Final slide deck for dr iglesia


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  • Although OAB has been traditionally seen as a disease of the elderly, in reality the prevalence of OAB in younger women is also significant. OAB is a common condition even among younger women, affecting 10% of those younger than 40 years of age and 11% of those 40-49 years of age. In the EPIC study, OAB affected nearly 13% of women overall. References: Milsom I, Irwin DE. A cross-sectional, population-based, multinational study of the prevalence of overactive bladder and lower urinary tract symptoms: results from the EPIC study. Eur Urol Suppl. 2007;6:4-9. Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006:50:1306-1315.
  • Obstet Gynecol. 2008;111(2 Pt 1):324-331. Urinary incontinence in women: variation in prevalence estimates and risk factors. Minassian VA , Stewart WF , Wood GC .
  • Obstet Gynecol. 2008 Feb;111(2 Pt 1):324-31. Urinary incontinence in women: variation in prevalence estimates and risk factors. Minassian VA , Stewart WF , Wood GC .
  • OAB prevalence ranges from 15 million - 33 million people in the US Urinary incontinence (UI) affects approximately 13 million Americans In women urge incontinence (UI) and OAB are 2 of the 10 most chronic conditions OAB and UI affect a higher percentage of people of all age groups than does HTN, depression or diabetes. Of the 33.3 million adults with overactive bladder in the US, the National Overactive BLadder Evaluation (NOBLE) Program found that overactive bladder without incontinence was more prevalent in men, whereas overactive bladder with incontinence was more prevalent in women Thirty-seven percent of people with overactive bladder have overactive bladder with incontinence; the remaining 63% have overactive bladder without incontinence In a study conducted by Stewart et al determined that prevalence of OAB in men at 16% Men have more frequency than UI Need to rule out obstruction in men (BPH) Cartwright, R., Renganathan, A., and Cardozo, L. ( 2008) Current Management of overactive bladder. Current Opinions in Obstetrics and Gynecology. 20: 489-495 Newman D., and Wein A. (2009) Managing and Treating Urinary Incontinence Second Edition. Health Profession Press, Inc. Baltimore, MD Stuart, W., Van Rooyen, J., Cundiff, G., Abrams, P., Herzog, A., Corey, R., Hunt, T and Wein, A. (2003) Prevalence and burden of Overactive bladder in the United States. World J Urol 20: 327-336.
  • The pelvic nerve (parasympathetic) originates from the sacral spinal cord; it stimulates the bladder using acetylcholine and relaxes the urethra employing nitric oxide. The M 3 receptor subtype is currently seen as the receptor responsible for contraction of the detrusor muscle.  -adrenergic receptors also exist in the bladder; stimulation of these receptors results in direct relaxation of the detrusor smooth muscle. It appears that the action of the  3 receptor is responsible for detrusor muscle relaxation. This does not appear to be true for  1 or  2 selective antagonists. The hypogastric nerve (sympathetic) originates from the lumbar spinal cord and uses norepinephrine to contract the urethra. Somatic control via the pudendal nerve originates from the sacral spinal cord causing contraction of the striated urethral sphincter. Activity is mediated by acetylcholine. Van Arsdalen K, Wein AJ. Physiology of Micturition and Continence. In: Krane RJ, Siroky MD, eds. Clinical Neurourology. 2nd ed. Boston: Little Brown & Co; 1991:25-82.
  • How does serotonin affect this? Decreases sensory throughput. Increases sphincter tone.
  • History and medication review Quality-of-life assessment Physical exam Functional assessment (eg, impaired mobility) Cognitive assessment Pelvic exam (estrogen status, prolapse) Digital rectal exam Diagnostic tests Urinalysis, urine culture Residual urine after voiding (catheterization or ultrasound)
  • Nocturic frequency is related to severity of obstructive sleep apnea, improves with continuous positive airways treatment. Fitzgerald MP , Mulligan M, Parthasarathy S. Am J Obstet Gynecol. 2006 May;194(5):1399-403.
