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May 2016

OVERACTIVE BLADDER. May 2016. OAB Syndrome: Definition. International Continence Society: Symptom syndrome: lower urinary tract (LUT) dysfunction Urgency, with or without urge incontinence, usually with frequency & nocturia No proven infection / other obvious pathology. 2.

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May 2016

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  1. OVERACTIVE BLADDER May 2016

  2. OAB Syndrome: Definition International Continence Society: • Symptom syndrome: lower urinary tract (LUT) dysfunction • Urgency, with or without urge incontinence, usually with frequency & nocturia • No proven infection / other obvious pathology 2 Abrams P, et al, NeurourolUrodyn, 2002; 21: 167-178 / Wein AJ, et al, Urology, 2002; 60 (suppl 5A); 7-12

  3. Bladder: Anatomy Ureter Serosa Detrusor Ureteric opening Mucosa Trigone Neck Urethra

  4. Physiology of micturition IS: internal sphincter ES: external sphincter

  5. Symptoms of urinary incontinence…  Sudden urge to urinate that's difficult to control  Awaken 2 or more times in night to urinate (nocturia)  Urinate frequently, usually 8 or more times in 24 hrs  Involuntary loss of urine Significantly impacts QoL 1. Minassian VA, et al. Obstet Gynecol. 2008 Feb;111(2 Pt 1):324-31/ OAB symptom ref: Mayo clinic

  6. z • Frequency • Daytime • Nighttime • Urgency Spectrum of OAB Overactive Bladder Overactive Bladder Mixed (UUI +SUI) SUI UUI 6 Wein AJ, et al, Urol, 2006; 175 (3 PT 2): S5-S10

  7. Urinary incontinence Urge Urinary Incontinence Urine loss accompanied by urgency resulting from abdominal bladder contractions Sudden  in intra-abdominal pressure Stress Urinary Incontinence Uninhibited detrusor contractions Urine loss resulting from sudden increase in intra-abdominal pressure Urethral pressure 7

  8. OAB: Treatment Goals • Eliminate or  in urinary urge incontinence •  urgency & frequency episodes • Ensure treatment compliance: long-term benefits • Meet patients treatment expectations 8 Hegde SS. Br J Pharmacol. 2006;147 (suppl 2):S80-S87, Staskin DR, et al, Am J Med.2006;119 (suppl 3A):9S-15S, Marschall-Kehrel D, et al. Urology, 2006, 68 (suppl 2A), Brubaker L, et al Urology.2006;68(suppl 2A) 3-8

  9. OAB: Management • Behavioral therapies • Pharmacology therapy • Combined pharmacologic & behavioral therapy provides improved outcomes Fluid strategies Timed voiding 9 Mattiasson A. Urology. 2000;55(suppl 5a):12-13, Mattiasson A. Neuro Urodyn. 2001;20:403-404, Burgio et al. JAGS. 2000;48:370-374.

  10. LAUREN HERSH . Am Fam Physician. 2013;87(9):634-640.

  11. Initial management of urinary incontinence in women History/ Symptom assessment Incontinence on physical activity Incontinence with mixed symptoms Incontinence with urgency/ frequency Clinical Assessment Evaluation Presumed diagnosis SUI due to sphincteric incompetence Mixed incontinence UUI due to detrusoroveractivity Lifestyle interventions Pelvic floor muscle training Bladder retraining Treatment Duloxetine Other Physical therapies Devices Antimuscarinics Failure Specialized Management Chapple C. EurUrol Suppl. 2006; 5: 837-841.

  12. Behavioral treatments for UI

  13. Fluid intake EAU Guidelines 2015: Urinary Incontinence.

  14. EAU Guidelines 2015: Urinary Incontinence.

  15. Pelvic Floor Muscle Exercises Stress UI management includes PFMEs, more commonly known as Kegel exercises PFMEs facilitate continence by increasing strength, endurance, and contractibility of the pelvic muscles, which support the bladder neck, contribute to optimal anatomical positioning of the urethra, and facilitate neuromuscular control necessary for continence Women Teach PFMEs during the pelvic examination Instruct the patient to squeeze (contract) her vaginal muscles around the examiner’s gloved hand Men During the rectal examination, male patients are instructed to squeeze the rectal muscles

  16. “I’ve reached that age where I’ve given up on Mind Over Matter and am concentrating on Mind Over Bladder.”

  17. OAB: Pharmacotherapy Drug therapy: becoming increasingly important & currently mainstay in treatment for OAB Antimuscarinic agents: Gold standard 23 Mattiasson A. Urology. 2000;55(suppl 5a):12-13, Mattiasson A. Neuro Urodyn. 2001;20:403-404, Burgio et al. JAGS. 2000;48:370-374.

  18. Anticholinergic agents have been 1st line treatment for OAB for many years, efficacious pharmacologic management of this condition has been compromised by concerns regarding tolerability - Hesch K. Proc (BaylUniv Med Cent) 2007; 20(3): 307–314.

