Committee 8 Pharmacological Treatment of Urinary Incontinence Chairman KARL-ERIK ANDERSSON (USA) Co-Chairman C. R CHAPPLE (U.K) Members L. CARDOZO (U.K), F. C RUZ (Portugal), H. HASHIM (U.K), M.C. MICHEL (The Netherlands), C. TANNENBAUM (Canada), A.J. WEIN (USA) 631 CONTENTS A. INTRODUCTION X. OTHER DRUGS I. PUBLICATION SEARCHES XI. COMBINATIONS II. CENTRAL NERVOUS CONTROL XII. FUTURE POSSIBILITIES III.PERIPHERALNERVOUS CONTROL C.DRUGS USED FOR IV. PATHOGENESIS OF BLADDER TREATMENT OF STRESS CONTROL DISORDERS URINARY INCONTINENCE V. BLADDER CONTRACTION I. α-ADRENCEPTOR AGONISTS VI. MUSCARINIC RECEPTORS II. β-ADRENOCEPTOR ANTAGONISTS B. DRUGS USED FOR TREATMENT OF OVERACTIVE III. β-ADRENOCEPTOR AGONISTS BLADDER SYMPTOMS/ DETRUSOR OVERACTIVITY IV. SEROTONIN-NORADRENALINE UPTAKE INHIBITORS I. ANTIMUSCARINIC (ANTICHOLINERGIC) DRUGS D.DRUGS USED FOR II. DRUGS ACTING ON MEMBRANE TREATMENT OF CHANNELS OVERFLOW INCONTINENCE III. DRUGS WITH “MIXED” ACTION E. HORMONALTREATMENT OF URINARY INCONTINENCE IV. α-ADRENOCEPTOR (AR) ANTAGONISTS I. ESTROGENS V. β-ADRENOCEPTOR AGONISTS II. OTHER STEROID HORMONE VI. PHOSPHODIESTERASE (PDE) RECEPTOR LIGANDS INHIBITORS III. DESMOPRESSIN VII. ANTIDEPRESSANTS VIII. CYCLOOXYGENASE (COX) INHIBITORS F. CONSIDERATIONS IN THE ELDERLY IX. TOXINS REFERENCES 632 Pharmacological Treatment of Urinary Incontinence KARL-ERIK ANDERSSON C. R CHAPPLE, L. CARDOZO, F. CRUZ, H. HASHIM, M.C. MICHEL, C. TANNENBAUM, A.J. WEIN Table 1. ICI assessments 2008: Oxford guidelines (modified) A. INTRODUCTION Levels of evidence Level 1: Systematic reviews, meta-analyses, good The function of the lower urinary tract (LUT) is to store quality randomized controlled clinical trials and periodically release urine, and is dependent on (RCTs) the activity of smooth and striated muscles in the Level 2: RCTs , good quality prospective cohort bladder, urethra, and pelvic floor. The bladder and studies the urethra constitute a functional unit, which is controlled by a complex interplay between the central Level 3: Case-control studies, case series and peripheral nervous systems and local regulatory Level 4: Expert opinion factors [Andersson, 1993; de Groat and Yoshimura, 2001; Andersson and Wein, 2004]. Malfunction at Grades of recommendation various levels may result in bladder control disorders, Grade A: Based on level 1 evidence (highly which roughly can be classified as disturbances of recommended) filling/storage or disturbances of voiding/emptying. Failure to store urine may lead to various forms of Grade B: Consistent level 2 or 3 evidence incontinence (mainly urgency and stress incontinence), (recommended) and failure to empty can lead to urinary retention, Grade C: Level 4 studies or ”majority evidence” which may result in overflow incontinence. A disturbed (optional) filling/storage function can, at least theoretically, be improved by agents decreasing detrusor activity, Grade D: Evidence inconsistent/inconclusive (no recommendation possible) or the evidence increasing bladder capacity, and/or increasing outlet indicates that the drug should not be resistance [Wein, 2007]. recommended Many drugs have been tried, but the results are often disappointing, partly due to poor treatment efficacy and/or side effects. The development of pharmacologic treatment of the different forms of urinary incontinence has been slow, but several promising targets and I. PUBLICATION SEARCHES drug principles have been identified [Andersson et al., 2002; 2005; Andersson, 2007; Colli et al., 2007]. The review undertook a comprehensive search of all major literature databases and the abstract books In this report, we update the recommendations from from several major conferences: American Urological the 2004 International Consensus meeting [Andersson Association, ICS, European Association of Urology, et al., 2005]. The most relevant information obtained International Urogynaecological Association, since the last meeting is reviewed and summarised. International Consultation of Incontinence and Societe Agents specifically used for treatment of urinary tract Internationale d’Urologie. There were no restrictions infections and interstitial cystitis, have not been on the inclusion of publications by language; included. Our clinical drug recommendations are publications in languages other than English were based on evaluations made using a modification of the translated into English. Oxford system (Table 1). The terminology used is that recommended by the International Continence Society (ICS) [Abrams et al., 2002]. 