Women suffer in silence

Transcription

1 Women suffer in silence Stress urinary incontinence is the involuntary loss of urine resulting from increased intra-abdominal pressure. In people who suffer with this condition, forms of exertion such as laughing, sneezing, coughing or lifting have the unpleasant consequence of uncontrolled loss of urine. This loss of an important bodily control function leads to fear of unpleasant accidents, loss of selfconfidence and ultimately to a restricted ability to go about activities of daily livings. 98% of stress urinary incontinence sufferers are women. Affected women often suffer in silence. To date there are no globally approved drugs for use in this condition.

2 Healthy people pass ml of urine each day in a controlled and voluntary fashion. The average amount of urine passed with each emptying of the bladder is about 300 ml. In people with urinary incontinence, by contrast, urine is passed unintentionally as a result of functional disturbances of the various systems that control normal, intentional emptying of the bladder, namely: the muscle of the bladder wall, the closure system of the urethra and/or the central nervous system. The uncontrollable loss of urine and the resulting hygienic and social problems can greatly limit sufferers quality of life. Experts estimate that in the seven biggest pharmaceutical markets million people suffer from some form of urinary incontinence [1]. There are various forms of urinary incontinence: stress urinary incontinence (SUI), urge urinary incontinence (UUI), overactive bladder (OAB): urgency and frequency with or without UUI, and mixed urinary incontinence (MUI): the concomitant occurrence of SUI and UUI. SUI accounts for 60 % of cases of urinary incontinence. In this condition, urine is passed unintentionally as a result of increased intra-abdominal pressure resulting from physical stress of laughing, coughing, sneezing, vigorous movement or other forms of exertion. UUI accounts for % of cases of urinary incontinence and occurs with greater prevalence in elderly people. Urinary urgency can be so powerful that the bladder contracts spontaneously and discharges urine involuntarily, i. e. urge incontinence. 1 See p

3 Control of bladder How it works... function The lower urinary tract (Fig. 1) consists of the urinary bladder and the urethra. The bladder is a hollow muscular organ that is responsible for the storage and elimination of urine. In addition to providing an outlet for the passage of urine, the urethra and associated internal and external sphincter muscles play an important role in the maintenance of urinary continence. Normal bladder function is controlled by a complex set of interactions between the voluntary and involuntary nervous systems. During bladder filling, for example, storage of urine is achieved by increased tension in the bladder neck and the urethral smooth muscle via activation of the sympathetic and somatic nervous systems, in the absence of parasympathetic drive to the bladder and urethra. When urine volume reaches a threshold level, distension of the bladder activates reflexes leading to a sensation of bladder fullness. Elimination of urine results from parasympathetic drive to the bladder and urethra with simultaneous inhibition of sympathetic and somatic drive to internal and external sphincter muscles. Several pharmacological mediators and their respective receptors have been identified in both the local and systemic ureter uterus musculature of the urinary bladder urinary bladder internal urethral sphincler muscle external urethral sphincler muscle vagina urethra FIGURE 1: Lateral view of a female pelvis showing the lower urinary tract. Therapy: Alpha 1 -adrenoceptor agonist for stress urinary incontinence 67

4 control of bladder function. For example, acetylcholine causes a considerable bladder contraction through its interaction with specific muscarinic receptors on bladder muscle cells. Alphaand beta-adrenergic receptors 2 have been implicated in the local sympathetic neural control of bladder and urethra Bladder neck and urethral smooth muscle tone is stimulated by 1A/1L -adrenergic receptors located on the muscle cells (shown as blue dots in Fig. 2). Activation of these a-adrenoceptors increases muscle tone....and what happens when it doesn t work in stress urinary incontinence In SUI, involuntary loss of urine occurs when increased pressure in the bladder resulting from increased intra-abdominal pressure overcomes the resistance of the closure mechanisms of the bladder neck and urethra. The bladder neck and the urethra are unable to counteract the increase in bladder pressure, resulting in the leakage of urine in the absence of a bladder contraction (Fig. 2, right). 48 million people suffer significantly from SUI, whether alone or in combination with UUI. 98 % of sufferers are women, two thirds of whom are less than 65 years old. The many contributing factors include: childbirth, hormonal changes resulting from hysterectomy or menopause and general weakness of the pelvic floor muscles. Physical changes resulting from pregnancy, childbirth and other forms of mechanical trauma can impair the closure mechanism of the bladder and weaken the pelvic floor muscles that support the bladder. Such damage can also be caused by the hormonal changes associated with the menopause and can occur even in young women who have not yet borne children. Everyday activities such as coughing, laughing, lifting heavy loads and other forms of exertion that increase intra-abdominal pressure can cause involuntary leakage of urine. In particularly severe cases, leakage of urine can be triggered even by standing or walking. 2 Adrenoceptors, also known as adrenergic receptors, are membrane-bound receptors. They are activated by substances known as agonists. Their natural agonists are the catecholamines adrenaline and noradrenaline (see p. 61). 68