  • Medication Alpha-adrenergic receptor agonists Tricyclic Antidepressants Psychotropics(sedatives, hypnotics) Cholinesterase inhibitors Narcotic analgesics, opioids Calcium Channel blockers Diuretics Methylxanthines NSAIDS Effect on bladder Contraction of the bladder neck and proximal urethra sooth muscle leading to increased urethral resistance, causing post void dribbling, straining, and hesitancy in urine flow. Anticholinergic effect and alpha-adrenergic receptor antagonist effect causing post void dribbling, straining, and hesitancy in urine flow. May decrease afferent input: some may decrease bladder contractility, leading to urinary retention. Can accumulate causing confusion and result in functional incontinence. Increase bladder contractility and may cause OAB symptoms. Decrease bladder contractility, decrease afferent input; common side effect is constipation Impair bladder contractility, causing urinary retention. Cause constipation Rapid-acting or loop diuretics overwhelm the bladder with rapidly produced urine, resulting in frequency and urgency for up to 6 hours. Polyuria, bladder irritant Can cause edema, resulting in nocturia.
  • Patient education : fundamental basis for behavioral intervention. Patient counseling : bladder diary resourceful tool for initial evaluation and patient counseling Weiss, B., (1998). Diagnostic evaluation of urinary incontinence in geriatric patients, Journal of American Academy of Family Physicians. 44, 579- 586. Wyman, J., Burgio, K, Newman, D., (2009) Practical aspects of lifestyle modifications and behavioural interventions in the treatment of overactive bladder and urgency incontinence, The International Journal of Clinical Practice, 63(8) 1177-1191. Urology. 2000 May;55(5A Suppl):3-6; discussion 14-6. Behavioral therapy for overactive bladder. Payne CK . Clin Geriatr Med. 2004 Aug;20(3):499-509, vii. Urinary incontinence: behavioral modification therapy in older adult. Khan IJ , Tariq SH . Bladder Retraining Bladder retraining helps the bladder to hold urine for longer periods of time. The individual is instructed to empty the bladder at scheduled times during the day, and then to gradually extend the time between bathroom trips.   Kegel Exercises For overactive bladder, a doctor may recommend Kegel exercises to strengthen the muscles below the bladder (pelvic floor muscles) that hold in urine. These exercises for women and men involve repeatedly tightening, holding, and then relaxing the pelvic floor muscles.   Biofeedback Biofeedback uses measuring devices to help you become aware of your body's functioning. By using electronic devices or diaries to track when your bladder and urethral muscles contract, you can gain control over these muscles. Biofeedback can be used with pelvic muscle exercises and electrical stimulation, to relieve stress and urge incontinence.
  • Obstet Gynecol. 2005;105(5 Pt 1):999-1005. Lower urinary tract symptoms and pelvic floor muscle exercise adherence after 15 years. Bø K , Kvarstein B , Nygaard I .