633 activation of parasympathetic neurones located in the II. CENTRAL NERVOUS CONTROL sacral parasympathetic nucleus (SPN) in the spinal cord at the level of S2-S4 [de Groat et al., 1993]. The In the adult individual, the normal micturition reflex is postganglionic neurones in the pelvic nerve mediate mediated by a spinobulbospinal pathway, which the excitatory input to the human detrusor smooth passes through relay centers in the brain (Figure 1). muscle by releasing acetylcholine (ACh) acting on In infants, the central pathways seem to be organized muscarinic receptors. However, an atropine-resistant as on-off switching circuits, but after the age of four component has been demonstrated, particularly in to six years, voiding is initiated voluntarily by the functionally and morphologically altered human bladder cerebral cortex [de Groat et al., 1999]. Studies in tissue (see below). The pelvic nerve also conveys humans and animals have identified areas in the parasympathetic fibres to the outflow region and the brainstem and diencephalon that are specifically urethra. These fibres exert an inhibitory effect and implicated in micturition control, including Barrington’s thereby relax the outflow region. This is mediated nucleus or the pontine micturition center (PMC) in partly by release of nitric oxide [Andersson and the dorsomedial pontine tegmentum [Griffiths, 2004., Persson, 1993], although other transmitters might be Fowler et al., 2008]. These structures directly excite involved [Bridgewater and Brading, 1993; Hashimoto bladder motoneurons and indirectly inhibit urethral et al., 1993; Werkström et al., 1995]. sphincter motoneurons via inhibitory interneurons in the medial sacral cord. The periaqueductal grey (PAG) Most of the sympathetic innervation of the bladder receives bladder filling information, and the pre-optic and urethra originates from the intermediolateral nuclei area of the hypothalamus is probably involved in the in the thoraco-lumbar region (T10-L2) of the spinal initiation of micturition. According to PET-scan and cord. The axons travel either through the inferior functional imaging studies in humans, these mesenteric ganglia and the hypogastric nerve, or pass supraspinal regions are active during micturition through the paravertebral chain and enter the pelvic [Griffiths, 2004; Blok et al., 1998; Nour et al., 2000; nerve. Thus, sympathetic signals are conveyed in Athwal et al., 2001; Griffiths et al., 2007; Hruz et al., both the hypogastric and pelvic nerves [Lincoln and 2008; Mehnert et al., 2008; Tadic et al., 2008]. Burnstock, 1993]. The predominant effects of the sympathetic innervation III. PERIPHERALNERVOUS CONTROL of the lower urinary tract are inhibition of the parasympathetic pathways at spinal and ganglion Bladder emptying and urine storage involve a complex levels (demonstrated in animals), and mediation of pattern of efferent and afferent signalling in contraction of the bladder base and the urethra (shown parasympathetic, sympathetic, somatic, and sensory in animals and man, see Andersson, 1993). However, nerves (Figures 2-4). These nerves are parts of reflex the adrenergic innervation of the bladder body is pathways, which either keep the bladder in a relaxed believed to inactivate the contractile mechanisms in state, enabling urine storage at low intravesical the detrusor directly. Noradrenaline (norepinephrine) pressure, or which initiate micturition by relaxing the is released in response to electrical stimulation of outflow region and contracting the bladder smooth detrusor tissues in vitro, and the normal response of muscle. Contraction of the detrusor smooth muscle detrusor tissues to released noradrenaline is relaxation and relaxation of the outflow region result from [Andersson, 1993]. Figure 1 : Components of the mic- turition reflex. 634 Figure 2 : Activity in the micturition reflex during storage. The pontine micturition center is inhibited by impulses from the prefrontal cortex, afferent impulses unable to initiate micturition. Activities in the hypo- gastric and pudendal nerves keep the bladder relaxed and the outflow region contracted. Figure 3 : Activity in the micturition reflex during voluntary voiding. The inhibitory impulses from the prefrontal cortex pontine micturition center are removed and afferent impulses are able to initiate micturition. Activities in the hypogastric and pudendal nerves are inhibited, the outflow region is relaxed, and the bladder is contracted by the activity in the pelvic nerve. Figure 4 : Detrusor overactivity. Despite the inhibitory impulses from the prefrontal to the cortex pontine micturition center the enhanced (?) afferent impulses are able to initiate micturition. 635 The somatic innervation of the urethral rhabdosphincter Storage problems can occur as a result of weakness and of some perineal muscles (for example or anatomical defects in the urethral outlet, causing compressor urethrae and urethrovaginal sphincter), stress urinary incontinence. Failure to