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1040122 oab diagnosis, management and current trend of therapy

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1040122 oab diagnosis, management and current trend of therapy

  1. 1. 馬偕紀念醫院婦產部 婦女泌尿科 黃文助
  2. 2. Overactive bladder (OAB)  OAB is a symptom syndrome.  OAB is a filling disorder in which abnormal sensations leads to urinary urgency, frequency and incontinence.
  3. 3. Overactive bladder (OAB)  ICS (International Continence Society, 2002) definition:  Urgency, with or without urge incontinence, usually with frequency and nocturia  In the absence of obvious pathologic or metabolic disorders (such as UTI, BPE or bladder cancer, which might cause such symptoms)
  4. 4. Prevalence of OAB  European: 16.6% (age ≧40 y/o) female: 17.4% male: 15.6%  USA: 16.4% (age>18y/o) female: 16.9% male: 16.0%  Taiwan: 16.9% (age>30y/o) female: 18.3% male: 16.0% Milsom et al. BJU Int 2001 Stewart et al. World J Urol. 2003 Yu et al. Urol Int 2006
  5. 5. 膀胱過動症的發生率(台灣) 膀胱過動症的推估病人數 18.2% 1,289萬人 30-79歲人口 膀胱過動症 234萬人 81.8% 30-79歲人口之中,5人中約有1人 HJ Yu . Urol Int 2006;77:327–333 內政部人口統計資料 有漏尿 58萬人 無漏尿 176萬人 13.7% 4.5%
  6. 6. Urge Incontinence Involuntary leakage preceded by urgency Frequency • Daytime frequency: complaint by the patient who considers that they void too often by day • Nocturia (urination at night): complaint that the patient has to wake up at night I or more times to void OAB OAB Symptoms Urgency (core symptom) • Sudden, compelling desire to pass urine that is difficult to defer
  7. 7. 什麼是膀胱過動症? 膀胱過動症的症狀 「頻尿」「尿急」 「尿失禁」 「漏尿」
  8. 8. 急尿 (Urgency) 難以延後的突發、強迫性、強烈排尿欲望 頻尿 (Frequency) 白天排尿過於頻繁 (每天解尿次數8次或以上) 急迫性尿失禁 (Urge Incontinence) 伴隨或緊接於急尿之後無法控制的漏尿 夜尿 (Nocturia) 夜間必須醒來排尿一次以上
  9. 9. 膀胱過動症的發生原因為何? 由於腦中風或脊髓損傷的後遺症,造成連結腦部與膀胱肌肉的神經迴路 出現障礙。 原因① 骨盆底肌的問題 由於生產或年齡增長,支撐子宮、膀胱、尿道等稱為骨盆底肌肉功能減 弱。 原因② 神經系統的問題 因某種原因造成膀胱神經敏感作用,或許多無法鎖定原因的狀況。 原因③ 其他原因
  10. 10. Physical • Limitations or cessation of physical activities Impact on QoL Quality of Life Sexual • Avoidance of sexual contact and intimacy Occupational • Absence from work • Decreased productivity Social • Reduction in social interaction • Limiting and planning travel around toilet accessibility Domestic • Requirements for specialized underwear, bedding • Special precautions with clothing Psychological • Guilt/depression • Loss of self-esteem • Fear of – being a burden – lack of bladder control – urine odor
  11. 11. Assessment of OAB  History  Bladder Diary  Physical Examination  Laboratory tests  Residual Urine Measurement  Symptoms & Questionnaire  Urodynamic study
  12. 12. History • Focus on medical, neurologic, and genitourinary symptoms • Voiding patterns and symptoms – bladder diary • Review medications • Evaluate functional and mental status
  13. 13. Bladder diary
  14. 14. Medications that may affect bladder function  Diuretics  Antidepressants  Antihypertensives  Hypnotics  Analgesics  Narcotics  Sedatives  OTC sleep aids and cold remedies  Antipsychotics  Herbal remedies
  15. 15. Physical examination  Focus on detecting anatomical and neurological abnormality accounting for OAB symptoms.  General, abdominal (including bladder palpations), and neurologic exams  Pelvic and rectal exams in women and rectal exam in men  Observe for urine loss with stress (eg, cough, Valsalva)
  16. 16. Laboratory tests  Urinalysis  to rule out hematuria, pyuria, bacteriuria, glucosuria, proteinuria  Blood work as appropriate  glucose  prostate serum antigen  others
  17. 17. Symptoms and questionnaires  OABSS  OAB-q  American urological association symptom index  Urinary symptom scoring system
  18. 18. OABSS Homma et al. Urology 68(2), 2006
  19. 19. OAB-q Yes No Do you urinate more than 8 times in a 24-hour period? Do you frequently get up 2 or more times during the night to go to the bathroom? Do you have the uncontrollable urges to urinate that sometime resulted in wetting accidents? Do you frequently limit your fluid intake when you are away from home so that you won’t have to worry about finding a bathroom? When you are in a new place, do you make sure you know where the bathroom is? Do you avoid places if you think there won’t a bathroom nearby? Do you frequently have strong , sudden urges to urinate? Do you go to he bathroom so often that it interferes with the things you want to do? Do you use pads to protect your clothes from wetting?