5 normal bladder stress incontinent bladder intra-abdominal pressure prolapse pelvic floor muscles leak point pressure damaged pelvic floor muscles external sphincter less efficient sphincter FIGURE 2: Schematic representation of the situation in a normal urinary bladder (left) as compared to that in stress urinary incontinence. The blue dots indicate the location of 1A/1L -adrenoceptors on the surface of muscle cells. What can be done about Though extremely widespread, SUI often remains leakage of urine? undiagnosed. Historically, women have suffered in silence and been reluctant to discuss the problem with their friends, family or physicians due to the social stigma, embarrassment and unsatisfactory treatment options. Now, however, the growing number of drugs available for overactive bladder (OAB) and the advertising of such drugs has fuelled awareness of urinary incontinence in general and has motivated more women to ask their physicians about the options available for the treatment of this condition. Current approaches to the treatment of urinary incontinence include: use of absorbent materials (e.g. pads, towels), exercises to strengthen the pelvic floor muscles, nonspecific treatments such as hormone replacement therapy and surgery. At present, surgery is the most effective, but also the most invasive and expensive, form of treatment. An oral medicine that Therapy: Alpha 1 -adrenoceptor agonist for stress urinary incontinence 69

6 could reduce leakage episodes and restore a measure of control over urine loss would significantly improve the quality of life of patients with SUI. One strategy for treating SUI is to increase urethral and bladder neck smooth muscle tone with drugs. As stated above, such smooth muscle tone is brought about to a large extent by stimulation of -adrenoceptors located on the urethral muscle cells. These receptors are therefore a potential target for drug therapy of SUI [3]. Specific treatment by means of specific agonists Given also that to date only one adrenoceptor subtype, namely the 1A/1L -adrenoceptor, has been found in the human bladder neck and urethra [2], the potential for specific drug therapy is promising. On this basis the search should therefore be for an agonist that specifically activates only this adrenoceptor subtype in the urinary tract. Such a drug would increase muscle tone and help prevent involuntary discharge of urine. In preclinical studies, R450, an active agent developed by Roche for this purpose, was found to exert a significant effect on bladder outlet smooth muscle tone with minimal cardiovascular effects 3.In a phase IIa proof-of-concept study, administration of R450 to woman patients significantly reduced the number of incontinence episodes per week and was generally well tolerated. In another study, the compound has also been shown to produce no significant effects on blood pressure or heart rate in women subjects with hypertension. A further phase II study to determine the therapeutic window and thereby maximise the efficacy and safety of long-term therapy is underway. 3 Adrenoreceptors are also found on the vasular smooth musle cells. (see p. 61). 70

7 References 1. Abrams, P., Lowry, S.K., Wein, A. J. et al.: Consensus. Assessment and treatment of urinary incontinence. The Lancet. 355: , Dunn, C.: Outlook for urinary incontinence therapeutics, perspective to Spectrum Therapy Markets and Emerging Technologies. 19/11/ Anderson, K. E.: Drug therapy for urinary incontinence. Bailleres Best Pract Res Clin Obstet Gynaecol 14 (2): , 2000 Therapy: Alpha 1 -adrenoceptor agonist for stress urinary incontinence 71