馬偕紀念醫院婦產部

婦女泌尿科 黃文助

Overactive bladder (OAB)

OAB is a symptom syndrome.

OAB is a filling disorder in which abnormal sensations

leads to urinary urgency, frequency and incontinence.

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)

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. 2003Yu et al. Urol Int 2006

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％

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

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」

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

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

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

Assessment of OAB

History

Bladder Diary

Physical Examination

Laboratory tests

Residual Urine Measurement

Symptoms & Questionnaire

Urodynamic study

History

• Focus on medical, neurologic, and genitourinary symptoms

• Voiding patterns and symptoms

– bladder diary

• Review medications

• Evaluate functional and mental status

Bladder diary

Medications that may affect bladder function

Diuretics

Antidepressants

Antihypertensives

Hypnotics

Analgesics

Narcotics

Sedatives

OTC sleep aids and cold remedies

Antipsychotics

Herbal remedies

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)

Laboratory tests

Urinalysis

to rule out hematuria, pyuria, bacteriuria, glucosuria, proteinuria

Blood work as appropriate

glucose

prostate serum antigen

others

Symptoms and questionnaires

OABSS

OAB-q

American urological association symptom index

Urinary symptom scoring system

OABSS

Homma et al. Urology 68(2), 2006

OAB-qYes 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?

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。

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.

Detrusor overactivity

DO vs.OAB

Urodynamically proven detrusor overactivity :

~ two-thirds of women with symptoms of OAB

Detrusor overactivity: 83% have OAB symptoms

Definition of OAB

Based on symptoms: OAB syndrome

Based on urodynamics: DO

~ Filling disorder

~ Afferent bladder function

正常的解尿週期

儲存期 排空期

膀胱壓

Bladder

fillingFirst sensation

to void

Normal

desire

to void

Bladder

filling

Wein AJ, Rovner ES. Int J Fertil. 1999;44:56-66.

25

Goal for treatment of OAB

To improve symptoms that cause a problem for the individual patient.

Urgency is the key symptom to OAB treatment.

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

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

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

Lifestyle modification

Klutke et al. J Urol 2009; 181: 2599-2607.

骨盆底肌肉訓練

●刻意緊縮、放鬆陰道及肛門的運動

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

!!

Pharmacological therapy of OAB

Myogenic and urothelial signaling pathway

Myogenic and urothelial signaling pathway

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

Pharmacological therapyAnticholinergic 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

Autonomic Efferent Innervation Contributing to Bladder Contraction and Urine Storage

Sensory Innervation of the Bladder

Antimuscarinics: site of action within bladder wall

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

Affinity for muscarinic receptor subtypes

Physiologic Effect Clinical Impact

M1The 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

Antimuscarinic medications licensed for OAB

Oxybutynin (oral or transdermal)

Propiverine

Solifenacin

Darifenacin

Tolterodine

Fesoterodine

Trospium chloride

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)

Antimuscarinic structures

Structure of antimuscarinics

Feature Physiologic Effect Clinical Impact

Tertiary amine •Allows transfer across theBBB into CNS

•Allows good absorption across GI tract

•May result in adverse cognitive effectsParticularly among elderly patients

Quaternary amines

•Limits transfer across theBBB into CNS

•Limits absorption across GItract

•Reduces the potentialfor cognitive adverseeffects

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

Tertiary amine

Oxybutynin

Propiverine

Solifenacin

Darifenacin

Tolterodine

Fesoterodine

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

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.

Propiverine

Anticholinergic and calcium channel blocking actions

Popular drug for detrusor overactivity in Germany, Austria and Japan.

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

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

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

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

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

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)

CNSM3 receptor

M3 receptor

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

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

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

Drugs acting on membrane channels

Level of evidence Grade of recommendation

Calcium antagonist 2 D

K-channel opener 2 D

α -Adrenoceptor antagonists

Level of evidence Grade of recommendation

Alfuzosin 3 C

Doxazosin 3 C

Prazosin 3 C

Terazosin 3 C

Tamsulosin 3 C

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.).

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.

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

β3 -AR agonists :

pronounced effect on spontaneous contractile activity in det muscle in vitro

~an important basis for their clinical effects

Muscarinic and β3-adrenoceptor mediated pathways mediatingrelaxation of the detrusor

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

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

Prespecified pooled efficacy analysis and pooledsafety analysis of three randomised, double-blind,

placebo-controlled, phase III studies(SCORPIO, ARIES,and CAPRICORN)

Adjusted mean change from baseline in mean number of micturitions/24 hr

Adjusted mean change from baseline in the mean number of incontinence episodes/24 hr

Improvements in frequency, urgency incontinence, mean volume voided/micturition

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

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

Adverse events~ dry mouthantimuscarinics 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

Adverse events~ discontinuation rates

Placebo: 3.8 %

Mirabegron 50mg: 4.1 %

Mirabegron 100mg: 4.4 %

Nitti et al. J urol. 2012

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.

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

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

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

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 solifenacindemonstrated greater efficacy than solifenacin 5 mg alone on MVV and MF.

Rekik M et al, 2013: Abrams P et al., 2013

Cyclooxygenase inhibitors

Level of evidence Grade of recommendation

Indomethacin 2 C

Flurbiprofen 2 C

Antidepressants

Level of evidence Grade of recommendation

Imipramine 3 C

Duloxetine 2 C

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

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

Capsaicin/Resiniferatoxin

Act on sensory afferent pathway

Desensitization afferent C fiber

Intravesical route

Hormone Level of evidence Grade of

recommendation

Estrogen 2 C

Desmopressin * 1 A

*Nocturia

Neuromodulation

Treatment for refractory OAB

Pudendal nerve stimulation

Sacral nerve stimulation: most common used

Tibial nerve stimulation

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

Surgery

Types of surgery

Augmentation cystoplasty

Detrusor myectomy

Urinary diversion

Conclusion Treatment algorithm for overactive bladder

FluidManagement

Timed Voiding

Bladder Training

Pelvic FloorPhysical Therapy

AntimuscarinicTherapy

β3 AR agonist

SacralNeuromodulation

Botulinum ToxinInjection

Enterocystoplasty

Urinary Diversion