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1040122 oab diagnosis, management and current trend of therapy
This document discusses overactive bladder (OAB). It defines OAB as a symptom syndrome characterized by urgency, with or without urge incontinence, usually accompanied by frequency and nocturia. The prevalence of OAB is estimated to be around 16-17% globally. Common causes include problems with the pelvic floor muscles, nervous system issues, and other factors. OAB can negatively impact quality of life by limiting physical, sexual, occupational, social, domestic, and psychological activities. Treatment involves behavioral modifications, pharmacotherapy such as anticholinergic medications, and in some cases neuromodulation procedures or surgery.
1040122 oab diagnosis, management and current trend of therapy
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- 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. 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. 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. 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. Urge Incontinence Involuntary leakagepreceded 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
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- 10. Physical • Limitations orcessation 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. Assessment of OAB History Bladder Diary Physical Examination Laboratory tests Residual Urine Measurement Symptoms & Questionnaire Urodynamic study
- 12. History • Focus onmedical, neurologic, and genitourinary symptoms • Voiding patterns and symptoms – bladder diary • Review medications • Evaluate functional and mental status
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- 14. Medications that mayaffect bladder function Diuretics Antidepressants Antihypertensives Hypnotics Analgesics Narcotics Sedatives OTC sleep aids and cold remedies Antipsychotics Herbal remedies
- 15. Physical examination Focuson 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. Laboratory tests Urinalysis to rule out hematuria, pyuria, bacteriuria, glucosuria, proteinuria Blood work as appropriate glucose prostate serum antigen others
- 17. Symptoms and questionnaires OABSS OAB-q American urological association symptom index Urinary symptom scoring system
- 18. OABSS Homma et al.Urology 68(2), 2006
- 19. OAB-q Yes No Do youurinate 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. 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 18～14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. Urodynamic study Itis 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.
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- 23. DO vs.OAB Urodynamicallyproven detrusor overactivity : ~ two-thirds of women with symptoms of OAB Detrusor overactivity: 83% have OAB symptoms
- 24. Definition of OAB Based on symptoms: OAB syndrome Based on urodynamics: DO ~ Filling disorder ~ Afferent bladder function
- 25. 正常的解尿週期 儲存期 排空期 膀胱壓 Bladder filling First sensation tovoid Normal desire to void Bladder filling Wein AJ, Rovner ES. Int J Fertil. 1999;44:56-66. 25
- 26. Goal for treatmentof OAB To improve symptoms that cause a problem for the individual patient. Urgency is the key symptom to OAB treatment.
- 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
- 29. Management of overactivebladder Standard first-line therapy Behavior therapy Pharmacological therapy Specialized therapy Neuromodulation Reconstructive and invasive surgery Botulinum neurotoxin-A injections Potential new targets
- 30. Behavior therapy Initialtreatment (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
- 31. Lifestyle modification Klutke etal. J Urol 2009; 181: 2599-2607.
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- 37. Myogenic and urothelialsignaling pathway
- 38. Myogenic and urothelialsignaling pathway
- 39. Two types ofdetrusor 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
- 40. 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
- 42. Autonomic Efferent InnervationContributing to Bladder Contraction and Urine Storage
- 44. Sensory Innervation ofthe Bladder
- 45. Antimuscarinics: site ofaction within bladder wall
- 46. Antimuscarinic mechamism ofaction 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
- 47. Affinity for muscarinicreceptor 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
- 48. Antimuscarinic medications licensedfor OAB Oxybutynin (oral or transdermal) Propiverine Solifenacin Darifenacin Tolterodine Fesoterodine Trospium chloride
- 49. Level Grade Antimuscarinics Tolterodine 1A (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)
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- 51. Structure of antimuscarinics FeaturePhysiologic 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
- 52. Quaternary amines Trospiumchloride 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
- 53. Tertiary amine Oxybutynin Propiverine Solifenacin Darifenacin Tolterodine Fesoterodine
- 54. 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
- 55. 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.
