Pharmacotherapeutics Pharmacological Therapy for Urinary Incontinence Kyu Sung Lee, MD Young Suk Lee, MD Department of Urology, Sungkyunkwan University School of Medicine E mail : ksleedr@skku.edu ysuro.lee@samsung.com J Korean Med Assoc 2007; 50(11): 1025-1036 Abstract Urinary incontinence is an important lower urinary tract symptom that negatively affects the quality of life. Urgency incontinence (UI) is urine loss accompanied by urgency, which is the chief complaint of overactive bladder (OAB) syndrome. OAB is defined as urgency, with or without UI, usually with frequency and nocturia. In contrast, stress urinary incontinence (SUI) involves involuntary urine leakage caused by a sudden increase in abdominal pressure. Treatment for urinary incontinence depends on the type of incontinence, the severity, and the underlying causes. Treatment options fall into four broad categories: lifestyle intervention, bladder retraining and/or pelvic floor muscle training, pharmacotherapy, and surgery. Pharmacotherapy is often the first-line therapy for OAB/UI, either alone or as an adjunct to various nonpharmacological therapies. Effectiveness of anticholinergic drugs for OAB/UI has been assessed in various observational and randomized controlled trials. Despite their side effects, anticholinergics are the first line agents for UI. Tricyclic antidepressants have complex pharmacological actions such as anticholinergic, alpha adrenergic, antihistaminic, and local anesthetic properties. Recently approved anticholinergics, solifenacin and darifenacin, are selective M 3 antagonists that may have tolerable side effects. Transdermal oxybutynin may offer comparable efficacy with oral formulation but lower side effects. In the absence of an effective and well tolerated drug for SUI, pharmacological therapy for this condition has remained in the off label prescription of some products, particularly estrogens and adrenergic agonists. Duloxetine is the drug of choice specifically aimed at SUI. This article outlines the current state and future development in pharmacological therapy for urinary incontinence. Keywords : Urinary incontinence; Stress urinary incontinence; Urgency incontinence; Pharmacotherapy 1025
Lee KS Lee YS Table 1. The standardization of terminology in lower urinary tract function (1) Types of urinary incontinence Stress urinary incontinence Urgency incontinence Mixed incontinence Unconscious incontinence Continuous incontinence Overflow incontinence Extraurethral incontinence Nocturnal enuresis Postmicturition dribble Definitions Involuntary leakage of urine during increases in abdominal pressure in the absence of a detrusor contraction Involuntary leakage accompanied by or immediately preceded by urgency Involuntary leakage of urine associated with urgency and also with exertion, effort, sneezing, or coughing Involuntary leakage of urine that is unaccompanied by either urge or stress Complaint of a continuous leakage Not a symptom or condition but rather a term used to describe leakage of urine associated with urinary retention Involuntary leakage of urine through channels other than the urethra Complaint of loss of urine occurring during sleep Involuntary leakage of urine immediately after passing urine Table 2. Causes of overactive bladder Neurogenic Detrusor Overactivity Supraspinal neurologic lesions Stroke Parkinson's disease Hydrocephalus Brain tumor Traumatic brain injury Multiple sclerosis Suprasacral spinal lesions Spinal cord injury Spinal cord tumor Multiple sclerosis Myelodysplasia Transverse myelitis Diabetes mellitus Non neurogenic Detrusor Overactivity Bladder infection Bladder outlet obstruction Men prostatic and bladder neck obstruction, strictures Women pelvic organ prolapse, postsurgical, urethral, diverticulum, primary bladder neck obstruction, strictures Bladder tumor Bladder stones Foreign body Aging 1026
Urinary Incontinence Figure 1. Prevalence (%) of urinary incontinence by age in female. 1027
Lee KS Lee YS Figure 2. Initial management of urinary incontinence in men (3rd International Consultation on Incontinence, Monaco, 2004). 1028
Urinary Incontinence Figure 3. Initial management of urinary incontinence in women (3rd International Consultation on Incontinence, Monaco, 2004). 1029