  20. 20. 症狀問卷 膀胱過動症: 尿急每週1次以上、且合計 分數達3分以上 膀胱過動症症狀問卷 問題 症狀 分 數 頻率 1 自清晨醒來到夜間就寢為止,大約如 廁幾次? 0 7次以下 1 8~14次 2 15次以上 2 自夜間就寢至清晨醒來為止,為了如 廁大約起床幾次? 0 0次 1 1次 2 2次 3 3次以上 3 是否曾經感到急迫尿意,而幾乎無法 忍耐? 0 無 1 每週少於1次 2 每週1次以上 3 1天1次左右 4 1天2~4次 5 1天5次以上 4 是否曾經感到急迫尿意,並因無法忍 耐而漏尿? 0 無 1 每週少於1次 2 每週1次以上 3 1天1次左右 4 1天2~4次 5 1天5次以上 合計分數 分 以下症狀的出現頻率為何? 請選出最近一週內您的狀態 之選項,並在分數的數字上 打圈。
  21. 21. Urodynamic study  It is appropriate to treat lower urinary tract symptoms based upon history and physical exam alone  Reserve urodynamics for  persistence despite appropriate therapy  potential hazards of therapy  incontinence  outflow obstruction  neurogenic bladder Campbell’s Urology. Philadelphia, Pa: WB Saunders; 2002; 8th ed: 905-906.
  22. 22. Detrusor overactivity
  23. 23. DO vs.OAB  Urodynamically proven detrusor overactivity : ~ two-thirds of women with symptoms of OAB  Detrusor overactivity: 83% have OAB symptoms
  24. 24. Definition of OAB  Based on symptoms: OAB syndrome  Based on urodynamics: DO ~ Filling disorder ~ Afferent bladder function
  25. 25. 正常的解尿週期 儲存期 排空期 膀胱壓 Bladder filling First sensation to void Normal desire to void Bladder filling Wein AJ, Rovner ES. Int J Fertil. 1999;44:56-66. 25
  26. 26. Goal for treatment of OAB  To improve symptoms that cause a problem for the individual patient.  Urgency is the key symptom to OAB treatment.
  27. 27. Aims of treatment  Quantitative aspects  Decrease in urge urinary incontinence episodes  Reduction of frequency/24 hrs  Increase in volume voided  Absence/decrease in number of urgency episodes  Increase in urgency-free time  Qualitative aspects  Reduction of severity of each urgency episode  Improvements in QoL
  28. 28. Management of overactive bladder  Standard first-line therapy  Behavior therapy  Pharmacological therapy  Specialized therapy  Neuromodulation  Reconstructive and invasive surgery  Botulinum neurotoxin-A injections  Potential new targets
  29. 29. Behavior therapy  Initial treatment (first line) (level 1 evidence)  Lifestyle intervention (behavior modification)  Weight reduction, caffeine reduction, smoking cessation, modified fluid intake (fluid reduction, avoid water-containing foods, avoid fluid intake from 4 hours before sleep, empty bladder before sleep or going out)  Pelvic floor muscle training  Bladder retraining
  30. 30. Lifestyle modification Klutke et al. J Urol 2009; 181: 2599-2607.