  • Kegel (1948) used pelvic floor muscle exercises with a perineometer for resistance and biofeedback
  • Mgmt of fluid intake: 300cc, 4-5 times a day CASE 1
  • May need trx while losing weight Realistic goals for weight loss Obesity has been associated with promoting UI by increasing intra-abdominal pressure that leads to chronic stress on the pelvic floor that may cause overt structural damage and neurological dysfunction resulting in UI. Studies have shown that significant weight loss and surgical weight loss has improved UI symptoms and reduce UUI in women
  • This slide depicts the relative M 3 /M 2 ratios of the current and imminent antimuscarinic agents. In general, the groups may be classified as balanced, primarily M 3 selective, and highly M 3 selective. Trospium and Detrol ® LA show approximately equal affinity for both receptor subtypes; solifenacin and oxybutynin are primarily M 3 selective; and darifenacin, with an affinity ratio of approximately 60:1, is considered highly M 3 selective. Going forward, we will investigate how the variant receptor selectivity profiles might influence the optimal balance between efficacy and tolerability for these agents. Heading CE. YM-905 (Yamanouchi Pharmaceutical Co Ltd). Curr Opin CPNS Investig Drugs . 2002;2:321-325. Napier C, Gupta P. Darifenacin is selective for the human recombinant M 3 receptor subtype [abstract]. Proc ICS . 2002:445. Note: Inhibition constant ratio for solifenacin was generated from Heading et al. K i for M 2 = 120; K i for M 3 = 9.9. M 2 /M 3 = 12. Key Messages: Agents that are highly selective for the M 3 receptors may be associated with more significant anticholinergic adverse effects, including dry mouth and constipation Detrol ® LA exhibits a balanced affinity for M 2 /M 3 muscarinic receptor subtypes
  • Yes
  • Reference: 1. Chapple CR, Martinez-Garcia R, Selvaggi L, et al, for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol . In press. A 12-week, European, prospective, randomized, double-blind, double-dummy, 2-arm, parallel-group trial that compared the efficacy of dose titration of solifenacin (5 mg or 10 mg qd) or a single dose of DETROL ® LA (tolterodine tartrate extended release capsules) 4 mg qd in 1200 adult patients with overactive bladder symptoms. 1 Patients completed a 3-day micturition diary prior to each visit, at baseline and at Weeks 4, 8, and 12. 1 The primary end point of the trial was micturition frequency, and the primary objective was to show non-inferiority of solifenacin compared with DETROL LA. 1 A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Chapple CR , Martinez-Garcia R, Selvaggi L, Toozs-Hobson P, Warnack W, Drogendijk T, Wright DM, Bolodeoku J; for the STAR study group. Eur Urol. 2005 Sep;48(3):464-70.
  • Reference: 1. Chapple CR, Martinez-Garcia R, Selvaggi L, et al, for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol . In press. The primary end point was micturition frequency, and the primary objective was to show non-inferiority of solifenacin compared with DETROL ® LA (tolterodine tartrate extended release capsules). 1 Solifenacin was proven to be non-inferior to, or not any worse than, DETROL LA in the STAR trial. 1 Based on the available results in this publication, superiority claims should not be concluded since the trial did not confirm superiority on the primary end point. 1 Secondary end points included incontinence episodes, urge incontinence episodes, urgency, volume voided, and tolerability. 1 The publication did not disclose if P values were adjusted for multiple comparisons. The STAR trial presents only pooled data of the 5-mg/10-mg doses of solifenacin. As a result, any potential benefits of the 10-mg dose are unclear. Chapple CR, Martinez-Garcia R, Selvaggi L, Toozs-Hobson P, Warnack W, Drogendijk T, Wright DM, Bolodeoku J; for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol. 2005;48(3):464-470.
  • Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Haab F, Stewart L, Dwyer P. Eur Urol. 2004 ;45(4):420-9
  • J Urol. 2004;171(6 Pt 1):2311-2315. Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. Zinner N , Gittelman M , Harris R , Susset J , Kanelos A , Auerbach S ; Trospium Study Group .
  • Side effects tend to be the same for the majority of patients. The biggest side effect profile for the anticholinergic.anti muscarinics are dry mouth and constipation. A few items stand out All drugs except oxybutynin have undergone cardiac safety studies for QT interval elongation as part of the FDA approval process. Darifenacin and trospium were the only drugs that dod not prolong the QT interval. Drugs can also cause increased heart rate. Oxytrol and Gelnique the transdermal delivery systems have shown to have decreased incidence of side effects, Oxytrol, however, has had difficulties with skin rashes and skin breakdown with use of the patch. Urinary retention can be a side effect of all the medications .
  • Passive Diffusion Across the BBB This slide illustrates the factors that are involved in allowing penetration across the blood-brain barrier, including lipophilicity, charge, and molecular “ bulkiness ” J Neurochem. 1998 May;70(5):1781-92. CNS drug design based on principles of blood-brain barrier transport. Pardridge WM . Cell Mol Neurobiol. 2000 Apr;20(2):231-53. Determinants of passive drug entry into the central nervous system. Habgood MD , Begley DJ , Abbott NJ .