Lee KS Lee YS Table 3. Condition specific treatments for incontinence Condition Detrusor overactivity Treatment Treat underlying condition (e.g., UTI, bladder stone, urethral obstruction) Behavioral modification/lifestyle lchanges Pelvic floor muscle therapy Oral pharmacologic agents* Antimuscarinics Musculotropic relaxants Tricyclic antidepressants Intravesical agents Oxybutynin Capsaicin Resiniferatoxin Botulinum toxin Neuromodulation Augmentation enterocystoplasty* Autoaugmentation* Denervation procedures Urinary diversion Low bladder compliance Oral pharmacologic agents* Antimuscarinics Musculotropic relaxants Tricyclic antidepressants Augmentation enterocystoplasty* Autoaugmentation* Denervation Procedures Sphincteric dysfunction Behavioral modification/lifestyle changes Pelvic floor muscle therapy Oral pharmacologic agents Adrenergic agonists Serotonin norepinephrine reuptake inhibitors Urethral bulking agents Surgery Midurethral sling Pubovaginal sling Urethral/colposuspension Artificial urinary sphincter * With or without intermittent self catheterization. These treatments must be considered investigational and are off label in most countries. 1030
Urinary Incontinence Table 4. Drugs used in the treatment of detrusor overactivity Assessments according to the Oxford system (modified) Level of evidence Antimuscarinic drug Tolterodine 1 A Trospium 1 A Solifenacin 1 A Darifenacin 1 A Propantheline 2 B Atropine, hyoscyamine 3 C Drug with mixed action Oxybutinin 1 A Propiverin 1 A Dicyclomine 3 C Flavoxate 2 D Antidepressant Imipramine 3 C Alpha AR antagonists Alfuzosin 3 C Doxazosin 3 C Prazosin 3 C Terazosin 3 C Tamsulosin 3 C Beta AR antagonist Terbutaline 3 C Salbutamol 3 C COX inhibitors Indomethacin 2 C Flurbiprofen 2 C Other drugs Baclofen* 3 C Capsaicin** 2 C Resiniferatoxin** 2 C Botulinum toxin*** 2 B Estrogen 2 C Desmopressin**** 1 A Grade of recommendation * intrathecal, ** intravesical, *** bladder wall, **** nocturia 1031
Lee KS Lee YS Urothelium derived ATP Activation of suburothelial afferent nerves Antimuscarinics Release of Ach from nerves and urothelium(?) Enhancement of myogenic activity Increases afferent nerve activity Initiation of micturition Figure 4. Bladder Effects of Antimuscarinics. By inhibiting the effects of acetylcholine, generated from non nervous sources (urothelium) or leaking from cholinergic nerves during the filling phase, antimuscarinics may inhibit detrusor overactivity and urgency. Filling induced stretch of detrusor cells Activation of intramural afferent nerves 1032
Urinary Incontinence Table 5. Drugs used in the treatment of stress urinary incontinence Assessments according to the Oxford system (modified) Drug Level of evidence Duloxetine 1 A Imipramine 3 D Clenbuterol Methoxamine 2 D Midodrine 2 C Ephedrine 3 D Norephedrine 3 D (phenylpropanolamine) Estrogen 2 D Grade of recommendation 1033
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Urinary Incontinence 11. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, Van Kerrebroeck P, Victor A, Wein A.The standardisation of terminology in lower urinary tract function: Report from the standardisation sub committee of the International Continence Society. Urology 2003; 61: 37-39. 12. Andersson KE, Appell R, Cardozo L, Chapple C, Drutz HP, Finkbeiner AE, Haab F, Vela Navarrete R. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence, 3rd International Consultation on Incontinence. France: Health Publication Ltd, Editions 21, 2005: 811-854. 13. Nitti VW, Raz S. Obstruction following anti incontinence procedures: Diagnosis and treatment with transvaginal urethrolysis. J Urol 1994; 152: 93-98. 14. Lee KS, Choo MS, Kim DY, Kim JC, Kim HJ, Min KS, Lee JB, Jeong HJ, Lee T, Park WH. Combination treatment with propiverine hydrochloride plus doxazosin controlled release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign prostatic obstruction: a prospective, randomized, controlled multicenter study. J Urol. 2005 Oct; 174(4 Pt 1): 1334-1338. 15. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose anesthesized female cat. J Pharmacol Exp Ther 1995; 274: 1014-1024. 1035
Lee KS Lee YS Peer Reviewer Commentary 1036