  31. 31. 骨盆底肌肉訓練 ●刻意緊縮、放鬆陰道及肛門的運動
  32. 32. 膀胱訓練 特徵 出現頻尿.尿急症狀的病人,嘗試忍耐排尿感。 進行骨盆底肌肉訓練時,同時忍耐排尿感,可提升效果(提升 副交感神經的作用)。 憋尿訓練 具體而言… ●以15~60分鐘為單位,慢慢 延長忍耐的間隔。目標為 可忍耐2~3小時的狀態。 ●如果訓練至一次排尿量達到 500 mL,必須增加排尿次 數。 忍 !!
  33. 33. Pharmacological therapy of OAB
  34. 34. Myogenic and urothelial signaling pathway
  35. 35. Myogenic and urothelial signaling pathway
  36. 36. Two types of detrusor contraction  Voiding contraction:  well coordinated bladder contraction caused by release of Ach and other contractant transmitters, eg ATP, from cholinergic nerves.  requires parasympathetic output from sacral spinal cord.  Spontaneous (autonomous) contractile activity:  occurs during bladder filling
  37. 37. Pharmacological therapy Anticholinergic agnets  Antimuscarinics are efficacious, safe, and well- tolerated treatments for OAB.  These agents currently remain the first-line pharmacologic treatment for OAB. Chapple CR, Eur Urol 2008
  38. 38. Autonomic Efferent Innervation Contributing to Bladder Contraction and Urine Storage
  39. 39. Sensory Innervation of the Bladder
  40. 40. Antimuscarinics: site of action within bladder wall
  41. 41. Antimuscarinic mechamism of action  Detrusor muscle →inhibit Ach binding to M receptor → stablize det muscle → ↑ bladder capacity  Sensory receptors in uro/suburothelium → ↓ afferent nerve activity (Aδ-fiber and C-fiber )  Significant reductions in urinary frequency, urgency and UUI episodes
  42. 42. Affinity for muscarinic receptor subtypes Physiologic Effect Clinical Impact M1 The receptor may play an important role in cognition ↓ M1 :↓cognitive adverse effects M2 •80 % (detrusor muscle) : M2 •detrusor smooth muscle contraction (indirectly): ↓muscle relaxation of β- adrenoceptors ↓ M2 :↓ cardiac adverse effects M3 •20% (detrusor muscle): M3 •the main receptor subtype responsible for normal micturition contraction Overly aggressive M3 blockade → constipation M4 M5 Not present in the bladder in significant numbers Unknown
  43. 43. Antimuscarinic medications licensed for OAB  Oxybutynin (oral or transdermal)  Propiverine  Solifenacin  Darifenacin  Tolterodine  Fesoterodine  Trospium chloride
  44. 44. Level Grade Antimuscarinics Tolterodine 1 A (highly recommended) Trospium 1 A (highly recommended) Darifenacin 1 A (highly recommended) Solifenacin 1 A (highly recommended) Propantheline 2 B (Recommended) Atropine, hyoscyamine 3 C (optional) Mixed Action Drugs Oxybutynin (muscle relaxant effect) 1 A (highly recommended) Propiverine (CC blocker) 1 A (highly recommended) Dicyclomine 3 C (Optional) Flavoxate 2 D ( possible)
  45. 45. Antimuscarinic structures
  46. 46. Structure of antimuscarinics Feature Physiologic Effect Clinical Impact Tertiary amine •Allows transfer across the BBB into CNS •Allows good absorption across GI tract •May result in adverse cognitive effects Particularly among elderly patients Quaternary amines •Limits transfer across the BBB into CNS •Limits absorption across GI tract •Reduces the potential for cognitive adverse effects
  47. 47. Quaternary amines  Trospium chloride  Non-selectivity for M receptor subtype  Low biological availability  Cross BBB to a limited extent  Few cognitive effect  Trospium ER: once daily  Launched in 2008  Lower max plasma concentration  Decrease incidence of side-effect and increase tolerability
  48. 48. Tertiary amine  Oxybutynin  Propiverine  Solifenacin  Darifenacin  Tolterodine  Fesoterodine
  49. 49. Oxybutynin  3 formulations: IR, ER, transdermal patch  Well documented efficacy  Active metabolite, N-desmethyl oxybutynin: higher affinity for M1/M3 receptor over M2  Relative non-selectiviy for bladder  Common AEs: dry mouth, constipation, dyspepsia  Poor long-term tolerability
  50. 50. Oxybutynin topical gel  FDA approval in Jan 2009  once-daily to abdomen, thigh, shoulder, or upper arm  Evolution of transdermal gel may allow greater tolerability  Improve compliance compared with previously available OXY formulations.
