologic conditions, M2 are predominant in the urothelium and may be associated with pathologic changes in the bladder [
49]. It has been commonly and reasonably thought that the main mechanism of action of antimuscarinics in the treatment of LUTS is mediated by a reduction of detrusor contractility. Specimens from patients with bladder overactivity are consistently denervated, and as such it has been hypothesized that possible denervation supersensibility to acetylcholine may be crucial in OAB physiopathology [
50]. However MR are also present in the urothelium and are here involved in urothelial sensory function. The urothelium in fact releases multiple signal molecules, including acetylcholine, which activate unmyelinated afferent C-fibers present in the suburothelial layer of the bladder wall, and this release of acetylcholine is increased by bladder overstretching . This, associated to the denervation supersensitivity of the detrusor to acetylcholine, may induce disorganized contraction of small muscular units in the detrusor, generating pathologic afferent signals which in turn may determine urgency symptoms [
51].
Antimuscarinics have been prevalently used in female patients with OAB: however today it is clear that in men with BPH, storage symptoms are partially caused by the bladder, with urodynamically proven OAB being a common cause [
52]. As such antimuscarinic therapy has emerged as a new option in male LUTS management [
8]. Chun-Hou Liao et al. have studied the predictors of therapeutic success with a first line antimuscarinic treatment in BPH men with predominant storage symptoms. In their 197 patients group, receiving tolterodine in monotherapy, higher baseline IPSS, higher baseline Qmax and lower prostate volume were each associated with a better response [
53]. Treatment with antimuscarinics alone is still felt as dangerous in patients with BOO by many urologists, due to the possible increased risk of AUR. Abrams et al. reported that in men with mild to moderate BOO, the antimuscarinic tolterodine 2 mg twice daily for 12 weeks caused a significant increase in post void residual (PVR) urine compared to placebo (49 ml vs 16 ml): however, rates of AUR (3 %) and Q
max were equal across both groups [
54]. This is probably a consequence of the action of antimuscarinics on the storage phase of micturition and not on voiding, as there is little evidence that these agents, at the therapeutic recommended doses, determine a significant reduction of voiding contraction [
55]. Nonetheless, in daily clinical practice, the majority of patients is already under treatment with an α1-antagonist, and present with persisting storage symptoms. In this context, several trials have explored the efficacy and safety of the addition of an antimuscarinic to the α1-antagonist in these patients [
56‐
58]. The TIMES study included 879 men with symptoms of BPH and OAB [
56]. Patients were randomized to receive either tolterodine 4 mg ER + tamsuloin, one of the two drugs alone or placebo. After 12 weeks, in the combination arm the patients reported significant decrease in urgency incontinence episodes (−0.88 vs −0.31,
p = 0.005), frequency (−2.54 vs −1.41,
p < 0.001) and an amelioration of QoL. Although higher than for placebo and for tamsulosin alone, the rate of AUR was low for the combination (0.4 %) and the tolterodine arm alone (0.5 %). MacDiarmid et al. reported significant amelioration of both storage and voiding symptoms (
p = 0.006) in men affected by BPH treated with tamsulosin + oxybutinin 10 mg, with a non-significant increase in PVR in treated patients compared to placebo [
57]. Similarly, in the VICTOR study, 398 men were randomized to receive tamsulosin plus either solifenacin 5 mg or placebo. In the solifenacin group, patients showed a significant reduction of urgency episodes (−2.18 vs −1.10,
p = 0.001) but a non-significant reduction of frequency (−1.05 vs −0.67,
p = 0.135) [
58]. In most trials the most frequent AE associated with antimuscarinics is xerostomia [
56,
57]. Increase in PVR urine, though statistically significant in many studies, frequently did not determine a significant increase in the risk of AUR requiring catheterization [
56,
57]. However, as recommended by current EAU guidelines, antimuscarinics are therefore medications which can be prescribed in men with BPH with residual storage symptoms after treatment with α1-antagonists. Before to start a treatment with an antimuscarinic, BPH patients should be monitored for PVR and then closely followed [
8]. Some authors have been questioning the compliance to bi-therapy, considering the fact that the common chronic combination of antimuscarinics and αl-antagonists could be a burden for the patients. Barkin et al. reported a retrospective analysis based on patients prescriptions reimbursement data. They concluded that patients treated in combination therapy showed an improved persistence over a year period, compared to those on αl-antagonists monotherapy [
59].
Concerning anticholinergic drugs, great care is necessary when prescribing these drugs in the elderly, as cognitive deterioration may be a serious consequence and one must bear in mind that 16 % of patients >70 years show some form of cognitive impairment [
60]. Indeed, encephalic cholinergic activity, and in particular M1 and M2 receptors which represent over 60 % of the brains cholinergic receptors, are vital in cognitive function [
61]. The only antimuscarinic which was accorded a beneficial safety profile in the elderly is Fesoterodine, as this drug was studied specifically in the ageing population [
62‐
64]. In the SOFIA trial 581 patients >65, of which 33 % were >75 years old and frequently on polypharmacy, completed a 3 month double-blind randomized trial of Fesoterodine versus placebo [
62]. At 12 weeks, patients in the treatment arm demonstrated reduced urgency (−3.8 episodes), pollakiuria and nycturia (−0.55 episodes) (all
p < 0.001) compared to placeebo. Fesoterodine determined a similar rate of adverse events compared to placebo (39.8 % vs 36.1 %), mostly mild xerostomia. Of note, no clinically relevant changes in cognitive function (evaluated through the mini-mental status examination) were observed throughout the study in both arms. This may be attributed to the high affinity of Fesoterodine for the M3 receptor and its inability to pass the blood–brain barrier [
65]. In any case, great care is advised with anticholinergic drugs and a high level of suspiciousness in case of cognitive deterioration while receiving treatment.