  • TOO MANY ON THIS ONE STUDY?- yes- deleted next slide This was a 3-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study in male and female volunteers aged 60 years and over. Both study drugs were administered according to standard prescribing titration practice, as defined in the US prescribing information of the respective drugs. 1, 2 Following a 2-week screening period to assess eligibility, subjects were randomized in a 1:1:1 ratio to one of the following treatment groups: - Darifenacin extended release (starting dose 7.5 mg qd with sham dose titration at Week 2 [continuing 7.5 mg qd], and titration to 15 mg qd at Week 3) - Oxybutynin extended release (ER; starting dose 10 mg qd with titration to 15 mg qd at Week 2 and 20 mg qd at Week 3) - Matching placebo (sham dose titration at Week 1 and Week 2). In order to ensure adherence to the protocol, the daily intake of study medication was supervised during Week 3. Inclusion criteria Age ≥ 60; English as primary language; ability to follow or understand test instructions; Mini-Mental State Exam (MMSE) Score > 26 Exclusion criteria Current history of urinary retention or bladder outlet obstruction; Body Mass Index (BMI) < 18.5 or > 29.9 kg/m 2 ; concomitant sedating medications; Geriatric Depression Scale ≥ 9 References 1. Enablex ® (darifenacin) Extended Release Tablets. Prescribing Information. Novartis Pharmaceuticals Corporation, December 2004 (available at: ). 2. Ditropan XL ® (oxybutynin chloride) Extended Release Tablets. Prescribing Information. Ortho-McNeil Pharmaceutical, Inc., June 2004 (available at: ).
  • Darifenacin treatment did not significantly affect delayed recall compared with placebo in the Name-Face Association Test at Weeks 1, 2 or 3. The mean score increased from baseline to Week 3 (i.e. accuracy improved) both for darifenacin and placebo, representing a learning effect as a result of repeating the test. In contrast, oxybutynin ER was associated with significant memory impairment, with inferior scores compared with darifenacin and placebo at Weeks 2 and 3. (See Table 1) Table1: Scores for accuracy (least square mean) in delayed memory recall in the name-face association test
  • Tertiary endpoint Memory Self Assessment In addition to the computerized cognitive battery, self-rated memory questionnaires, in a traditional paper/pencil format, were also administered to assess subjects’ perceptions of memory loss. Memory Assessment Clinics Self Rating Scale (MAC-S) This is a self-report instrument, in which each subject is asked to rate his abilities on 10 specific memory tasks and two global items. Subjects were asked to rate how their memory has changed since the beginning of the study. In contrast with the objective tests of memory, many of which showed lower performance in the oxybutynin ER group compared with placebo, there were no significant differences between treatment groups in the MAC-S total scores over time. Thus, memory impairment is unrecognized by patients, which means that they are unlikely to report these problems in a clinical setting. This is particularly important, since although impairment of memory was noted in the objective assessments with oxybutynin ER, they may go unnoticed by and unreported by patients.
  • Botulinum toxin (Botox) is a potent neurotoxin that inhibits the release of acetylcholine from presynaptic cholinergic nerve endings. This inhibition results in a localized reversible chemical denervation, with decreased detrusor contractility. It is currently not FDA-approved for the treatment of OAB. For patients who fail oral therapies for OAB, botulinum toxin injection may be a choice. Current data primarily address only patients with refractory detrusor overactivity. In the most recent Cochrane review, randomized trials of intravesical botulinum versus placebo reported results favoring botulinum toxin. [32] However, many questions remain regarding its use, including the optimal dose and site of injection , the appropriate population, and long-term safety . To address this issue, Schurch et al [33] randomized 59 patients with neurogenic detrusor overactivity to intravesical botulinum A (200 or 300 U) or placebo. These investigators noted significant improvements when compared to placebo using the Incontinence Quality of Life Questionnaire. There was no clear difference between botulinum doses. Intravesical botulinum toxin has a variable duration of action, with loss of efficacy typically seen within one year. [34] Based upon these early data, there may be a role for intravesical botulinum for patients with proven detrusor overactivity when other therapies fail. One of the adverse effects is urinary retention; therefore, this option should be used judiciously, as the effects can last up to three months after a single injection.