  51. 51. Propiverine  Anticholinergic and calcium channel blocking actions  Popular drug for detrusor overactivity in Germany, Austria and Japan.
  52. 52. Tolterodine  FDA approval for tx of OAB in 1998  Two formulations: IR(2mg,bid) and ER(4mg,qd)  Selectivity for bladder M receptor over salivary glands  ER tolterodine: more effective and better tolerability
  53. 53. Solifenacin  Launched in Europe in 2004  Competitive , selective M1 and M3 receptor antagonist  Higher potency against M3 receptor in SM than salivary gland  Selectivity for bladder over salivary gland was greater than tolterodine, oxybutynin, darifenacin or atropine
  54. 54. Darifenacin  Launched in 2004 in Europe and North America  Highly selective M3 receptor antagonist  5 fold higher affinity for M3 receptor relative to M1  Salivary responses are inhibited at doses 6–10-fold higher than those required to inhibit bladder responses.  Common AEs: mild-to-moderate dry mouth, constipation with a CNS and cardiac safety profile  Most M3 specific of newer anti-muscarinic agents  Offer a better balance between efficacy and unwanted effects
  55. 55. Fesoterodine  Active metabolite: 5-hydroxymethy tolterodine (5-HMT)  lower permeability across BBB and gut wall due to its lipophilic properties  Providing advantage over tolterodine with respect to side effect profile
  56. 56. Adverse events of antimuscarinics  Due to inhibition of muscarinic receptors in organs other than bladder  Intensity of side effects varies significantly dependent on:  1) Receptor selectivity  2) Bladder selectivity  3) Other physicochemical properties (lipophilicity, molecular size, polarity) that influence diffusion and the ability to cross BBB
  57. 57. Abrams P, Wein AJ. The Overactive Bladder— A Widespread and Treatable Condition. 1998. Muscarinic Receptor Distribution 口乾 虹膜/睫狀體 淚腺 視覺模糊 眼乾 膀胱的逼尿肌 Bladder (detrusor muscle) (M2 & M3 receptor) 唾腺 大腸 便秘 心臟 胃和食道 消化不良 心博過速 (M2 receptor) • 頭暈(Dizziness) • 嗜睡(Somnolence) • 認知損害(Cognitive impairment),特別是 對 記憶(memory)的 影響 (M1 receptor) CNS M3 receptor M3 receptor
  58. 58. Adverse events of antimuscarinics  Dry mouth: most common  Constipation: 2nd most common  Blurred vision  Cardiac effect: ↑HR, QT prolongation  CNS effect: Dizziness, insomnia, cognitive impairment
  59. 59. Antimuscarinics  Generally recognized as safe and effective in the treatment of OAB  However~ low persistence rates:  fading efficacy  well-known adverse effects such as dry mouth, constipation and blurred vision Anderson KE, Curr Urol Rep 2013
  60. 60. 限符合下列診斷標準條件之一者: (1)頻尿:每天(24小時)排尿次數超過八次,並有詳實病 歷紀錄。 (2)急尿:病患自述經常有一種很突然、很強烈想解尿的感 覺。 (3)急迫性尿失禁:對於尿急的感覺無法控制,並於24小時 內至少也有一次漏尿之情形。 發布日期:096.03.02 健保藥字第0960007608號
  61. 61. Drugs acting on membrane channels Level of evidence Grade of recommendation Calcium antagonist 2 D K-channel opener 2 D
  62. 62. α -Adrenoceptor antagonists Level of evidence Grade of recommendation Alfuzosin 3 C Doxazosin 3 C Prazosin 3 C Terazosin 3 C Tamsulosin 3 C
  63. 63. β -Adrenoceptor agonists Level of evidence Grade of recommendation Terbutaline (β-2) 3 C Salbutamol (β-2) 3 C Mirabegron ((β-3) 2 B  Several β 3-adrenoceptor selective agonists are currently being evaluated as potential tx for OAB in humans: GW-427353 (Solabegron®, GlaxoSmithKline), YM-178 (Acetanilide®, Astellas) KUC-7483 (Kissei Pharmaceuticals Co., Ltd.).