  19. Muscarinic Receptors: Functions 25

  20. Hesch K. Proc (BaylUniv Med Cent) 2007; 20(3): 307–314.

  21. Hesch K. Proc (BaylUniv Med Cent) 2007; 20(3): 307–314.

  22. Lam S, et al. Clinical Interventions in Aging 2007; 2(3): 337–345.

  23. Lam S, et al. Clinical Interventions in Aging 2007; 2(3): 337–345.

  24. Lam S, et al. Clinical Interventions in Aging 2007; 2(3): 337–345.

  25. Incidence of AEs associated with anticholinergic agents Hesch K. Proc (BaylUniv Med Cent) 2007; 20(3): 307–314.

  26. Ideal muscarinic receptor antagonist • Efficacious: • Inhibits involuntary bladder contractions • Does not adversely affect voluntary detrusor activity • Organ selective: • Preferentially affects bladder over other organs • Minimal side effects & improves tolerability • Tolerable: • Improves compliance 34

  27. A drug with selectivity for muscarinic M3 receptor, subtype primarily responsible for mediating human detrusor contraction might be effective in treating OAB symptoms & with narrower side-effect profile

  28. Darifenacin • Darifenacin hydrobromide: Novel highly selective M3 receptor antagonist • 59-fold higher affinity for M3 receptors Approved: US FDA 2004 • M1/M2 receptor sparing profile • Low incidence: Dry mouth & constipation • No impairment of cardiac function • No significant effect on cognitive function • No CNS safety concerns • AE withdrawal rates similar to placebo 36 Chapple CR. Expert Opin Investig Drugs. 2004 Nov;13(11):1493-500.

  29. Darifenacin targets M3receptor in vitro M3 M1 over 9-fold greater M3 receptors in bladder are primarily responsible for detrusor contraction2* M3 M2 over 59-fold greater M3 receptors involved in GI smooth muscle contraction, saliva production & iris sphincter function2+ *Dry mouth, constipation & abnormal vision may be mediated through effects on M3 receptors +Muscarinic M3 receptors are also found in other tissues but their role at these locations is as yet unclear 1. Napier C et al. Neurourol Urodyn 2002; 21(4): A445/ 2. Abrams P et al. Br J Pharmacol 2006; 148: 565-78.

  30. Darifenacin: Effect on different muscarinic receptors 38

  31. Darifenacin: MOA Darifenacin blocks muscarinic receptors in bladder & Reduces unnecessary bladder voiding 39

  32. Darifenacin: Dosage and Administration • For oral use • Adults (≥ 18 years): • Starting dose 7.5 mg daily, after 2 weeks of therapy, should be reassessed • For greater symptom relief, dose may be increased to 15 mg daily • Darifenacin should be taken OD • Elderly patients (≥ 65 years): • Starting dose 7.5 mg daily, after 2 weeks of therapy, to be reassessed • Patients who have acceptable tolerability profile but require greater symptom relief, dose may be increased to 15 mg daily 40

  33. Ref: François Haab, et al Darifenacin 7.5 mg OD x2 weeks then to titrate to 15 mg as desired Total 716 patients mean age - 57 years 85% - women 41 Haab F, et al. BJU international. 2006; 98: 1025-1032.

  34. Long-term (2 year): Efficacy parameter Up to 84% reduction in incontinence episodes sustained Haab F, et al. BJU international. 2006; 98: 1025-1032.

  35. Patients, % Treatment duration, months Long-term (2 year): Safety 43 Haab F, et al. BJU international. 2006; 98: 1025-1032.

  36. Summary of the long term study (2 years) • Up to 84% reduction in incontinence episodes sustained • Favourable safety & tolerability • Low discontinuation rates Darifenacin (7.5 & 15 mg OD): Effective in treatment of patients with OAB Haab F, et al. BJU international. 2006; 98: 1025-1032.

  37. 84.1% women Assessed for eligibility n = 813 Excluded; n = 316 Enrolment Open-label, non-randomised: Rx with Darifenacin 7.5/15 mg & stratified by previous treatment; n = 500 Previous Oxybutynin ER: n = 218 Previous Tolterodine ER: n = 279 Completed; n = 187 (85.8%) Completed; n = 250 (89.6%) Zinner N, et al. Int J Clin Pract. 2008 Nov;62(11):1664-74. .

  38. Increasing degree of improvement in PPBC scores *PPBC score: Patient Perception of Bladder Condition Zinner N, et al. Int J Clin Pract. 2008 Nov;62(11):1664-74. .

  39. Improvement in daily micturition frequency Zinner N, et al. Int J Clin Pract. 2008 Nov;62(11):1664-74. .

  40. Improvement in daily urgency episodes Zinner N, et al. Int J Clin Pract. 2008 Nov;62(11):1664-74. .

  41. Improvement: Weekly urge urinary incontinence (UUI) episodes Zinner N, et al. Int J Clin Pract. 2008 Nov;62(11):1664-74.

  42. Conclusion In patients who were dissatisfied with previous extended release antimuscarinic treatment (oxybutynin / tolterodine) • PPBC score & OAB symptoms were significantly improved • Satisfaction was high during treatment with darifenacin (7.5 ⁄ 15 mg) Zinner N, et al. Int J Clin Pract. 2008 Nov;62(11):1664-74.

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