  • This should go after slide 59
  • MORE???- you’re welcome to put a data slide in here but I think it’s plenty long enough already
  • Final slide deck for dr iglesia

    1. 1. Faculty DisclosureDr. Iglesia has no relevant conflictsto disclose.
    2. 2. Objectives• Develop effective treatment plans for women with overactive bladder.• Describe how to communicate realistic goals of overactive bladder treatment with patients.• Review how to minimize medication side effects in treatment plans for women with overactive bladder.• Describe the efficacy and safety of new and emerging therapies for women with overactive bladder.
    3. 3. Urinary Incontinence (UI): Prevalence • 13 million Americans • Gender – Female: 10%-55% – Male: 2%-5% • Prevalence and severity increase with age • Seen in over 50% of nursing home patients
    4. 4. Changing the Face of UIStereotype RealityFor illustrative purposes only. Not indicative of population distribution.
    5. 5. Prevalence of Any UI By Age and SeverityMinassian VA, et al. Obstet Gynecol. 2008;111(2 Pt 1):324-331.
    6. 6. Prevalence of Urge UI By Age and SeverityMinassian VA, et al. Obstet Gynecol. 2008;111(2 Pt 1):324-331.
    7. 7. Patient Case: Background (1)• Mrs. D is a 48-year-old, perimenopausal, White female.• Approximately one month ago, she began experiencing urgency, frequency, and occasional urge urinary incontinence (UI).• In the past 6 months she has gained nearly 25 lbs, which she attributes to perimenopause. She now has a BMI of 28.5.
    8. 8. Patient Case: Background (2)• She has noticed a significant decline in sexual desire and satisfaction since the onset of her bladder problems.• She feels anxious and is nervous that she will embarrass herself in public.• She takes HCTZ and propranolol for hypertension, and SSRI for mild depression.
    9. 9. Defining Overactive Bladder The International Continence Society defines OAB as: • Urinary urgency, with or without urge incontinence, usually with urinary frequency and nocturia, in the absence of pathologic or metabolic factors that would explain these symptoms Therefore, ask about URGENCYNational Association for Continence (2008)
    10. 10. Major Types of Urinary IncontinenceStressUrgeOverflow Transient Functional
    11. 11. OAB in the United States Incontinent Versus Continent: NOBLE 12.2 million (6.1% of the population) 37% 33.3 Incontinent million OAB (>16% of pop.) 63% Continent 21.2 million (10.5% of the adult population)Stewart WF, et al. World J Urol. 2003;20(6):327-336.
    12. 12. Functional Incontinence: Causes(AKA Transient or Reversible Incontinence)• Patient-related “DIAPPERS”Mnemonic• Environmental-related • Delirium• Disease-related • Infection • Atrophy• Medication-related • Pharmacologic • Psychologic • Endocrinologic • Restricted mobility • Stool impaction
    13. 13. Impact on Quality of Life: The Silent Sufferers Physical Psychological • Limitations or • Guilt/depression cessation of physical • Loss of self-esteem Sexual activities • Fear of: • Avoidance of sexual – Being a burden contact and – Lack of bladder intimacy control Quality – Urine odor Occupational • Absence from work of Life Social • Reduction in social • Decreased interaction productivity • Limit and plan travel Domestic around toilet accessibility • Require specialized underwear, bedding • Special precautions with clothingTubaro A. Urology. 2004;64(6 suppl 1):2-6.