  64. 64. Mirabegron – a novel β3 agonist  Japan approval in 2011: 25 mg/day dose level  FDA approval in 2012 June: 25 or 50 mg/day dose in the USA  Europe and Canada  For symptomatic treatment of urgency, increased micturition frequency and/or UUI~ OAB syndrome.
  65. 65. β3 agonist- mechanism of action  Release nitric oxide (NO) by increasing intracellular Ca2+ through cAMP accumulation  Also inhibits detrusor muscle contraction by releasing an urothelial derived inhibiting factor (UDIF) β3-AR agonists helps bladder storing capacity through:  Direct inhibition of detrusor  Inhibition of bladder afferent neurotransduction ~ without impairing bladder contraction during voiding
  66. 66. β3 -AR agonists : pronounced effect on spontaneous contractile activity in det muscle in vitro ~an important basis for their clinical effects
  67. 67. Muscarinic and β3-adrenoceptor mediated pathways mediating relaxation of the detrusor
  68. 68. β3 AR agonists- Mirabegron  Rapidly absorbed after oral administration  Circulation in plasma as unchanged form  Administered dose: 55% excreted in urine, mainly unchanged form  Highly lipophilic  Metabolized in the liver via multiple pathways, mainly by cytochrome P450 3A4 and 2D6 (CYP2D6). Takusagawa S et al. 2012
  69. 69. Pharmacokinetics of Mirabegron  Absorption:  Tmax: 3-4hr  T1/2: ~40 hr  Bioavailability:  ~29% at a 25mg dose  34% at a 50mg dose  Terminal elimination half-life: ~50 hr  Excretion: in urine and faeces mainly as unchanged form
  70. 70. Prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies (SCORPIO, ARIES,and CAPRICORN)
  71. 71. Adjusted mean change from baseline in mean number of micturitions/24 hr
  72. 72. Adjusted mean change from baseline in the mean number of incontinence episodes/24 hr
  73. 73. Improvements in frequency, urgency incontinence, mean volume voided/micturition
  74. 74. Safety of Mirabegron  50 or 100mg: did not cause QTc prolongation  Change from baseline to final visit for PR( 50mg) ~ approximately 1 bpm.  Associated with an increase of 1mm Hg in BP vs. placebo  No clinically relevant effects on PVR volume.  No episodes of acute urinary retention.  Didn’t increase intraocular pressure (IOP) in healthy volunteers (mirabegron 100mg orally QD ) Malik Mv et al. 2012, Chapple CR et al. 2013, Novack GD et al. 2013
  75. 75. Adverse events~ dry mouth  The North American phase III trial~  Most common for tolterodine : 10.1 %  2.8 % for both mirabegron doses (50, 100mg)  Placebo rate :2.6 % Nitti et al. J uro. 2012
  76. 76. Adverse events~ dry mouth antimuscarinics vs. β3 agonist  Dry mouth: most common AE of anticholinergic drugs.  Incidence of dry mouth with 50 / 100 mg mirabegron: similar to placebo.  Mirabegron may be very useful for pts with OAB who experience AE secondary to anticholinergic agents.  Mirabegron causes less dry mouth, constipation, urinary retention, or blurred vision than tolterodine. Chapple C et al. 2013, Khullar V et al.2013, Nitti VW et al. 2012
  77. 77. Adverse events~ discontinuation rates  Placebo: 3.8 %  Mirabegron 50mg: 4.1 %  Mirabegron 100mg: 4.4 % Nitti et al. J urol. 2012
  78. 78. Theoretical advantages of mirabegron over antimuscarinics  Two other safety advantages over antimuscarinics: First:  Mirabegron could be helpful in cognitively impaired p’ts.  Most commonly CNS AEs in antimuscarinics: headache, somnolence, and cognitive impairment.  All five muscarinic receptor subtypes (M1–M5) in brain tissue and the possibility of BBB penetration.
