Bju_6258.fm

SENSORY ACTIONS OF ANTIMUSCARINICSFINNEY et al.
Antimuscarinic drugs in detrusor overactivity and the
overactive bladder syndrome: motor or sensory actions?
STEVEN M. FINNEY, KARL-ERIK ANDERSSON*, JAMES I. GILLESPIE† and LAURENCE H. STEWART
Western General Hospital, Edinburgh, UK, *Department of Clinical and Experimental, Pharmacology, Lund University Hospital, Sweden, and †The
Urophysiology Research Group, School of Surgical and Reproductive Sciences, The Medical School, The University, Newcastle upon Tyne, UK
Antimuscarinic drugs are generally thought to exert their therapeutic action on detrusor (seven papers). Variables relating to bladder overactivity by reducing the ability of the function during the filling phase (time of (idiopaths/not stated), reported no change in first desire to void, time to first unstable bladder contractility with antimuscarinic drugs. Thus the available data do not support establish whether there is any evidence to identified. Similarly, variables relating to the conclusion that antimuscarinic drugs at voiding were identified and compared (e.g. doses used in current clinical practice exert their therapeutic action by inhibiting detrusor (including two abstracts) were found that contractility, but they suggest effects on contained cystometric data for both filling variables associated with sensation.
and voiding phases and where the actions of significant effect on sensations of urge, time to first sensation to void, maximum bladder in detail. These articles were separated into capacity, decrease in voiding frequency and KEYWORDS
reduction in incontinence episodes. However, anticholinergic drugs, bladder overactivity, idiopathic overactive bladder (four papers) INTRODUCTION
relieve the symptoms. There is no doubt that the antimuscarinic drugs currently used in predominate. Although M2 receptors might clinical practice (oxybutynin, tolterodine, predominate in number over M3 receptors, it detrusor overactivity (DO) is defined as ‘a trospium, solifenacin and darifenacin) are is the M3 receptors that are mainly responsible effective in reducing the symptoms of OAB. for the normal micturition contraction [5]. involuntary detrusor contractions during the Also, there is no doubt that at high doses filling phase which may be spontaneous or antimuscarinics can reduce the amplitude of bladder urothelial cells and on structures in provoked’. The overactive bladder syndrome detrusor contraction. Indeed, patients given the suburothelium (interstitial cells, nerves) (OAB) is a symptom complex characterized an excess of antimuscarinic drugs retain urine [6]. Therefore antimuscarinics block, more or less selectively, muscarinic receptors not just on the detrusor muscle, where they decrease frequency and nocturia [1]. It is a common therapeutic effect of these drugs is to reduce condition affecting 17% of the populations of However, clinically, antimuscarinics act mainly Europe and the USA [2,3]. Most patients with during the storage phase, decreasing urgency OAB have urodynamically confirmed DO, and Our aim in this review is to analyse previously and increasing bladder capacity. During this the vast majority of patients with DO have reported data related to therapeutic doses of phase it is generally considered that there is antimuscarinics in current routine use on no activity in the parasympathetic nerves. bladder contractility and sensory variables.
Furthermore, antimuscarinics are usually The symptoms of DO/OAB have been generally competitive antagonists. This implies that considered to be due to abnormal bladder PRECLINICAL STUDIES
acetylcholine, as during micturition, the during the filling phase. On this assumption effects of the drugs should be decreased, contraction in humans is mainly mediated by otherwise the reduced ability of the detrusor to contract would eventually lead to urinary the contention that they will reduce the retention. The question is whether there are contractility of the detrusor muscle. The other effects of antimuscarinics that can myocytes. Although all muscarinic receptor contribute to their beneficial effects in the subtypes have been detected in the human 2 0 0 6 T H E A U T H O R SJ O U R N A L C O M P I L A T I O N 2 0 0 6 B J U I N T E R N A T I O N A L | 9 8 , 5 0 3 – 5 07 | doi:10.1111/j.1464-410X.2006.06258.x TABLE 1 Details of the papers reporting results in group I attracted considerable interest as a target for antimuscarinics. Yoshida et al. [7] found that there is a basal acetylcholine release in isolated human bladder tissue. This release origin and, at least partly, generated by the urothelium. Intravesical administration of muscarinic receptor agonists can generate DO, which can be inhibited by antimuscarinics [8] and it was suggested that such an effect suburothelium. Further supporting an effect of antimuscarinics on afferent nerves, Yokoyama et al. [9] found that low i.v. doses of tolterodine significantly increased bladder capacity in vehicle-treated rats with DO caused by cerebral infarction, but had TABLE 2 Details of the papers reporting results in group II no effects on bladder capacity in rats treated with resiniferatoxin. Intravesical administration of tolterodine significantly increased bladder capacity in control rats with cerebral infarction, but had no effect on bladder capacity in resiniferatoxin-treated rats. Yokoyama et al. therefore suggested that at low doses tolterodine has an inhibitory effect on C-fibre bladder afferent nerves, thereby improving bladder capacity during EVIDENCE FROM STUDIES ON PATIENTS