    14. 14. Lower Urinary Tract Function• Bladder and urethral functions – Storage – Micturition• These functions are controlled by the central nervous system (CNS) through reflexes that coordinate the activity of: – Bladder (smooth muscle) – Urethra (smooth and striated muscles) – Pelvic floor muscles
    15. 15. Lower Urinary Tract Innervation Pelvic Nerve (Parasympathetic) ACh +M3 -β 3 Hypogastric Nerve NE +α 1 (Sympathetic) +N Pudendal Nerve (Somatic) AChAcetylcholine (ACh)
    16. 16. NeuroUrology Periaqueductal Pontine Micturition Gray Center Storage Reflex Micturition Reflex Inhibition Spinal Reflex Hypogastric Nerve SYM Spinal Pelvic Nerve Relay - ß3 Neuron Bladder PAR + M2,3 + α1 +N ONRhabdosphincter Pudendal Nerve
    17. 17. Initial Assessment• Medical history• Screening questions• Urinalysis• Physical examination
    18. 18. Evaluation and Management• Urinalysis• Simple pelvic examination
    19. 19. Patient Case: Continued• Based on her assessment, you learned she suffers from constipation and has tried to increase her water intake to address that issue.• With further questioning, she also reports that she has been getting up to urinate at least 4 times a night. – Is it nocturia or nocturnal polyuria?
    20. 20. Screening: Intake/Output Diary
    21. 21. Nocturia vs Nocturnal Polyuria • Assessed with simple 24-hour urine collection • Common causes: Sleep apnea, CHF, diabetes mellitus • Sleep apnea – Most under-recognized cause of nocturnal polyuria – Treatment with CPAP significantly reduces nocturic frequencyFitzgerald MP, et al. Am J Obstet Gynecol. 2006;194(5):1399-1403.
    22. 22. Drugs That Cause OAB-Like Symptoms • Alpha-adrenergic receptor agonists • Tricyclic antidepressants • Psychotropics (sedatives, hypnotics) • Cholinesterase inhibitors • Narcotic analgesics, opioids • Calcium channel blockers • Diuretics • Methylxanthines • NSAIDSOuslander JG. New Engl J Med. 2004;350(8):786-799.
    23. 23. Patient Case: Management• Change HTN medication• Eliminate caffeine• Decrease fluid consumption• Manage constipation• Lose weight
    24. 24. Behavioral Interventions • Behavioral Training Techniques – Pelvic floor muscle (PFM) training • Physical therapy (PT) • Kegel exercises – Bladder training: • Biofeedback • Timed voiding • Behavioral Modification – Lifestyle modifications: Eliminating bladder irritants from diet, managing fluid intake, weight control, monitoring bowel regularity, smoking cessation, and patient educationWyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.
    25. 25. Pelvic Muscle Rehabilitation
    26. 26. Pelvic PT and Exercise Adherence Study • Less than ¼ of women continued exercises. • No difference in rate of subsequent SUI surgery in women who had intensive pelvic PT vs those who did not. • Marked benefit of initial therapy not maintained 15 years later.Bo K, et al. Obstet Gynecol. 2005;105(5 Pt 1):999-1005.
    27. 27. Pelvic Floor Muscle (PFM) Training (Kegel Exercises)• Rationale: strong and fast PFM contraction increases urethral pressure and prevents leakage during sudden increase in abdominal pressure• Recommendation: – 3 sets of 8-12 slow-velocity maximum voluntary contractions, sustained for 6-8 seconds, performed 3-4 times a week for at least 15-20 weeks• Effectiveness: depends upon type of exercise, frequency, intensity, and duration of training
    28. 28. Weighted Vaginal Cones
    29. 29. Pessary for Incontinence:Useful for Stress, Not Urge Pessary in position
    30. 30. Behavioral Modification • Elimination of bladder irritants from diet – Eliminate stimulants, such as caffeine and over-the- counter prescription medication with caffeine. – Evidence suggests aspartame and other artificial sweeteners may contribute to OAB symptoms. • Smoking cessation – Smoking may cause chronic coughing, which in turn may increase the intra-abdominal pressure and cause UI. – Smoking cessation education should be offered, stressing the relationship between smoking and UI.Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.