  79. 79. Theoretical advantages of mirabegron over antimuscarinics  Two other safety advantages over antimuscarinics: Second:  Mirabegron decreases frequency of rhythmic bladder contractions during filling phase without suppressing amplitude during micturition. (animal study)  Could also be useful for treating OAB symptoms associated with bladder outlet obstruction (BOO),with a lower risk of voiding difficulty than with antimuscarinics
  80. 80. Theoretical advantages of mirabegron over antimuscarinics  Favorable efficacy/tolerability ratio of mirabegron:  This new therapeutic class could be considered as first-line treatment of OAB  Specifically in cognitively impaired and OAB p’ts with symptoms associated with PVR due to BOO. => must be proven by RCT in comparison with placebo => head-to head comparison against anticholinergics
  81. 81. Anticholinergic drugs vs. Mirabegron ~At present ~  Anticholinergic drugs: ~should remain the first-line pharmacologic tx for OAB until head-to-head comparative study eventually shows that mirabegron has equivalent or superior efficacy.  Mirabegron : ~considering mechanism of action, seems logical to use mirabegron as second-line treatment for OAB p’ts who are poor responders or intolerant to anticholinergics. ~ could be considered as first-line treatment in the future
  82. 82. Monotherapy vs. Combined Treatment  Combination of an antimuscarinic and β3-AR agonists:  Theoretically attractive  There is evidence both in vitro and vivo supporting this assumption.  Mirabegron combination therapy with solifenacin demonstrated greater efficacy than solifenacin 5 mg alone on MVV and MF. Rekik M et al, 2013: Abrams P et al., 2013
  83. 83. Cyclooxygenase inhibitors Level of evidence Grade of recommendation Indomethacin 2 C Flurbiprofen 2 C
  84. 84. Antidepressants Level of evidence Grade of recommendation Imipramine 3 C Duloxetine 2 C
  85. 85. Toxins Level of evidence Grade of recommendation Botulinum toxin (neurogenic) 2 A Botulinum toxin (idiopathic) 3 B Capsaicin (neurogenic) 2 C Resiniferatoxin (idiopathic) 2 C
  86. 86. Botulinum toxin  Neurotoxin produced by G(+) anaerobic organism Clostridium botulinum.  Inhibit release of acetylcholine at neuromuscular junction => causes muscle relaxations =>chemodenervation  Not yet licensed for use in bladder symptoms.  2nd line treatment in pts refractory to conventional antimuscarinic therapy
  87. 87. Capsaicin/Resiniferatoxin  Act on sensory afferent pathway  Desensitization afferent C fiber  Intravesical route
  88. 88. Hormone Level of evidence Grade of recommendation Estrogen 2 C Desmopressin * 1 A *Nocturia
  89. 89. Neuromodulation  Treatment for refractory OAB  Pudendal nerve stimulation  Sacral nerve stimulation: most common used  Tibial nerve stimulation
  90. 90. Surgery  Last resort in management of refractory OAB.  Aims  Abolish urgency and urgency incontinence  Achieve convenient voiding intervals  Stabilize upper urinary tracts and safeguard renal function
  91. 91. Surgery  Types of surgery  Augmentation cystoplasty  Detrusor myectomy  Urinary diversion
  92. 92. Conclusion Treatment algorithm for overactive bladder Fluid Management Timed Voiding Bladder Training Pelvic Floor Physical Therapy Antimuscarinic Therapy β3 AR agonist Sacral Neuromodulation Botulinum Toxin Injection Enterocystoplasty Urinary Diversion

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