Articles containing cystometric data for patients treated with antimuscarinics, *G refers to a subclassification of patients with OAB determined by their volume and pressure of first OC, currently used in routine clinical practice, i.e. G2, high-volume (>250 mL)/high-pressure (>25 cmH O); G3, low-volume (<250 mL)/low-pressure were identified through a standard Medline (<25 cmH O); G4, low-volume (<250 mL)/high-pressure (>25 cmH O). NC, no change; inc, increased; dec, search. Generic and brand names were cross- decreased; Oxy, oxybutynin; Tol, Tolterodine. referenced with terms used to describe urodynamic assessments, in addition to filling/voiding variables. Few studies were identified, which is surprising given the prevalence of OAB and the global usage of subdivision in data would occur. In view of the two treatment groups [10], in all making four limitations in this approach, the data from filling all treatment arms commented upon an There are only 14 original articles (including significant or not, based upon P < 0.05, and increase in maximum cystometric capacity descriptive analysis used to compare results cystometric data for both filling and voiding phases in patients with OAB before and after (Pdetmaxfilling). The effects on compliance treatment. In these articles there is much ANALYSIS OF PUBLISHED DATA
were equivocal, with two arms showing no variation in the way cystometric variables are significant change and two a significant reported, the numbers of patients involved For the purpose of this analysis the published increase. In reported voiding variables, Pdetmax and methods of analysis. These factors make a was significantly decreased in two arms (both significant formal statistical analysis difficult. depending on the patient group described, i.e. In addition, the changing definition of an ‘neuropaths’, ‘idiopaths’ and mixed (or not significant change in maximum urinary flow ‘overactive contraction’ during cystometry, specifically stated), labelled groups I to III, (Qmax) and the effects on residual volume were from those restricted to >15 cmH2O to all clinically relevant involuntary rises in detrusor pressure (Pdet), makes a cumulative In group I (Table 1) data were reviewed from In group II (Table 2) data were reviewed from three articles [10–12], one of which contained three articles and one abstract [13–16]. One J O U R N A L C O M P I L A T I O N 2 0 0 6 B J U I N T E R N A T I O N A L S E N S O R Y A C T I O N S O F A N T I M U S C A R I N I C S TABLE 3 Details of the papers reporting results in group III IT, individually titrated; NC, no change; inc, increased. article, the only article to do so, subdivided The effects on variables associated with the suggested an increase in residual volume, and voiding phase were unequivocal, although in one there was no significant change in Pdet depending on the volume and magnitude of relatively few arms were available for analysis. at either urethral opening (UO) or closure the first overactive contraction (OC) [13]. There were no significant changes in either low-pressure, high-volume/high-pressure, In general there was a uniform trend between In group III (Table 3) data were reviewed from groups II and III, but the main exception to an six articles [17–22] and one abstract [23]. overall trend was the effect on reported Pdet and pressure of the first OC in relation Group III contained a combination of mixed in group I (neuropaths), with two arms from respectively. This subdivision was used to decrease in Pdet during both filling and assess two antimuscarinics, resulting in eight emptying. This might be a result of the few treatment arms. However, as two of these examining the effect of an antimuscarinic in patients involved or signify differences in the arms had too few patients, only six from this aetiologies of ‘idiopathic’ and ‘neuropathic’ article were available for analysis, with one containing data for an older medication, propantheline, was not analysed). In one article [21], antimuscarinic and behavioural In examining the data as a whole, a more In group II the effects of antimuscarinics on modification therapy was compared solely convincing view emerges as to the effects of variables associated with the storage phase with behavioural modification. Although the were not clear. First desire to void (FDV) was results for the effects of antimuscarinics were Variables associated with storage, e.g. FDV significantly increased in five treatment arms, not directly presented, they can be deduced and CCmax, are significantly greater in the vast with two reporting no significant change. This majority of articles, with variables associated is mirrored by the volume at first OC (VFOC), with voiding, e.g. PdetQmax and Qmax not being with six showing a significant increase and significantly changed. However, the effect on two no change. Interestingly, in group II, CCmax significantly increased both the VFOC and Pdetmax seems equivocal, with two articles was only significantly increased in three of CCmax, suggested by four and six articles, suggesting a decrease and one suggesting no the arms, and not significantly changed in respectively. In addition, the PFOC and the five, conflicting with data from group I. The Pdetmax-OC were not significantly changed, Pdetmax of the largest OC (Pdetmax-OC) again although only one article each described some conclusions to be formulated for most significant decrease and one no significant urodynamic variables, as either the results are change. However, in all groups reporting the There were no conflicting results in the consistent among articles, or in the case of pressure of the first OC (PFOC), there was no voiding variables. Three articles reported no some disparity, the vast majority suggest one significant change in Qmax or PdetQmax; six variable over another. In cases of equivocal 2 0 0 6 T H E A U T H O R SJ O U R N A L C O M P I L A T I O N 2 0 0 6 B J U I N T E R N A T I O N A L results, articles were divided between either ACKNOWLEDGEMENTS
Yokoyama O, Yusup A, Miwa Y, Oyama
similar changes or no change. There were no N, Aoki Y, Akino H. Effects of tolterodine
cases of opposing results between articles, i.e. We acknowledge the support of Novartis in facilitating discussions which led to the activity in rats. J Urol 2005; 174: 2032–6
10 Madersbacher H, Stöhrer M, Richter R,
DISCUSSION
Burgdörfer H, Hachen HJ, Mürtz G.
CONFLICT OF INTEREST
integral part of the treatment of DO/OAB. trial in the treatment of detrusor hyper- Being designed to reduce the strength of reflexia. Br J Urol 1995; 75: 452–6
OCs, they were confirmed to do so in higher 11 Goessl C, Sauter T, Michael T, Bergé B,
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