    31. 31. Behavioral Modification (cont) • Management of fluid intake – When is too much, too much? – When is too little, not enough? • Management of bowel regularity – Avoid constipation – Increase dietary fiber – Engage in regular exercise – Establish regular defecation plan • Weight control – First-line option for treatment of UI for obese clients – Goal should be set to decrease BMI to <30 kg/m2Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.
    32. 32. Patient Case• Mrs. D eliminates caffeine from her diet; reduces her HTN medication; and tries do Kegel exercises regularly.• She is still experiencing some leaking and continued, though less frequent, night urgencies.• You suggest trying a pharmacologic agent.
    33. 33. Drugs for OABHave I got the pill for you?
    34. 34. Receptor Selectivity 59.2 60 M3 selective Inhibition Constant Ratio (Ki) for Muscarinic Receptor Subtypes* 50 40 Primarily 30 Nonselective M3 selective 20 (M3/M2) 12 12.3 10 3.6 1.3 0 Trospium Tolterodine Solifenacin Oxybutynin Darifenacin *Animal models.Heading CE. Curr Opin CPNS Inves Drugs. 2000;3:321-325.Napier C, et al. Proc ICS. 2002:445. Abstract.
    35. 35. Muscarinic Receptor Distribution and Potential Adverse Events With Antagonist Use Tissue Distribution Potential AEs Brain Decreased cognitive function M1-M5 Short-term memory loss Altered sleep cycle Eye M3 Decreased lacrimation Decreased accommodation Salivary glands M3 Xerostomia (dry mouth) Heart Cardiovascular M2-M3 Intestine Constipation M3 Bladder Urinary retention M2-M3 • M2 reverses sympathetically mediated smooth muscle relaxation • M3 causes detrusor contractionAbrams P, et al. Br J Pharmacol. 2006;148(5):565-578.
    36. 36. M-3 Selective Antagonists• Solifenacin• Darifenacin
    37. 37. STAR Trial: N=1200 • 12-week, European, prospective, randomized, double- blind, double-dummy, 2-arm, parallel-group trial • Dose titration regimen of solifenacin (5 mg or 10 mg qd) or a single dose of tolterodine LA 4 mg qd • Primary objective: Non-inferiority study • Primary endpoint: Micturition frequency • Secondary endpoints: Incontinence episodes, urge incontinence episodes, urgency, volume voided, and tolerabilityChapple CR, et al. Eur Urol. 2005;48(3):464-470.
    38. 38. STAR Trial Reported Endpoints Solifenacin Tolterodine Endpoint (pooled P value (4 mg qd) 5 mg/10 mg) PRIMARY (non-inferiority) [PPS]* (n=525) (n=524) Micturition frequency/24 h –2.45 –2.24 .004 SECONDARY (FAS)† (n=578) (n=599) Urgency episodes/24 h –2.85 –2.42 .035 Incontinence episodes/24 h –1.60 –1.11 .006 Nocturia episodes –0.71 –0.63 .730 Urge incontinence episodes/24 h –1.42 –0.83 <.01 Mean volume voided (mL/void) 38.00 31.00 .01 Patients dry (%) 59.00 49.00 .006 Pads/24 h –1.72 –1.19 .0023 Perception of bladder condition –1.51 –1.33 .0061Chapple CR, et al. Eur Urol, 2005:48(3):464-470. *Per protocol set. †Full analysis set.
    39. 39. Darifenacin • Bladder selectivity (marginal) in animal studies: Not more than tolterodine or oxybutynin in guinea pigs • Multicenter, placebo-controlled RCT (n=561) • Reduction in incontinent episodes: – 67.7% Darifenacin 7.5 mg (P = .010) – 72.8% Darifenacin 15 mg (P = .017) – 55.9% Placebo – No reductions in nocturiaHaab F, et al. Eur Urol. 2004;45(4):420-429.