- 56. Propiverine Anticholinergic andcalcium channel blocking actions Popular drug for detrusor overactivity in Germany, Austria and Japan.
- 57. Tolterodine FDA approvalfor 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
- 58. Solifenacin Launched inEurope 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
- 59. Darifenacin Launched in2004 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
- 60. 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
- 61. Adverse events ofantimuscarinics 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
- 62. Abrams P, WeinAJ. 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
- 63. Adverse events ofantimuscarinics Dry mouth: most common Constipation: 2nd most common Blurred vision Cardiac effect: ↑HR, QT prolongation CNS effect: Dizziness, insomnia, cognitive impairment
- 65. Antimuscarinics Generally recognizedas 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
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- 67. Drugs acting onmembrane channels Level of evidence Grade of recommendation Calcium antagonist 2 D K-channel opener 2 D
- 68. α -Adrenoceptor antagonists Levelof evidence Grade of recommendation Alfuzosin 3 C Doxazosin 3 C Prazosin 3 C Terazosin 3 C Tamsulosin 3 C
- 69. β -Adrenoceptor agonists Levelof 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.).
- 70. Mirabegron – anovel 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.
- 73. β3 agonist- mechanismof 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
- 74. β3 -AR agonists: pronounced effect on spontaneous contractile activity in det muscle in vitro ~an important basis for their clinical effects
- 75. Muscarinic and β3-adrenoceptormediated pathways mediating relaxation of the detrusor
- 76. 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
- 77. 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
- 79. Prespecified pooled efficacyanalysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies (SCORPIO, ARIES,and CAPRICORN)
- 80. Adjusted mean changefrom baseline in mean number of micturitions/24 hr
- 81. Adjusted mean changefrom baseline in the mean number of incontinence episodes/24 hr
- 84. Improvements in frequency,urgency incontinence, mean volume voided/micturition
- 85. 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
- 86. Adverse events~ drymouth 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
- 87. Adverse events~ drymouth 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
- 88. Adverse events~ discontinuationrates Placebo: 3.8 % Mirabegron 50mg: 4.1 % Mirabegron 100mg: 4.4 % Nitti et al. J urol. 2012
- 91. Theoretical advantages of mirabegronover 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.
- 92. Theoretical advantages of mirabegronover 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
- 93. Theoretical advantages of mirabegronover 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
- 94. 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
- 95. Monotherapy vs. CombinedTreatment 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
- 96. Cyclooxygenase inhibitors Level ofevidence Grade of recommendation Indomethacin 2 C Flurbiprofen 2 C
- 97. Antidepressants Level of evidenceGrade of recommendation Imipramine 3 C Duloxetine 2 C
- 98. Toxins Level of evidenceGrade of recommendation Botulinum toxin (neurogenic) 2 A Botulinum toxin (idiopathic) 3 B Capsaicin (neurogenic) 2 C Resiniferatoxin (idiopathic) 2 C
- 99. Botulinum toxin Neurotoxinproduced 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
- 100. Capsaicin/Resiniferatoxin Act onsensory afferent pathway Desensitization afferent C fiber Intravesical route
- 101. Hormone Level of evidenceGrade of recommendation Estrogen 2 C Desmopressin * 1 A *Nocturia
- 102. Neuromodulation Treatment forrefractory OAB Pudendal nerve stimulation Sacral nerve stimulation: most common used Tibial nerve stimulation
- 103. Surgery Last resortin management of refractory OAB. Aims Abolish urgency and urgency incontinence Achieve convenient voiding intervals Stabilize upper urinary tracts and safeguard renal function
- 104. Surgery Types ofsurgery Augmentation cystoplasty Detrusor myectomy Urinary diversion
- 105. Conclusion Treatment algorithm foroveractive bladder Fluid Management Timed Voiding Bladder Training Pelvic Floor Physical Therapy Antimuscarinic Therapy β3 AR agonist Sacral Neuromodulation Botulinum Toxin Injection Enterocystoplasty Urinary Diversion