    40. 40. Darifenacin and Warning Time? Difference in Medians at Week 2 = 4.3 minutes (P = .003) 8 7 6 5 4 Baseline Week 2 3 2 1 0 Darifenacin 30 mg n 0 g Placebo o n=32 n=35Cardozo L, et al. J Urol. 2005;173:1214-1218.
    41. 41. Non-Selective Muscarinic Antagonists: Trospium • Quaternary amine • Used in Europe for 20 years: Many studies • Efficacy not different from standard agents • Poor bioavailability • RCT in US (phase 3, N=523):* – 20 mg bid – Urge UI: 59% drug vs 44% placebo – Nocturnal frequency decreased by week 4 – Side effects: Dry mouth 21.8%*Zinner N, et al. J Urol. 2004;171(6 Pt 1):2311-2315.
    42. 42. Reasons for NonadherenceAdapted from: BCG analysis, Harris interactive 10,000 Patient Survey, 2002.
    43. 43. Tailor Therapy to Each Patient to Improve Adherence• Does it fit into their schedule? Do they need reminders to take?• Cost: Have you reviewed formularies, copayments, availability of generics?• Do they understand how long it might take to work? Is it working for them?• Can you reduce potentiality of side effects?
    44. 44. Side Effects• Dry mouth (higher than M2 agents)• Constipation (higher than M2 agents)• Blurred vision• Exacerbation of gastroesophageal reflux• Cardiac changes• Urinary retention
    45. 45. CNS Considerations in the Treatment of Overactive Bladder: Passive Diffusion Across the BBB Vasculature BBB CNS ↑ Lipophilicity ↑ Diffusion ↑ Charge/polarity, + + - - hydrogen bonding + + - + - -+ - - ↓ Diffusion + ↓ Molecular “bulkiness” ↑ DiffusionPardridge WM. J Neurochem. 1998;70:1781-1792.Habgood MD, et al. Cell Mol Neurobiol. 2000;20:231-253. BBB: blood-brain barrier
    46. 46. Effect of Darifenacin and Oxybutynin ER on Memory in Older Subjects • 3-week, randomized, double-blind, double-dummy, parallel-group, placebo-controlled, multicenter study • 150 healthy volunteers ‑ age range 60–83 (12.7% ≥75 years) ‑ 62% female • 2-week screening to assess eligibility • Active treatments administered according to US prescribing information • Computerized battery of cognitive function tests assessed effect of each drug at end of weeks 1, 2, & 3Kay GG, et al. Eur Urol. 2006;50:317-326.
    47. 47. Primary Endpoint: Delayed Memory Recall in The Name-Face Association Test Score for accuracy (least square mean) Mean Score for delayed recall Name-Face Association Test *† *† Darifenacin (n=46) Oxybutynin ER (n=49) Placebo (n=50) Week *P < .05 vs placebo; †P < .05 vs darifenacinReprinted with permission from Elsevier (ANCOVA, adjusted for baseline score, age, and sex)Kay GG, et al. Eur Urol. 2006;50:317-326. Patient (n) numbers reflect baseline values
    48. 48. Self-Rated Memory Assessment (MAC-S) MAC-S score (least square mean) Darifenacin (n=46) Oxybutynin ER (n=49) Placebo (n=50) Patient (n) numbers reflect baseline valuesKay GG, et al. Eur Urol. 2006;50:317-326.Novartis Pharmaceuticals. Data on File
    49. 49. Alternative Therapies/Treatments• Botulinum• InterStim Therapy• Tension-Free Vaginal Tape- only for mixed UI
    50. 50. InterStim Therapy
    51. 51. Tension-Free Vaginal Tape
    52. 52. Treatment for OAB: Never Surgery• Mixed UI may be managed with mid- urethral slings, but efficacy is lower than pure SUI
    53. 53. Conclusions• UI is common.• Most women go untreated.• Highly efficacious therapies exist.• Encourage women to be proactive about treating quality-of-life conditions.